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1.  The Respiratory Arsenite Oxidase: Structure and the Role of Residues Surrounding the Rieske Cluster 
PLoS ONE  2013;8(8):e72535.
The arsenite oxidase (Aio) from the facultative autotrophic Alphaproteobacterium Rhizobium sp. NT-26 is a bioenergetic enzyme involved in the oxidation of arsenite to arsenate. The enzyme from the distantly related heterotroph, Alcaligenes faecalis, which is thought to oxidise arsenite for detoxification, consists of a large α subunit (AioA) with bis-molybdopterin guanine dinucleotide at its active site and a 3Fe-4S cluster, and a small β subunit (AioB) which contains a Rieske 2Fe-2S cluster. The successful heterologous expression of the NT-26 Aio in Escherichia coli has resulted in the solution of its crystal structure. The NT-26 Aio, a heterotetramer, shares high overall similarity to the heterodimeric arsenite oxidase from A. faecalis but there are striking differences in the structure surrounding the Rieske 2Fe-2S cluster which we demonstrate explains the difference in the observed redox potentials (+225 mV vs. +130/160 mV, respectively). A combination of site-directed mutagenesis and electron paramagnetic resonance was used to explore the differences observed in the structure and redox properties of the Rieske cluster. In the NT-26 AioB the substitution of a serine (S126 in NT-26) for a threonine as in the A. faecalis AioB explains a −20 mV decrease in redox potential. The disulphide bridge in the A. faecalis AioB which is conserved in other betaproteobacterial AioB subunits and the Rieske subunit of the cytochrome bc1 complex is absent in the NT-26 AioB subunit. The introduction of a disulphide bridge had no effect on Aio activity or protein stability but resulted in a decrease in the redox potential of the cluster. These results are in conflict with previous data on the betaproteobacterial AioB subunit and the Rieske of the bc1 complex where removal of the disulphide bridge had no effect on the redox potential of the former but a decrease in cluster stability was observed in the latter.
doi:10.1371/journal.pone.0072535
PMCID: PMC3758308  PMID: 24023621
2.  Development and validation of a new global well-being outcomes rating scale for integrative medicine research 
Background
Researchers are finding limitations of currently available disease-focused questionnaire tools for outcome studies in complementary and alternative medicine/integrative medicine (CAM/IM).
Methods
Three substudies investigated the new one-item visual analogue Arizona Integrative Outcomes Scale (AIOS), which assesses self-rated global sense of spiritual, social, mental, emotional, and physical well-being over the past 24 hours and the past month. The first study tested the scale's ability to discriminate unhealthy individuals (n = 50) from healthy individuals (n = 50) in a rehabilitation outpatient clinic sample. The second study examined the concurrent validity of the AIOS by comparing ratings of global well-being to degree of psychological distress as measured by the Brief Symptom Inventory (BSI) in undergraduate college students (N = 458). The third study evaluated the relationships between the AIOS and positively- and negatively-valenced tools (Positive and Negative Affect Scale and the Positive States of Mind Scale) in a different sample of undergraduate students (N = 62).
Results
Substudy (i) Rehabilitation patients scored significantly lower than the healthy controls on both forms of the AIOS and a current global health rating. The AIOS 24-hours correlated moderately and significantly with global health (patients r = 0.50; controls r = 0.45). AIOS 1-month correlations with global health were stronger within the controls (patients r = 0.36; controls r = 0.50). Controls (r = 0.64) had a higher correlation between the AIOS 24-hour and 1-month forms than did the patients (r = 0.33), which is consistent with the presumptive improvement in the patients' condition over the previous 30 days in rehabilitation. Substudy (ii) In undergraduate students, AIOS scores were inversely related to distress ratings, as measured by the global severity index on the BSI (rAIOS24h = -0.42, rAIOS1month = -0.40). Substudy (iii) AIOS scores were significantly correlated with positive affect (rAIOS24h = 0.56, rAIOS1month = 0.57) and positive states of mind (rAIOS24h = 0.42, rAIOS1month = 0.45), and inversely correlated with negative affect (rAIOS24h = -0.41, rAIOS1month = -0.59).
Conclusions
The AIOS is able to distinguish relatively sicker from relatively healthier individuals; and correlates in expected directions with a measure of distress and indicators of positive and negative affect and positive states of mind. The AIOS offers a tool for CAM/IM research that extends beyond a disease emphasis.
doi:10.1186/1472-6882-4-1
PMCID: PMC343287  PMID: 14725717
complementary and alternative medicine; well-being; global outcomes; questionnaire; validation; rehabilitation
3.  SMALL INTESTINAL OBSTRUCTION FROM PERITONEAL ADHESIONS IN CHILDREN SMALL INTESTINAL OBSTRUCTION FROM PERITONEAL ADHESIONS IN CHILDREN  
Abstract
Purpose: The purpose of this study was to assess the incidence of peritoneal adhesions leading to small intestinal obstruction after laparotomy in children in a tertiary paediatric surgical centre.
Methods: A retrospective review of 430 children aged <15 years who had trans-abdominal procedures over a 7 year period.
Results: Four hundred and fifty nine abdominal procedures were performed in 430 children during the study period. The follow up period ranged from 4 months – 7 years (Median 33 months). 22 (4.8%) had intra-operative confirmation of small intestinal obstruction. Their ages ranged from 21 days – 14 years (median 7 years). Postoperative adhesions due to laparotomy for typhoid perforation were the commonest, occurring in 10 (45%). Children undergoing emergency laparotomy were more likely to develop post operative small intestinal obstruction compared to elective laparotomy (p<0.025). Six (27.3%) children had bowel gangrene at laparotomy requiring bowel resection and anastomosis. Post-operative small intestinal obstruction developed in 6 (27.3%). One child died due to sepsis from intestinal gangrene. Conclusion: Small bowel obstruction due to adhesions requiring operative intervention in children in our setting is not un-common. Bowel gangrene is a common complication of postoperative small intestinal obstruction in children in our setting and should be suspected to avoid serious postoperative mortality and morbidity.
PMCID: PMC4170251  PMID: 25452942
Adhesions; Intestinal obstruction; children
4.  Neoadjuvant chemoradiotherapy for locally advanced rectal cancer: The debate continues 
Rectal carcinoma represents the 30% of all colorectal cancers, with about 40000 new cases/years. In the past two decades, the management of rectal cancer has made important progress, highlighting the main role of a multimodality strategy approach, combining surgery, radiation therapy and chemotherapy. Nowadays, surgery remains the primary treatment and neo-adjuvant chemoradiotherapy, based on fluoropyrimidine (5-FU) continuous infusion, is considered the standard in locally advanced rectal carcinoma. The aim is to reduce the incidence of local recurrence and to perform a conservative surgery. To improve these purposes different drugs combination have been tested in the neo-adjuvant setting. At American Society of Clinical Oncology 2014 an important abstract was presented focusing on the role of adding oxaliplatin to concomitant treatment, in patients with locally advanced rectal carcinoma. Rodel et al reported on the CAO/ARO/AIO-04 randomized phase III trial that compared standard treatment with 5-FU and radiation therapy, to oxaliplatin plus 5-FU in association with radiation therapy. The addition of oxaliplatin to the neo-adjuvant treatment has been shown to improve disease-free survival from 71.2% to 75.9% (P = 0.03). This editorial was planned to clarify the optimal treatment in patients with locally advanced rectal cancer, considering the results from CAO/ARO/AIO-04 study.
doi:10.4251/wjgo.v6.i12.438
PMCID: PMC4266815  PMID: 25516776
Chemoradiotherapy; Rectal cancer; Locally advanced disease; Neoadjuvant; Debate
5.  Evaluation of Innotrac Aio! Second-Generation Cardiac Troponin I Assay: The Main Characteristics for Routine Clinical Use 
The availability of a simple, sensitive, and rapid test using whole blood to facilitate processing and to reduce the turnaround time could improve the management of patients presenting with chest pain. The aim of this study was an evaluation of the Innotrac Aio! second-generation cardiac troponin I (cTnI) assay. The Innotrac Aio! second-generation cTnI assay was compared with the Abbott AxSYM first-generation cTnI, Beckman Access AccuTnI, and Innotrac Aio! first-generation cTnI assays. We studied serum samples from 15 patients with positive rheumatoid factor but with no indication of myocardial infarction (MI). Additionally, the stability of the sample with different matrices and the influence of hemodialysis on the cTnI concentration were evaluated. Within-assay CVs were 3.2%–10.9%, and between-assay precision ranged from 4.0% to 17.2% for cTnI. The functional sensitivity (CV = 20 %) and the concentration giving CV of 10% were approximated to be 0.02 and 0.04, respectively. The assay was found to be linear within the tested range of 0.063–111.6 μ g/L. The correlations between the second-generation Innotrac Aio!, Access, and AxSYM cTnI assays were good (r coefficients 0.947–0.966), but involved differences in the measured concentrations, and the biases were highest with cTnI at low concentrations. The second-generation Innotrac Aio! cTnI assay was found to be superior to the first-generation assay with regard to precision in the low concentration range. The stability of the cTnI level was best in the serum, lithium-heparin plasma, and lithium-heparin whole blood samples (n = 10 , decrease < 10 % in 24 hours at +20°C and at +4°C. There was no remarkable influence of hemodialysis on the cTnI release. False-positive cTnI values occurred in the presence of very high rheumatoid factor values, that is, over 3000 U/L. The 99th percentile of the apparently healthy reference group was ≤ 0.03   μ g/L. The results demonstrate the very good analytical performance of the second-generation Innotrac Aio! cTnI assay.
doi:10.1155/JAMMC/2006/39325
PMCID: PMC1903460  PMID: 17671616
6.  Profound systemic inflammatory response syndrome following non-emergent intestinal surgery in children☆ 
Journal of pediatric surgery  2013;48(9):1936-1940.
Purpose
Systemic inflammatory response syndrome (SIRS) is an uncommon but severe complication in surgical patients. While SIRS is well known, it is poorly described in the pediatric population. The goal of this study was to describe the incidence of profound SIRS following non-emergent intestinal surgery in children and to identify potential risk factors.
Methods
A retrospective review was conducted for patients 0–19 years of age following intestinal surgery and/or lysis of adhesions from 01/01/1999-02/28/2012. Children were excluded for preoperative instability or frank bowel perforation. Patients were then placed in a post-operative SIRS or non-SIRS group as defined by the 2005 International Pediatric Sepsis Consensus Conference Guidelines (6. B. Goldstein, B. Giroir, A. Randolph, and Sepsis International Consensus Conference on Pediatric, ‘International Pediatric Sepsis Consensus Conference: Definitions for Sepsis and Organ Dysfunction in Pediatrics’, Pediatr Crit Care Med, 6 (2005), 2–8.).
Results
SIRS was identified in 17 of the 381 patients. Logistic regression analysis was performed and showed heart disease, kidney disease, PN dependence, and intestinal obstruction to be predictive of post-operative SIRS.
Conclusion
This study represents one of the first reports to identify a previously poorly described process of significant SIRS after intestinal surgery in children. Both systemic organ failure and intestinal dysfunction are strong risk factors for post-operative SIRS in children. Potentially, these pre-existing conditions may lead to disruption of normal intestinal flora or barrier function, which in turn may predispose these children for dramatic SIRS after intestinal surgery. Understanding how these factors lead to SIRS will be critical to developing prevention strategies.
doi:10.1016/j.jpedsurg.2013.05.065
PMCID: PMC3787315  PMID: 24074671
Systemic inflammatory response syndrome; SIRS; Intestinal surgery; Parenteral nutrition
7.  MicroRNA-21 Knockout Improve the Survival Rate in DSS Induced Fatal Colitis through Protecting against Inflammation and Tissue Injury 
PLoS ONE  2013;8(6):e66814.
Background
MicroRNA-21 (miR-21) is overexpressed in most inflammatory diseases, but its physiological role in gut inflammation and tissue injury is poorly understood. The goal of this work is to understand the role of miR-21 in colitis and damage progression of intestine in a genetically modified murine model.
Methods
Experimental colitis was induced in miR-21 KO and wild-type (WT) mice by 3.5% dextran sulphate sodium (DSS) administration for 7 days. Disease activity index(DAI), blood parameters, intestinal permeability, histopathologic injury, cytokine and chemokine production, and epithelial cells apoptosis were examined in colons of miR-21 KO and WT mice.
Results
miR-21 was overexpressed in intestine of inflammatory bowel diseases (IBD) and acute intestinal obstruction (AIO) patients when compared with normal intestinal tissues. Likewise, miR-21 was up-regulated in colon of IL-10 KO mice when compared with control mice. WT mice rapidly lost weight and were moribund 5 days after treatment with 3.5% DSS, while miR-21 KO mice survived for at least 6 days. Elevated leukocytes and more severe histopathology were observed in WT mice when compared with miR-21 KO mice. Elevated levels of TNF-α and macrophage inflammatory protein-2(MIP-2) in colon culture supernatants from WT mice exhibited significant higher than miR-21 KO mice. Furthermore, CD3 and CD68 positive cells, intestinal permeability and apoptosis of epithelial cells were significantly increased in WT mice when compared with miR-21 KO mice. Finally, we found that miR-21 regulated the intestinal barrier function through modulating the expression of RhoB and CDC42.
Conclusion
Our results suggest that miR-21 is overexpressed in intestinal inflammation and tissue injury, while knockout of miR-21 in mice improve the survival rate in DSS-induced fatal colitis through protecting against inflammation and tissue injury. Therefore, attenuated expression of miR-21 in gut may prevent the onset or progression of inflammatory bowel disease in patients.
doi:10.1371/journal.pone.0066814
PMCID: PMC3691313  PMID: 23826144
8.  A randomized, phase III trial of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in first-line treatment of metastatic colorectal cancer: The AIO KRK 0110 Trial/ML22011 Trial 
BMC Cancer  2011;11:367.
Background
Several randomized trials have indicated that combination chemotherapy applied in metastatic colorectal cancer (mCRC) does not significantly improve overall survival when compared to the sequential use of cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present study investigates the question whether this statement holds true also for bevacizumab-based first-line treatment including escalation- and de-escalation strategies.
Methods/Design
The AIO KRK 0110/ML22011 trial is a two-arm, multicenter, open-label randomized phase III trial comparing the efficacy and safety of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in the first-line treatment of metastatic colorectal cancer. Patients with unresectable metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, will be assigned in a 1:1 ratio to receive either capecitabine 1250 mg/m2 bid for 14d (d1-14) plus bevacizumab 7.5 mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m2 BID for 14d (d1-14), irinotecan 200 mg/m2 (d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B). Patients included into this trial are required to consent to the analysis of tumour tissue and blood for translational investigations. In Arm A, treatment escalation from Cape-Bev to CAPIRI-Bev is recommended in case of progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to Cape-Bev is possible after 6 months of treatment or in case of irinotecan-associated toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The primary endpoint is time to failure of strategy (TFS). Secondary endpoints are overall response rate (ORR), overall survival, progression-free survival, safety and quality of life.
Conclusion
The AIO KRK 0110 trial is designed for patients with disseminated, but asymptomatic mCRC who are not potential candidates for surgical resection of metastasis. Two bevacizumab-based strategies are compared: one starting as single-agent chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and another starting with combination chemotherapy (CAPIRI-Bev) and allowing de-escalation to Cape-Bev and subsequent re-escalation if necessary.
Trial Registration
ClinicalTrials.gov Identifier NCT01249638
EudraCT-No.: 2009-013099-38
doi:10.1186/1471-2407-11-367
PMCID: PMC3173448  PMID: 21861888
9.  Conservative treatment of adhesive small bowel obstruction in children: a systematic review 
BMJ Open  2014;4(9):e005789.
Objective
To assess the effectiveness of conservative treatment for adhesive small bowel obstruction (ASBO) in children.
Design
Systematic review of studies involved children with ASBO who received initial conservative/non-operative treatment.
Setting
The search was performed in April 2013 using PubMed (see online supplementary file 1), current contents, and the Cochrane database.
Participants
Children with ASBO.
Interventions
Conservative treatment included nasogastric decompression, parenteral fluids and correction of electrolyte and fluid imbalance.
Primary outcome
Treatment success.
Secondary outcomes
Length of hospital stay and the time to first feeding after hospital admission.
Results
7 studies (six retrospective, one prospective), involving 8–109 patients (age: 1 month to 16 years) treated conservatively, were included in the review. The nature of conservative treatment was generally consistent between studies (nasogastric decompression, parenteral fluids and correction of electrolyte and fluid imbalance), although patients in one study also received Gastrografin. The rate of conservative treatment success ranged from 16% to 75% among the five studies, but one trial showed 0% successful rate. The hospital length of stay ranged from 3 to 6.5 days for conservative treatment (vs 10.2–13 days for operative treatment). The time to first feeding ranged from 31 to 84 h for conservative treatment.
Conclusions
In conclusion, in the majority of cases, conservative treatment is an effective means of managing ASBO in children.
doi:10.1136/bmjopen-2014-005789
PMCID: PMC4166136  PMID: 25223569
QUALITATIVE RESEARCH
10.  Developing and Implementing All-in-One Standard Paediatric Parenteral Nutrition 
Nutrients  2013;5(6):2006-2018.
Parenteral nutrition (PN) is a feeding mode suitable for children that do not achieve requirements via the enteral route. For this intervention to be successful, healthcare professionals require: knowledge on nutrient requirements; access to an aseptic compounding facility; and a system that ensures adequate and safe delivery of PN. Previously, it was thought that individualised PN was the “gold standard” for delivering nutrients to children; however, studies have highlighted concerns regarding inadequate delivery of nutrients, prescribing and compounding errors. We, therefore, set out to develop and implement all-in-one (AIO) paediatric PN solutions. Through a systematic approach, four AIO PN solutions were developed: birth–two months of age (Ped 1); two months–10 kg (Ped 2); 11–15 kg (Ped 3); and 16–30 kg (Ped 4). We implemented them with the help of a teaching pack, over a one month time period, and reviewed usage at six months. At that time, five children initially received standard PN without electrolyte changes; but after a few days, electrolytes needed amendments, and three required individualised PN. A change to AIO PN is feasible and safe; however, some may require electrolyte changes, and there will always be those that will require individualised PN.
doi:10.3390/nu5062006
PMCID: PMC3725489  PMID: 23739142
parenteral nutrition; all-in-one parenteral nutrition; paediatrics; development; implementation
11.  Palliative first-line therapy with weekly high-dose 5-fluorouracil and sodium folinic acid as a 24-hour infusion (AIO regimen) combined with weekly irinotecan in patients with metastatic adenocarcinoma of the stomach or esophagogastric junction followed by secondary metastatic resection after downsizing 
Summary
Background
The aim of this retrospective study was to evaluate the efficacy and safety of weekly high-dose 5-fluorouracil (5-FU)/folinic acid (FA) as 24-h infusion (AIO regimen) plus irinotecan in patients with histologically proven metastatic gastroesophageal adenocarcinoma (UICC stage IV).
Material/Methods
From 08/1999 to 12/2008, 76 registered, previously untreated patients were evaluable. Treatment regimen: irinotecan (80 mg/m2) as 1-h infusion followed by 5-FU (2000 mg/m2) combined with FA (500 mg/m2) as 24-h infusion (d1, 8, 15, 22, 29, 36, qd 57).
Results
Median age: 59 years; male/female: 74%/26%; ECOG ≤1: 83%; response: CR: 1%, PR: 16%, SD: 61%, PD: 17%, not evaluable in terms of response: 5%; tumor control: 78%; median OS: 11.2 months; median time-to-progression: 5.3 months; 1-year survival rate: 49%; 2-year survival rate: 17%; no evidence of disease: 6.6%; higher grade toxicities (grade 3/4): anemia: 7%, leucopenia: 1%, ascites: 3%, nausea: 3%, infections: 12%, vomiting: 9%, GI bleeding of the primary tumor: 4%, diarrhea: 17%, thromboembolic events: 4%; secondary metastatic resection after downsizing: 16 patients (21%), R-classification of secondary resections: R0/R1/R2: 81%/6%/13%, median survival of the 16 patients with secondary resection: 23.7 months.
Conclusions
Combined 5-FU/FA as 24-h infusion plus irinotecan may be considered as an active palliative first-line treatment accompanied by tolerable toxicity; thus offering an alternative to cisplatin-based treatment regimens. Thanks to efficient interdisciplinary teamwork, secondary metastatic resections could be performed in 16 patients. In total, the patients who had undergone secondary resection had a median survival of 23.7 months, whereas the median survival of patients without secondary resection was 10.1 months (p≤0.001).
doi:10.12659/MSM.881764
PMCID: PMC3539586  PMID: 21525806
gastroesophageal cancer; palliative chemotherapy; irinotecan; 5-fluorouracil
12.  Diversity of arsenite oxidizing bacterial communities in arsenic-rich deltaic aquifers in West Bengal, India 
High arsenic (As) concentration in groundwater has affected human health, particularly in South-East Asia putting millions of people at risk. Biogeochemical cycling of As carried out by different bacterial groups are suggested to control the As fluxes in aquifers. A functional diversity approach in link with As precipitation was adopted to study bacterial community structures and their variation within the As contaminated Bengal Delta Plain (BDP) aquifers of India. Groundwater samples collected from two shallow aquifers in Karimpur II (West Bengal, India), during years 2010 and 2011, were investigated to trace the effects immediately after monsoon period (precipitation) on community structure and diversity of bacterial assemblages with a focus on arsenite oxidizing bacterial phyla for two successive years. The study focused on amplification, clone library generation and sequencing of the arsenite oxidase large sub-unit gene aioA and 16S rRNA marker, with respect to changes in elemental concentrations. New set of primers were designed to amplify the aioA gene as a phylogenetic marker to study taxonomically diverse arsenite oxidizing bacterial groups in these aquifers. The overall narrow distribution of bacterial communities based on aioA and 16S rRNA sequences observed was due to poor nutrient status and anoxic conditions in these As contaminated aquifers. Proteobacteria was the dominant phylum detected, within which Acidovorax, Hydrogenophaga, Albidiferax, Bosea, and Polymorphum were the major arsenite oxidizing bacterial genera based on the number of clones sequenced. The structure of bacterial assemblages including those of arsenite oxidizing bacteria seems to have been affected by increase in major elemental concentrations (e.g., As, Fe, S, and Si) within two sampling sessions, which was supported by statistical analyses. One of the significant findings of this study is detection of novel lineages of 16S rRNA-like bacterial sequences indicating presence of indigenous bacterial communities BDP wells that can play important role in biogeochemical cycling of elements including As.
doi:10.3389/fmicb.2014.00602
PMCID: PMC4240177  PMID: 25484877
Arsenic; aquifer; arsenite oxidation; aioA gene; phylogeny
13.  Removing the Age Restrictions for Rotavirus Vaccination: A Benefit-Risk Modeling Analysis 
PLoS Medicine  2012;9(10):e1001330.
A modeling analysis conducted by Manish Patel and colleagues predicts the possible number of rotavirus deaths prevented, and number of intussusception deaths caused, by use of an unrestricted rotavirus schedule in low- and middle-income countries.
Background
To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur.
Methods and Findings
We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th–95th percentile, to provide an indication of the uncertainty in the estimates.
We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th–95th centiles, 83,300–217,700) while causing potentially 253 intussusception deaths (76–689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000–281,500) while potentially causing 547 intussusception deaths (237–1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700–63,700) and cause an additional 294 (161–471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%–25% children, beyond the 63%–73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes.
Conclusions
Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Rotavirus causes severe diarrhea and vomiting. It is responsible for a large number of hospitalizations among young children in developed countries (an estimated 60,000 hospitalizations per year in the US in 2005, for example). In poor countries, rotavirus is a major cause of death in children under five. In 1998, the first rotavirus vaccine, called RotaShield, was approved in the US by the Food and Drug Administration. Shortly after the vaccine became widely used, doctors noticed a small increase in a problem called intussusception among the vaccinated infants. Intussusception is a rare type of bowel obstruction that occurs when the bowel telescopes in on itself. Prompt treatment of intussusception normally leads to full recovery, but some children with the condition need surgery, and when the disease is left untreated it can be fatal. Because intussusception is a serious condition and because very few children die from rotavirus infection in the United States, the US authorities stopped recommending vaccination with RotaShield in 1999. The manufacturer withdrew the vaccine from the market shortly thereafter.
Since then, two new vaccines (named Rotarix and RotaTeq) have been developed. Before they were approved in the US and elsewhere, they were extensively tested for any adverse side effects, especially intussusception. No increase in the risk for intussusception was found in these studies, and both are now approved and recommended for vaccination of infants around the world.
Why Was This Study Done?
Since 2006, hundreds of thousands of infants have been vaccinated with Rotarix or RotaTeq, with safety being closely monitored. Some countries have reported a small increase in intussusception (one to four additional cases per 100,000 vaccinated infants, compared with one per 2,000 of cases that occur in unvaccinated children). This increase is much lower than the one seen previously with RotaShield. In response to these findings, authorities in the US and other developed countries as well as the World Health Organization declared that the benefits of the vaccine outweigh the risks of the small number of additional intussusception cases in both developed and poor countries. However, because older infants have a higher risk of naturally occurring intussusception, they decided that the course of vaccination (three oral doses for Rotarix and two for RotaTeq) should be initiated before 15 weeks of age and completed before the age of 32 weeks. This is usually not a problem in countries with easy access to health facilities. However, in many poor countries where delays in infant vaccination are common, giving the vaccine only to very young children means that many others who could benefit from its protection will be excluded. In this study, the researchers examined the risks and benefits of rotavirus vaccination in poor countries where most of the rotavirus deaths occur. Specifically, they looked at the benefits and risks if the age restrictions were removed, with a particular emphasis on allowing infants to initiate rotavirus immunization even if they arrive after 15 weeks of age.
What Did the Researchers Do and Find?
The researchers used the most recent estimates for how well the vaccines protect children in Africa and Asia from becoming infected with rotavirus, how many deaths from rotavirus infection can be avoided by vaccination, how many additional cases of intussusception will likely occur in vaccinated children, and what proportion of children would be excluded from rotavirus vaccination because they are too old when they come to a health facility for their infant vaccination. They then estimated the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination in two scenarios. The first one (the restricted scenario) corresponds to previous guidelines from WHO and others, in which rotavirus vaccination needs to be initiated before 15 weeks and the full series completed before 32 weeks. The second one (called the unrestricted scenario) allows rotavirus vaccination of children alongside current routinely administered vaccines up to three years of age, recognizing that most children receive their vaccination by 1 year of life.
The researchers estimated that removing the age restriction would prevent an additional 154 rotavirus deaths for each intussusception death caused by the vaccine. Under the unrestricted scenario, roughly a third more children would get vaccinated, which would prevent an additional approximately 47,000 death from rotavirus while causing approximately 300 additional intussusception deaths.
They also calculated some best- and worst-case scenarios. The worst-case scenario assumed a much higher risk of intussusception for children receiving their first dose after 15 weeks of life than what has been seen anywhere, and also that an additional 20% of children with intussusception would die from it than what was already assumed in their routine scenario (again, a higher number than seen in reality). In addition, it assumes a lower protection from rotavirus death for the vaccine than has been observed in children vaccinated so far. In this pessimistic case, the number of rotavirus deaths prevented was 24 for each intussusception death caused by the vaccine.
What Do These Findings Mean?
If one accepts that deaths caused by a vaccine are not fundamentally different from deaths caused by a failure to vaccinate, then these results show that the benefits of lifting the age restriction for rotavirus vaccine clearly outweigh the risks, at least when only examining mortality outcomes. The calculations are valid only for low-income countries in Africa and Asia where both vaccination delays and deaths from rotavirus are common. The risk-benefit ratio will be different elsewhere. There are also additional risks and benefits that are not included in the study's estimates. For example, early vaccination might be seen as less of an urgent priority when this vaccine can be had at a later date, leaving very young children more vulnerable. On the other hand, when many children in the community are vaccinated, even the unvaccinated children are less likely to get infected (what is known as “herd immunity”), something that has not been taken into account in the benefits here. The results of this study (and its limitations) were reviewed in April 2012 by WHO's Strategic Advisory Group of Experts. The group then recommended that, while early vaccination is still strongly encouraged, the age restriction on rotavirus vaccination should be removed in countries where delays in vaccination and rotavirus mortality are common so that more vulnerable children can be vaccinated and deaths from rotavirus averted.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001330.
The World Health Organization provides information on rotavirus
Wikipedia has information on rotavirus vaccine and intussusception (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US Centers for Disease Control and Prevention rotavirus vaccination page includes a link to frequently asked questions
PATH Rotavirus Vaccine Access and Delivery has timely, useful updates on status of rotavirus vaccines globally
doi:10.1371/journal.pmed.1001330
PMCID: PMC3479108  PMID: 23109915
14.  Bologna Guidelines for Diagnosis and Management of Adhesive Small Bowel Obstruction (ASBO): 2010 Evidence-Based Guidelines of the World Society of Emergency Surgery 
Background
There is no consensus on diagnosis and management of ASBO. Initial conservative management is usually safe, however proper timing for discontinuing non operative treatment is still controversial. Open surgery or laparoscopy are used without standardized indications.
Methods
A panel of 13 international experts with interest and background in ASBO and peritoneal diseases, participated in a consensus conference during the 1st International Congress of the World Society of Emergency Surgery and 9th Peritoneum and Surgery Society meeting, in Bologna, July 1-3, 2010, for developing evidence-based recommendations for diagnosis and management of ASBO. Whenever was a lack of high-level evidence, the working group formulated guidelines by obtaining consensus.
Recommendations
In absence of signs of strangulation and history of persistent vomiting or combined CT scan signs (free fluid, mesenteric oedema, small bowel faeces sign, devascularized bowel) patients with partial ASBO can be managed safely with NOM and tube decompression (either with long or NG) should be attempted. These patients are good candidates for Water Soluble Contrast Medium (WSCM) with both diagnostic and therapeutic purposes. The appearance of water-soluble contrast in the colon on X-ray within 24 hours from administration predicts resolution. WSCM may be administered either orally or via NGT (50-150 ml) both immediately at admission or after an initial attempt of conservative treatment of 48 hours. The use of WSCM for ASBO is safe and reduces need for surgery, time to resolution and hospital stay.
NOM, in absence of signs of strangulation or peritonitis, can be prolonged up to 72 hours. After 72 hours of NOM without resolution surgery is recommended.
Patients treated non-operatively have shorter hospital stay, but higher recurrence rate and shorter time to re-admission, although the risk of new surgically treated episodes of ASBO is unchanged. Risk factors for recurrences are age <40 years and matted adhesions. WSCM does not affect recurrence rates or recurrences needing surgery when compared to traditional conservative treatment.
Open surgery is the preferred method for surgical treatment of strangulating ASBO as well as after failed conservative management. In selected patients and with appropriate skills, laparoscopic approach can be attempted using open access technique. Access in the left upper quadrant should be safe. Laparoscopic adhesiolysis should be attempted preferably in case of first episode of SBO and/or anticipated single band. A low threshold for open conversion should be maintained.
Peritoneal adhesions should be prevented. Hyaluronic acid-carboxycellulose membrane and icodextrin can reduce incidence of adhesions. Icodextrin may reduce the risk of re-obstruction. HA cannot reduce need of surgery.
doi:10.1186/1749-7922-6-5
PMCID: PMC3037327  PMID: 21255429
15.  Etiology and Outcome of Acute Intestinal Obstruction: A Review of 367 Patients in Eastern India 
Background/Aim:
The etiology of acute intestinal obstruction, which is one of the commonest surgical emergencies, varies between countries and has also changed over the decades. We aimed to provide a complete epidemiological description of acute intestinal obstruction in a tertiary care hospital in Eastern India.
Materials and Methods:
This was a retrospective study of patients admitted in our unit with a diagnosis of acute intestinal obstruction between the years 2005 and 2008 at Medical College, Calcutta. The study comprised of 367 patients.
Results:
Acute intestinal obstruction was the diagnosis in 9.87% of all patients admitted with males (75.20%) grossly outnumbering females. The commonest age group affected was 20-60 years. In our patients, the main cause of obstruction was obstructed hernia followed by malignancy with adhesions coming third. Intestinal tuberculosis was an important cause for obstruction in our patients comprising 14.17% of patients. Conservative management was advocated in 79 patients while the rest underwent surgery. Postoperative complications occurred in 95 patients and of these, 38 patients had a single complication and the rest, more than 1. The main complications were wound infection, basal atelectasis, burst abdomen and prolonged ileus. The mortality rate was 7.35% (27 patients). The highest mortality occurred in those with intestinal tuberculosis.
Conclusion:
This study demonstrates that the pattern of intestinal obstruction differs from the Western world with obstructed hernias being the most important cause and also emphasizes the fact that intestinal tuberculosis assumes a prominent role. It also highlights the necessity of using universal precautions because of the ever increasing number of HIV patients in those with intestinal obstruction.
doi:10.4103/1319-3767.70617
PMCID: PMC2995099  PMID: 20871195
Etiology; outcome; intestinal obstruction
16.  Robot-assisted surgery in children: current status 
Journal of Robotic Surgery  2008;1(4):243-246.
The horizon of robotic paediatric surgery has grown in leaps and bounds with advances in technology. The aim of this study was to analyse the extent of robotic involvement in paediatric surgical practice. A systematic database search was performed. Data about children who had undergone robot-assisted procedures were reviewed retrospectively from all published reports up to October 2007. Success rates were defined in term of completion of the procedures, their complications, and the time taken. These results were further studied in comparison with the procedures performed by open and laparoscopic methods. A total of 31 studies were identified describing 566 patients. Of these, four studies were case control, comparing with either laparoscopic or open procedures, one study was a prospective trial, and the rest of the studies were either case reports or series. The most common robotic system used was the da Vinci (23 studies) followed by the Zeus (four studies). The mean age of the children was 8.3 years. The commonest operation was pyeloplasty (141 cases), followed by fundoplication (122 cases) and patent ductus arteriosus ligation (50 cases). The mean operation time for robot-assisted pyeloplasty was 221 min (open pyeloplasty 214 min). The mean operation times for fundoplication were robotic, 170 min, laparoscopic, 158 min, and open, 121 min. The mean operation times for patent ductus arteriosus ligation were 166 min (robotic) and 83 min (open). Overall conversion rate for all paediatric robotic procedures was 4.7% and complications ranged from 0 to 15%. For robotic fundoplications the conversion and complication rates were 0.8 and 3.3%, respectively. For robotic pyeloplasties the conversion and complication rates were 2.1 and 3.5%, respectively. Many other major operations were performed successfully. All studies recommended robotic procedure as safe and feasible. Currently, the most common robotic operations in practice are pyeloplasties and fundoplications. Most of the authors concluded that, despite taking more time, robotic surgery enables more refined hand–eye coordination, superior suturing skills, better dexterity, and precise dissection with minimal conversion and complication rates. The widespread acceptance of this technology largely depends on solving the issues: learning curve; suitable machine size for neonates and infants; ensuring efficacy and safety in all operations; and, most importantly, making this procedure cost effective, so as to cater for the needs of most, if not all, children.
doi:10.1007/s11701-007-0054-6
PMCID: PMC4247450  PMID: 25484971
Children; Robotic; Paediatric surgery
17.  Pattern of Acute Intestinal Obstruction: Is There a Change in the Underlying Etiology? 
Background/Aim:
To study the changing pattern of acute intestinal obstruction at a teaching institute.
Patients and Methods:
It is a prospective descriptive study conducted at a teaching hospital during the period from June 2004 to June 2009. All patients with clinical or radiological evidence of acute intestinal obstruction were included in this study regardless of the gender of the patient. Patients below the age of 10 years were excluded from the study. The treatment strategy was planned ranging from conservative treatment to emergency laparotomy after resuscitation and rehydration of the patient. Details of individual patients were recorded on a pro forma sheet and data analyzed statistically on SPSS version 14.
Results:
A total of 229 patients with acute intestinal obstruction were admitted and treated. The mean age of the study population was 43.08 ± 13.07 years. Postoperative adhesions accounted for 41% (n= 95) of the total cases, followed by abdominal tuberculosis (25%, n= 58), obstructed/ strangulated hernias of different types (18%, n= 42). There was an obvious change in the pattern of etiology of acute intestinal obstruction as the common causes were postoperative adhesions and abdominal tuberculosis instead of obstructed inguinal hernias.
Conclusion:
An increase in the adhesive obstruction and a concomitant decrease in the incidence of obstructed hernias indicate a changing trend towards early operation before it gets complicated. Abdominal tuberculosis is emerging as another common cause of acute bowel obstruction.
doi:10.4103/1319-3767.70613
PMCID: PMC2995096  PMID: 20871192
Acute intestinal obstruction; adhesions; etiology; obstructed/strangulated hernias
18.  HIV-1 Drug Resistance Emergence among Breastfeeding Infants Born to HIV-Infected Mothers during a Single-Arm Trial of Triple-Antiretroviral Prophylaxis for Prevention of Mother-To-Child Transmission: A Secondary Analysis 
PLoS Medicine  2011;8(3):e1000430.
Analysis of a substudy of the Kisumu breastfeeding trial by Clement Zeh and colleagues reveals the emergence of HIV drug resistance in HIV-positive infants born to HIV-infected mothers treated with antiretroviral drugs.
Background
Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS), a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT) trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants.
Methods and Findings
All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR–positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75%) infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable), for 30% (6/20) at 6 wk, 63% (14/22) positive at 14 wk, and 67% (16/24) at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100%) and 7/15 (47%) infected infants whose mothers were on nelfinavir and nevirapine, respectively. No mutations were detected among the eight infants infected after the breastfeeding period (age 6 mo).
Conclusions
Emergence of HIV drug resistance mutations in HIV-infected infants occurred between 2 wk and 6 mo post partum, most likely because of exposure to maternal ARV drugs through breast milk. Our findings may impact the choice of regimen for ARV treatment of HIV-infected breastfeeding mothers and their infected infants.
Trial Registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, more than 2 million children are infected with the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS), and half a million children are newly infected every year. These infections are mainly the result of mother-to-child transmission (MTCT) of HIV during pregnancy, labor and delivery, or through breastfeeding. MTCT can be greatly reduced by treating HIV-positive mothers and their babies with antiretroviral drugs (ARVs). Without ARVs, up to half of babies born to HIV-positive mothers become infected with HIV. This rate of transmission falls to below 5% if a combination of three ARVs is given to the mother throughout pregnancy. Unfortunately, this triple-ARV therapy is too expensive for use in the resource-limited countries where most MTCT occurs. Instead, many such countries have introduced simpler, shorter ARV regimens such as a daily dose of zidovudine (a nucleoside reverse transcriptase inhibitor or NRTI) given to HIV-positive women during late pregnancy coupled with single-dose nevirapine (a non-nucleoside reverse transcriptase inhibitor or NNRTI) at the onset of labor, zidovudine and lamivudine (another NRTI) during labor and delivery, and single-dose nevirapine given to the baby at birth.
Why Was This Study Done?
More than 95% of HIV-exposed children are born in resource-limited settings where breastfeeding is the norm and is crucial for child survival even though it poses a risk of HIV transmission. Consequently, several recent studies have investigated whether MTCT can be further reduced by giving the mother ARVs while she is breastfeeding. In the Kisumu Breastfeeding Study (KiBS), for example, researchers assessed the effects of giving zidovudine, lamivudine, and either nevirapine or nelfinavir (a protease inhibitor) to HIV-infected women from 34 weeks of pregnancy through 6 months of breastfeeding. The results of KiBS indicate that this approach might be a safe, feasible way to reduce MTCT (see the accompanying paper by Thomas and colleagues). However, low amounts of nevirapine and lamivudine are transferred from mother to infant in breast milk and this exposure to ARVs could induce the development of resistance to ARVs among HIV-infected infants. In this KiBS substudy, the researchers investigate whether HIV drug resistance emerged in any of the HIV-positive infants in the parent study.
What Did the Researchers Do and Find?
In KiBS, 32 infants were HIV-positive at 24 months old; 24 were HIV-positive at 6 months old when their mothers stopped taking ARVs and when breastfeeding was supposed to stop. The researchers analyzed blood samples taken from these infants at various ages and from their mothers for the presence of HIV drug resistance mutations (DNA changes that make HIV resistant to killing by ARVs). They detected no resistance mutations in samples taken from 2-week old HIV-positive infants or from the infants who became infected after the age of 6 months. However, they found resistance mutations in a third and two-thirds of samples taken from 6-week and 6-month old HIV-positive infants, respectively. The commonest mutations conferred resistance to lamivudine and nevirapine. Moreover, resistance mutations were present in samples taken from all the HIV-positive infants whose mothers who had received nelfinavir but in only half those taken from infants whose mothers who had received nevirapine. Finally, most of the mothers of HIV-positive infants had no HIV drug resistance mutations, and only one mother-infant pair had an overlapping pattern of HIV drug resistance mutations.
What Do These Findings Mean?
These findings indicate that, in this KiBS substudy, the emergence of HIV drug resistance mutations in HIV-infected infants whose mothers were receiving ARVs occurred between 2 weeks and 6 months after birth. The pattern of mutations suggests that drug resistance most likely arose through exposure of the infants to low levels of ARVs in breast milk rather than through MTCT of drug-resistant virus. These findings need confirming but suggest that infants exposed to ARVs through breast milk—a situation that may become increasingly common given the reduction in MTCT seen in KiBS and other similar trials—should be carefully monitored for HIV infection. Providers should consider the mothers' regimen when choosing treatment for infants who are found to be HIV-infected despite maternal triple drug prophylaxis. Infants exposed to a maternal regimen with NNRTI drugs should receive first-line therapy with lopinavir/ritonavir, a protease inhibitor. The significance of the NRTI mutations such as M184V with regard to response to therapy needs further evaluation. The M184V mutation may result in hypersensitization to other NRTI drugs and delay or reverse zidovudine resistance. Given the limited availability of alternative drugs for infants in resource-limited settings, provision of the standard WHO-recommended first-line NRTI backbone, which includes 3TC, with enhanced monitoring of the infant to ensure virologic suppression, could be considered. Such an approach should reduce both illness and morbidity among infants who become HIV positive through breastfeeding.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1000430.
The accompanying PLoS Medicine Research article by Thomas and colleagues describes the primary findings of the Kisumu Breastfeeding Study
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV (in several languages), and guidance on the use of ARVs for preventing MTCT
doi:10.1371/journal.pmed.1000430
PMCID: PMC3066134  PMID: 21468304
19.  Inadequate Coordination of Maternal and Infant HIV Services Detrimentally Affects Early Infant Diagnosis Outcomes in Lilongwe, Malawi 
Objective
To assess the continuity of care and outcome of pediatric HIV prevention, testing, and treatment services, focusing on early infant diagnosis with DNA PCR.
Design
A retrospective observational cohort.
Methods
Maternal HIV antibody, infant HIV DNA PCR test results, and outcome data from HIV-infected infants from the prevention of mother-to-child transmission, early infant diagnosis, and pediatric HIV treatment programs operating in Lilongwe, Malawi between 2004 and 2008 were collected, merged and analyzed.
Results
Of the 14,669 pregnant women who tested HIV antibody positive, 7,875 infants (53.7%) received HIV DNA PCR testing. One thousand eighty-four infants (13.8%) were HIV-infected. 320 (29.5%) children enrolled into pediatric HIV care, with 202 (63.1%) at the Baylor Center of Excellence. Among these, antiretroviral therapy was initiated on 110 infants (54.5%) whose median age was 9.1 months (interquartile range, 5.4 to 13.8) and a median of 2.5 months (interquartile range, 1.4 to 9.2) after HIV clinic registration. Sixty-nine HIV-infected infants (34.2%) died or were lost by December 2008. Initiation of antiretroviral therapy increased the likelihood of survival seven-fold (odds ratio, 7.1; 95% confidence interval, 3.68 -13.70).
Conclusions
Separate programs for maternal and infant HIV prevention and care services demonstrated high attrition rates of HIV-exposed and HIV-infected infants, elevated levels of mother-to-child transmission, late infant diagnosis, delayed pediatric antiretroviral therapy initiation, and high HIV-infected infant mortality. Antiretroviral therapy increased HIV-infected infant survival, emphasizing the urgent need for improved service coordination and strategies that increase access to infant HIV diagnosis, improve patient retention, and reduce antiretroviral therapy initiation delays.
doi:10.1097/QAI.0b013e31820a7f2f
PMCID: PMC3112277  PMID: 21224736
Africa; antiretroviral therapy; early infant diagnosis; HIV testing; pediatric HIV; prevention of mother-to-child transmission; Malawi
20.  The Urine Circulating Cathodic Antigen (CCA) Dipstick: A Valid Substitute for Microscopy for Mapping and Point-Of-Care Diagnosis of Intestinal Schistosomiasis 
Background
The World Health Organization now recommends the provision of praziquantel treatment to preschool-aged children infected with schistosomiasis. For intestinal schistosomiasis the current operational field diagnostic standard is examination of a thick Kato-Katz smear by microscopy prepared from a single stool specimen, and although pragmatic, this methodology has well-known shortcomings. Here, as a potential alternative, the performance of the urine circulating cathodic antigen (CCA) dipstick test was assessed in terms of disease-mapping and point-of-care diagnosis for intestinal schistosomiasis in preschool-aged children. Our manuscript reports on findings at baseline and at the end of a one-year longitudinal treatment study.
Methodology/Principal Findings
A total of 925 children (mean age 2.8 years) were initially recruited from six lakeshore villages representative of high, moderate and low levels of disease transmission. At baseline, all children were tested for intestinal schistosomiasis by microscopic examination of duplicate Kato-Katz smears prepared from a single stool faecal, by antigen detection with the urine CCA dipstick test and by serology with a commercially available ELISA test (as ‘gold-standard’) that measures host antibody titres to soluble egg antigens. As a point-of-care diagnosis, the urine CCA dipstick test achieved sensitivity and specificity values ranging from 52.5–63.2% and 57.7–75.6%, respectively, with faecal microscopy achieving very high specificities (>87%) but sensitivities as low as 16.7% in the low transmission setting.
Conclusion/Significance
The urine CCA test was shown to be more effective than faecal microscopy especially in lower transmission settings. The diagnostic performance of this test was not significantly impacted by treatment history or co-infections with other intestinal helminths.
Author Summary
The World Health Organization (WHO) now recommends that all children (2–16 year olds) living in schistosomiasis endemic areas should have regular access to praziquantel treatment. While there is extensive information in current literature on the geographical distribution of this disease in school-aged children (6–16 year olds), very little is known about its distribution in infants and preschool-aged children. Although pragmatic for resource-poor settings, the current field-standard method, the Kato-Katz smear, lacks diagnostic sensitivity, especially in lower transmission settings or where there is a large proportion of recently acquired infections. The latter is of particular importance for preschool-aged children as many will have pre-egg patent infections. Here we investigate a commercial rapid diagnostic test alternative to microscopy, using a dipstick test that detects worm antigens in the patient's urine, and show that it can achieve better performance than the current field standard both during mapping efforts and as a point-of-care diagnosis. Importantly, we found this diagnostic tool to be as effective before and after praziquantel treatment, able to provide semi-quantitative information on intensity of infection, and to be far more sensitive for identifying recently acquired infections than any other present alternatives.
doi:10.1371/journal.pntd.0002008
PMCID: PMC3554525  PMID: 23359826
21.  Small Bowel Transplant 
EXECUTIVE SUMMARY
Objective
The Medical Advisory Secretariat undertook a review of the evidence on the effectiveness and cost-effectiveness of small bowel transplant in the treatment of intestinal failure.
Small Bowel Transplantation
Intestinal failure is the loss of absorptive capacity of the small intestine that results in an inability to meet the nutrient and fluid requirements of the body via the enteral route. Patients with intestinal failure usually receive nutrients intravenously, a procedure known as parenteral nutrition. However, long-term parenteral nutrition is associated with complications including liver failure and loss of venous access due to recurrent infections.
Small bowel transplant is the transplantation of a cadaveric intestinal allograft for the purpose of restoring intestinal function in patients with irreversible intestinal failure. The transplant may involve the small intestine alone (isolated small bowel ISB), the small intestine and the liver (SB-L) when there is irreversible liver failure, or multiple organs including the small bowel (multivisceral MV or cluster). Although living related donor transplant is being investigated at a limited number of centres, cadaveric donors have been used in most small bowel transplants.
The actual transplant procedure takes approximately 12-18 hours. After intestinal transplant, the patient is generally placed on prophylactic antibiotic medication and immunosuppressive regimen that, in the majority of cases, would include tacrolimus, corticosteroids and an induction agent. Close monitoring for infection and rejection are essential for early treatment.
Medical Advisory Secretariat Review
The Medical Advisory Secretariat undertook a review of 35 reports from 9 case series and 1 international registry. Sample size of the individual studies ranged from 9 to 155.
As of May 2001, 651 patients had received small bowel transplant procedures worldwide. According to information from the Canadian Organ Replacement Register, a total of 27 small bowel transplants were performed in Canada from 1988 to 2002.
Patient Outcomes
The experience in small bowel transplant is still limited. International data showed that during the last decade, patient survival and graft survival rates from SBT have improved, mainly because of improved immunosuppression therapy and earlier detection and treatment of infection and rejection. The Intestinal Transplant Registry reported 1-year actuarial patient survival rates of 69% for isolated small bowel transplant, 66% for small bowel-liver transplant, and 63% for multivisceral transplant, and a graft survival rate of 55% for ISB and 63% for SB-L and MV. The range of 1-year patient survival rates reported ranged from 33%-87%. Reported 1-year graft survival rates ranged from 46-71%.
Regression analysis performed by the International Transplant Registry in 1997 indicated that centres that have performed at least 10 small bowel transplants had better patient and graft survival rates than centres that performed less than 10 transplants. However, analysis of the data up to May 2001 suggests that the critical mass of 10 transplants no longer holds true for transplants after 1995, and that good results can be achieved at any multiorgan transplant program with moderate patient volumes.
The largest Centre reported an overall 1-year patient and graft survival rate of 72% and 64% respectively, and 5-year patient and graft survival of 48% and 40% respectively. The overall 1-year patient survival rate reported for Ontario pediatric small bowel transplants was 61% with the highest survival rate of 83% for ISB.
The majority (70% or higher) of surviving small bowel transplant recipients was able to wean from parenteral nutrition and meet all caloric needs enterally. Some may need enteral or parenteral supplementation during periods of illness. Growth and weight gain in children after ISB were reported by two studies while two other studies reported a decrease in growth velocity with no catch-up growth.
The quality of life after SBT was reported to be comparable to that of patients on home enteral nutrition. A study found that while the parents of pediatric SBT recipients reported significant limitations in the physical and psychological well being of the children compared with normal school children, the pediatric SBT recipients themselves reported a quality of life similar to other school children.
Survival was found to be better in transplants performed since 1991. Patient survival was associated with the type of organ transplanted with better survival in isolated small bowel recipients.
Adverse Events
Despite improvement in patient and graft survival rates, small bowel transplant is still associated with significant mortality and morbidity.
Infection with subsequent sepsis is the leading cause of death (51.3%). Bacterial, fungal and viral infections have all been reported. The most common viral infections are cytomegalorvirus (18-40%) and Epstein-Barr virus. The latter often led to ß-cell post-transplant lymphoproliferative disease.
Graft rejection is the second leading cause of death after SBT (10.4%) and is responsible for 57% of graft removal. Acute rejection rates ranged from 51% to 83% in the major programs. Most of the acute rejection episodes were mild and responded to steroids and OKT3. Antilymphocyte therapy was needed in up to 27% of patients. Isolated small bowel allograft and positive lymphocytotoxic cross-match were found to be risk factors for acute rejection.
Post-transplant lymphoproliferative disease occurred in 21% of SBT recipients and accounted for 7% of post-transplant mortality. The frequency was higher in pediatric recipients (31%) and in adults receiving composite visceral allografts (25%). The allograft itself is often involved in post-transplant lymphoproliferative disease. The reported incidence of host versus graft disease varied widely among centers (0% - 14%).
Surgical complications were reported to occur in 85% of SB-L transplants and 25% of ISB transplants. Reoperations were required in 45% - 66% of patients in a large series and the most common reason for reoperation was intra-abdominal abscess.
The median cost of intestinal transplant in the US was reported to be approximately $275,000US (approximately CDN$429,000) per case. A US study concluded that based on the US cost of home parenteral nutrition, small bowel transplant could be cost-effective by the second year after the transplant.
Conclusion
There is evidence that small bowel transplant can prolong the life of some patients with irreversible intestinal failure who can no longer continue to be managed by parenteral nutrition therapy. Both patient survival and graft survival rates have improved with time. However, small bowel transplant is still associated with significant mortality and morbidity. The outcomes are inferior to those of total parenteral nutrition. Evidence suggests that this procedure should only be used when total parenteral nutrition is no longer feasible.
PMCID: PMC3387750  PMID: 23074441
22.  Association of Adenotonsillectomy with Asthma Outcomes in Children: A Longitudinal Database Analysis 
PLoS Medicine  2014;11(11):e1001753.
Rakesh Bhattacharjee and colleagues use data from a US private health insurance database to compare asthma severity measures in children one year before and one year after they underwent adenotonsillectomy with asthma measures in those who did not undergo adenotonsillectomy.
Please see later in the article for the Editors' Summary
Background
Childhood asthma and obstructive sleep apnea (OSA), both disorders of airway inflammation, were associated in recent observational studies. Although childhood OSA is effectively treated by adenotonsillectomy (AT), it remains unclear whether AT also improves childhood asthma. We hypothesized that AT, the first line of therapy for childhood OSA, would be associated with improved asthma outcomes and would reduce the usage of asthma therapies in children.
Methods and Findings
Using the 2003–2010 MarketScan database, we identified 13,506 children with asthma in the United States who underwent AT. Asthma outcomes during 1 y preceding AT were compared to those during 1 y following AT. In addition, 27,012 age-, sex-, and geographically matched children with asthma without AT were included to examine asthma outcomes among children without known adenotonsillar tissue morbidity. Primary outcomes included the occurrence of a diagnostic code for acute asthma exacerbation (AAE) or acute status asthmaticus (ASA). Secondary outcomes included temporal changes in asthma medication prescriptions, the frequency of asthma-related emergency room visits (ARERs), and asthma-related hospitalizations (ARHs). Comparing the year following AT to the year prior, AT was associated with significant reductions in AAE (30.2%; 95% CI: 25.6%–34.3%; p<0.0001), ASA (37.9%; 95% CI: 29.2%–45.6%; p<0.0001), ARERs (25.6%; 95% CI: 16.9%–33.3%; p<0.0001), and ARHs (35.8%; 95% CI: 19.6%–48.7%; p = 0.02). Moreover, AT was associated with significant reductions in most asthma prescription refills, including bronchodilators (16.7%; 95% CI: 16.1%–17.3%; p<0.001), inhaled corticosteroids (21.5%; 95% CI: 20.7%–22.3%; p<0.001), leukotriene receptor antagonists (13.4%; 95% CI: 12.9%–14.0%; p<0.001), and systemic corticosteroids (23.7%; 95% CI: 20.9%–26.5%; p<0.001). In contrast, there were no significant reductions in these outcomes in children with asthma who did not undergo AT over an overlapping follow-up period. Limitations of the MarketScan database include lack of information on race and obesity status. Also, the MarketScan database does not include information on children with public health insurance (i.e., Medicaid) or uninsured children.
Conclusions
In a very large sample of privately insured children, AT was associated with significant improvements in several asthma outcomes. Contingent on validation through prospectively designed clinical trials, this study supports the premise that detection and treatment of adenotonsillar tissue morbidity may serve as an important strategy for improving asthma control.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma has been rising steadily over the past few decades. Nowadays, about 200–300 million adults and children worldwide are affected by asthma, a chronic condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs). Although asthma can develop at any age, it is often diagnosed in childhood—asthma is one of the commonest chronic diseases in children. In the US, for example, asthma affects around 7.1 million children under the age of 18 years and is the third leading cause of hospitalization of children under the age of 15 years. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke. Exercise, cold air, and infections can trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
Recent studies have found an association between severe childhood asthma and obstructive sleep apnea (OSA). In OSA, airway inflammation promotes hypertrophy (excess growth) of the adenoids and the tonsils, immune system tissues in the upper airway. During sleep, the presence of hypertrophic adenotonsillar tissues predisposes the walls of the throat to collapse, which results in apnea—a brief interruption in breathing. People with OSA often snore loudly and frequently wake from deep sleep as they struggle to breathe. Childhood OSA, which affects 2%–3% of children, can be effectively treated by removal of the adenoids and tonsils (adenotonsillectomy). Given the association between childhood OSA and severe asthma and given the involvement of airway inflammation in both conditions, might adenotonsillectomy also improve childhood asthma? Here, the researchers analyze data from the MarketScan database, a large database of US patients with private health insurance, to investigate whether adenotonsillectomy is associated with improvements in asthma outcomes and with reductions in the use of asthma therapies in children.
What Did the Researchers Do and Find?
The researchers used the database to identify 13,506 children with asthma who had undergone adenotonsillectomy and to obtain information about asthma outcomes among these children for the year before and the year after the operation. Because asthma severity tends to decrease with age, the researchers also used the database to identify 27,012 age-, sex-, and geographically matched children with asthma who did not have the operation so that they could examine asthma outcomes over an equivalent two-year period in the absence of complications related to adenotonsillar hypertrophy. Comparing the year after adenotonsillectomy with the year before the operation, adenotonsillectomy was associated with a 30% reduction in acute asthma exacerbations, a 37.9% reduction in acute status asthmaticus (an asthma attack that is unresponsive to the drugs usually used to treat attacks), a 25.6% reduction in asthma-related emergency room visits, and a 35.8% reduction in asthma-related hospitalizations. By contrast, among the control children, there was only a 2% reduction in acute asthma exacerbations and only a 7% reduction in acute status asthmaticus over an equivalent two-year period. Adenotonsillectomy was also associated with significant reductions (changes unlikely to have occurred by chance) in prescription refills for most types of drugs used to treat asthma, whereas there were no significant reductions in prescription refills among children with asthma who had not undergone adenotonsillectomy. The study was limited by the lack of measures of race and obesity, which are both associated with severity of asthma.
What Do These Findings Mean?
These findings show that in a large sample of privately insured children in the US, adenotonsillectomy was associated with significant improvements in several asthma outcomes. These results do not show, however, that adenotonsillectomy caused a reduction in the severity of childhood asthma. It could be that the children who underwent adenotonsillectomy (but not those who did not have the operation) shared another unknown factor that led to improvements in their asthma over time. To prove a causal link, it will be necessary to undertake a randomized controlled trial in which the outcomes of groups of children with asthma who are chosen at random to undergo or not undergo adenotonsillectomy are compared. However, with the proviso that there are some risks associated with adenotonsillectomy, these findings suggest that the detection and treatment of adenotonsillar hypertrophy may help to improve asthma control in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001753.
The US Centers for Disease Control and Prevention provides information on asthma, including videos, games, and links to other resources for children with asthma
The American Lung Association provides detailed information about asthma and a fact sheet on asthma in children; it also has information about obstructive sleep apnea
The National Sleep Foundation provides information on snoring and obstructive sleep apnea in children
The UK National Health Service Choices website provides information (including some personal stories) about asthma, about asthma in children, and about obstructive sleep apnea
The “Global Asthma Report 2014” will be available in October 2014
MedlinePlus provides links to further information on asthma, on asthma in children, on sleep apnea, and on tonsils and adenoids (in English and Spanish)
doi:10.1371/journal.pmed.1001753
PMCID: PMC4219664  PMID: 25369282
23.  Pediatric Femoral Neck Fractures: Our 10 Years of Experience 
Clinics in Orthopedic Surgery  2011;3(4):302-308.
Background
Femoral neck fractures are rare injuries in children, but the high incidence of long term complications make it an important clinical entity. The aim of this retrospective study was to analyze the clinical outcomes of pediatric femur neck fractures that we managed over a 10 year period.
Methods
The study included 36 children (20 boys and 16 girls) who sustained femoral neck fractures and completed a minimum follow-up of one year. The children were treated either conservatively, or by open reduction and internal fixation (ORIF), or closed reduction and internal fixation (CRIF). The outcomes were analyzed using Ratliff criteria and a detailed record of complications was kept for all patients.
Results
The mean age of included patients was 10 years (range, 3 to 16 years) and the average follow-up was 3.2 years (range, 1.1 to 8.5 years). Based on Delbet's classification system, there were 0 type I (transepiphyseal), 16 type II, 11 type III, and 9 type IV fractures. There were 8 undisplaced fractures, 4 of which later displaced after being managed initially in a hip spica. A satisfactory outcome was obtained in 27 (75%) children. Avascular necrosis (AVN) was the most common complication. It was seen in 7 of our patients, all of whom had an unsatisfactory outcome. Other complications included three cases each of coxa vara, non-union, and arthritic changes; and one case each of infection, primary screw perforation of head, and premature epiphyseal closure. Complications were lowest in the group treated by ORIF. Only 2 patients managed exclusively by conservative treatment ultimately achieved a satisfactory outcome.
Conclusions
We believe that internal fixation of pediatric femoral neck fractures is preferred whenever feasible because conservative treatment carries a high risk of failure of reduction. Aggressive operative treatments aimed at anatomical reduction should be the goal and there should be no hesitation in choosing ORIF over CRIF. Outcome of patients is influenced primarily by development of AVN which occurs as an independent entity without much relation to the mode of treatment carried out.
doi:10.4055/cios.2011.3.4.302
PMCID: PMC3232358  PMID: 22162793
Pediatric femur neck fracture; Avascular necrosis; Open reduction and internal fixation; Ratliff; Delbet classification
24.  Laparoscopic approach to Meckel's diverticulum 
AIM: To retrospective review the laparoscopic management of Meckel Diverticulum (MD) in two Italian Pediatric Surgery Centers.
METHODS: Between January 2002 and December 2012, 19 trans-umbilical laparoscopic-assisted (TULA) procedures were performed for suspected MD. The children were hospitalized for gastrointestinal bleeding and/or recurrent abdominal pain. Median age at diagnosis was 5.4 years (range 6 mo-15 years). The study included 15 boys and 4 girls. All patients underwent clinical examination, routine laboratory tests, abdominal ultrasound and technetium-99m pertechnetate scan, and patients with bleeding underwent gastrointestinal endoscopy. The abdominal exploration was performed with a 10 mm operative laparoscope. Pneumoperitoneum was established based on the body weight. Systematic overview of the peritoneal cavity allowed the ileum to be grasped with an atraumatic instrument. The complete exploration and surgical treatment of MD were performed extracorporeally, after intestinal exteriorization through the umbilicus. All patients’ demographics, main clinical features, diagnostic investigations, operative time, histopathology reports, conversion rate, hospital stay and complications were registered and analyzed.
RESULTS: MD was identified in 17 patients, while 1 had an ileal duplication and 1 a jejunal hemangioma. Fifteen patients had painless intestinal bleeding, while 4 had recurrent abdominal pain and exhibited cyst like structures in an ultrasound study. Eleven patients had a positive technetium-99m pertechnetate scan. In the patients with bleeding, gastrointestinal endoscopy did not name the source of hemorrhage. All patients were subjected to a TULA surgical procedure. An intestinal resection/anastomosis was performed in 14 patients, while 4 had a wedge resection of the diverticulum and 1 underwent stapling diverticulectomy. All surgical procedures were performed without conversion to open laparotomy. Mean operative time was 75 min (range 40-115 min). No major surgical complications were recorded. The median hospital stay was 5-7 d (range 4-13 d). All patients are asymptomatic at a median follow up of 4, 5 years (range 10 mo-10 years).
CONCLUSION: Trans-umbilical laparoscopic-assisted Meckel’s diverticulectomy is safe and effective in the treatment of MD, with excellent results.
doi:10.3748/wjg.v20.i25.8173
PMCID: PMC4081689  PMID: 25009390
Meckel’s diverticulum; Laparoscopy; One trocar surgery; Gastrointestinal bleeding; Minimal invasive surgery; Ileal duplication; Jejunal hemangioma
25.  FACTORS THAT AFFECTING HUMAN ISLET ISOLATION 
Transplantation proceedings  2008;40(2):343-345.
More than 10,000 IEQ/kg recipient weight islets are often necessary to achieve insulin independence in patients with type 1 diabetes. Several studies have identified high BMI donor and pancreas size are important factors for the success of human islet isolation. However, donor shortage underscores the need to improve isolation outcomes from lower BMI pancreas donors and/or small pancreata. Aim of this study was to identify the critical factors affecting isolation outcome. The data from 207 isolations performed from 2002 to 2006 were analyzed with respect to donor characteristics, pancreas condition and processing variables. More than 3,000 IEQ/g pancreas weight were considered as an acceptable isolation outcome (AIO). AIO were obtained from donors with a BMI>30kg/m2 (p=0.002). The pancreatic surface integrity was also a significant factor towards AIO (p=0.02). Moreover, a longer digestion time (p=0.04) and the proportion of trapped islet negatively affected AIO rates (p=0.004). As previously reported, pancreata from high BMI donors were suitable for islet isolation and transplantation, as they yielded higher total islet particle numbers and higher IEQ/g. Although BMI and pancreas size are not controllable due to organ donor shortage, factors such as pancreatic surface integrity, shorter digestion and lower proportions of trapped islet were found to be significant factors to obtain higher rates of AIO. The development of better protocol and systematic training of processing and procurement teams will be of assistance in increasing the number of successful human islet isolations.
doi:10.1016/j.transproceed.2007.12.019
PMCID: PMC2614209  PMID: 18374062

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