Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Murine leukemia virus RNA dimerization is coupled to transcription and splicing processes

Most of the cell biological aspects of retroviral genome dimerization remain unknown. Murine leukemia virus (MLV) constitutes a useful model to study when and where dimerization occurs within the cell. For instance, MLV produces a subgenomic RNA (called SD') that is co-packaged with the genomic RNA predominantly as FLSD' heterodimers. This SD' RNA is generated by splicing of the genomic RNA and also by direct transcription of a splice-associated retroelement of MLV (SDARE). We took advantage of these two SD' origins to study the effects of transcription and splicing events on RNA dimerization. Using genetic approaches coupled to capture of RNA heterodimer in virions, we determined heterodimerization frequencies in different cellular contexts. Several cell lines were stably established in which SD' RNA was produced by either splicing or transcription from SDARE. Moreover, SDARE was integrated into the host chromosome either concomitantly or sequentially with the genomic provirus. Our results showed that transcribed genomic and SD' RNAs preferentially formed heterodimers when their respective proviruses were integrated together. In contrast, heterodimerization was strongly affected when the two proviruses were integrated independently. Finally, dimerization was enhanced when the transcription sites were expected to be physically close. For the first time, we report that splicing and RNA dimerization appear to be coupled. Indeed, when the RNAs underwent splicing, the FLSD' dimerization reached a frequency similar to co-transcriptional heterodimerization. Altogether, our results indicate that randomness of heterodimerization increases when RNAs are co-expressed during either transcription or splicing. Our results strongly support the notion that dimerization occurs in the nucleus, at or near the transcription and splicing sites, at areas of high viral RNA concentration

Patterns of clinical presentation of adult coeliac disease in a rural setting

BACKGROUND: In recent years there has been increasing recognition that the pattern of presentation of coeliac disease may be changing. The classic sprue syndrome with diarrhoea and weight loss may be less common than the more subtle presentations of coeliac disease such as an isolated iron deficiency anaemia. As a result, the diagnosis of this treatable condition is often delayed or missed. Recent serologic screening tests allow non-invasive screening to identify most patients with the disease and can be applied in patients with even subtle symptoms indicative of coeliac disease. Both benign and malignant complications of coeliac disease can be avoided by early diagnosis and a strict compliance with a gluten free diet. AIM: The aim of this study is to evaluate the trends in clinical presentation of patients diagnosed with adult coeliac disease. In addition, we studied the biochemical and serological features and the prevalence of associated conditions in patients with adult coeliac disease. METHODS: This is an observational, retrospective, cross-sectional review of the medical notes of 32 adult patients attending the specialist coeliac clinic in a district general hospital. RESULTS: Anaemia was the most common mode of presentation accounting for 66% of patients. Less than half of the patients had any of the classical symptoms of coeliac disease and 25% had none of the classical symptoms at presentation. Anti-gliadin antibodies, anti-endomysial antibody and anti-tissue transglutaminase showed 75%, 68% and 90% sensitivity respectively. In combination, serology results were 100% sensitive as screening tests for adult coeliac disease. Fifty nine percent patients had either osteoporosis or osteopenia. There were no malignant complications observed during the follow up of our patients. CONCLUSION: Most adults with coeliac disease have a sub clinical form of the disease and iron deficiency anaemia may be its sole presenting symptom. Only a minority of adult coeliac disease patients present with classical mal-absorption symptoms of diarrhoea and weight loss. Patients with atypical form of disease often present initially to hospital specialists other than a gastro-enterologist. An awareness of the broad spectrum of presentations of adult coeliac disease, among doctors both in primary care and by the various hospital specialists in secondary care, is necessary to avoid delays in diagnosis. It is important to include serological screening tests for coeliac disease systematically in the evaluation of adult patients with unexplained iron deficiency anaemia or unexplained gastro-intestinal symptoms and in those who are considered to be at increased risk for coeliac disease

Vaccination against Heterologous R5 Clade C SHIV: Prevention of Infection and Correlates of Protection

A safe, efficacious vaccine is required to stop the AIDS pandemic. Disappointing results from the STEP trial implied a need to include humoral anti-HIV-1 responses, a notion supported by RV144 trial data even though correlates of protection are unknown. We vaccinated rhesus macaques with recombinant simian immunodeficiency virus (SIV) Gag-Pol particles, HIV-1 Tat and trimeric clade C (HIV-C) gp160, which induced cross-neutralizing antibodies (nAbs) and robust cellular immune responses. After five low-dose mucosal challenges with a simian-human immunodeficiency virus (SHIV) that encoded a heterologous R5 HIV-C envelope (22.1% divergence from the gp160 immunogen), 94% of controls became viremic, whereas one third of vaccinees remained virus-free. Upon high-dose SHIV rechallenge, all controls became infected, whereas some vaccinees remained aviremic. Peak viremia was inversely correlated with both cellular immunity (p<0.001) and cross-nAb titers (p<0.001). These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time

The characteristics of depressive symptoms in medical students during medical education and training: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Medical education and training can contribute to the development of depressive symptoms that might lead to possible academic and professional consequences. We aimed to investigate the characteristics of depressive symptoms among 481 medical students (79.8% of the total who matriculated).</p> <p>Methods</p> <p>The Beck Depression Inventory (BDI) and cluster analyses were used in order to better describe the characteristics of depressive symptoms. Medical education and training in Brazil is divided into basic (1^stand 2^ndyears), intermediate (3^rdand 4^thyears), and internship (5^thand 6^thyears) periods. The study organized each item from the BDI into the following three clusters: affective, cognitive, and somatic. Statistical analyses were performed using analysis of variance (ANOVA) with <it>post-hoc </it>Tukey corrected for multiple comparisons.</p> <p>Results</p> <p>There were 184 (38.2%) students with depressive symptoms (BDI > 9). The internship period resulted in the highest BDI scores in comparison to both the basic (p < .001) and intermediate (p < .001) periods. Affective, cognitive, and somatic clusters were significantly higher in the internship period. An exploratory analysis of possible risk factors showed that females (p = .020) not having a parent who practiced medicine (p = .016), and the internship period (p = .001) were factors for the development of depressive symptoms.</p> <p>Conclusion</p> <p>There is a high prevalence towards depressive symptoms among medical students, particularly females, in the internship level, mainly involving the somatic and affective clusters, and not having a parent who practiced medicine. The active assessment of these students in evaluating their depressive symptoms is important in order to prevent the development of co-morbidities and suicide risk.</p

A Systematic Guideline by the ASPN Workgroup on the Evidence, Education, and Treatment Algorithm for Painful Diabetic Neuropathy: SWEET

Dawood Sayed,1 Timothy Ray Deer,2 Jonathan M Hagedorn,3 Asim Sayed,4 Ryan S D’Souza,3 Christopher M Lam,1 Nasir Khatri,5 Zohra Hussaini,1 Scott G Pritzlaff,6 Newaj Mohammad Abdullah,7 Vinicius Tieppo Francio,1 Steven Michael Falowski,8 Yussr M Ibrahim,9 Mark N Malinowski,10 Ryan R Budwany,2 Natalie Holmes Strand,11 Kamil M Sochacki,12 Anuj Shah,13 Tyler M Dunn,11 Morad Nasseri,14 David W Lee,15 Leonardo Kapural,16 Marshall David Bedder,17,18 Erika A Petersen,19 Kasra Amirdelfan,20 Michael E Schatman,21,22 Jay Samuel Grider23 1Department of Anesthesiology and Pain Medicine, The University of Kansas Medical Center, Kansas City, KS, USA; 2Pain Services, Spine and Nerve Center of the Virginias, Charleston, WV, USA; 3Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, USA; 4Podiatry/Surgery, Susan B. Allen Memorial Hospital, El Dorado, KS, USA; 5Interventional Pain Medicine, Novant Spine Specialists, Charlotte, NC, USA; 6Department of Anesthesiology and Pain Medicine, University of California, Davis, Sacramento, CA, USA; 7Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA; 8Neurosurgery, Neurosurgical Associates of Lancaster, Lancaster, PA, USA; 9Pain Medicine, Northern Light Eastern Maine Medical Center, Bangor, ME, USA; 10OhioHealth Neurological Physicians, OhioHealth, Columbus, OH, USA; 11Anesthesiology and Pain Medicine, Mayo Clinic, Phoenix, AZ, USA; 12Department of Anesthesiology and Perioperative Medicine, Rutgers Robert Wood Johnson, New Brunswick, NJ, USA; 13Department of Physical Medicine and Rehabilitation, Detroit Medical Center, Detroit, MI, USA; 14Interventional Pain Medicine / Neurology, Boomerang Healthcare, Walnut Creek, CA, USA; 15Pain Management Specialist, Fullerton Orthopedic, Fullerton, CA, USA; 16Carolinas Pain Institute, Winston Salem, NC, USA; 17Chief of Pain Medicine Service, Augusta VAMC, Augusta, GA, USA; 18Associate Professor and Director, Addiction Medicine Fellowship Program, Department Psychiatry and Health Behavior, Medical College of Georgia at Augusta University, Augusta, GA, USA; 19Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 20Director of Clinical Research, Boomerang Healthcare, Walnut Creek, CA, USA; 21Department of Anesthesiology, Perioperative Care & Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 22Department of Population Health – Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USA; 23Anesthesiology, Division of Pain Medicine, University of Kentucky College of Medicine, Lexington, KY, USACorrespondence: Dawood Sayed, Anesthesiology and Pain Medicine, the University of Kansas Medical Center, Kansas City, KS, USA, Tel +1 785-550-5800, Email [email protected]: Painful diabetic neuropathy (PDN) is a leading cause of pain and disability globally with a lack of consensus on the appropriate treatment of those suffering from this condition. Recent advancements in both pharmacotherapy and interventional approaches have broadened the treatment options for PDN. There exists a need for a comprehensive guideline for the safe and effective treatment of patients suffering from PDN.Objective: The SWEET Guideline was developed to provide clinicians with the most comprehensive guideline for the safe and appropriate treatment of patients suffering from PDN.Methods: The American Society of Pain and Neuroscience (ASPN) identified an educational need for a comprehensive clinical guideline to provide evidence-based recommendations for PDN. A multidisciplinary group of international experts developed the SWEET guideline. The world literature in English was searched using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus to identify and compile the evidence for diabetic neuropathy pain treatments (per section as listed in the manuscript) for the treatment of pain. Manuscripts from 2000-present were included in the search process.Results: After a comprehensive review and analysis of the available evidence, the ASPN SWEET guideline was able to rate the literature and provide therapy grades for most available treatments for PDN utilizing the United States Preventive Services Task Force criteria.Conclusion: The ASPN SWEET Guideline represents the most comprehensive review of the available treatments for PDN and their appropriate and safe utilization.Keywords: diabetes, painful diabetic neuropathy, neuropathy, spinal cord stimulation, chronic pain, diabetic neuropath

Functional, Non-Clonal IgMa-Restricted B Cell Receptor Interactions with the HIV-1 Envelope gp41 Membrane Proximal External Region

The membrane proximal external region (MPER) of HIV-1 gp41 has several features that make it an attractive antibody-based vaccine target, but eliciting an effective gp41 MPER-specific protective antibody response remains elusive. One fundamental issue is whether the failure to make gp41 MPER-specific broadly neutralizing antibodies like 2F5 and 4E10 is due to structural constraints with the gp41 MPER, or alternatively, if gp41 MPER epitope-specific B cells are lost to immunological tolerance. An equally important question is how B cells interact with, and respond to, the gp41 MPER epitope, including whether they engage this epitope in a non-canonical manner i.e., by non-paratopic recognition via B cell receptors (BCR). To begin understanding how B cells engage the gp41 MPER, we characterized B cell-gp41 MPER interactions in BALB/c and C57BL/6 mice. Surprisingly, we found that a significant (∼7%) fraction of splenic B cells from BALB/c, but not C57BL/6 mice, bound the gp41 MPER via their BCRs. This strain-specific binding was concentrated in IgMhi subsets, including marginal zone and peritoneal B1 B cells, and correlated with enriched fractions (∼15%) of gp41 MPER-specific IgM secreted by in vitro-activated splenic B cells. Analysis of Igha (BALB/c) and Ighb (C57BL/6) congenic mice demonstrated that gp41 MPER binding was controlled by determinants of the Igha locus. Mapping of MPER gp41 interactions with IgMa identified MPER residues distinct from those to which mAb 2F5 binds and demonstrated the requirement of Fc CH regions. Importantly, gp41 MPER ligation produced detectable BCR-proximal signaling events, suggesting that interactions between gp41 MPER and IgMa determinants may elicit partial B cell activation. These data suggest that low avidity, non-paratopic interactions between the gp41 MPER and membrane Ig on naïve B cells may interfere with or divert bnAb responses