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

Impact of routine PCV7 (Prevenar) vaccination of infants on the clinical and economic burden of pneumococcal disease in Malaysia

<p>Abstract</p> <p>Background</p> <p>Pneumococcal disease is the leading cause of vaccine-preventable death in children younger than 5 years of age worldwide. The World Health Organization recommends pneumococcal conjugate vaccine as a priority for inclusion into national childhood immunization programmes. Pneumococcal vaccine has yet to be included as part of the national vaccination programme in Malaysia although it has been available in the country since 2005. This study sought to estimate the disease burden of pneumococcal disease in Malaysia and to assess the cost effectiveness of routine infant vaccination with PCV7.</p> <p>Methods</p> <p>A decision model was adapted taking into consideration prevalence, disease burden, treatment costs and outcomes for pneumococcal disease severe enough to result in a hospital admission. Disease burden were estimated from the medical records of 6 hospitals. Where local data was unavailable, model inputs were obtained from international and regional studies and from focus group discussions. The model incorporated the effects of herd protection on the unvaccinated adult population.</p> <p>Results</p> <p>At current vaccine prices, PCV7 vaccination of 90% of a hypothetical 550,000 birth cohort would incur costs of RM 439.6 million (US$128 million). Over a 10 year time horizon, vaccination would reduce episodes of pneumococcal hospitalisation by 9,585 cases to 73,845 hospitalisations with cost savings of RM 37.5 million (US$10.9 million) to the health system with 11,422.5 life years saved at a cost effectiveness ratio of RM 35,196 (US$10,261) per life year gained.</p> <p>Conclusions</p> <p>PCV7 vaccination of infants is expected to be cost-effective for Malaysia with an incremental cost per life year gained of RM 35,196 (US$10,261). This is well below the WHO's threshold for cost effectiveness of public health interventions in Malaysia of RM 71,761 (US$20,922).</p

MicroRNA-96 Directly Inhibits γ-Globin Expression in Human Erythropoiesis

Fetal hemoglobin, HbF (α2γ2), is the main hemoglobin synthesized up to birth, but it subsequently declines and adult hemoglobin, HbA (α2β2), becomes predominant. Several studies have indicated that expression of the HbF subunit γ-globin might be regulated post-transcriptionally. This could be confered by ∼22-nucleotide long microRNAs that associate with argonaute proteins to specifically target γ-globin mRNAs and inhibit protein expression. Indeed, applying immunopurifications, we found that γ-globin mRNA was associated with argonaute 2 isolated from reticulocytes that contain low levels of HbF (<1%), whereas association was significantly lower in reticulocytes with high levels of HbF (90%). Comparing microRNA expression in reticulocytes from cord blood and adult blood, we identified several miRNAs that were preferentially expressed in adults, among them miRNA-96. The overexpression of microRNA-96 in human ex vivo erythropoiesis decreased γ-globin expression by 50%, whereas the knock-down of endogenous microRNA-96 increased γ-globin expression by 20%. Moreover, luciferase reporter assays showed that microRNA-96 negatively regulates expression of γ-globin in HEK293 cells, which depends on a seedless but highly complementary target site located within the coding sequence of γ-globin. Based on these results we conclude that microRNA-96 directly suppresses γ-globin expression and thus contributes to HbF regulation

Lipid (per) oxidation in mitochondria:an emerging target in the ageing process?

Lipids are essential for physiological processes such as maintaining membrane integrity, providing a source of energy and acting as signalling molecules to control processes including cell proliferation, metabolism, inflammation and apoptosis. Disruption of lipid homeostasis can promote pathological changes that contribute towards biological ageing and age-related diseases. Several age-related diseases have been associated with altered lipid metabolism and an elevation in highly damaging lipid peroxidation products; the latter has been ascribed, at least in part, to mitochondrial dysfunction and elevated ROS formation. In addition, senescent cells, which are known to contribute significantly to age-related pathologies, are also associated with impaired mitochondrial function and changes in lipid metabolism. Therapeutic targeting of dysfunctional mitochondrial and pathological lipid metabolism is an emerging strategy for alleviating their negative impact during ageing and the progression to age-related diseases. Such therapies could include the use of drugs that prevent mitochondrial uncoupling, inhibit inflammatory lipid synthesis, modulate lipid transport or storage, reduce mitochondrial oxidative stress and eliminate senescent cells from tissues. In this review, we provide an overview of lipid structure and function, with emphasis on mitochondrial lipids and their potential for therapeutic targeting during ageing and age-related disease

Pooled analysis of who surgical safety checklist use and mortality after emergency laparotomy

Background: The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods: In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results: Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89⋅6 per cent) compared with that in countries with a middle (753 of 1242, 60⋅6 per cent; odds ratio (OR) 0⋅17, 95 per cent c.i. 0⋅14 to 0⋅21, P &lt; 0⋅001) or low (363 of 860, 42⋅2 percent; OR 0⋅08, 0⋅07 to 0⋅10, P &lt; 0⋅001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference −9⋅4 (95 per cent c.i. −11⋅9 to −6⋅9) per cent; P &lt; 0⋅001), but the relationship was reversed in low-HDI countries (+12⋅1 (+7⋅0 to +17⋅3) per cent; P &lt; 0⋅001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0⋅60, 0⋅50 to 0⋅73; P &lt; 0⋅001). The greatest absolute benefit was seen for emergency surgery in low-and middle-HDI countries. Conclusion: Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries

Activation of HIV-1 expression in latently infected CD4+ T cells by the small molecule PKC412

BACKGROUND: HIV-1 latency is a major obstacle for HIV-1 eradication. Extensive efforts are being directed toward the reactivation of latent HIV reservoirs with the aim of eliminating latently infected cells via the host immune system and/or virus-mediated cell lysis. RESULTS: We screened over 1,500 small molecules and kinase inhibitors and found that a small molecule, PKC412 (midostaurin, a broad-spectrum kinase inhibitor), can stimulate viral transcription and expression from the HIV-1 latently infected ACH2 cell line and primary resting CD4+ T cells. PKC412 reactivated HIV-1 expression in ACH2 cells in a dose- and time-dependent manner. Our results also suggest that the nuclear factor κB (NF-κB) signaling could be one of cellular pathways activated during PKC412-mediated activation of latent HIV-1 expression. Additionally, combining PKC412 with the HDAC inhibitor vorinostat (VOR) had an additive effect on HIV-1 reactivation in both ACH2 cells and infected resting CD4+ T cells. CONCLUSIONS: These studies provide evidence that PKC412 is a new compound with the potential for optimization as a latency-reactivator to eradicate HIV-1 infection

A systematic review of the implementation and impact of asthma protocols

BACKGROUND: Asthma is one of the most common childhood illnesses. Guideline-driven clinical care positively affects patient outcomes for care. There are several asthma guidelines and reminder methods for implementation to help integrate them into clinical workflow. Our goal is to determine the most prevalent method of guideline implementation; establish which methods significantly improved clinical care; and identify the factors most commonly associated with a successful and sustainable implementation. METHODS: PUBMED (MEDLINE), OVID CINAHL, ISI Web of Science, and EMBASE. Study Selection: Studies were included if they evaluated an asthma protocol or prompt, evaluated an intervention, a clinical trial of a protocol implementation, and qualitative studies as part of a protocol intervention. Studies were excluded if they had non-human subjects, were studies on efficacy and effectiveness of drugs, did not include an evaluation component, studied an educational intervention only, or were a case report, survey, editorial, letter to the editor. RESULTS: From 14,478 abstracts, we included 101 full-text articles in the analysis. The most frequent study design was pre-post, followed by prospective, population based case series or consecutive case series, and randomized trials. Paper-based reminders were the most frequent with fully computerized, then computer generated, and other modalities. No study reported a decrease in health care practitioner performance or declining patient outcomes. The most common primary outcome measure was compliance with provided or prescribing guidelines, key clinical indicators such as patient outcomes or quality of life, and length of stay. CONCLUSIONS: Paper-based implementations are by far the most popular approach to implement a guideline or protocol. The number of publications on asthma protocol reminder systems is increasing. The number of computerized and computer-generated studies is also increasing. Asthma guidelines generally improved patient care and practitioner performance regardless of the implementation method