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THIS REPORT SUMMARIZES ALL RECOMMENDATIONS FROM CDC'S ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES (ACIP) FOR THE USE OF LYOPHILIZED CVD 103-HGR VACCINE (CVD 103-HGR) (VAXCHORA, EMERGENT BIOSOLUTIONS, GAITHERSBURG, MD) IN THE UNITED STATES. THE LIVE ATTENUATED ORAL CHOLERA VACCINE IS DERIVED FROM: Vibrio cholerae O1 and is administered in a single dose. Cholera is a toxin-mediated bacterial gastrointestinal illness caused by toxigenic V. cholerae serogroup O1 or, uncommonly, O139. Up to 10% of infections manifest as severe cholera (i.e., cholera gravis), profuse watery diarrhea that can cause severe dehydration and death within hours. Fluid replacement therapy can reduce the fatality rate to1%. Risk factors for cholera gravis include high dose exposure, blood group O, increased gastric pH (e.g., from antacid therapy), and partial gastrectomy. Cholera is rare in the United States, but cases occur among travelers to countries where cholera is endemic or epidemic and associated with unsafe water and inadequate sanitation. Travelers might be at increased risk for poor outcomes from cholera if they cannot readily access medical services or if they have a medical condition that would be worsened by dehydration, such as cardiovascular or kidney disease. This report describes previously published ACIP recommendations about use of CVD 103-HgR for adults aged 18-64 years and introduces a new recommendation for use in children and adolescents aged 2-17 years. ACIP recommends CVD 103-HgR, the only cholera vaccine licensed for use in the United States, for prevention of cholera among travelers aged 2-64 years to an area with active cholera transmission. Health care providers can use these guidelines to develop the pretravel consultation for persons traveling to areas with active cholera transmission.

Introduction Despite prioritization, routine antenatal influenza vaccine coverage is Methods From 2015 through 2018, 40,230 additional doses of influenza vaccine were added to the available stock and administered as part of routine antenatal care. Educational talks were given daily and data were collected on women attending ANCs. We compared characteristics of vaccinated and unvaccinated women using multivariable logistic regression. Results We screened 62,979 pregnant women during the period when Southern Hemisphere influenza vaccines were available (27,068 in Gauteng and 35,911 in WC). Vaccine coverage at the targeted clinics was 78.7% (49,355/62682), although pregnant women in WC were more likely to be vaccinated compared to those in the Gauteng (Odds ratio (OR) =3.7 p 35 years were less likely to be vaccinated than women aged 18—24 years (OR = 0.9 p = 0.053; OR = 0.9 p < 0.001). HIV positive status was not associated with vaccination (OR = 1.0 p = 0.266). Reasons for not vaccinating included: vaccine stock-outs where ANCs depleted available stock of vaccines and/or were awaiting delivery of vaccines (54.6%, 6949/12723), refusal/indecision (25.8%, 3285), and current illness that contraindicated vaccination (19.6%, 2489). Conclusion Antenatal vaccination uptake was likely improved by the increased vaccine supply and vaccine education offered during our campaign.

Background Aberrant lipogenicity and deregulated autophagy are common in most advanced human cancer and therapeutic strategies to exploit these pathways are currently under consideration. Group III Phospholipase A2 (sPLA2-III/PLA2G3), an atypical secretory PLA2, is recognized as a regulator of lipid metabolism associated with oncogenesis. Though recent studies reveal that high PLA2G3 expression significantly correlates with poor prognosis in several cancers, however, role of PLA2G3 in ovarian cancer (OC) pathogenesis is still undetermined. Methods CRISPR-Cas9 and shRNA mediated knockout and knockdown of PLA2G3 in OC cells were used to evaluate lipid droplet (LD) biogenesis by confocal and Transmission electron microscopy analysis, and the cell viability and sensitization of the cells to platinum-mediated cytotoxicity by MTT assay. Regulation of primary ciliation by PLA2G3 downregulation both genetically and by metabolic inhibitor PFK-158 induced autophagy was assessed by immunofluorescence-based confocal analysis and immunoblot. Transient transfection with GFP-RFP-LC3B and confocal analysis was used to assess the autophagic flux in OC cells. PLA2G3 knockout OVCAR5 xenograft in combination with carboplatin on tumor growth and metastasis was assessed in vivo. Efficacy of PFK158 alone and with platinum drugs was determined in patient-derived primary ascites cultures expressing PLA2G3 by MTT assay and immunoblot analysis. Results Downregulation of PLA2G3 in OVCAR8 and 5 cells inhibited LD biogenesis, decreased growth and sensitized cells to platinum drug mediated cytotoxicity in vitro and in in vivo OVCAR5 xenograft. PLA2G3 knockdown in HeyA8MDR-resistant cells showed sensitivity to carboplatin treatment. We found that both PFK158 inhibitor-mediated and genetic downregulation of PLA2G3 resulted in increased number of percent ciliated cells and inhibited cancer progression. Mechanistically, we found that PFK158-induced autophagy targeted PLA2G3 to restore primary cilia in OC cells. Of clinical relevance, PFK158 also induces percent ciliated cells in human-derived primary ascites cells and reduces cell viability with sensitization to chemotherapy. Conclusions Taken together, our study for the first time emphasizes the role of PLA2G3 in regulating the OC metastasis. This study further suggests the therapeutic potential of targeting phospholipases and/or restoration of PC for future OC treatment and the critical role of PLA2G3 in regulating ciliary function by coordinating interface between lipogenesis and metastasis.

The management of human epidermal growth factor receptor (HER2)-positive breast cancer (BC) has rapidly evolved over the last 20 years. Major advances have led to US Food and Drug Administration approval of 7 HER2-targeted therapies for the treatment of early-stage and/or advanced-stage disease. Although oncologic outcomes continue to improve, most patients with advanced HER2-positive BC ultimately die of their disease because of primary or acquired resistance to therapy, and patients with HER2-positive early BC who have residual invasive disease after preoperative systemic therapy are at a higher risk of distant recurrence and death. The concept of treatment de-escalation and escalation is increasingly important to optimally tailor therapy for patients with HER2-positive BC and is a major focus of the current review. Research efforts in this regard are discussed as well as updates regarding the evolving standard of care in the (neo)adjuvant and metastatic settings, including the use of novel combination therapies. The authors also briefly discuss ongoing challenges in the management of HER2-positive BC (eg, intrinsic vs acquired drug resistance, the identification of predictive biomarkers, the integration of imaging techniques to guide clinical practice), and the treatment of HER2-positive brain metastases. Research aimed at superseding these challenges will be imperative to ensure continued progress in the management of HER2-positive BC going forward.

Typhoid fever remains an important public health problem in low- and middle-income countries, with large outbreaks reported from Africa and Asia. Although the WHO recommends typhoid vaccination for control of confirmed outbreaks, there are limited data on the epidemiologic characteristics of outbreaks to inform vaccine use in outbreak settings. We conducted a literature review for typhoid outbreaks published since 1990. We found 47 publications describing 45,215 cases in outbreaks occurring in 25 countries from 1989 through 2018. Outbreak characteristics varied considerably by WHO region, with median outbreak size ranging from 12 to 1,101 cases, median duration from 23 to 140 days, and median case fatality ratio from 0% to 1%. The largest number of outbreaks occurred in WHO Southeast Asia, 13 (28%), and African regions, 12 (26%). Among 43 outbreaks reporting a mode of disease transmission, 24 (56%) were waterborne, 17 (40%) were foodborne, and two (5%) were by direct contact transmission. Among the 34 outbreaks with antimicrobial resistance data, 11 (32%) reported Typhi non-susceptible to ciprofloxacin, 16 (47%) reported multidrug-resistant (MDR) strains, and one reported extensively drug-resistant strains. Our review showed a longer median duration of outbreaks caused by MDR strains (148 days versus 34 days for susceptible strains), although this difference was not statistically significant. Control strategies focused on water, sanitation, and food safety, with vaccine use described in only six (13%) outbreaks. As typhoid conjugate vaccines become more widely used, their potential role and impact in outbreak control warrant further evaluation.

Ceftriaxone-resistant Salmonella enterica serotype Typhi (Typhi), the bacterium that causes typhoid fever, is a growing public health threat. Extensively drug-resistant (XDR) Typhi is resistant to ceftriaxone and other antibiotics used for treatment, including ampicillin, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole (1). In March 2018, CDC began enhanced surveillance for ceftriaxone-resistant Typhi in response to an ongoing outbreak of XDR typhoid fever in Pakistan. CDC had previously reported the first five cases of XDR Typhi in the United States among patients who had spent time in Pakistan (2). These illnesses represented the first cases of ceftriaxone-resistant Typhi documented in the United States (3). This report provides an update on U.S. cases of XDR typhoid fever linked to Pakistan and describes a new, unrelated cluster of ceftriaxone-resistant Typhi infections linked to Iraq. Travelers to areas with endemic Typhi should receive typhoid vaccination before traveling and adhere to safe food and water precautions (4). Treatment of patients with typhoid fever should be guided by antimicrobial susceptibility testing whenever possible (5), and clinicians should consider travel history when selecting empiric therapy.

Author(s): Yang, Bo; Wendland, Michael F; O'Connell, Grace D | Abstract: BackgroundWater content is a key parameter for simulating tissue swelling and nutrient diffusion. Accurately measuring water content throughout the intervertebral disc (NP = nucleus pulposus; AF = annulus fibrosus) is important for developing patient-specific models. Water content is measured using destructive techniques, Quantitative MRI has been used to estimate water content and detect early degeneration, but it is dependent on scan parameters, concentration of free water molecules, and fiber architecture.PurposeTo directly measure disc-tissue water content using quantitative MRI and compare MRI-based measurements with biochemical assays, and to quantify changes in disc geometry due to compression.Study typeBasic science, controlled.SpecimenTwenty bone-disc-bone motion segments from skeletally mature bovines.Field strength/sequence7T/3D fast low angle shot (FLASH) pulse sequence and a T2 rapid imaging with refocused echoes (RARE) sequence.AssessmentDisc volumes, NP and AF volumetric water content, and T2 relaxation times were measured through MRI; NP and AF tissue gravimetric water content, mass density, and glycosaminoglycan content were measured through a biochemical assay.Statistical testsCorrelations between MRI-based measurement and biochemical composition were evaluated using Pearson's linear regression.ResultsMechanical dehydration resulted in a decrease in disc volume by up to 20% and a decrease in disc height by up to 35%. Direct water content measurements for the NP was achieved by normalizing MRI-based spin density by NP mass density (1.10 ± 0.03 g/cm3 ). However, the same approach underestimated water content in the AF by ~10%, which may be due to a higher concentration of collagen fibers and bound water molecules.Data conclusionSpin density or spin density normalized by mass density to estimate NP and AF water content was more accurate than correlations between water content and relaxation times. Mechanical dehydration decreased disc volume and disc height, and increased maximum cross-sectional area.Level of evidenceTECHNICAL EFFICACY STAGE: J. Magn. Reson. Imaging 2020;52:1152-1162.

The intervertebral disc is a complex structure that experiences multiaxial stresses regularly. Disc failure through herniation is a common cause of lower back pain, which causes reduced mobility and debilitating pain, resulting in heavy socioeconomic burdens. Unfortunately, herniation etiology is not well understood, partially due to challenges in replicating herniation in vitro. Previous studies suggest that flexion elevated risks of herniation. Thus, the objective of this study was to use a multiscale and multiphasic finite element model to evaluate the risk of failure under torque- or muscle-driven flexion. Models were developed to represent torque-driven flexion with the instantaneous center of rotation (ICR) located on the disc, and the more physiologically representative muscle-driven flexion with the ICR located anterior of the disc. Model predictions highlighted disparate disc mechanics regarding bulk deformation, stress-bearing mechanisms, and intradiscal stress–strain distributions. Specifically, failure was predicted to initiate at the bone-disc boundary under torque-driven flexion, which may explain why endplate junction failure, instead of herniation, has been the more common failure mode observed in vitro. By contrast, failure was predicted to initiate in the posterolateral annulus fibrosus under muscle-driven flexion, resulting in consistent herniation. Our findings also suggested that muscle-driven flexion combined with axial compression could be sufficient for provoking herniation in vitro and in silico. In conclusion, this study provided a computational framework for designing in vitro testing protocols that can advance the assessment of disc failure behavior and the performance of engineered disc implants.

Zhou and colleagues are commended for their innovative research on the tolerability of "low-viscosity" fibre supplements in symptomatic diabetic gastroparesis patients [...].

The Open Science (OS) movement is rapidly gaining traction among policy-makers, research funders, scientific journals and individual scientists. Despite these tendencies, the pace of implementing OS throughout the scientific process and across the scientific community remains slow. Thus, a better understanding of the conditions that affect OS engagement, and in particular, of how practitioners learn, use, conduct and share research openly can guide those seeking to implement OS more broadly. We surveyed participants at an OS workshop hosted by the Living Norway Ecological Data Network in 2020 to learn how they perceived OS and its importance in their research, supervision and teaching. Further, we wanted to know what OS practices they had encountered in their education and what they saw as hindering or helping their engagement with OS. The survey contained scaled-response and open-ended questions, allowing for a mixed-methods approach. We obtained survey responses from 60 out of 128 workshop participants (47%). Responses indicated that usage and sharing of open data and code, as well as open access publication, were the most frequent OS practices. Only a minority of respondents reported having encountered OS in their formal education. A majority also viewed OS as less important in their teaching than in their research and supervisory roles. The respondents’ suggestions for what would facilitate greater OS engagement in the future included knowledge, guidelines, and resources, but also social and structural support. These are aspects that could be strengthened by promoting explicit implementation of OS practices in higher education and by nurturing a more inclusive and equitable OS culture. We argue that incorporating OS in teaching and learning of science can yield substantial benefits to the research community, student learning, and ultimately, to the wider societal objectives of science and higher education.

OBJECTIVES: In 2010, WHO published guidelines emphasizing parasitological confirmation of malaria prior to treatment. We present data on changes in fever case management in a low malaria transmission setting of northern Tanzania after 2010. METHODS: We compared diagnoses, treatments, and outcomes from two hospital-based prospective cohort studies, Cohort 1 (2011–2014) and Cohort 2 (2016–2019), that enrolled febrile children and adults. All participants underwent quality-assured malaria blood smear-microscopy. Participants who were malaria smear-microscopy negative but received a diagnosis of malaria or received an antimalarial were categorized as malaria over-diagnosis and over-treatment, respectively. RESULTS: We analyzed data from 2,098 participants. The median (IQR) age was 27 (3–43) years and 1,047 (50.0%) were female. Malaria was detected in 23 (2.3%) participants in Cohort 1 and 42 (3.8%) in Cohort 2, (P = 0.059). Malaria over-diagnosis occurred in 334 (35.0%) participants in Cohort 1 and 190 (17.7%) in Cohort 2, (P

Advanced-glycation end products (AGEs) are known to accumulate in biological tissues with age and at an accelerated rate in patients with diabetes and chronic kidney disease. Clinically, diabetes has been linked to increased frequency and severity of back pain, accelerated disc degeneration, and an increased risk of disc herniation. Despite significant clinical evidence suggesting that diabetes-induced AGEs may play a role in intervertebral disc failure and substantial previous work investigating the effects of AGEs on bone, cartilage, and tendon mechanics, the effects of AGEs on annulus fibrosus (AF) failure mechanics have not yet been reported. Thus, the aim of this study was to determine the relationship between physiological levels of AGEs and AF tensile mechanics at two distinct loading rates. In vitro glycation treatments with methylglyoxal were applied to minimize changes in tissue hydration and induce two distinct levels of AGEs based on values measured from human AF tissues. In vitro glycation increased modulus by 48-99% and failure stress by 45-104% versus control and decreased post-failure energy absorption capacity by 15-32% versus control (ANOVA p 0.0001 on means; range given across two loading rates and glycation levels). AGE content correlated strongly with modulus (R = 0.74, p 0.0001) and failure stress (R = 0.70, p 0.0001) and moderately with post-failure energy absorption capacity (R = 0.62, p 0.0001). Failure strain was reduced by 10-17% at the high-glycation level (ANOVA p = 0.01). Tissue water content remained near or just above fresh-tissue levels for all groups. The alterations in mechanics with glycation reported here are consistent with trends from other connective tissues but do not fully explain the clinical predisposition of diabetics to disc herniation. The results from this study may be used in the development of advanced computational models that aim to study disc disease progression and to provide a deeper understanding of altered structure-function relationships that may lead to tissue dysfunction and failure with aging and disease.

Type I hypersensitivity reactions (HSR) to dabrafenib are rare but have been previously described. We present a case where a 72-year-old woman with recurrent, metastatic BRAF-mutated melanoma developed a type I HSR to dabrafenib. We, therefore, developed a desensitization protocol with encorafenib, a similar class agent, to allow the patient to continue with treatment. Patients with a history of HSR to dabrafenib may be considered for encorafenib desensitization when other therapeutic options are limited.

Background: In an exploratory analysis of an inactivated quadrivalent influenza vaccine (IIV4) trial in children 6-35 months without risk factors for influenza, we evaluated clinical presentation of influenza illness and vaccine impact on health outcomes. Methods: This phase III trial was conducted in 13 geographically diverse countries across 5 influenza seasons (2011-2014). Children were randomized 1:1 to IIV4 or control. Active surveillance was performed for influenza-like episodes (ILE); influenza was confirmed by reverse transcription polymerase chain reaction (RT-PCR). The total vaccinated cohort was evaluated (N = 12,018). Results: 5702 children experienced >= 1 ILE; 356 (IIV4 group) and 693 (control group) children had RT-PCR-confirmed influenza. Prevalence of ILE was similar in RT-PCR-positive and RT-PCR-negative cases regardless of vaccination. Breakthrough influenza illness was attenuated in children vaccinated with IIV4; moderate-to-severe illness was 41% less likely to be reported in the IIV4 group than the control group [crude odds ratio: 0.59 (95% confidence intervals: 0.44-0.77)]. Furthermore, fever >39 degrees C was 46% less frequent following vaccination with IIV4 than with control [crude odds ratio: 0.54 (95% confidence intervals: 0.39-0.75)] in children with breakthrough illness. Health outcome analysis showed that, each year, IIV4 would prevent 54 influenza cases per 1000 children and 19 children would need to be vaccinated to prevent 1 new influenza case. Conclusions: In addition to preventing influenza in 50% of participants, IIV4 attenuated illness severity and disease burden in children who had a breakthrough influenza episode despite vaccination.

Growing evidence suggests considerable variation in endemic typhoid fever incidence at some locations over time, yet few settings have multi-year incidence estimates to inform typhoid control measures. We sought to describe a decade of typhoid fever incidence in the Kilimanjaro Region of Tanzania. Cases of blood culture confirmed typhoid were identified among febrile patients at two sentinel hospitals during three study periods: 2007–08, 2011–14, and 2016–18. To account for under-ascertainment at sentinel facilities, we derived adjustment multipliers from healthcare utilization surveys done in the hospital catchment area. Incidence estimates and credible intervals (CrI) were derived using a Bayesian hierarchical incidence model that incorporated uncertainty of our observed typhoid fever prevalence, of healthcare seeking adjustment multipliers, and of blood culture diagnostic sensitivity. Among 3,556 total participants, 50 typhoid fever cases were identified. Of typhoid cases, 26 (52%) were male and the median (range) age was 22 (

Over five seasons, we determined the proportion of outpatients with laboratory-confirmed, influenza-associated illness who were hospitalized within 30 days following the outpatient visit. Overall, 136 (1.7%) of 7813 influenza-positive patients were hospitalized a median of 4 days after an outpatient visit. Patients aged ≥ 65 years and those with high-risk conditions were at increased risk of hospitalization. After controlling for age and high-risk conditions, vaccination status and infecting influenza virus type were not associated with hospitalization risk among adults.

Changes in brain resting-state functional connectivity (rsFC) were investigated using a longitudinal design by following a 2-month focused attention meditation (FAM) practice and analyzing their association with FAM practice time. Ten novice meditators were recruited from a university meditation course. Participants were scanned with a resting-state fMRI sequence with multi-echo EPI acquisition at baseline and at the 2-month follow-up. Total FAM practice time was calculated from the daily log of the participants. We observed significantly increased rsFC between the posterior cingulate cortex (PCC) and dorsal attention network (DAN), the right middle temporal (RMT) region and default mode network (DMN), the left and right superior parietal lobules (LSPL/RSPL) and DMN, and the LSPL/RSPL and DAN. Furthermore, the rsFC between the LSPL and medial prefrontal cortex was significantly associated with the FAM practice time. These results demonstrate increased connectivity within the DAN, between the DMN and DAN, and between the DMN and visual cortex. These findings demonstrate that FAM can enhance the brain connection among and within brain networks, especially DMN and DAN, indicating potential effect of FAM on fast switching between mind wandering and focused attention and maintaining attention once in the attentive state.

BACKGROUND: This is the first longitudinal study to assess regional cerebral blood flow (rCBF) changes during the progression from normal control (NC) through mild cognitive impairment (MCI) and Alzheimer’s disease (AD). OBJECTIVE: We aim to determine if perfusion MRI biomarkers, derived from our prior cross-sectional study, can predict the onset and cognitive decline of AD. METHODS: Perfusion MRIs using arterial spin labeling (ASL) were acquired in 15 stable-NC, 14 NC-to-MCI, 16 stable-MCI, and 18 MCI/AD-to-AD participants from the Cardiovascular Health Study (CHS) cognition study. Group comparisons, predictions of AD conversion and time to conversion, and Modified Mini-Mental State Examination (3MSE) from rCBF were performed. RESULTS: Compared to the stable-NC group: 1) the stable-MCI group exhibited rCBF decreases in the right temporoparietal (p=0.00010) and right inferior frontal and insula (p =0.0094) regions; and 2) the MCI/AD-to-AD group exhibited rCBF decreases in the bilateral temporoparietal regions (p=0.00062 and 0.0035). Compared to the NC-to-MCI group, the stable-MCI group exhibited a rCBF decrease in the right hippocampus region (p=0.0053). The baseline rCBF values in the posterior cingulate cortex (PCC) (p=0.0043), bilateral superior medial frontal regions (BSMF) (p=0.012), and left inferior frontal (p= 0.010) regions predicted the 3MSE scores for all the participants at follow-up. The baseline rCBF in the PCC and BSMF regions predicted the conversion and time to conversion from MCI to AD (p

Invasive Salmonella infection is a common cause of acute febrile illness (AFI) among children in sub-Saharan Africa; however, diagnosing Salmonella bacteremia is challenging in settings without blood culture. The Uganda AFI surveillance system includes blood culture-based surveillance for etiologies of bloodstream infection (BSIs) in hospitalized febrile children in Uganda. We analyzed demographic, clinical, blood culture, and antimicrobial resistance data from hospitalized children at six sentinel AFI sites from July 2016 to January 2019. A total of 47,261 children were hospitalized. Median age was 2 years (interquartile range, 1–4) and 26,695 (57%) were male. Of 7,203 blood cultures, 242 (3%) yielded bacterial pathogens including Salmonella (N = 67, 28%), Staphylococcus aureus (N = 40, 17%), Escherichia spp. (N = 25, 10%), Enterococcus spp. (N = 18, 7%), and Klebsiella pneumoniae (N = 17, 7%). Children with BSIs had longer median length of hospitalization (5 days versus 4 days), and a higher case-fatality ratio (13% versus 2%) than children without BSI (all P < 0.001). Children with Salmonella BSIs did not differ significantly in length of hospitalization or mortality from children with BSI resulting from other organisms. Serotype and antimicrobial susceptibility results were available for 49 Salmonella isolates, including 35 (71%) non-typhoidal serotypes and 14 Salmonella serotype Typhi (Typhi). Among Typhi isolates, 10 (71%) were multi-drug resistant and 13 (93%) had decreased ciprofloxacin susceptibility. Salmonella strains, particularly non-typhoidal serotypes and drug-resistant Typhi, were the most common cause of BSI. These data can inform regional Salmonella surveillance in East Africa and guide empiric therapy and prevention in Uganda.

Typhoid fever transmission occurs through ingestion of food or water contaminated with Salmonella Typhi, and case–control studies are often conducted to identify outbreak sources and transmission vehicles. However, there is no current summary of the associations among water, sanitation, and hygiene (WASH); and food exposures and typhoid from case–control studies. We conducted a systematic review and meta-analysis of case–control studies to evaluate the associations among typhoid fever and predicted WASH or food exposure risk factors (13), and protective factors (7). Overall, 19 manuscripts describing 22 case–control studies were included. Two studies were characterized as having low risk of bias, one as medium risk, and 19 as high risk. In total, nine of 13 predicted risk factors were associated with increased odds of typhoid (odds ratio [OR] = 1.4–2.4, I(2) = 30.5–74.8%.), whereas five of seven predicted protective factors were associated with lower odds of typhoid (OR = 0.52–0.73, I(2) = 38.7–84.3%). In five types of sensitivity analyses, two (8%) of 26 summary associations changed significance from the original analysis. Results highlight the following: the importance of household hygiene transmission pathways, the need for further research around appropriate food interventions and the risk of consuming specific foods and beverages outside the home, and the absence of any observed association between sanitation exposures and typhoid fever. We recommend that typhoid interventions focus on interrupting household transmission routes and that future studies provide more detailed information about WASH and food exposures to inform better targeted interventions.

During January 1, 2020-May 18, 2020, approximately 1.3 million cases of coronavirus disease 2019 (COVID-19) and 83,000 COVID-19-associated deaths were reported in the United States (1). Understanding the demographic and clinical characteristics of decedents could inform medical and public health interventions focused on preventing COVID-19-associated mortality. This report describes decedents with laboratory-confirmed infection with SARS-CoV-2, the virus that causes COVID-19, using data from 1) the standardized CDC case-report form (case-based surveillance) (https://www.cdc.gov/coronavirus/2019-ncov/php/reporting-pui.html) and 2) supplementary data (supplemental surveillance), such as underlying medical conditions and location of death, obtained through collaboration between CDC and 16 public health jurisdictions (15 states and New York City).

Triclosan (TCS) is an antimicrobial agent that was effectively banned by the FDA from hand soaps in 2016, hospital soaps in 2017, and hand sanitizers in 2019; however, TCS can still be found in a few products. At consumer-relevant, non-cytotoxic doses, TCS inhibits the functions of both mitochondria and mast cells, a ubiquitous cell type. Via the store-operated Ca(2+) entry mechanism utilized by many immune cells, mast cells undergo antigen-stimulated Ca(2+) influx into the cytosol, for proper function. Previous work showed that TCS inhibits Ca(2+) dynamics in mast cells, and here we show that TCS also inhibits Ca(2+) mobilization in human Jurkat T cells. However, the biochemical mechanism behind the Ca(2+) dampening has yet to be elucidated. Three-dimensional super-resolution microscopy reveals that TCS induces mitochondrial swelling, in line with and extending the previous finding of TCS inhibition of mitochondrial membrane potential via its proton ionophoric activity. Inhibition of plasma membrane potential (PMP) by the canonical depolarizer gramicidin can inhibit mast cell function. However, use of the genetically encoded voltage indicators (GEVIs) ArcLight (pH-sensitive) and ASAP2 (pH-insensitive), indicates that TCS does not disrupt PMP. In conjunction with data from a plasma membrane-localized, pH-sensitive reporter, these results indicate that TCS, instead, induces cytosolic acidification in mast cells and T cells. Acidification of the cytosol likely inhibits Ca(2+) influx by uncoupling the STIM1/ORAI1 interaction that is required for opening of plasma membrane Ca(2+) channels. These results provide a mechanistic explanation of TCS disruption of Ca(2+) influx and, thus, of immune cell function.

Background Typhoid fever in the United States is acquired primarily through international travel by unvaccinated travelers. There is currently no typhoid vaccine licensed in the United States for use in children Methods We reviewed Salmonella enterica serotype Typhi infections reported to the Centers for Disease Control and Prevention (CDC) and antimicrobial-resistance data on Typhi isolates in CDC’s National Antimicrobial Resistance Monitoring System from 1999 through 2015. Results 5131 cases of typhoid fever were diagnosed and 5004 Typhi isolates tested for antimicrobial susceptibility. Among 1992 pediatric typhoid fever patients, 1616 (81%) had traveled internationally within 30 days of illness onset, 1544 (81%) of 1906 were hospitalized (median duration, 6 days; range, 0–50), and none died. Forty percent (799) were Conclusions Approximately 95% of currently vaccine-eligible pediatric travelers were unvaccinated, and antimicrobial-resistant infections were common. New public health strategies are needed to improve coverage with currently licensed vaccines. Introduction of an effective pretravel typhoid vaccine for children

When introduced into a naive population, chikungunya virus generally spreads rapidly, causing large outbreaks of fever and severe polyarthralgia. We randomly selected households in the U.S. Virgin Islands (USVI) to estimate seroprevalence and symptomatic attack rate for chikungunya virus infection at approximately 1 year following the introduction of the virus. Eligible household members were administered a questionnaire and tested for chikungunya virus antibodies. Estimated proportions were calibrated to age and gender of the population. We enrolled 509 participants. The weighted infection rate was 31% (95% confidence interval [CI]: 26–36%). Among those with evidence of chikungunya virus infection, 72% (95% CI: 65–80%) reported symptomatic illness and 31% (95% CI: 23–38%) reported joint pain at least once per week approximately 1 year following the introduction of the virus to USVI. Comparing rates from infected and noninfected study participants, 70% (95% CI: 62–79%) of fever and polyarthralgia and 23% (95% CI: 9–37%) of continuing joint pain in patients infected with chikungunya virus were due to their infection. Overall, an estimated 43% (95% CI: 33–52%) of the febrile illness and polyarthralgia in the USVI population during the outbreak was attributable to chikungunya virus and only 12% (95% CI: 7–17%) of longer term joint pains were attributed to chikungunya virus. Although the rates of infection, symptomatic disease, and longer term joint symptoms identified in USVI are similar to other outbreaks of the disease, a lower proportion of acute fever and joint pain was found to be attributable to chikungunya virus.

Context The osteopathic medical profession traditionally emphasized the education of primary care physicians. A common thread for both osteopathic and allopathic residency matches, however, has been an increase in the interest in specialties outside of primary care. Objective To determine whether there are critical points in medical school associated with residency selection decision-making, what factors affect residency selection decisions, and whether any identifiable shifts or trends exist. Methods This mixed-methods study sequentially used qualitative and quantitative research approaches. The study population was a convenience sample of osteopathic medical students, interns and residents, and practicing physicians from partner medical schools, associated hospitals, and a regional association of osteopathic physicians. In the first phase, interviews and focus group discussions were analyzed for codes, categories, and themes relating to factors that influence residency selection. In the second phase, a survey was created from the results of the first phase and administered to study participants. Results Of the 3450 potential participants, 282 completed the survey. Ninety-one of 209 participants (43.5%) indicated that the third year of medical school was the time they will or did decide what type of residency program to pursue. There were no significant differences in the mean scores between the respondent groups (ie, students, residents, and physicians) when ranking the importance of the 10 influential factors associated with residency selection decision-making (P>.05 for all). Conclusion The highest percentage of participants indicated the third year of medical school was the time that they made residency selection decisions regarding what specialty they were interested in entering. No shifts regarding the importance of specific primary care residency choice factors were found between training status of respondents.

In February 2018, a typhoid fever outbreak caused by Salmonella enterica serotype Typhi (Typhi), resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporins, was reported in Pakistan. During November 2016-September 2017, 339 cases of this extensively drug-resistant (XDR) Typhi strain were reported in Pakistan, mostly in Karachi and Hyderabad; one travel-associated case was also reported from the United Kingdom (1). More cases have been detected in Karachi and Hyderabad as surveillance efforts have been strengthened, with recent reports increasing the number of cases to 5,372 (2). In the United States, in response to the reports from Pakistan, enhanced surveillance identified 29 patients with typhoid fever who had traveled to or from Pakistan during 2016-2018, including five with XDR Typhi. Travelers to areas with endemic disease, such as South Asia, should be vaccinated against typhoid fever before traveling and follow safe food and water practices. Clinicians should be aware that most typhoid fever infections in the United States are fluoroquinolone nonsusceptible and that the XDR Typhi outbreak strain associated with travel to Pakistan is only susceptible to azithromycin and carbapenems.

Cation-π interactions arise as a result of strong attractive forces between positively charged entities and the π-electron cloud of aromatic groups. The physicochemical characteristics of cation-π interactions are particularly well-suited to the dual hydrophobic/hydrophilic environment of membrane proteins. As high-resolution structural data of membrane proteins bring molecular features into increasingly sharper view, cation-π interactions are gaining traction as essential contributors to membrane protein chemistry, function, and pharmacology. Here we review the physicochemical properties of cation-π interactions and present several prominent examples which demonstrate significant roles for this specialized biological chemistry.

Circadian cues in children (sunlight, exercise, diet patterns) may be associated with health outcomes. The primary objective was to assess associations of daily cortisol fluctuations (morning, night) with cardiovascular health outcomes. A secondary objective was to determine if 1-year longitudinal changes in circadian cortisol levels are associated with longitudinal changes in health outcomes.The Cardiovascular Health Intervention Program (CHIP) was a cross-sectional and longitudinal study of cardiovascular risk profiles in public elementary school children in Southern Maine. Participants were 689 students in 4th grade (baseline; age = 9.20 ± 0.41 years), and 647 students in 5th grade (age = 10.53 ± 0.52 years). Longitudinal data (4th and 5th grade) was available for 347 participants. Clinical outcomes were blood pressure, hip/waist ratios, body mass index, percent fat. Laboratory measures were fasting glucose, lipids, and salivary cortisol measures (morning and evening).Lower first-in-morning diurnal cortisol levels were associated with increased blood pressure (β -0.23 ± 0.05; p 0.001), increased body fat (β -0.22 ± 0.05; p 0.001), and poor lipid profiles (β -0.15 ± 0.07; p 0.05). Inclusion of night cortisol in the model (stress-related) improved associations of the model with bodyfat composition (morning β -0.27 ± 0.05; p 0.001; night β +0.16 ± 0.06; p 0.01). Adjustments for potential confounding variables improved associations of morning cortisol with lipids (β -0.19 ± 0.07; p 0.01). Longitudinal analysis showed that lower morning diurnal cortisol in 4th grade was associated with increases in blood pressure a year later (β -0.18 ± 0.08; p = 0.017) after adjusting for confounding variables.Data presented suggest adding circadian misalignment (lower amplitude of first-in-morning cortisol) to existing models of metabolic syndrome in children. Further, circadian misalignment may be a factor contributing to high blood pressure.

The intervertebral disc is a complex fibro-cartilaginous material, consisting of a pressurized nucleus pulposus surrounded by the annulus fibrosus, which has an angle-ply structure. Disc injury and degeneration are noted by significant changes in tissue structure and function, which significantly alters stress distribution and disc joint stiffness. Differences in fibre orientation are thought to contribute to changes in disc torsion mechanics. Therefore, the objective of this study was to evaluate the effect of collagen fibre orientation on internal disc mechanics under compression combined with axial rotation. We developed and validated a finite element model (FEM) to delineate changes in disc mechanics due to fibre orientation from differences in material properties. FEM simulations were performed with fibres oriented at [Formula: see text] throughout the disc (uniform by region and fibre layer). The initial model was validated by published experimental results for two load conditions, including [Formula: see text] axial compression and [Formula: see text] axial rotation. Once validated, fibre orientation was rotated by [Formula: see text] or [Formula: see text] towards the horizontal plane, resulting in a decrease in disc joint torsional stiffness. Furthermore, we observed that axial rotation caused a sinusoidal change in disc height and radial bulge, which may be beneficial for nutrient transport. In conclusion, including anatomically relevant fibre angles in disc joint FEMs is important for understanding stress distribution throughout the disc and will be important for understanding potential causes for disc injury. Future models will include regional differences in fibre orientation to better represent the fibre architecture of the native disc.

Using population-based surveillance data, we analyzed antiviral treatment among hospitalized patients with laboratory-confirmed influenza. Treatment increased after the influenza A(H1N1) 2009 pandemic from 72% in 2010–2011 to 89% in 2014–2015 (P < .001). Overall, treatment was higher in adults (86%) than in children (72%); only 56% of cases received antivirals on the day of admission.

Supplemental Digital Content is available in the text., Background: We evaluated an inactivated quadrivalent influenza vaccine (IIV4) in children 6–35 months of age in a phase III, observer-blind trial. Methods: The aim of this analysis was to estimate vaccine efficacy (VE) in preventing laboratory-confirmed influenza in each of 5 independent seasonal cohorts (2011−2014), as well as vaccine impact on healthcare utilization in 3 study regions (Europe/Mediterranean, Asia-Pacific and Central America). Healthy children were randomized 1:1 to IIV4 or control vaccines. VE was estimated against influenza confirmed by reverse transcription polymerase chain reaction on nasal swabs. Cultured isolates were characterized as antigenically matched/mismatched to vaccine strains. Results: The total vaccinated cohort included 12,018 children (N = 1777, 2526, 1564, 1501 and 4650 in cohorts 1−5, respectively). For reverse transcription polymerase chain reaction confirmed influenza of any severity (all strains combined), VE in cohorts 1−5 was 57.8%, 52.9%, 73.4%, 30.3% and 41.4%, respectively, with the lower limit of the 95% confidence interval >0 for all estimates. The proportion of vaccine match for all strains combined in each cohort was 0.9%, 79.3%, 72.5%, 24.1% and 28.6%, respectively. Antibiotic use associated with influenza illness was reduced with IIV4 by 71% in Europe, 36% in Asia Pacific and 59% in Central America. Conclusions: IIV4 prevented influenza in children 6−35 months of age in each of 5 separate influenza seasons in diverse geographical regions. A possible interaction between VE, degree of vaccine match and socioeconomic status was observed. The IIV4 attenuated the severity of breakthrough influenza illness and reduced healthcare utilization, particularly antibiotic use.

Intervertebral disc research has sought to develop a deeper understanding of spine biomechanics, the complex relationship between disc health and back pain, and the mechanisms of spinal injury and repair. To do so, many researchers have focused on characterizing tissue-level properties of the disc, where the roles of tissue subcomponents can be more systematically investigated. Unfortunately, experimental challenges often limit the ability to measure important disc tissue- and subtissue-level behaviors, including fiber–matrix interactions, transient nutrient and electrolyte transport, and damage propagation. Numerous theoretical and numerical modeling frameworks have been introduced to explain, complement, guide, and optimize experimental research efforts. The synergy of experimental and computational work has significantly advanced the field, and these two aspects have continued to develop independently and jointly. Meanwhile, the relationship between experimental and computational work has become increasingly complex and interdependent. This has made it difficult to interpret and compare results between experimental and computational studies, as well as between solely computational studies. This paper seeks to explore issues of model translatability, robustness, and efficient study design, and to propose and motivate potential future directions for experimental, computational, and combined tissue-level investigations of the intervertebral disc.

Tissues in the intervertebral disc have a large capacity to absorb water, partially due to the high glycosaminoglycan (GAG) content, which decreases linearly from the nucleus pulposus (NP) in the center to the outer annulus. Our recent work showed that fiber network and GAG distribution contributes to development of residual stresses and strains that were compressive in the inner annulus to tensile in the outer annulus. GAG loss in the inner annulus, as observed with early to moderate degeneration, reduced swelling capacity and circumferential-direction stress by over 50%. However, our previous model was not capable of evaluating interactions between the NP and annulus fibrosus (AF) during swelling. In this study, we evaluated the effect of degeneration (GAG content or swelling capacity) on residual stress development throughout the disc. Simulations of moderate to severe degeneration showed a 40% decrease in NP swelling capacity, with a 25% decrease in AF and cartilaginous endplate swelling. Together, these changes in tissue swelling resulted in a decrease in NP pressure (healthy = 0.21 MPa; severe degeneration = 0.03 MPa) that was comparable to observations in human discs. There was a 60% decrease in circumferential-direction residual deformations with early degeneration. Radial-direction stretch switched from compressive to tensile with degeneration, which may increase the risk for tears or delamination. Degeneration had a significant impact on residual stress/stretch and fiber stretch in the posterior AF, which is important for understanding herniation risk. In conclusion, degenerative changes in disc geometry and intradiscal deformations was recreated by only altering NP and AF GAG composition. Since most computational models simulate degeneration by altering material stiffness, this work highlights the importance of directly simulating biochemical composition and distribution to study disc biomechanics with degeneration. Statement of significance Tissues in the intervertebral disc have a large swelling capacity, due to its high glycosaminoglycan content. Our recent work demonstrated the importance of fiber network and glycosaminoglycan distribution residual stresses and strains development. In this study, we evaluated the effect of swelling on intradiscal deformations between the nucleus pulposus and annulus fibrosus. We also investigated the effect of degenerative glycosaminoglycan loss on swelling-based intradiscal deformations of the intact disc and its subcomponents. Decreases in nucleus glycosaminoglycan content resulted in morphological changes observed with degenerated discs and may help to explain mechanisms behind the increases in annular tears and mechanical dysfunction with degeneration.

In 2012 the Manila Doctors Hospital became the first hospital in the Philippines to launch and commit to a Social Vision. Since then, this Social Vision has served as a guide for good governance and a blueprint for its Corporate Social Responsibility (CSR) programs focusing on health, environment and gender. The goal of the Manila Doctors comprehensive CSR health program is to render the fundamental right to health care available to marginalized patients. Through our CSR programs, more than 20,000 financially challenged patients gain access to quality medical services annually. This directly contributed to the country's health development agenda 2016-2020 of achieving the health related SDG Targets of Financial Risk Protection, Better Health Outcomes and Responsiveness.

Author(s): Gignac, Elizabeth; Dogbey, Godwin Y.; Capece, Gregory; McMichael, Benjamin; Aldrich, Julie; Brannan, Grace | Abstract: Introduction: Emergency department (ED) visits for mental health and substance use disorders have been on the rise, with substance use disorders frequently coexisting with mental health disorders. This study evaluated substances commonly used/abused by patients presenting to the ED of a rural, regional medical center with subsequent admission for mental health treatment in Robeson County, North Carolina. Methods: This retrospective, single-center study was approved by the Southeastern Health Institutional Review Board. We reviewed medical records of psychiatric patients presenting to the ED with ultimate admission to the inpatient psychiatric unit between January 1, 2016, and June 30, 2016. Frequencies of controlled substances testing positive on urine drug and alcohol screenings in admitted patients were obtained and analyzed. We also made ethnic and gender comparisons. Results: A total of 477 patients met inclusion criteria. The percentage of patients testing positive were as follows: tetrahydrocannabinol (THC) (40%); cocaine (28.7%); alcohol (15.1%); benzodiazepines (13%); opiates (9.6%); amphetamines (2.9%); barbiturates (2.3%); and methadone (0.8%). A relatively higher proportion of patients tested positive for THC than any other substance (p≤.0002). We found statistically significant differences for gender (p=.0004) and ethnicity (pl.0001) compositions regarding substance use/abuse. Conclusion: The majority of admitted psychiatric patients in this study tested positive for at least one controlled substance. The two substances that most often returned positive on the urine drug screen test in our sample were THC (marijuana) and cocaine. These findings may provide insight into concomitant substance abuse and psychiatric disorders, which could instigate public policy development of preventative health initiatives that explore the relationship between controlled substance use/abuse and mental health disorders in rural counties like Robeson County.

Contains fulltext : 201728.pdf (Author’s version postprint ) (Open Access) Contains fulltext : 201728sup.pdf (Author’s version postprint ) (Open Access) Background: Efavirenz is commonly prescribed for children with HIV infection, yet little is known about risks of neuropsychiatric side-effects. We aimed to compare competence (social involvement, activities, and school performance) and psychopathology (internalising and externalising problems), cognitive performance (intelligence and working memory), and adherence in Tanzanian children on an efavirenz-based versus a non-efavirenz-based regimen. Methods: In this multicentre, cross-sectional, observational study, we included consecutive children (aged 6-12 years) with HIV infection, on combination antiretroviral therapy (cART) for at least 6 months, and with viral loads of less than 1000 copies per mL from HIV care clinics of three primary health facilities and three referral hospitals in Moshi, Kilimanjaro, Tanzania. Children with acute illnesses, medication switch in the 6 months before the study visit, and any history of brain injury or developmental delay before cART initiation were excluded. All interviews and assessments were done by trained local research nurses under the supervision of a medical doctor. The primary outcomes, competence and psychopathology, were measured with the Child Behavior Checklist. We used ANCOVA to assess differences between groups. This study is registered with ClinicalTrials.gov, number NCT03227653. Findings: Between June 19, 2017, and Dec 14, 2017, 141 children were analysed, of whom 72 (51%) used efavirenz-based cART and 69 (49%) used non-efavirenz-based cART. After controlling for age, sex, and clinical and demographic confounders, we observed lower competence (adjusted mean difference -2·43 [95% CI -4·19 to -0·67], p=0·0071), largely driven by lower school performance scores (adjusted mean difference -0·91 [-1·42 to -0·40], p=0·00055), in the efavirenz group than in the non-efavirenz group. More total (adjusted mean difference 5·96 [95% CI -1·12 to 13·04], p=0·098) and internalising (adjusted mean difference 2·00 [-0·29 to 4·29], p=0·086) behavioural problems were seen in the efavirenz group than in the non-efavirenz group, although these findings were non-significant. No differences were found in externalising problems (adjusted mean difference 0·78 [95% CI -1·55 to 3·11], p=0·51). Interpretation: Our results suggest that treatment with efavirenz in children is associated with a mild increase in neuropsychiatric symptoms, especially in children who receive doses higher than or equal to the WHO recommended doses for efavirenz. Clinical awareness and adequate follow-up of neuropsychiatric symptoms in efavirenz in children remain warranted. Funding: Aidsfonds, Radboud University Medical Center. 9 p.

Biological tissues with a high glycosaminoglycan (GAG) content have an excellent ability to swell by absorbing water molecules from the surrounding environment. Our recent work showed that anisotropy in tissue swelling depends on the fiber-network architecture, including fiber angle, fiber stiffness, and lamellae structure. However, that work did not evaluate the effect of in situ boundary conditions, such as the kidney-bean shape of the annulus fibrosus (AF), on swelling behavior. The biochemical composition of intact AF is inhomogeneous with respect to GAG composition, collagen fiber angle, and fiber stiffness. Moreover, the GAG content in the inner AF decreases significantly with degeneration. In this study, we investigated the role of GAG content, fiber angle, and fiber stiffness in AF swelling and residual strain development using a finite element model based on a human lumbar disk. Our results showed that the annular ring structure had a great impact on swelling by developing region-dependent compressive stress/stretch in the inner layers and tensile stress/stretch in the outer AF. Swelling-based residual stretch was comparable to experimentally measured values, suggesting an important role of tissue swelling in maintaining residual stresses. Moreover, GAG loss in the inner AF, as observed with degeneration, decreased circumferential-direction stress by over 65%. Homogeneous distributions of fiber angle and stiffness overestimated or underestimated AF swelling behavior, such as swelling ratio, circumferential/axial stretch, and fiber stretch/reorientation. These findings demonstrate the need to include native fiber architecture in finite element models, to accurately predict tissue failure, as well as to cultivate engineered disks.

OBJECTIVES: The aim of this study was to examine how changing the electronic ordering sequences for opioid analgesics affected ED outpatient prescribing, and subsequent unused opioid tablets remaining in the community available for diversion. METHODS: A descriptive before and after study in adult patients prescribed an opioid analgesic by an ED prescriber for use in the outpatient setting. The hospital electronic prescribing system (FirstNet™) was modified to include smaller quantities of opioid analgesics for discharge. The change in quantity of opioid prescribed and change in quantity of opioid analgesic remaining in the community at follow up was measured pre- and post-intervention using a structured telephone interview. RESULTS: Pre- and post-intervention, 102 and 106 patients were interviewed, respectively. Percentage of prescriptions for oxycodone quantity five tablets increased from 3% to 32% and for quantity 20 tablets fell from 40% to 24% post-intervention. For paracetamol with codeine, prescriptions for quantity 10 tablets increased from 2% to 24% while for quantity 20 tablets fell from 98% to 76%. Mean number of tablets prescribed per patient fell from 13.8 (SD = 5.1) to 10.8 (SD = 5.6) for oxycodone and from 19.8 (SD = 1.5) to 17.6 (SD = 4.2) for paracetamol with codeine. Fifty-eight percent of patients in both pre- and post-intervention groups used half or less of the medication prescribed. CONCLUSION: Modification of an ED electronic prescribing system reduced overall quantities of opioid analgesics supplied and subsequently stored in the community but did not change the proportion of patients (>50%) who reported using half or less of their prescribed opioid medication.

Chemical aminoacylation of orthogonal tRNA allows for the genetic encoding of a wide range of synthetic amino acids without the need to evolve specific aminoacyl-tRNA synthetases. This method, when paired with protein expression in the Xenopus laevis oocyte expression system, can extract atomic scale functional data from a protein structure to advance the study of membrane proteins. The utility of the method depends on the orthogonality of the tRNA species used to deliver the amino acid. Here, we report that the pyrrolysyl tRNA (pylT) from Methanosarcina barkeri fusaro is orthogonal and highly competent for genetic code expansion experiments in the Xenopus oocyte. The data show that pylT is amendable to chemical acylation in vitro; it is then used to rescue a cytoplasmic site within a voltage-gated sodium channel. Further, the high fidelity of the pylT is demonstrated via encoding of lysine within the selectivity filter of the sodium channel, where sodium ion recognition by the distal amine of this side-chain is essential. Thus, pylT is an appropriate tRNA species for delivery of amino acids via nonsense suppression in the Xenopus oocyte. It may prove useful in experimental contexts wherein reacylation of suppressor tRNAs have been observed.

Contains fulltext : 187484.pdf (Publisher’s version ) (Closed access) 1 p.

Objectives To explore the relationship between Efavirenz (EFV) and neuropsychiatric symptoms among adults and adolescents living with human immunodeficiency virus (HIV) in Kilimanjaro, Tanzania. Methods Cross-sectional study among HIV-infected adults (age 18-65) and adolescents (age 12-17) on antiretroviral treatment attending Kilimanjaro Christian Medical Centre, Moshi, Tanzania. Neuropsychiatric symptoms were measured using the Hospital Anxiety and Depression Scale (HADS), the Symptom Checklist 90 (SCL-90) and the Mini-International Neuropsychiatric Interview (MINI). manova and chi-squared tests were used to test differences between EFV and non-EFV-treated participants. Results A total of 215 adults and 150 adolescents participated. About 52% of adults and 37% of adolescents used EFV. Among adults, depression scores were higher for those on EFV (HADS (Cohen's D: 0.38; P = 0.02) and SCL-90 (Cohen's D: 0.24; P = 0.03). Among adolescents, those on EFV had lower scores on depression (HADS (Cohen's D: 0.3; P = 0.02) and SCL-90 (Cohen's D: 0.1; P = 0.02). About 10% of adults reported suicidal thoughts, but there was no difference between those on EFV and those without. Lastly, adults on EFV reported higher levels of problematic alcohol use (P = 0.003). Conclusions In line with the previous studies, EFV is associated with depressive symptoms and problematic alcohol use among HIV-infected adults in Tanzania. In contrast, EFV was associated with lower levels of depressive symptoms in adolescents in Tanzania. Particularly among adults, close monitoring of depressive symptoms and alcohol use is indicated.

Background & Aims Pediatric functional abdominal pain has been linked to functional gastrointestinal disorders (FGIDs) in adulthood, but little is known about patient characteristics in childhood that increase the risk for FGID in young adulthood. We investigated the contribution of gastrointestinal symptoms, extraintestinal somatic symptoms, and depressive symptoms in pediatric patients with functional abdominal pain and whether these predicted FGIDs later in life. Methods In a longitudinal study, consecutive new pediatric patients, diagnosed with functional abdominal pain in a subspecialty clinic, completed a comprehensive baseline evaluation of the severity of their physical and emotional symptoms. They were contacted 5 to 15 years later and evaluated, based on Rome III symptom criteria, for abdominal pain–related FGIDs, including irritable bowel syndrome, functional dyspepsia, functional abdominal pain syndrome, and abdominal migraine. Controlling for age, sex, baseline severity of abdominal pain, and time to follow-up evaluation, multivariable logistic regression was used to evaluate the association of baseline gastrointestinal, extraintestinal somatic, and depressive symptoms in childhood with FGID in adolescence and young adulthood. Results Of 392 patients interviewed an average of 9.2 years after their initial evaluation, 41% (n = 162) met symptom criteria for FGID; most met the criteria for irritable bowel syndrome. Extraintestinal somatic and depressive symptoms at the initial pediatric evaluation were significant predictors of FGID later in life, after controlling for initial levels of GI symptoms. Age, sex, and abdominal pain severity at initial presentation were not significant predictors of FGID later in life. Conclusions In pediatric patients with functional abdominal pain, assessment of extraintestinal and depressive symptoms may be useful in identifying those at risk for FGID in adolescence and young adulthood.

BackgroundDespite the importance of vaccinating children younger than 5 years, few studies evaluating vaccine prevention of influenza have been reported in this age group. We evaluated efficacy of an inactivated quadrivalent influenza vaccine (IIV4) in children aged 6–35 months.MethodsIn this phase 3, observer-blinded, multinational trial, healthy children from 13 countries in Europe, Central America, and Asia were recruited in five independent cohorts, each in a different influenza season. Participants were randomly assigned (1:1) to either IIV4 (15 μg haemagglutinin antigen per strain per 0·5 mL dose; a single dose on day 0 for vaccine-primed children, and two doses, on days 0 and 28, for vaccine-unprimed children) or to one or two doses of a non-influenza control vaccine. Primary endpoints were moderate-to-severe influenza or all influenza (irrespective of disease severity) confirmed by RT-PCR on nasal swabs. Cultured isolates were further characterised as antigenically matched or mismatched to vaccine strains. Efficacy was assessed in the per-protocol cohort and total vaccinated cohort (time-to-event analysis), and safety was assessed in the total vaccinated cohort.FindingsBetween Oct 1, 2011, and Dec 31, 2014, 12 018 children were recruited into the total vaccinated cohort (6006 children in the IIV4 group and 6012 children in the control group). 356 (6%) children in the IIV4 group and 693 (12%) children in the control group had at least one case of RT-PCR-confirmed influenza. Of these 1049 influenza strains, 138 (13%) were A/H1N1, 529 (50%) were A/H3N2, 69 (7%) were B/Victoria, and 316 (30%) were B/Yamagata. Overall, 539 (64%) of 848 antigenically characterised isolates were vaccine-mismatched (16 [15%] of 105 for A/H1N1; 368 [97%] of 378 for A/H3N2; 54 [86%] of 63 for B/Victoria; 101 [33%] of 302 for B/Yamagata). Vaccine efficacy was 63% (97·5% CI 52–72) against moderate-to-severe influenza and 50% (42–57) against all influenza in the per-protocol cohort, and 64% (53–73) against moderate-to-severe influenza and 50% (42–57) against all influenza in the total vaccinated cohort. There were no clinically meaningful safety differences between IIV4 and control.InterpretationIIV4 prevented influenza A and B in children aged 6–35 months despite high levels of vaccine mismatch. Vaccine efficacy was highest against moderate-to-severe disease, which is the most clinically important endpoint associated with greatest burden.FundingGlaxoSmithKline Biologicals SA.

Objectives We tested the social action theory hypotheses that (a) psychological stress induced by struggling to control others (agonistic striving) is associated with higher levels of subjective somatic symptoms than stress induced by struggling to control the self (transcendence striving); (b) the association between agonistic striving and symptoms is moderated by the ability to tolerate pain; and (c) associations among agonistic goals, pain tolerance, and subjective symptoms are not explained by personality and affective traits or negative emotional responses to personal stressors. Methods Implicit motives and negative emotional reactivity to recurring personal stressors were assessed by Social Competence Interview in 333 adolescents and adults who participated in longitudinal research on functional abdominal pain at a university medical center. Pain tolerance was assessed by graduated thermal pain protocol; subjective somatic symptoms, and personality/affective traits assessed by questionnaires. The primary outcome measure was the self-reported severity of 35 somatic symptoms often experienced in the absence of diagnosable disease. Results All hypotheses were supported. Conclusions Nonconscious agonistic strivings may increase the perceived frequency and severity of subjective somatic symptoms; this tendency is greatly magnified by difficulty in self-regulating responses to painful stimuli. Implicit agonistic motives and their associations with symptoms are not explained by individual differences in trait neuroticism, anxiety, depression, anger, or low self-esteem or by negative emotional reactivity to a personal stressor. These findings may afford fruitful insights into mechanisms by which stressful social environments undermine health and suggest promising directions for clinical intervention.