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IntroductionEstimates for cause-specific mortality for neonates are generally available for all countries for neonates overall (0 to 28 days). However, cause-specific mortality is generally not being estimated at higher age resolution for neonates, despite evidence of heterogeneity in the causes of deaths during this period. We aimed to use the adapted log quadratic model in a setting where verbal autopsy was the primary means of determining cause of death.MethodsWe examined the timing and causes of death among a cohort of neonates in rural Nepal followed as part of the Nepal Oil Massage Study (NOMS). We adapted methods defined by Wilmoth et al (2012) and Guillot et al. (2022) to estimate age and cause-specific mortality among neonates. We used cross validation to estimate the accuracy of this model, holding out each three month period. We took the average cross validation across hold out as our measure of model performance and compared to a standard approach which did not account for the heterogeneity in cause-specific mortality rate within this age group.ResultsThere were 957 neonates in the NOMS cohort with known age and cause of death. We estimated an average cross-validation error of 0.9 per 1000 live births for mortality due to prematurity in the first week, and 1.1 for mortality due to birth asphyxia, compared to the standard approach, having error 7.4 and 7.8 per 1000 live births, respectively. Generally mortality rates for less common causes such as congenital malformations and pneumonia were estimated with higher cross-validation error.ConclusionsThe stability and precision of these estimates compare favorably with similar estimates developed with higher quality cause-specific mortality surveillance from China, demonstrating that reliably estimating causes of mortality at high resolution is possible for neonates in low resources areas.

ObjectivesPro-inflammatory molecules are thought to underpin the development of chronic low back pain (LBP). Although research has begun to explore the association between pro-inflammatory molecules in acute LBP and long-term outcome, no study has explored the role of anti-inflammatory molecules. We aimed to explore whether levels of systemic pro- and anti-inflammatory molecules 1) changed over a period of six months from the onset of acute LBP; 2) differed between people who were recovered (N = 11) and unrecovered (N = 24) from their episode of LBP at six months; 3) baseline psychological factors were related to inflammatory molecule serum concentrations at baseline, three and six months.MethodsWe retrospectively included participants with acute LBP included from a larger prospective trial and examined blood samples for the measurement of pro- and anti-inflammatory molecules and measures of pain, disability, and psychological factors at baseline, three and six months.ResultsThe serum concentrations of pro- and anti-inflammatory molecules did not differ over time when compared between participants who recovered and those who did not recover at six-month follow-up. At three months, the unrecovered group had higher interleukin (IL)-8 and IL-10 serum concentrations than the recovered group. Baseline psychological factors were not related to inflammatory molecules at any time point.DiscussionThis exploratory study showed that levels of systemic inflammatory molecules did not change over the course of LBP, irrespective of whether people were recovered or unrecovered at six months. There was no relationship between acute-stage psychological factors and systemic inflammatory molecules. Further investigation is needed to elucidate the contribution of pro- and anti-inflammatory molecules to long-term LBP outcome.

We aimed to develop a metformin dosing strategy to optimise efficacy and safety in patients with reduced kidney function. Metformin data from two studies stratified by kidney function were analysed. The relationship between metformin clearance and kidney function estimates was explored using a regression analysis. The maintenance dose range was predicted at different bands of kidney function to achieve an efficacy target of 1 mg/L for steady-state plasma concentrations. The dosing strategy was evaluated using simulations from a published metformin pharmacokinetic model to determine the probability of concentrations exceeding those associated with lactic acidosis risk, i.e. a steady-state average concentration of 3 mg/L and a maximum (peak) concentration of 5 mg/L. A strong relationship between metformin clearance and estimated kidney function using the Cockcroft and Gault (r2 = 0.699), MDRD (r2 = 0.717) and CKD-Epi (r2 = 0.735) equations was found. The probability of exceeding the safety targets for plasma metformin concentration was

Infants born to HIV-infected mothers are more likely to be low birthweight (LBW) than other infants, a condition that is stigmatized in many settings worldwide, including sub-Saharan Africa. Few studies have characterized the social-cultural context and response to LBW stigma among mothers in sub-Saharan Africa or explored the views of women living with HIV (WLHIV) on the causes of LBW. We purposively sampled thirty postpartum WLHIV, who had given birth to either LBW or normal birthweight infants, from two tertiary hospitals in Accra, Ghana. Using semi-structured interviews, we explored women's understanding of the etiology of LBW, and their experiences of caring for a LBW infant. Interviews were analyzed using interpretive phenomenology. Mothers assessed their babies' smallness based on the baby's size, not hospital-recorded birthweight. Several participants explained that severe depression and a loss of appetite, linked to stigma following an HIV diagnosis during pregnancy, contributed to infants being born LBW. Women with small babies also experienced stigma due to the newborns' "undesirable" physical features and other people's unfamiliarity with their size. Consequently, mothers experienced blame, reluctance showing the baby to others, and social gossip. As a result of this stigma, women reported self-isolation and depressive symptoms. These experiences were layered on the burden of healthcare and infant feeding costs for LBW infants. LBW stigma appeared to attenuate with increased infant weight gain. A few of the women also did not breastfeed because they thought their baby's small size indicated pediatric HIV infection. Among WLHIV in urban areas in Ghana, mother and LBW infants may experience LBW-related stigma. A multi-component intervention that includes reducing LBW incidence, treating antenatal depression, providing psychosocial support after a LBW birth, and increasing LBW infants' weight gain are critically needed.

In coastal aquatic ecosystems, prokaryotic communities play an important role in regulating the cycling of nutrients and greenhouse gases. In the coastal zone, estuaries are complex and delicately balanced systems containing a multitude of specific ecological niches for resident microbes. Anthropogenic influences (i.e. urban, industrial and agricultural land uses) along the estuarine continuum can invoke physical and biochemical changes that impact these niches. In this study, we investigate the relative abundance of methanogenic archaea and other prokaryotic communities, distributed along a land use gradient in the subtropical Burnett River Estuary, situated within the Great Barrier Reef catchment, Australia. Microbiological assemblages were compared to physicochemical, nutrient and greenhouse gas distributions in both pore and surface water. Pore water samples from within the most urbanised site showed a high relative abundance of methanogenic Euryarchaeota (7.8% of all detected prokaryotes), which coincided with elevated methane concentrations in the water column, ranging from 0.51 to 0.68 μM at the urban and sewage treatment plant (STP) sites, respectively. These sites also featured elevated dissolved organic carbon (DOC) concentrations (0.66 to 1.16 mM), potentially fuelling methanogenesis. At the upstream freshwater site, both methane and DOC concentrations were considerably higher (2.68 μM and 1.8 mM respectively) than at the estuarine sites (0.02 to 0.66 μM and 0.39 to 1.16 mM respectively) and corresponded to the highest relative abundance of methanotrophic bacteria. The proportion of sulfate reducing bacteria in the prokaryotic community was elevated within the urban and STP sites (relative abundances of 8.0%- 10.5%), consistent with electron acceptors with higher redox potentials (e.g. O2, NO3-) being scarce. Overall, this study showed that ecological niches in anthropogenically altered environments appear to give an advantage to specialized prokaryotes invoking a potential change in the thermodynamic landscape of the ecosystem and in turn facilitating the generation of methane-a potent greenhouse gas.

Higher Red Blood Cell Distribution Width (RDW or anisocytosis) predicts incident coronary artery disease (CAD) plus all-cause and cardiovascular mortality, but its predictive value for other common diseases in healthy volunteers is less clear. We aimed to determine the shorter and longer term associations between RDW and incident common conditions in participants free of baseline disease, followed for 9 years. We undertook a prospective analysis of RDW% using 240,477 healthy UK Biobank study volunteers aged 40-70 years at baseline, with outcomes ascertained during follow-up (≤9 years). Participants were free of anemia, CAD, type-2 diabetes, stroke, hypertension, COPD, and any cancer (except non-melanoma skin cancer) at baseline. Survival models (with competing Hazards) tested associations with outcomes from hospital admission records and death certificates. High RDW (≥15% variation, n = 6,050) compared to low (

Unwanted variation can be highly problematic and so its detection is often crucial. Relative log expression (RLE) plots are a powerful tool for visualizing such variation in high dimensional data. We provide a detailed examination of these plots, with the aid of examples and simulation, explaining what they are and what they can reveal. RLE plots are particularly useful for assessing whether a procedure aimed at removing unwanted variation, i.e. a normalization procedure, has been successful. These plots, while originally devised for gene expression data from microarrays, can also be used to reveal unwanted variation in many other kinds of high dimensional data, where such variation can be problematic.

Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers.A large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%,

BACKGROUND:While community health workers are being recognized as an integral work force with growing responsibilities, increased demands can potentially affect motivation and performance. The ubiquity of mobile phones, even in hard-to-reach communities, has facilitated the pursuit of novel approaches to support community health workers beyond traditional modes of supervision, job aids, in-service training, and material compensation. We tested whether supportive short message services (SMS) could improve reporting of pregnancies and pregnancy outcomes among community health workers (Health Surveillance Assistants, or HSAs) in Malawi. METHODS AND FINDINGS:We designed a set of one-way SMS that were sent to HSAs on a regular basis during a 12-month period. We tested the effectiveness of the cluster-randomized intervention in improving the complete documentation of a pregnancy. We defined complete documentation as a pregnancy for which a specific outcome was recorded. HSAs in the treatment group received motivational and data quality SMS. HSAs in the control group received only motivational SMS. During baseline and intervention periods, we matched reported pregnancies to reported outcomes to determine if reporting of matched pregnancies differed between groups and by period. The trial is registered as ISCTRN24785657. CONCLUSIONS:Study results show that the mHealth intervention improved the documentation of matched pregnancies in both the treatment (OR 1.31, 95% CI: 1.10-1.55, p

Borrelia mayonii, a Borrelia burgdorferi sensu lato (Bbsl) genospecies, was recently identified as a cause of Lyme borreliosis (LB) among patients from the upper midwestern United States. By microscopy and PCR, spirochete/genome loads in infected patients were estimated at 105 to 106 per milliliter of blood. Here, we present the full chromosome and plasmid sequences of two B. mayonii isolates, MN14-1420 and MN14-1539, cultured from blood of two of these patients. Whole genome sequencing and assembly was conducted using PacBio long read sequencing (Pacific Biosciences RSII instrument) followed by hierarchical genome-assembly process (HGAP). The B. mayonii genome is ~1.31 Mbp in size (26.9% average GC content) and is comprised of a linear chromosome, 8 linear and 7 circular plasmids. Consistent with its taxonomic designation as a new Bbsl genospecies, the B. mayonii linear chromosome shares only 93.83% average nucleotide identity with other genospecies. Both B. mayonii genomes contain plasmids similar to B. burgdorferi sensu stricto lp54, lp36, lp28-3, lp28-4, lp25, lp17, lp5, 5 cp32s, cp26, and cp9. The vls locus present on lp28-10 of B. mayonii MN14-1420 is remarkably long, being comprised of 24 silent vls cassettes. Genetic differences between the two B. mayonii genomes are limited and include 15 single nucleotide variations as well as 7 fewer silent vls cassettes and a lack of the lp5 plasmid in MN14-1539. Notably, 68 homologs to proteins present in B. burgdorferi sensu stricto appear to be lacking from the B. mayonii genomes. These include the complement inhibitor, CspZ (BB_H06), the fibronectin binding protein, BB_K32, as well as multiple lipoproteins and proteins of unknown function. This study shows the utility of long read sequencing for full genome assembly of Bbsl genomes, identifies putative genome regions of B. mayonii that may be linked to clinical manifestation or tissue tropism, and provides a valuable resource for pathogenicity, diagnostic and vaccine studies.

BACKGROUND:More than half of malaria cases in Zimbabwe are concentrated in Manicaland Province, where seasonal malaria epidemics occur despite intensified control strategies. Recently, high levels of pyrethroid and carbamate resistance were detected in Anopheles funestus, the major malaria vector in eastern Zimbabwe. In response, a single round of indoor residual spraying (IRS) using pirimiphos-methyl (an organophosphate) was implemented in four high burden districts of Manicaland Province from November 1, 2014 to December 19, 2014. The objective of this study was to evaluate the effect of this programmatic switch in insecticides on malaria morbidity reported from health care facilities in Mutasa District, one of the worst affected districts in Manicaland Province. METHODS:The number of weekly malaria cases for each health facility 24 months prior to the 2014 IRS campaign and in the subsequent high transmission season were obtained from passive case surveillance. Environmental variables were extracted from remote-sensing data sources and linked to each health care facility. Negative binomial regression was used to model the weekly number of malaria cases, adjusted for seasonality and environmental variables. RESULTS:From December 2012 to May 2015, 124,206 malaria cases were reported from 42 health care facilities in Mutasa District. Based on a higher burden of malaria, 20 out of 31 municipal wards were sprayed in the district. Overall, 87.3% of target structures were sprayed and 92.1% of the target population protected. During the 6 months after the 2014 IRS campaign, a period when transmission would have otherwise peaked, the incidence of malaria was 38% lower than the preceding 24 months at health facilities in the sprayed wards. CONCLUSIONS:Pirimiphos-methyl had a measurable impact on malaria incidence and is an effective insecticide for the control of An. funestus in eastern Zimbabwe.

Decades of conflict in eastern Myanmar have resulted in high prevalence of human rights violations and poor health outcomes. While recent ceasefire agreements have reduced conflict in this area, it is unknown whether this has resulted in concomitant reductions in human rights violations.We conducted a two-stage cluster survey of 686 households in eastern Myanmar to assess health status, access to healthcare, food security, exposure to human rights violations and identification of alleged perpetrators over the 12 months prior to January 2012, a period of near-absence of conflict in this region. Household hunger (FANTA-2 scale) was moderate/high in 91 (13.2%) households, while the proportion of households reporting food shortages in each month of 2011 ranged from 19.9% in December to 47.0% in September, with food insecurity peaking just prior to the harvest. Diarrhea prevalence in children was 14.2% and in everyone it was 5.8%. Forced labor was the most common human rights violation (185 households, 24.9%), and 210 households (30.6%) reported experiencing one or more human rights violations in 2011. Multiple logistic regression analysis identified associations between human rights violations and poor health outcomes.Human rights violations and their health consequences persist despite reduced intensity of conflict in eastern Myanmar. Ceasefire agreements should include language that protects human rights, and reconciliation efforts should address the health consequences of decades of human rights violations.

We use data from rural Nepal and South India to compare the prevalence of small-for-gestational-age (SGA) and neonatal mortality risk associated with SGA using different birth-weight-for-gestation reference populations.We identified 46 reference populations in low-, middle-, and high-income countries, of which 26 met the inclusion criteria of being commonly cited and having numeric 10th percentile cut points published. Those reference populations were then applied to populations from two community-based studies to determine SGA prevalence and its relative risk of neonatal mortality.The prevalence of SGA ranged from 10.5% to 72.5% in Nepal, and 12.0% to 78.4% in India, depending on the reference population. Females had higher rates of SGA than males using reference populations that were not sex specific. SGA prevalence was lowest when using reference populations from low-income countries. Infants who were both preterm and SGA had much higher mortality risk than those who were term and appropriate-for-gestational-age. Risk ratios for those who are both preterm and SGA ranged from 7.34-17.98 in Nepal and 5.29-11.98 in India, depending on the reference population.These results demonstrate the value of a common birth-weight-for-gestation reference population that will facilitate comparisons of SGA prevalence and mortality risk across research studies.

Next generation, "deep", sequencing has increasing applications both clinically and in disparate fields of research. This study investigates the accuracy and reproducibility of "deep" sequencing as applied to co-receptor prediction using the V3 loop of Human Immunodeficiency Virus-1. Despite increasing use in HIV co-receptor prediction, the accuracy and reproducibility of deep sequencing technology, and the factors which can affect it, have received only a limited level of investigation. To accomplish this, repeated deep sequencing results were generated using the Roche GS-FLX (454) from a number of sources including a non-homogeneous clinical sample (N = 47 replicates over 18 deep sequencing runs), and a large clinical cohort from the MOTIVATE and A400129 studies (N = 1521). For repeated measurements of a non-homogeneous clinical sample, increasing input copy number both decreased variance in the measured proportion of non-R5 using virus (p<

The evolution of drug resistance mutations in plasma samples is relatively well-characterized. However, the viral population and diversity in other body compartments such as peripheral blood mononuclear cells (PBMC) remains poorly understood. Previous studies have mostly focused on protease and reverse transcriptase drug resistance mutations (DRMs). In this study, we used 454 "deep" sequencing technology to observe and quantify longitudinally the prevalence of resistance mutations associated with the integrase inhibitor, raltegravir, in plasma versus PBMC samples from a San Francisco-based cohort. Four heavily treatment-experienced subjects were monitored in this study over a median of 1.2 years since the initiation of raltegravir-containing regimens. We observed a consistent discordance in the prevalence of DRMs, but not resistance pathway(s), in the plasma versus PBMC viral populations. In the final paired samples that were tested while the subjects were on a raltegravir-containing regimen, DRM prevalence reached 100% in plasma but remained 1% in PBMC on day 177 post-therapy in Subject 3180 (Q148H/G140S), 100% in plasma and 36% in PBMC on day 224 in Subject 3242 (N155H), 78% in plasma and 11-12% in PBMC on day 338 in Subject 3501 (Q148H/G140S), and 100% in plasma and 0% in PBMC on day 197 in Subject 3508 (Y143R). Furthermore, absolute sequence homology comparison between the two compartments revealed that 21% - 99% of PBMC sequences had no match in plasma, whereas 14% - 100% of plasma sequences had no match in PBMC. Overall, our observations suggested that plasma and PBMC hosted drastically different HIV-1 populations even after a prolonged exposure to raltegravir selection pressure.

The lower limit of detection of the original Roche Amplicor HIV plasma viral load (pVL) assay (50 copies/mL) has defined HIV treatment success. The Amplicor assay, however, has been replaced by the Roche TaqMan assay(s). Changes to the limits of detection and calibration have not been validated for clinical utility. Sudden increases in the number of patients with detectable pVL have been reported following the introduction of the TaqMan version 1 assay.Between October 2009 and April 2010 all routine pVL samples from British Columbia, Canada, with 40-250 copies/mL by TaqMan were re-tested by Amplicor (N = 1198). Subsequent short-term virological and resistance outcomes were followed in patients with unchanged therapy (N = 279; median 3.2 months follow-up).TaqMan and Amplicor values correlated poorly at low pVL values. Low-level pVL by TaqMan was not associated with impending short-term virological failure; only 17% of patients with 40-250 copies/mL by TaqMan had detectable pVL by Amplicor at follow-up. During the follow-up period only 20% of patients had an increase in pVL by TaqMan (median [IQR]: 80 [36-283] copies/mL). In addition, in ~2.4% of samples pVL was dramatically underestimated by TaqMan due to poor binding of the proprietary TaqMan primers.The replacement of Amplicor with the TaqMan assay has altered the previously accepted definition of HIV treatment failure without any evidence to support the clinical relevance of the new definition. Given the systematic differences in measurement in the low pVL range the British Columbia HIV treatment guidelines now use a threshold of >250 copies/mL by TaqMan to define treatment failure.

Background'Virtual' or inferred phenotypes (vPhenotypes) are commonly used to assess resistance to antiretroviral agents in patients failing therapy. In this study, we provide a clinical context for understanding vPhenotype values.MethodsAll HIV-infected persons enrolled in the British Columbia Drug Treatment Program with a baseline plasma viral load (pVL) and follow-up genotypic resistance and pVL results were included up to October 29, 2008 (N = 5,277). Change from baseline pVL was determined as a function of Virco vPhenotype, and the "dynamic range" (defined here by the 10th and 90th percentiles for fold-change in IC₅₀ amongst all patients) was estimated from the distribution of vPhenotye fold-changes across the cohort.ResultsThe distribution of vPhenotypes from a large cohort of HIV patients who have failed therapy are presented for all available antiretroviral agents. A maximum change in IC₅₀ of at least 13-fold was observed for all drugs. The dideoxy drugs, tenofovir and most PIs exhibited small "dynamic ranges" with values of 99% of samples. In contrast, zidovudine, lamivudine, emtricitabine and the non-nucleoside reverse transcriptase inihibitors (excluding etravirine) had large dynamic ranges.ConclusionWe describe the populational distribution of vPhenotypes such that vPhenotype results can be interpreted relative to other patients in a drug-specific manner.

Diver-based Underwater Visual Censuses (UVCs), particularly transect-based surveys, are key tools in the study of coral reef fish ecology. These techniques, however, have inherent problems that make it difficult to collect accurate numerical data. One of these problems is the diver effect (defined as the reaction of fish to a diver). Although widely recognised, its effects have yet to be quantified and the extent of taxonomic variation remains to be determined. We therefore examined relative diver effects on a reef fish assemblage on the Great Barrier Reef. Using common UVC methods, the recorded abundance of seven reef fish groups were significantly affected by the ongoing presence of SCUBA divers. Overall, the diver effect resulted in a 52% decrease in the mean number of individuals recorded, with declines of up to 70% in individual families. Although the diver effect appears to be a significant problem, UVCs remain a useful approach for quantifying spatial and temporal variation in relative fish abundances, especially if using methods that minimise the exposure of fishes to divers. Fixed distance transects using tapes or lines deployed by a second diver (or GPS-calibrated timed swims) would appear to maximise fish counts and minimise diver effects.

BACKGROUND:Despite the extensive genetic diversity of HIV-1, viral evolution in response to immune selective pressures follows broadly predictable mutational patterns. Sites and pathways of Human Leukocyte-Antigen (HLA)-associated polymorphisms in HIV-1 have been identified through the analysis of population-level data, but the full extent of immune escape pathways remains incompletely characterized. Here, in the largest analysis of HIV-1 subtype B sequences undertaken to date, we identify HLA-associated polymorphisms in the three HIV-1 proteins most commonly considered in cellular-based vaccine strategies. Results are organized into protein-wide escape maps illustrating the sites and pathways of HLA-driven viral evolution. METHODOLOGY/PRINCIPAL FINDINGS:HLA-associated polymorphisms were identified in HIV-1 Gag, Pol and Nef in a multicenter cohort of >1500 chronically subtype-B infected, treatment-naïve individuals from established cohorts in Canada, the USA and Western Australia. At q< or =0.05, 282 codons commonly mutating under HLA-associated immune pressures were identified in these three proteins. The greatest density of associations was observed in Nef (where close to 40% of codons exhibited a significant HLA association), followed by Gag then Pol (where approximately 15-20% of codons exhibited HLA associations), confirming the extensive impact of immune selection on HIV evolution and diversity. Analysis of HIV codon covariation patterns identified over 2000 codon-codon interactions at q< or =0.05, illustrating the dense and complex networks of linked escape and secondary/compensatory mutations. CONCLUSIONS/SIGNIFICANCE:The immune escape maps and associated data are intended to serve as a user-friendly guide to the locations of common escape mutations and covarying codons in HIV-1 subtype B, and as a resource facilitating the systematic identification and classification of immune escape mutations. These resources should facilitate research in HIV epitope discovery and host-pathogen co-evolution, and are relevant to the continued search for an effective CTL-based AIDS vaccine.

Hypertrophic cardiomyopathy (HCM) is the most common heart disease in domestic cats, often leading to congestive heart failure and death, with current treatment strategies unable to reverse or prevent progression of the disease. The underlying pathological processes driving HCM remain unclear, which hinders novel drug discovery. The aim of this study was to generate a cellular model of the feline HCM-causing MYBPC3 mutation R820W. Using CRISPR/Cas9 gene editing we introduced the R820W mutation into a human induced pluripotent stem cell (iPSC) line. We differentiated both homozygous mutant clones and isogenic control clones to cardiomyocytes (iPSC-CMs). Protein quantification indicated that haploinsufficiency is not the disease mechanism of the mutation. Homozygous mutant iPSC-CMs had a larger cell area than isogenic controls, with the sarcomere structure and incorporation of cMyBP-C appearing similar between mutant and control iPSC-CMs. Contraction kinetic analysis indicated that homozygous iPSC-CMs have impaired relaxation and are hypocontractile compared to isogenic control iPSC-CMs. In summary, we demonstrate successful generation of an iPSC model of a feline MYBPC3 mutation, with the cellular model recapitulating aspects of HCM including cellular hypertrophy and impaired relaxation kinetics. We anticipate that further study of this model will lead to improved understanding of the disease-causing molecular mechanism, ultimately leading to novel drug discovery. [ABSTRACT FROM AUTHOR]

Introduction: Estimates for cause-specific mortality for neonates are generally available for all countries for neonates overall (0 to 28 days). However, cause-specific mortality is generally not being estimated at higher age resolution for neonates, despite evidence of heterogeneity in the causes of deaths during this period. We aimed to use the adapted log quadratic model in a setting where verbal autopsy was the primary means of determining cause of death. Methods: We examined the timing and causes of death among a cohort of neonates in rural Nepal followed as part of the Nepal Oil Massage Study (NOMS). We adapted methods defined by Wilmoth et al (2012) and Guillot et al. (2022) to estimate age and cause-specific mortality among neonates. We used cross validation to estimate the accuracy of this model, holding out each three month period. We took the average cross validation across hold out as our measure of model performance and compared to a standard approach which did not account for the heterogeneity in cause-specific mortality rate within this age group. Results: There were 957 neonates in the NOMS cohort with known age and cause of death. We estimated an average cross-validation error of 0.9 per 1000 live births for mortality due to prematurity in the first week, and 1.1 for mortality due to birth asphyxia, compared to the standard approach, having error 7.4 and 7.8 per 1000 live births, respectively. Generally mortality rates for less common causes such as congenital malformations and pneumonia were estimated with higher cross-validation error. Conclusions: The stability and precision of these estimates compare favorably with similar estimates developed with higher quality cause-specific mortality surveillance from China, demonstrating that reliably estimating causes of mortality at high resolution is possible for neonates in low resources areas. [ABSTRACT FROM AUTHOR]

Modern slot machines are among the more harmful forms of gambling. Psychophysiological measures may provide a window into mental processes that underpin these harms. Here we investigated pupil dilation derived from eye tracking as a means of capturing changes in sympathetic nervous system arousal following outcomes on a real slot machine. We hypothesized that positively reinforcing slot machine outcomes would be associated with increases in arousal, reflected in larger pupil diameter. We further examined the contribution of game luminance fluctuations on pupil diameter. In Experiment 1A, experienced slot machine gamblers (N = 53) played a commercially-available slot machine in a laboratory for 20 minutes while wearing mobile eye tracking glasses. Analyses differentiated loss outcomes, wins, losses-disguised-as-wins, and (free-spin) bonus features. Bonus features were associated with rapid increases in pupil diameter following the onset of outcome-related audiovisual feedback, relative to losses. In Experiment 1B, luminance data were extracted from captured screen videos (derived from Experiment 1A) to characterize on-screen luminance changes that could modulate pupil diameter. Bonus features and wins were associated with pronounced and complex fluctuations in screen luminance (≈50 L and ≈25L, respectively). However, the pupil dilation that was observed to bonus features in Experiment 1A coincided temporally with only negligible changes in screen luminance, providing partial evidence that the pupil dilation to bonus features may be due to arousal. In Experiment 2, 12 participants viewed pairs of stimuli (scrambled slot machine images) at luminance difference thresholds of ≈25L, ≈50L, and ≈100L. Scrambled images presented at luminance differences of ≈25L and greater were sufficient to cause pupillary responses. Overall, pupillometry may detect event-related changes in sympathetic nervous system arousal following gambling outcomes, but researchers must pay careful attention to substantial in-game luminance changes that may confound arousal-based interpretations.

Under favourable conditions, perennial ryegrass (Lolium perenne) engineered to accumulated high lipid (HL) carbon sink in their leaves was previously shown to also enhance photosynthesis and growth. The greater aboveground biomass was found to be diminished in a dense canopy compared to spaced pots. Besides, the underlying genetic regulatory network linking between leaf lipid sinks and these physiological changes remains unknown. In this study, we demonstrated that the growth advantage was not displayed in HL Lolium grown in spaced pots under low lights. Under standard lights, analysis of differentiating transcripts in HL Lolium reveals that the plants had elevated transcripts involved in lipid metabolism, light capturing, photosynthesis, and sugar signalling while reduced expression of genes participating in sugar biosynthesis and transportation. The plants also had altered several transcripts involved in mitochondrial oxidative respiration and redox potential. Many of the above upregulated or downregulated transcript levels were found to be complemented by growing the plants under low light. Overall, this study emphasizes the importance of carbon and energy homeostatic regulatory mechanisms to overall productivity of the HL Lolium through photosynthesis, most of which are significantly impacted by low irradiances.

Background Intermittent claudication (IC) is a common manifestation of peripheral arterial disease. Some patients with IC experience a rise in Urinary N-acetyl-β-D-Glucosaminidase (NAG)/ Creatinine (Cr) ratio, a marker of renal injury, following exercise. In this study, we aim to investigate whether peripheral blood mononuclear cells (PBMC) from patients with IC who exhibit a rise in urinary NAG/ Cr ratio following exercise exhibit differential IL-10/ IL-12 ratio and gene expression compared to those who do not have a rise in NAG/ Cr ratio. Methods We conducted a single center observational cohort study of patients diagnosed with IC. Blood and urine samples were collected at rest and following a standardised treadmill exercise protocol. For comparative analysis patients were separated into those with any rise in NAG/Cr ratio (Group 1) and those with no rise in NAG/Cr ratio (Group 2) post exercise. Isolated PBMC from pre- and post-exercise blood samples were analysed using flow cytometry. PBMC were also cultured for 20 hours to perform further analysis of IL-10 and IL-12 cytokine levels. RNA-sequencing analysis was performed to identify differentially expressed genes between the groups. Results 20 patients were recruited (Group 1, n = 8; Group 2, n = 12). We observed a significantly higher IL-10/IL-12 ratio in cell supernatant from participants in Group 1, as compared to Group 2, on exercise at 20 hours incubation; 47.24 (IQR 9.70–65.83) vs 6.13 (4.88–12.24), p = 0.04. 328 genes were significantly differentially expressed between Group 1 and 2. The modulated genes had signatures encompassing hypoxia, metabolic adaptation to starvation, inflammatory activation, renal protection, and oxidative stress. Discussion Our results suggest that some patients with IC have an altered immune status making them ‘vulnerable’ to systemic inflammation and renal injury following exercise. We have identified a panel of genes which are differentially expressed in this group of patients.

Cryptococcal infections are an important cause of morbidity and mortality in tropical Australia. This retrospective audit was conducted to characterise the aetiology, temporospatial epidemiology, and clinical course of 49 cryptococcal infections in Far North Queensland between 1 January 1999 and 31 December 2019. Cryptococcus gattii was identified in 15/32 (47%) in whom it was possible to speciate the organism. Among these 15 patients, 13 (87%) had a rural residential address, 10 (67%) were Indigenous Australians and 11 (73%) presented during the May-November dry season. When compared to the 17 patients with Cryptococcus neoformans infection, patients with C. gattii were less likely to be immunocompromised (0/15 versus 8/17 (47%), p = 0.003). Neurosurgery was necessary in 5/15 C. gattii cases and 3/17 (18%) C. neoformans cases (p = 0.42). Outcomes were generally good with 42/49 (86%) cases-and 14/15 (93%) with C. gattii infection-surviving to hospital discharge. These positive outcomes are likely to be explained by the development of standardised treatment guidelines during the study period, low rates of comorbidity in the patients with C. gattii infection and access to liposomal amphotericin and neurosurgical support in the well-resourced Australian healthcare system.

Background: More than half of malaria cases in Zimbabwe are concentrated in Manicaland Province, where seasonal malaria epidemics occur despite intensified control strategies. Recently, high levels of pyrethroid and carbamate resistance were detected in Anopheles funestus, the major malaria vector in eastern Zimbabwe. In response, a single round of indoor residual spraying (IRS) using pirimiphos-methyl (an organophosphate) was implemented in four high burden districts of Manicaland Province from November 1, 2014 to December 19, 2014. The objective of this study was to evaluate the effect of this programmatic switch in insecticides on malaria morbidity reported from health care facilities in Mutasa District, one of the worst affected districts in Manicaland Province. Methods: The number of weekly malaria cases for each health facility 24 months prior to the 2014 IRS campaign and in the subsequent high transmission season were obtained from passive case surveillance. Environmental variables were extracted from remote-sensing data sources and linked to each health care facility. Negative binomial regression was used to model the weekly number of malaria cases, adjusted for seasonality and environmental variables. Results: From December 2012 to May 2015, 124,206 malaria cases were reported from 42 health care facilities in Mutasa District. Based on a higher burden of malaria, 20 out of 31 municipal wards were sprayed in the district. Overall, 87.3% of target structures were sprayed and 92.1% of the target population protected. During the 6 months after the 2014 IRS campaign, a period when transmission would have otherwise peaked, the incidence of malaria was 38% lower than the preceding 24 months at health facilities in the sprayed wards. Conclusions: Pirimiphos-methyl had a measurable impact on malaria incidence and is an effective insecticide for the control of An. funestus in eastern Zimbabwe. [ABSTRACT FROM AUTHOR]