IMPORTANCE: Estimates from claims-based analyses suggest that the incidence of sepsis is increasing and mortality rates from sepsis are decreasing. However, estimates from claims data may lack ...clinical fidelity and can be affected by changing diagnosis and coding practices over time. OBJECTIVE: To estimate the US national incidence of sepsis and trends using detailed clinical data from the electronic health record (EHR) systems of diverse hospitals. DESIGN, SETTING, AND POPULATION: Retrospective cohort study of adult patients admitted to 409 academic, community, and federal hospitals from 2009-2014. EXPOSURES: Sepsis was identified using clinical indicators of presumed infection and concurrent acute organ dysfunction, adapting Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria for objective and consistent EHR-based surveillance. MAIN OUTCOMES AND MEASURES: Sepsis incidence, outcomes, and trends from 2009-2014 were calculated using regression models and compared with claims-based estimates using International Classification of Diseases, Ninth Revision, Clinical Modification codes for severe sepsis or septic shock. Case-finding criteria were validated against Sepsis-3 criteria using medical record reviews. RESULTS: A total of 173 690 sepsis cases (mean age, 66.5 SD, 15.5 y; 77 660 42.4% women) were identified using clinical criteria among 2 901 019 adults admitted to study hospitals in 2014 (6.0% incidence). Of these, 26 061 (15.0%) died in the hospital and 10 731 (6.2%) were discharged to hospice. From 2009-2014, sepsis incidence using clinical criteria was stable (+0.6% relative change/y 95% CI, −2.3% to 3.5%, P = .67) whereas incidence per claims increased (+10.3%/y 95% CI, 7.2% to 13.3%, P < .001). In-hospital mortality using clinical criteria declined (−3.3%/y 95% CI, −5.6% to −1.0%, P = .004), but there was no significant change in the combined outcome of death or discharge to hospice (−1.3%/y 95% CI, −3.2% to 0.6%, P = .19). In contrast, mortality using claims declined significantly (−7.0%/y 95% CI, −8.8% to −5.2%, P < .001), as did death or discharge to hospice (−4.5%/y 95% CI, −6.1% to −2.8%, P < .001). Clinical criteria were more sensitive in identifying sepsis than claims (69.7% 95% CI, 52.9% to 92.0% vs 32.3% 95% CI, 24.4% to 43.0%, P < .001), with comparable positive predictive value (70.4% 95% CI, 64.0% to 76.8% vs 75.2% 95% CI, 69.8% to 80.6%, P = .23). CONCLUSIONS AND RELEVANCE: In clinical data from 409 hospitals, sepsis was present in 6% of adult hospitalizations, and in contrast to claims-based analyses, neither the incidence of sepsis nor the combined outcome of death or discharge to hospice changed significantly between 2009-2014. The findings also suggest that EHR-based clinical data provide more objective estimates than claims-based data for sepsis surveillance.
Missing data in clinical trials can have a major effect on the validity of the inferences that can be drawn from the trial. This article reviews methods for preventing missing data and, failing that, ...dealing with data that are missing.
Background
Missing data have seriously compromised inferences from clinical trials, yet the topic has received little attention in the clinical-trial community.
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Existing regulatory guidances
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on the design, conduct, and analysis of clinical trials have little specific advice on how to address the problem of missing data. A recent National Research Council (NRC) report
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on the topic seeks to address this gap, and this article summarizes some of the main findings and recommendations of that report. The authors of this article served on the panel that prepared the report.
Missing data have seriously compromised inferences from clinical trials.
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For example, . . .
The objective of this study was to examine the impact of increasing proportions of grazed pasture in the diet on the composition, quality, and functionality of bovine milk across a full lactation. ...Fifty-four spring-calving cows were randomly assigned to 1 of 3 groups (n = 18), blocked on the basis of mean calving date (February 15, 2020 ± 0.8 d), pre-experimental daily milk yield (24.70 ± 3.70 kg), milk solids yield (2.30 ± 0.27 kg), lactation number (3.10 ± 0.13), and economic breeding index (182 ± 19). Raw milk samples were obtained weekly from each group between March and November 2020. Group 1 (GRS) consumed perennial ryegrass and was supplemented with 5% concentrates (dry matter basis); group 2 was maintained indoors and consumed a total mixed ration (TMR) diet consisting of maize silage, grass silage, and concentrates; and group 3 consumed a partial mixed ration diet (PMR), rotating between perennial ryegrass during the day and indoor TMR feeding at night. Raw milk samples consisted of a pooled morning and evening milking and were analyzed for gross composition, free amino acids, fatty acid composition, heat coagulation time, color, fat globule size, and pH. The TMR milks had a significantly higher total solids, lactose, protein, and whey protein as a proportion of protein content compared with both GRS and PMR milks. The GRS milks demonstrated a significantly lower somatic cell count (SCC), but a significantly higher pH and b*-value than both TMR and PMR milks. The PMR milks exhibited significantly lower total solids and fat content, but also demonstrated significantly higher SCC and total free amino acid content compared with GRS and TMR. Partial least squares discriminant analysis of fatty acid profiles displayed a distinct separation between GRS and TMR samples, while PMR displayed an overlap between both GRS and TMR groupings. Variable importance in projection analysis identified conjugated linoleic acid cis-9,trans-11, C18:2n-6 cis, C18:3n-3, C11:0, and C18:2n-6 trans as the largest contributors to the variation between the diets. Milk fats derived from GRS diets exhibited the highest proportion of unsaturated fats and higher unsaturation, health-promoting, and desaturase indices. The lowest proportions of saturated fats and the lowest atherogenic index were also exhibited by GRS-derived milk fats. This work highlights the positive influence of grass-fed milk for human consumption through its more nutritionally beneficial fatty acid profile, despite the highest milk solid percentages derived from TMR feeding systems. Furthermore, this study demonstrates the proportional response of previously highlighted biomarkers of pasture feeding to the proportion of pasture in the cow's diet.
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Visual hallucinations are a common feature of Lewy body dementia. Previous studies have shown that visual hallucinations are highly specific in differentiating Lewy body dementia from Alzheimer's ...disease dementia and Alzheimer-Lewy body mixed pathology cases. Computational models propose that impairment of visual and attentional networks is aetiologically key to the manifestation of visual hallucinations symptomatology. However, there is still a lack of experimental evidence on functional and structural brain network abnormalities associated with visual hallucinations in Lewy body dementia. We used EEG source localisation and Network Based Statistics to assess differential topographical patterns in Lewy body dementia between 25 participants with visual hallucinations and 17 participants without hallucinations. Diffusion tensor imaging was used to assess structural connectivity between thalamus, basal forebrain and cortical regions belonging to the functionally affected network component in the hallucinating group, as assessed with Network Based Statistics. Number of white matter streamlines within the cortex and between subcortical and cortical regions was compared between hallucinating and not hallucinating groups and correlated with average EEG source connectivity of the affected subnetwork. Moreover, modular organisation of the EEG source network was obtained, compared between groups, and tested for correlation with structural connectivity. Network analysis showed that compared to non-hallucinating patients, those with hallucinations feature consistent weakened connectivity within the visual ventral network, and between this network and default mode and ventral attentional networks, but not between or within attentional networks. The occipital lobe was the most functionally disconnected region. Structural analysis yielded significantly affected white matter streamlines connecting the cortical regions to the nucleus basalis of Meynert and the thalamus in hallucinating compared to not hallucinating patients. The number of streamlines in the tract between the basal forebrain and the cortex correlated with cortical functional connectivity in non-hallucinating patients, whilst a correlation emerged for the white matter streamlines connecting the functionally affected cortical regions in the hallucinating group. This study proposes, for the first time, differential functional networks between hallucinating and not hallucinating Lewy body dementia patients, and provides an empirical evidence for existing models of visual hallucinations. Specifically, the outcome of the present study shows that the hallucinating condition is associated with functional network segregation in Lewy body dementia and supports the involvement of the cholinergic system as proposed in the current literature.
Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis ...that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from in-vivo ischemia-reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting-induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEB-mediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fasting-induced autophagy in myocardial ischemia-reperfusion injury.
Mechanisms that control aging are important yet poorly defined. To discover longevity control genes, we performed a forward genetic screen for delayed reproductive aging in C. elegans. Here, we show ...that am117 is a nonsense mutation in the phm-2 gene, which encodes a protein homologous to human scaffold attachment factor B. phm-2(lf) mutant worms have an abnormal pharynx grinder, which allows live bacteria to accumulate in the intestine. This defect shortens lifespan on highly pathogenic bacteria but extends lifespan and health span on the standard E. coli diet by activating innate immunity pathways that lead to bacterial avoidance behavior and dietary restriction. eat-2(lf) mutants displayed a similar phenotype, indicating accumulation of live bacteria also triggers extended longevity in this mutant. The analysis of phm-2 elucidates connections between pathogen response and aging by defining a mechanism of longevity extension in C. elegans—bacterial colonization, innate immune activation, and bacterial avoidance behavior.
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•phm-2 encodes a SAFB protein conserved in mammals•phm-2 and eat-2 mutants have a defective pharynx and accumulate bacteria in the gut•Bacterial accumulation activates innate immunity and bacterial avoidance behavior•Bacterial avoidance leads to dietary restriction and delays aging
Kumar et al. link immunity and aging in C. elegans. The authors characterize phm-2 and eat-2, mutants that allow live bacteria to accumulate in the intestine, causing delayed reproductive and somatic aging. The mechanism combines molecular immune activation and behavioral food avoidance, leading to dietary restriction and extended lifespan.
Little is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm ...from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicle-exposed rats (p < 0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use.
Parental cannabis use has been associated with adverse neurodevelopmental outcomes in offspring, but how such phenotypes are transmitted is largely unknown. Using reduced representation bisulphite ...sequencing (RRBS), we recently demonstrated that cannabis use is associated with widespread DNA methylation changes in human and rat sperm. Discs-Large Associated Protein 2 (DLGAP2), involved in synapse organization, neuronal signaling, and strongly implicated in autism, exhibited significant hypomethylation (p < 0.05) at 17 CpG sites in human sperm. We successfully validated the differential methylation present in DLGAP2 for nine CpG sites located in intron seven (p < 0.05) using quantitative bisulphite pyrosequencing. Intron 7 DNA methylation and DLGAP2 expression in human conceptal brain tissue were inversely correlated (p < 0.01). Adult male rats exposed to delta-9-tetrahydrocannabinol (THC) showed differential DNA methylation at Dlgap2 in sperm (p < 0.03), as did the nucleus accumbens of rats whose fathers were exposed to THC prior to conception (p < 0.05). Altogether, these results warrant further investigation into the effects of preconception cannabis use in males and the potential effects on subsequent generations.
IMPORTANCE: Emerging evidence suggests that risk of bacterial sexually transmitted infections (STIs) increases among gay and bisexual men following initiation of HIV preexposure prophylaxis (PrEP). ...OBJECTIVE: To describe STI incidence and behavioral risk factors among a cohort of predominantly gay and bisexual men who use PrEP, and to explore changes in STI incidence following PrEP commencement. DESIGN, SETTING, AND PARTICIPANTS: The Pre-exposure Prophylaxis Expanded (PrEPX) Study, a multisite, open-label intervention study, was nested within the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS) clinic network. A total of 4275 participants were enrolled (July 26, 2016–April 1, 2018) in Victoria, Australia. Of these, 2981 enrolled at 5 ACCESS clinics (3 primary care, 1 sexual health, and 1 community-based HIV rapid testing service), had at least 1 follow-up visit, and were monitored until April 30, 2018. EXPOSURES: Upon enrollment, participants received daily oral tenofovir disoproxil fumurate and emtricitabine for HIV PrEP, quarterly HIV and STI testing, and clinical monitoring. MAIN OUTCOMES AND MEASURES: The primary outcome was incidence of chlamydia, gonorrhea, or syphilis. Incidence rates and hazard ratios describing behavioral risk factors of STI diagnosis were calculated. Incidence rate ratios (IRRs), adjusted for change in testing frequency, described changes in STI incidence from 1-year preenrollment to study follow-up among participants with preenrollment testing data (n = 1378). RESULTS: Among the 2981 individuals (median age, 34 years interquartile range, 28-42), 98.5% identified as gay or bisexual males, 29% used PrEP prior to enrollment, 89 (3%) withdrew and were censored at date of withdrawal, leaving 2892 (97.0%) enrolled at final follow-up. During a mean follow-up of 1.1 years (3185.0 person-years), 2928 STIs were diagnosed among 1427 (48%) participants (1434 chlamydia, 1242 gonorrhea, 252 syphilis). STI incidence was 91.9 per 100 person-years, with 736 participants (25%) accounting for 2237 (76%) of all STIs. Among 2058 participants with complete data for multivariable analysis, younger age, greater partner number, and group sex were associated with greater STI risk, but condom use was not. Among 1378 participants with preenrollment testing data, STI incidence increased from 69.5 per 100 person-years prior to enrollment to 98.4 per 100 person-years during follow-up (IRR, 1.41 95% CI, 1.29-1.56). After adjusting for testing frequency, the increase in incidence from 1 year preenrollment to follow-up was significant for any STI (adjusted IRR, 1.12 95% CI, 1.02-1.23) and for chlamydia (adjusted IRR, 1.17 95% CI, 1.04-1.33). CONCLUSIONS AND RELEVANCE: Among gay and bisexual men using PrEP, STIs were highly concentrated among a subset, and receipt of PrEP after study enrollment was associated with an increased incidence of STIs compared with preenrollment. These findings highlight the importance of frequent STI testing among gay and bisexual men using PrEP.
Laser acceleration of ions to MeV energies has been achieved on a variety of Petawatt laser systems, raising the prospect of ion beam applications using compact ultra-intense laser technology. ...However, translation from proof-of-concept laser experiment into real-world application requires MeV-scale ion energies and an appreciable repetition rate (>Hz). We demonstrate, for the first time, proton acceleration up to 2 MeV energies at a kHz repetition rate using a milli-joule-class short-pulse laser system. In these experiments, 5 mJ of ultrashort-pulse laser energy is delivered at an intensity near 5 × 10 18 W cm − 2 onto a thin-sheet, liquid-density target. Key to this effort is a flowing liquid ethylene glycol target formed in vacuum with thicknesses down to 400 nm and full recovery at 70 s, suggesting its potential use at >kHz rate. Novel detectors and experimental methods tailored to high-repetition-rate ion acceleration by lasers were essential to this study and are described. In addition, particle-in-cell simulations of the laser-plasma interaction show good agreement with experimental observations.
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