Haasgrossman6630

correlations between the Socio-demographic index and the mortality rates of COPD, pneumoconiosis, and asthma. Regions with a low Socio-demographic index had the highest mortality and DALYs. Smoking remained the major risk factor for mortality due to COPD and asthma. Pollution from particulate matter was the major contributor to deaths from COPD in regions with a low Socio-demographic index. Since 2013, a high body mass index has become the principal risk factor for asthma. CONCLUSIONS Regions with a low Socio-demographic index had the greatest burden of disease. The estimated contribution of risk factors (such as smoking, environmental pollution, and a high body mass index) to mortality and DALYs supports the need for urgent efforts to reduce exposure to them. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http//group.bmj.com/group/rights-licensing/permissions.OBJECTIVE To study the clinical characteristics of patients in Zhejiang province, China, infected with the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) responsible for coronavirus disease 2019 (covid-2019). DESIGN Retrospective case series. SETTING Seven hospitals in Zhejiang province, China. PARTICIPANTS 62 patients admitted to hospital with laboratory confirmed SARS-Cov-2 infection. Data were collected from 10 January 2020 to 26 January 2020. MAIN OUTCOME MEASURES Clinical data, collected using a standardised case report form, such as temperature, history of exposure, incubation period. If information was not clear, the working group in Hangzhou contacted the doctor responsible for treating the patient for clarification. RESULTS Of the 62 patients studied (median age 41 years), only one was admitted to an intensive care unit, and no patients died during the study. According to research, none of the infected patients in Zhejiang province were ever exposed to the Huanan seafood market, the original source of the virus; all studied cases were infected by human to human transmission. The most common symptoms at onset of illness were fever in 48 (77%) patients, cough in 50 (81%), expectoration in 35 (56%), headache in 21 (34%), myalgia or fatigue in 32 (52%), diarrhoea in 3 (8%), and haemoptysis in 2 (3%). Only two patients (3%) developed shortness of breath on admission. The median time from exposure to onset of illness was 4 days (interquartile range 3-5 days), and from onset of symptoms to first hospital admission was 2 (1-4) days. CONCLUSION As of early February 2020, compared with patients initially infected with SARS-Cov-2 in Wuhan, the symptoms of patients in Zhejiang province are relatively mild. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http//group.bmj.com/group/rights-licensing/permissions.INTRODUCTION Although bacteria contribute significantly to acute exacerbations of chronic obstructive pulmonary disease (AECOPD), the added value of antibiotics remains controversial, especially in outpatient settings. Age may affect antibiotic effectiveness, but real-world evidence is lacking. We aimed to assess the influence of age on the effectiveness of doxycycline for AECOPD. METHODS A retrospective cohort study among outpatients with the first recorded AECOPD treated with oral corticosteroids was conducted using a large pharmacy dispensing database. The primary outcome was treatment failure within 15-31 days after treatment start. Secondary outcome was time to second exacerbation. All analyses were stratified by age groups. RESULTS We identified 6300 outpatients with the first AECOPD. 2261 (36%) received doxycycline and 4039 (64%) did not receive any antibiotic (reference group). Overall, there was no difference in treatment failure (adjusted OR 0.97, 95% CI 0.84 to 1.12) between two groups. Similarly, ployer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.BACKGROUND Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), the most common bariatric surgeries performed worldwide, increase the risk to develop an alcohol use disorder. This might be due, in part, to surgery-related changes in alcohol pharmacokinetics. Another risk factor, unexplored within this population, is having a reduced subjective response to alcohol's sedative effects. OBJECTIVES To assess whether the alcohol sensitivity questionnaire (ASQ), a simple self-report measure, could pinpoint reduced alcohol sensitivity in the bariatric population. SETTING University medical centers in Missouri and Illinois. METHODS Women who had RYGB (n = 16), SG (n = 28), or laparoscopic adjustable gastric banding surgery (n = 11) within the last 5 years completed the ASQ for both pre- and postsurgical timeframes, and 45 of them participated in oral alcohol challenge testing postsurgery. Blood alcohol concentration (BAC) and subjective stimulation and sedation were measured before and for 3.5 hours after drinking. RESULTS In line with faster and higher peak BACs after RYGB and SG than laparoscopic adjustable gastric banding surgery (P less then .001), postsurgery ASQ scores were more reduced from presurgery scores after RYGB/SG than after laparoscopic adjustable gastric banding surgery (-2.3 ± .3 versus -1.2 ± .2; P less then .05). However, despite the dramatic changes in BAC observed when ingesting alcohol after RYGB/SG surgeries, which resulted in peak BAC that were approximately 50% above the legal driving limit, a third of these women felt almost no alcohol-related sedative effects. CONCLUSIONS Although RYGB/SG dramatically increased sensitivity to alcohol in all participants, meaningful interindividual differences remained. The ASQ might help identify patients at increased risk to develop an alcohol use disorder after surgery. BACKGROUND Gastric bypasses were the most common bariatric surgery for many years, and long-term complications after gastric bypass are known to be relatively common. Symptomatic hiatal hernia (HH) with pouch migration is a less-known complication. However, when these are symptomatic, they require surgical repair. OBJECTIVE We present a case series of late-term HH after gastric bypass and discuss the common presentation and treatment. SETTING University program in the United States. METHODS A retrospective chart review was performed of patients presenting with late-term HH after gastric bypass performed by a single surgeon during 2002 through 2018. The review captured presentation and symptoms, age, body mass index, time from index surgery, radiologic studies, and the reoperative details. If available, the original operative note was reviewed along with any preoperative imaging studies. A review of the literature was also performed. RESULTS Seven patients were included in the case series. The average time from the index surgery was 11.9 years (range 9-16) and the average age of the patient at time of presentation was 60.1. The average body mass index at the time of the HH repair was 34 kg/m2. The most common presenting symptom was gastroesophageal reflux. Both computed tomography and upper gastrointestinal series were used for diagnosis with a common finding of HH and pouch migration into the mediastinum. HH repair with bioabsorbable mesh was performed in all patients, with an average operative time of 105 minutes. CONCLUSION HH can present late after gastric bypass become symptomatic. When symptomatic, it needs to be addressed surgically and can usually be done through a minimally invasive approach. Compensatory endocytosis of released synaptic vesicles (SVs) relies on coordinated signaling at the lipid-protein interface. Here, we address the synaptic function of C-terminal binding protein 1 (CtBP1), a ubiquitous regulator of gene expression and membrane trafficking in cultured hippocampal neurons. In the absence of CtBP1, synapses form in greater density and show changes in SV distribution and size. The increased basal neurotransmission and enhanced synaptic depression could be attributed to a higher vesicular release probability and a smaller fraction of release-competent SVs, respectively. Rescue experiments with specifically targeted constructs indicate that, while synaptogenesis and release probability are controlled by nuclear CtBP1, the efficient recycling of SVs relies on its synaptic expression. The ability of presynaptic CtBP1 to facilitate compensatory endocytosis depends on its membrane-fission activity and the activation of the lipid-metabolizing enzyme PLD1. Thus, CtBP1 regulates SV recycling by promoting a permissive lipid environment for compensatory endocytosis. Cells have developed protein quality-control strategies to manage the accumulation of misfolded substrates during heat stress. Lazertinib Using a soluble reporter of misfolding in fission yeast, Rho1.C17R-GFP, we demonstrate that upon mild heat shock, the reporter collapses in protein aggregate centers (PACs). They contain and/or require several chaperones, such as Hsp104, Hsp16, and the Hsp40/70 couple Mas5/Ssa2. Stress granules do not assemble at mild temperatures and, therefore, are not required for PAC formation; on the contrary, PACs may serve as nucleation centers for the assembly of stress granules. In contrast to the general belief, the dominant fate of these PACs is not degradation, and the aggregated reporter can be disassembled by chaperones and recovers native structure and activity. Using mass spectrometry, we show that thermo-unstable endogenous proteins form PACs as well. In conclusion, formation of PACs during heat shock is a chaperone-mediated adaptation strategy. Cells deficient in ataxia telangiectasia mutated (ATM) are hypersensitive to ionizing radiation and other anti-cancer agents that induce double-strand DNA breaks. ATM inhibitors may therefore sensitize cancer cells to these agents. Some cancers may also have underlying genetic defects predisposing them to an ATM inhibitor monotherapy response. We have conducted a genome-wide CRISPR screen to identify genetic vulnerabilities that sensitize lung cancer cells to ATM inhibitors. Knockout of genes in the Fanconi anemia (FA)/BRCA pathway results in hypersensitivity to the ATM inhibitor M3541. Knockdown of either an FA gene or of ATM results in reduced double-strand break end resection, enhanced non-homologous end joining (NHEJ) repair, and decreased homologous recombination repair. Knockout of both the FA/BRCA pathway and ATM strongly inhibits end resection and generates toxic levels of NHEJ, thereby elucidating a mechanism of cellular death by synthetic lethality. ATM inhibitors may therefore be useful for the treatment of tumors with a defective FA/BRCA pathway. Degradation of transcripts in human nuclei is primarily facilitated by the RNA exosome. To obtain substrate specificity, the exosome is aided by adaptors; in the nucleoplasm, those adaptors are the nuclear exosome-targeting (NEXT) complex and the poly(A) (pA) exosome-targeting (PAXT) connection. How these adaptors guide exosome targeting remains enigmatic. Employing high-resolution 3' end sequencing, we demonstrate that NEXT substrates arise from heterogenous and predominantly pA- 3' ends often covering kilobase-wide genomic regions. link2 In contrast, PAXT targets harbor well-defined pA+ 3' ends defined by canonical pA site use. link3 Irrespective of this clear division, NEXT and PAXT act redundantly in two ways (1) regional redundancy, where the majority of exosome-targeted transcription units produce NEXT- and PAXT-sensitive RNA isoforms, and (2) isoform redundancy, where the PAXT connection ensures fail-safe decay of post-transcriptionally polyadenylated NEXT targets. In conjunction, this provides a two-layered targeting mechanism for efficient nuclear sorting of the human transcriptome.