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IMPORTANCE: The etiology and significance of diffusion-weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear. OBJECTIVE: To evaluate which factors are associated with DWI lesions, whether associated factors differ by ICH location, and whether DWI lesions are associated with functional outcomes. DESIGN, SETTING, AND PARTICIPANTS: This analysis pooled individual patient data from 3 randomized clinical trials (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial, Antihypertensive Treatment of Acute Cerebral Hemorrhage trial, and Intracerebral Hemorrhage Deferoxamine phase 2 trial) and 1 multicenter prospective study (Ethnic/Racial Variations of Intracerebral Hemorrhage). Patients were enrolled from August 1, 2010, to September 30, 2018. Of the 4782 patients, 1788 who underwent magnetic resonance imaging scans of the brain were included. Data were analyzed from July 1 to December 31, 2019. MAIN OUTCOMES AND MEASURES: The primary outcome consisted of factors associated with DWI lesions. Secondary outcomes were poor functional outcome, defined as a modified Rankin score (mRS) of 4 to 6, and mortality, both assessed at 3 months. Mixed-effects logistic regression was used to evaluate the association between exposures and outcomes. Subgroup analyses stratified by hematoma location were performed. RESULTS: After exclusion of 36 patients with missing data on DWI lesions, 1752 patients were included in the analysis (1019 men [58.2%]; mean [SD] age, 60.8 [13.3] years). Diffusion-weighted imaging lesions occurred in 549 patients (31.3%). In mixed-effects regression models, factors associated with DWI lesions included younger age (odds ratio [OR] per year, 0.98; 95% CI, 0.97-0.99), black race (OR, 1.64; 95% CI, 1.17-2.30), admission systolic blood pressure (OR per 10–mm Hg increase, 1.13; 95% CI, 1.08-1.18), baseline hematoma volume (OR per 10-mL increase, 1.12; 95% CI, 1.02-1.22), cerebral microbleeds (OR, 1.85; 95% CI, 1.39-2.46), and leukoaraiosis (OR, 1.59; 95% CI, 1.67-2.17). Diffusion-weighted imaging lesions were independently associated with poor mRS (OR, 1.50; 95% CI, 1.13-2.00), but not with mortality (OR, 1.11; 95% CI, 0.72-1.71). In subgroup analyses, similar factors were associated with DWI lesions in lobar and deep ICH. Diffusion-weighted imaging lesions were associated with poor mRS in deep but not lobar ICH. CONCLUSIONS AND RELEVANCE: In a large, heterogeneous cohort of prospectively identified patients with ICH, results were consistent with the hypothesis that DWI lesions represent acute sequelae of chronic cerebral small vessel disease, particularly hypertensive vasculopathy. Diffusion-weighted imaging lesions portend a worse prognosis after ICH, mainly deep hemorrhages.

Obesity is highly prevalent and a major risk factor for deep vein thrombosis (DVT) and chronic venous disease. It can also technically limit duplex ultrasound evaluations for lower extremity DVT. We compared the rates and results of repeat lower extremity venous duplex ultrasound (LEVDUS) after an initial incomplete and negative (IIN) LEVDUS in overweight (body mass index [BMI] ≤25-30 kg/m2) and obese (BMI ≥30 kg/m2) patients with those of patients with a BMI <25 kg/m2to evaluate whether increasing the rate of follow-up examinations in overweight and obese patients might facilitate improved patient care.

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H4. To ascertain whether targeting HAT1 is a viable anticancer treatment strategy, we sought to identify small-molecule inhibitors of HAT1 by developing a high-throughput HAT1 acetyl-click assay. Screening of small-molecule libraries led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity. Compounds were refined by synthesis and testing of over 70 analogs, which yielded structure–activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl side chain improved enzymatic potency and cellular growth suppression. One compound (JG-2016 [24a]) showed relative specificity toward HAT1 compared to other acetyltransferases, suppressed the growth of human cancer cell lines, impaired enzymatic activity in cellulo, and interfered with tumor growth. This is the first report of a small-molecule inhibitor of the HAT1 enzyme complex and represents a step toward targeting this pathway for cancer therapy.

Spawning of the Southern Distinct Population Segment of Green Sturgeon Acipenser medirostrisoccurs annually within the Sacramento River in California. Artificial substrate samplers were used to collect Green Sturgeon eggs between 2008 and 2012 and in a reach of the river 94 river kilometers (rkm) long (rkm 426–332). A total of 268 eggs and 5 posthatch larvae were sampled from seven identified spawning sites between April 2 and July 7, primarily from medium gravel substrates. At these sites the mean water column velocities were 0.8 m/s at depths ranging from 0.6 to 11.3 m (6.4 ± 2.3 m, mean ± SD). We noted an average discharge of 314 m3/s and a median turbidity value of 3.9 NTU during estimated spawning events. Spawning at all sites occurred when average water temperatures were 13.5 ± 1.0°C and during water year types ranging from critically dry to wet. Green Sturgeon eggs averaged 4.11 ± 0.20 mm in diameter (n= 207), were very adhesive, and were between developmental stages 2 (just fertilized) and 44 (posthatch larva). We estimated that eggs were collected from a minimum of 54 different spawning events, based on sample date and location, egg developmental stage at capture, and water temperatures. Green Sturgeon spawning data indicates there is spatial separation from sympatric White Sturgeon A. transmontanus, but some temporal overlap exists. The thermally and hydrologically managed Sacramento River with its numerous diversions and competing water demands appears to have an approximate reach of 120 rkm in the 405-km-long river that is favorable for Green Sturgeon spawning in most years. Management decisions need to assess and incorporate the spawning habitat requirements of Green Sturgeon and coordinate this information with that of endangered winter-run Chinook Salmon Oncorhynchus tshawytschawhile attempting to meet the diverse demands of the limited Sacramento River water resources.

AbstractSpawning of the Southern Distinct Population Segment of Green Sturgeon Acipenser medirostrisoccurs annually within the Sacramento River in California. Artificial substrate samplers were used to collect Green Sturgeon eggs between 2008 and 2012 and in a reach of the river 94 river kilometers (rkm) long (rkm 426–332). A total of 268 eggs and 5 posthatch larvae were sampled from seven identified spawning sites between April 2 and July 7, primarily from medium gravel substrates. At these sites the mean water column velocities were 0.8 m/s at depths ranging from 0.6 to 11.3 m (6.4 ± 2.3 m, mean ± SD). We noted an average discharge of 314 m3/s and a median turbidity value of 3.9 NTU during estimated spawning events. Spawning at all sites occurred when average water temperatures were 13.5 ± 1.0°C and during water year types ranging from critically dry to wet. Green Sturgeon eggs averaged 4.11 ± 0.20 mm in diameter (n= 207), were very adhesive, and were between developmental stages 2 (just fertilized) and 44 (posthatch larva). We estimated that eggs were collected from a minimum of 54 different spawning events, based on sample date and location, egg developmental stage at capture, and water temperatures. Green Sturgeon spawning data indicates there is spatial separation from sympatric White Sturgeon A. transmontanus, but some temporal overlap exists. The thermally and hydrologically managed Sacramento River with its numerous diversions and competing water demands appears to have an approximate reach of 120 rkm in the 405-km-long river that is favorable for Green Sturgeon spawning in most years. Management decisions need to assess and incorporate the spawning habitat requirements of Green Sturgeon and coordinate this information with that of endangered winter-run Chinook Salmon Oncorhynchus tshawytschawhile attempting to meet the diverse demands of the limited Sacramento River water resources.Received April 20, 2015; accepted June 30, 2015

Studies of health risks associated with recreational water exposure require investigators to make choices about water quality indicator averaging techniques, exposure definitions, follow-up periods, and model specifications; however, investigators seldom describe the impact of these choices on reported results. Our objectives are to report illness risk from swimming at a marine beach affected by nonpoint sources of urban runoff, measure associations between fecal indicator bacteria levels and subsequent illness among swimmers, and investigate the sensitivity of results to a range of exposure and outcome definitions.

IMPORTANCE: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation. OBJECTIVE: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions. DESIGN, SETTING, AND PARTICIPANTS: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children’s hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020. EXPOSURES: Prescription of 38 level A medications based on electronic health records. MAIN OUTCOMES AND MEASURES: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally. RESULTS: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10?629 per 100?000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100?000 children). Among commonly prescribed opioids, annual prevalence per 100?000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100?000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100?000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes. CONCLUSIONS AND RELEVANCE: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.

Individuals with a single functional copy of the BRCA2tumor suppressor have elevated risks for breast, ovarian, and other solid tumor malignancies. The exact mechanisms of carcinogenesis due to BRCA2haploinsufficiency remain unclear, but one possibility is that at-risk cells are subject to acute periods of decreased BRCA2 availability and function (“BRCA2-crisis”), which may contribute to disease. Here, we establish an in vitromodel for BRCA2-crisis that demonstrates chromatin remodeling and activation of an NF-κB survival pathway in response to transient BRCA2 depletion. Mechanistically, we identify BRCA2 chromatin binding, histone acetylation, and associated transcriptional activity as critical determinants of the epigenetic response to BRCA2-crisis. These chromatin alterations are reflected in transcriptional profiles of pre-malignant tissues from BRCA2carriers and, therefore, may reflect natural steps in human disease. By modeling BRCA2-crisis in vitro, we have derived insights into pre-neoplastic molecular alterations that may enhance the development of preventative therapies.