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Transcriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, largely lacking so far. TFs play central roles in both normal-range and disease-associated variation in craniofacial morphology; we therefore developed an approach to precisely modulate TF levels in human facial progenitor cells and applied it to SOX9, a TF associated with craniofacial variation and disease (Pierre Robin sequence (PRS)). Most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, but REs directly and primarily regulated by SOX9 show heightened sensitivity to SOX9 dosage; these RE responses partially predict gene expression responses. Sensitive REs and genes preferentially affect functional chondrogenesis and PRS-like craniofacial shape variation. We propose that such REs and genes underlie the sensitivity of specific phenotypes to TF dosage, while buffering of other genes leads to robust, nonlinear dosage-to-phenotype relationships. ispartof: NATURE GENETICS vol:55 issue:5 ispartof: location:United States status: Published online

Introduction: During the COVID-19 pandemic, studies reported less number of hospitalizations for acute stroke and reduction in the use of recanalization treatments. This study analyzes nationwide data on stroke admissions and management in the Czech Republic during the first wave of the COVID-19 pandemic. Methods: We compared the early COVID-19 pandemic (March–May 2020) with the pre-pandemic period (January–February 2020 and March–May 2019): (a) the National Register of Reimbursed Health Services provided volume of all admissions for subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and ischemic stroke (IS), and volume of recanalization treatments (intravenous thrombolysis [IVT] and mechanical thrombectomy [MT]); (b) Registry of Stroke Care Quality provided door-to-needle time (DNT), onset-to-door time (ODT), and stroke severity at admission (National Institutes of Health Stroke Scale, NIHSS) for IS. Results: During the pandemic (March–May 2020), the peak number of COVID-19 patients treated in Czech hospitals was 39 per million. In March–May 2020 versus March–May 2019, hospital admissions decreased as follows: stroke overall by 14% (p < 0.001), IS by 14% (p < 0.001), SAH by 15% (p = 0.07), and ICH by 7% (p = 0.17). The mean age was 74 years versus 74 years (p = 0.33), and 52% versus 51% were men (p = 0.34). The volumes of IVT and MT decreased by 14% (p = 0.001) and 19% (p = 0.01), respectively. The proportions of all IS patients receiving IVT or MT remained unchanged, with, respectively, 17% versus 17% receiving IVT (p = 0.86) and 5% versus 5% receiving MT (p = 0.48). DNT and ODT were 24 versus 25 min (p = 0.58) and 168 versus 156 min (p = 0.23), respectively. NIHSS at admission did not differ (6 vs. 6; p = 0.54). Conclusion: Even with a low burden of COVID-19 during the first wave and no change in organization and logistics of stroke services, stroke admissions and volume of recanalization treatments decreased. Public health communication campaigns should encourage people to seek emergency medical care for stroke symptoms during the COVID-19 pandemic.

Background and Objectives Islatravir (MK-8591) is a novel nucleoside analogue in development for the treatment and prevention of HIV-1 infection. Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. This study evaluated the pharmacokinetics, safety, and tolerability of islatravir and doravirine coadministration in a double-blind, placebo-controlled, randomized, fixed-sequence study. Methods Adult participants without HIV infection were administered oral doravirine 100 mg (n = 10) or placebo (n = 4) once daily (QD) for 5 days, immediately followed by oral islatravir 2.25 mg (n = 10) or placebo QD (n = 4) for 14 days; islatravir 2.25 mg and doravirine 100 mg QD, or placebo QD, were then coadministered for 5 days. Pharmacokinetic and safety data were collected. Results Doravirine geometric least-squares mean ratios (90% confidence intervals (CIs)) of (doravirine + islatravir)/doravirine for the area under the plasma drug concentration-time curve over 24 h (AUC0–24h), maximum plasma concentration (Cmax), and plasma concentration at 24 h post-dose (C24h) were not meaningfully impacted. Islatravir geometric least-squares mean ratios (90% CI) of (islatravir + doravirine)/islatravir for AUC0–24h and Cmax were both close to unity, 1.06 (1.01, 1.12) and 1.08 (0.91, 1.27), respectively. All study regimens were generally well tolerated. Conclusion These results indicate that coadministration of islatravir and doravirine had no clinically meaningful effect on the pharmacokinetics of either drug, and support further clinical investigation of islatravir in combination with doravirine for the treatment of HIV-1 infection. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-021-01046-1.

The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study meta-analysis of 8,246 European individuals, we identified 203 genome-wide-significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses indicate that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants. In summary, our analyses provide insights into the understanding of how complex morphological traits are shaped by both individual and coordinated genetic actions. ispartof: Nature Genetics vol:53 issue:1 ispartof: location:United States status: Published online

Summary Aims To investigate the clinical benefit of routine procalcitonin (PCT) measurement in the medical intensive care unit (ICU) of a tertiary referral hospital. Methods Adult patients with suspected infections were included. White blood cells, C‑reactive protein (CRP), and PCT were measured. Results In this study 129 patients of median age 64 years (interquartile range 39–89 years) were prospectively included. The Acute Physiology And Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were 21 ± 14 and 7 ± 6, respectively. Intensive care unit (ICU) mortality was 22.5%. Immunocompromised patients constituted 39.5%. A significant correlation was observed between PCT and APACHE II (Spearman’s rho 0.461, p

ObjectiveTo undertake an effectiveness and safety analysis of EVT in patients with LVO and NIH Stroke Scale (NIHSS) score ≤6 using datasets of multicenter and multinational nature.MethodsWe pooled patients with anterior circulation occlusion from 3 prospective international cohorts. Patients were eligible if presentation occurred within 12 hours from last known well and baseline NIHSS ≤6. Primary outcome was modified Rankin Scale (mRS) score 0–1 at 90 days. Secondary outcomes included neurologic deterioration at 24 hours (change in NIHSS of ≥2 points), mRS 0–2 at 90 days, and 90-day all-cause mortality. We used propensity score matching to adjust for nonrandomized treatment allocation.ResultsAmong 236 patients who fit inclusion criteria, 139 received EVT and 97 received medical management. Compared to medical management, the EVT group was younger (65 vs 72 years; p < 0.001), had more proximal occlusions (p < 0.001), and less frequently received concurrent IV thrombolysis (57.7% vs 71.2%; p = 0.04). After propensity score matching, clinical outcomes between the 2 groups were not significantly different. EVT patients had an 8.6% (95% confidence interval [CI] −8.8% to 26.1%) higher rate of excellent 90-day outcome, despite a 22.3% (95% CI, 3.0%–41.6%) higher risk of neurologic deterioration at 24 hours.ConclusionsEVT for LVO in patients with low NIHSS score was associated with increased risk of neurologic deterioration at 24 hours. However, both EVT and medical management resulted in similar proportions of excellent clinical outcomes at 90 days.Classification of evidenceThis study provides Class III evidence that for patients with acute anterior circulation ischemic strokes and LVO with NIHSS < 6, EVT and medical management result in similar outcomes at 90 days.

Previous research found adolescents with low self-worth often utilize delinquency as a method of "self-enhancing" as proposed by Kaplan, which suggests the effects of delinquency can be both enhancing and damaging to adolescents' later reports of self-worth. We tested Kaplan's self-enhancing thesis to determine the extent to which different levels of self-worth in early adolescents foretell long-term levels of self-worth associated with delinquency among adolescents placed at-risk. Data from a sample of 982 primarily Black American (95%) adolescents living in high-poverty neighborhoods were analyzed using global and behavioral self-worth measures collected annually between the ages of 12-17, with school delinquency as the self-enhancing mechanism. Gender (45% female, 55% male) and baseline self-worth measures were included in the model. We found empirical support for the positive effects of school delinquency consistent with self-enhancing theories, although with younger female participants only. Specifically, engaging in delinquent behaviors at age 12 had a positive effect on a females' behavioral self-worth. There were, however, differential effects for males. Although delinquency increased self-worth among females in the short-term, long-term effects were negative, as greater school delinquency resulted in lower self-worth at age 17. Additional gender results and implications for findings are discussed.

To evaluate cerebral hemodynamic, metabolic and anatomic changes occurring in patients with unilateral occlusion of the internal carotid artery (ICA). Twenty-two patients with unilateral occlusion of ICA and twenty age and sex matched healthy subjects were included in the study. Single voxel proton magnetic resonance spectroscopy (1H-MRS) of the centrum semiovale, semi-automated hippocampal volumetry in T1-weighted scans and transcranial Doppler examination (TCD) with calculation of Breath Holding Index (BHI) were performed in both groups. Metabolic, anatomic, and hemodynamic features were compared between the two groups. The N-acetylaspartate (NAA)/choline (Cho) ratio was significantly lower in both hemispheres of enrolled patients compared to controls (p = 0.005 for the side with occlusion, p = 0.04 for the side without occlusion). The hippocampus volume was significantly reduced bilaterally in patients compared to healthy subjects (p = 0.049). A statistically significant difference in BHI values was observed between the side with occlusion and without occlusion (p = 0.037) of the patients, as well as between BHI values of the side with occlusion and healthy volunteers (p = 0.014). Patients with unilateral ICA occlusion have reduced NAA/Cho ratio in the white matter of both hemispheres and have bilateral atrophy of hippocampus. The alteration of hemodynamics alone cannot explain these changes.

Background The benefit of intravenous thrombolysis is time dependent. It remains unclear, however, whether dramatic shortening of door‐to‐needle time (DNT) among different types of hospitals nationwide does not compromise safety and still improves outcome. Methods and Results Multifaceted intervention to shorten DNT was introduced at a national level, and prospectively collected data from a registry between 2004 and 2019 were analyzed. Generalized estimating equation was used to identify the association between DNT and outcomes independently from prespecified baseline variables. The primary outcome was modified Rankin score 0 to 1 at 3 months, and secondary outcomes were parenchymal hemorrhage/intracerebral hemorrhage (ICH), any ICH, and death. Of 31 316 patients treated with intravenous thrombolysis alone, 18 861 (60%) had available data: age 70±13 years, National Institutes of Health Stroke Scale at baseline (median, 8; interquartile range, 5–14), and 45% men. DNT groups 0 to 20 minutes, 21 to 40 minutes, 41 to 60 minutes, and >60 minutes had 3536 (19%), 5333 (28%), 4856 (26%), and 5136 (27%) patients. National median DNT dropped from 74 minutes in 2004 to 22 minutes in 2019. Shorter DNT had proportional benefit: it increased the odds of achieving modified Rankin score 0 to 1 and decreased the odds of parenchymal hemorrhage/ICH, any ICH, and mortality. Patients with DNT ≤20 minutes, 21 to 40 minutes, and 41 to 60 minutes as compared with DNT >60 minutes had adjusted odds ratios for modified Rankin score 0 to 1 of the following: 1.30 (95% CI, 1.12–1.51), 1.33 (95% CI, 1.15–1.54), and 1.15 (95% CI, 1.02–1.29), and for parenchymal hemorrhage/ICH: 0.57 (95% CI, 0.45–0.71), 0.76 (95% CI, 0.61–0.94), 0.83 (95% CI, 0.70–0.99), respectively. Conclusions Ultrashort initiation of thrombolysis is feasible, improves outcome, and makes treatments safer because of fewer intracerebral hemorrhages. Stroke management should be optimized to initiate thrombolysis as soon as possible optimally within 20 minutes from arrival to a hospital.

Gefapixant (MK‐7264) is a first‐in‐class, selective antagonist of the P2X3 purinergic receptor currently being investigated as a therapeutic agent for the treatment of refractory or unexplained chronic cough. In non‐clinical studies, gefapixant was eliminated primarily by renal excretion of the parent drug. The objective of this study was to assess the disposition of gefapixant in humans. The absorption, metabolism, and excretion profiles of gefapixant were assessed after oral administration of a single dose of [14C]gefapixant to six healthy adult males. Following a single‐oral [14C]gefapixant dose to healthy adult males, the mass balance was achieved, with 98.9% of the administered radioactivity recovered in urine and feces. Elimination of gefapixant occurred primarily via renal excretion of the intact drug (64%); metabolism was a minor pathway of elimination of gefapixant (12% and 2% recovered in urine and feces, respectively). Single‐dose administration of [14C]gefapixant 50 mg was generally well tolerated in healthy adult males. The fraction of the anticipated therapeutic oral dose of gefapixant absorbed is estimated to be at least 78%. Gefapixant is expected to be the major circulating drug‐related material in plasma, and the majority of the dosed drug will be excreted unchanged in urine.

Patent foramen ovale (PFO) is a risk factor of decompression sickness (DCS). However, data on risk stratification of divers with a PFO are sparse. This study sought to evaluate the risk of neurological DCS (DCSneuro), based on the presence and grade of a right-to-left shunt (RLS).A total of 640 divers were screened for a RLS using TCD between 1/2006 and 4/2017. RLS was graded as low, medium, or high grade with two subgroups - after a Valsalva maneuver or at rest. Divers were questioned about their DCS history. Survival analysis techniques were used to assess risk factors for unprovoked DCS.A RLS was found in 258 divers (40.3 %). 44 (17.1 %) divers with a RLS experienced DCSneuro compared to 5 (1.3 %) divers without a RLS (p0.001). The proportion of DCSneuro increased from 4.6 % in the low-grade RLS subgroup to 57.1 % in the subgroup with high-grade RLS at rest. The hazard ratio for DCSneuro and RLS was11.806 (p0.001).Divers with a RLS had a higher risk of DCSneuro and the risk increased with RLS grade. We suggest that TCD is an appropriate method for RLS screening and risk stratification in divers (Tab. 4, Fig. 2, Ref. 29).

Background and ObjectivesCOVID-19–related inflammation, endothelial dysfunction, and coagulopathy may increase the bleeding risk and lower the efficacy of revascularization treatments in patients with acute ischemic stroke (AIS). We aimed to evaluate the safety and outcomes of revascularization treatments in patients with AIS and COVID-19.MethodsThis was a retrospective multicenter cohort study of consecutive patients with AIS receiving intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) between March 2020 and June 2021 tested for severe acute respiratory syndrome coronavirus 2 infection. With a doubly robust model combining propensity score weighting and multivariate regression, we studied the association of COVID-19 with intracranial bleeding complications and clinical outcomes. Subgroup analyses were performed according to treatment groups (IVT-only and EVT).ResultsOf a total of 15,128 included patients from 105 centers, 853 (5.6%) were diagnosed with COVID-19; of those, 5,848 (38.7%) patients received IVT-only and 9,280 (61.3%) EVT (with or without IVT). Patients with COVID-19 had a higher rate of symptomatic intracerebral hemorrhage (SICH) (adjusted OR 1.53; 95% CI 1.16–2.01), symptomatic subarachnoid hemorrhage (SSAH) (OR 1.80; 95% CI 1.20–2.69), SICH and/or SSAH combined (OR 1.56; 95% CI 1.23–1.99), 24-hour mortality (OR 2.47; 95% CI 1.58–3.86), and 3-month mortality (OR 1.88; 95% CI 1.52–2.33). Patients with COVID-19 also had an unfavorable shift in the distribution of the modified Rankin score at 3 months (OR 1.42; 95% CI 1.26–1.60).DiscussionPatients with AIS and COVID-19 showed higher rates of intracranial bleeding complications and worse clinical outcomes after revascularization treatments than contemporaneous non–COVID-19 patients receiving treatment. Current available data do not allow direct conclusions to be drawn on the effectiveness of revascularization treatments in patients with COVID-19 or to establish different treatment recommendations in this subgroup of patients with ischemic stroke. Our findings can be taken into consideration for treatment decisions, patient monitoring, and establishing prognosis.Trial Registration InformationThe study was registered under ClinicalTrials.gov identifierNCT04895462.

IntroductionAorto-left ventricular tunnel (ALVT) accounts for

Background and Purpose: The National Institutes of Health Stroke Scale (NIHSS) underestimates clinical severity in posterior circulation stroke and patients presenting with low NIHSS may be considered ineligible for reperfusion therapies. This study aimed to develop a modified version of the NIHSS, the Posterior NIHSS (POST-NIHSS), to improve NIHSS prognostic accuracy for posterior circulation stroke patients with mild-moderate symptoms. Methods: Clinical data of consecutive posterior circulation stroke patients with mild-moderate symptoms (NIHSS Results: We included 202 patients (mean [SD] age 63 [14] years, median NIHSS 3 [interquartile range, 1–5]) in the derivation cohort and 65 patients (mean [SD] age 63 [16] years, median NIHSS 2 [interquartile range, 1–4]) in the validation cohort. In the derivation cohort, age, NIHSS, abnormal cough, dysphagia and gait/truncal ataxia were ranked as the most important predictors of functional outcome. POST-NIHSS was calculated by adding 5 points for abnormal cough, 4 points for dysphagia, and 3 points for gait/truncal ataxia to the baseline NIHSS. In receiver operating characteristic analysis adjusted for age, POST-NIHSS area under receiver operating characteristic curve was 0.80 (95% CI, 0.73–0.87) versus NIHSS area under receiver operating characteristic curve, 0.73 (95% CI, 0.64–0.83), P =0.03. In the validation cohort, POST-NIHSS area under receiver operating characteristic curve was 0.82 (95% CI, 0.69–0.94) versus NIHSS area under receiver operating characteristic curve 0.73 (95% CI, 0.58–0.87), P =0.04. Conclusions: POST-NIHSS showed higher prognostic accuracy than NIHSS and may be useful to identify posterior circulation stroke patients with NIHSS

Rigorous and regular evaluation of defined quality indicators is crucial for further improvement of both technical and clinical results after mechanical thrombectomy (MT) for acute ischemic stroke (AIS). Following the recent international multi-society consensus quality indicators, we aimed to assess trend in these indicators on national level.The prospective multicenter study (METRICS) was conducted in Czech Republic (CR) in year 2019. All participating centers collected technical and clinical data including defined quality indicators and results were subsequently compared with those from year 2016.In the 2019, 1375 MT were performed in the CR and 1178 (86%) patients (50.3% males, mean age 70.5 ± 13.0 years) were analyzed. Recanalization (TICI 2b-3) was achieved in 83.7% of patients and 46.2% of patients had good 3-month clinical outcome. Following time intervals were shortened in comparison to 2016: "hospital arrival - GP" (77 vs. 53 min; p0.0001), "hospital arrival - maximal achieved recanalization" (122 vs. 93 min; p0.0001), and "stroke onset - maximal achieved recanalization" (240 vs. 229 min; p p0.0001). More patients with tandem occlusion were treated in 2019 (7.8 vs. 16.5%; p0.0001) and more secondary transports were in 2019 (31.3 vs. 37.8%; p=0.002). No difference was found in 3-month clinical outcome and in the rate of periprocedural complications. Results of the METRICS study met all criteria of multi-society consensus quality indicators.Nationwide comparison between 2016 and 2019 showed improvement in the key time intervals, but without better overall clinical outcomes after MT.

MK-8507 is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor in clinical development with potential for once-weekly oral administration for the treatment of HIV-1 infection. Two randomized, double-blind, placebo-controlled phase 1 studies in adults without HIV-1 evaluated the safety, tolerability, and pharmacokinetics of single and multiple doses of MK-8507; drug interaction with midazolam (a cytochrome P450 3A4 substrate) and food effect were also assessed. In Study 1, 16 participants received oral ascending single doses of MK-8507 (2-400 mg) or placebo in an alternating fashion. In Study 2, 24 participants received ascending single doses of MK-8507 (400-1200 mg) or placebo and multiple doses (once weekly for 3 weeks) of MK-8507 (100-400 mg) or placebo. MK-8507 pharmacokinetics were approximately dose proportional at 2-1200 mg. MK-8507 had a time to maximum concentration of 2-7 hours and a mean terminal half-life of ∼58-84 hours. MK-8507 doses ≥100 mg achieved a plasma concentration at 168 hours post-dose (7 days) associated with antiviral efficacy. A high-fat meal had no clinically meaningful effect on MK-8507 pharmacokinetics, and MK-8507 400 mg once weekly had no clinically meaningful effect on midazolam pharmacokinetics. Single and multiple doses of MK-8507 were generally well tolerated. No trends with dose and no clinically meaningful changes were observed in vital signs, electrocardiograms, and laboratory safety tests. The pharmacokinetics and safety data are supportive of once-weekly oral administration and support further clinical investigation of MK-8507 for the treatment of HIV-1 infection. Over the last 3 decades, substantial improvements have been made in oral HIV antiretroviral therapies (ART), which now offer people living with HIV (PLWH) the potential for a near-normal life expectancy (1, 2). To achieve this, individuals must maintain life-long viral suppression, which requires daily administration of efficacious medication (3). Issues surrounding tolerability, complicated regimens, and treatment fatigue from daily dosing can lead to poor adherence and suboptimal viral suppression (3-6). Regimens can become complex when there is the need to take multiple pills, requirement to take a medication fasted or with food, or the potential for interactions with other medications, including those required to treat HIV-related comorbidities (3, 78). New treatment options that are not only highly effective but also offer excellent tolerability, a high barrier to resistance, favorable drug interaction profiles, and the potential for less frequent dosing remain the focus of much clinical research (7, 9). While 1 pill once a day meets the needs of many PLWH, for others daily administration poses challenges, including treatment fatigue and daily reminders and/or stigma associated with ART (10, 11). While treatment regimens that can be taken less often than daily are attractive to many PLWH, the long-acting injectable combination of cabotegravir/rilpivirine is currently the only treatment option available without daily dosing; however, administration requires injection by a health care professional (12), potentially posing other challenges.

Alemtuzumab as a treatment of highly active multiple sclerosis causes a rapid decrease in inflammatory activity due the lysis of immune cells. Subsequent cytokine release determines the infusion-associated reaction that is a frequent adverse event of alemtuzumab treatment. Recently, serious cardiovascular and thrombotic adverse reactions following alemtuzumab infusion have been described. In our study, the dynamics of coagulation parameters were analyzed in 13 multiple sclerosis patients treated with alemtuzumab. An immediate, significant increase in the level of D-dimer was observed after the first administration of alemtuzumab. This observation provides evidence of coagulation activation and the potential risk of thrombotic complications with this therapy. Prophylactic low molecular weight heparin pretreatment maybe considered in patients receiving alemtuzumab.

Aims Recombinant PEGylated human granulocyte colony-stimulating factor (pegfilgrastim) is indicated for the reduction of chemotherapy-induced neutropenia and prevention of febrile neutropenia. Biosimilar pegfilgrastim is expected to reduce the financial burden of this complication of chemotherapy. The aim of this study was to demonstrate biosimilarity between Sandoz biosimilar pegfilgrastim and its US- and EU-approved reference biologics. Methods Phase I, randomized, double-blind, single-dose, 3-period, 6-sequence cross-over, multicentre study to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of Sandoz biosimilar pegfilgrastim with US- and EU-references in healthy adults. Results Pharmacokinetic and pharmacodynamic similarity was demonstrated between the 3 biologics, as the 90% confidence interval for all primary pharmacokinetic and pharmacodynamic endpoint comparisons were contained within the predefined similarity margins of 0.80-1.25. Safety, immunogenicity and tolerability were also similar. Conclusions Sandoz biosimilar pegfilgrastim demonstrated pharmacokinetic and pharmacodynamic similarity to both US- and EU-reference biologics. No meaningful differences in safety, local tolerability and immunogenicity were identified.

Patent foramen ovale (PFO), male sex, age, and body mass index (BMI) were all identified as potential risk factors of decompression sickness (DCS). It has been debated whether PFO might cause unprovoked DCS (i.e. without violation of decompression procedure) due to paradoxical embolization of venous gas emboli. To date, there are no data on the incidence or risk factors of unprovoked DCS. This study sought to evaluate the risk factors of unprovoked DCS in recreational divers.A total of 489 consecutive divers were screened for PFO between January 2006 and January 2014 by means of transcranial Doppler. All patients were prospectively included in the study registry. Survival analysis techniques were used to assess for risk factors for unprovoked DCS. Age, sex, BMI, PFO presence, and grade were analyzed. The total sum of dives was used as a measure of time.The group performed a total of 169,411 dives (mean 346±636). Thirty-six (7%) of the divers suffered from an unprovoked DCS. The frequency of PFO was 97.2% in divers with a history of unprovoked DCS and 35.5% in controls (p0.001). There was no difference in sex, age, BMI, or total number of dives between the respective groups. In the adjusted Cox proportional hazards model, PFO grade 3 was a major risk factor for unprovoked DCS; there was a slight protective effect of increasing age.We demonstrated that a high-grade PFO was a major risk factor for unprovoked DCS in recreational scuba divers.

MK-8507 is an investigational HIV-1 nonnucleoside reverse transcriptase inhibitor being developed for the treatment of HIV-1 infection. MK-8507 contains 2 trifluoromethyl groups that may result in fluoride release through metabolism, but the extent of MK-8507-related fluoride release in humans has yet to be determined. This double-blind, placebo-controlled, 2-period, parallel-group, multiple-dose trial in healthy participants without HIV-1 who were administered a fluoride-restricted diet and once-weekly doses of MK-8507 aimed to estimate the relationship between MK-8507 dose and fluoride exposure. A total of 15 adult male and 3 adult female (of non-childbearing potential) participants were randomized to receive MK-8507 200 mg (n = 6), MK-8507 800 mg (n = 6), or placebo (n = 6). Change from baseline in mean daily fluoride excretion averaged over 7 days following the administration of MK-8507 200 mg resulted in a net mean increase of 19.8 μmol (90% confidence interval, 12.2-27.4) relative to placebo and did not exceed 57 μmol, a threshold related to the mean difference between the daily reference dose set by the US Environmental Protection Agency and the average dietary fluoride intake in the United States. However, daily urinary fluoride excretion exceeded the threshold following administration of 800 mg MK-8507 (75.1 μmol [90% confidence interval, 67.5-82.7]). Assuming a linear relationship between MK-8507 dose and estimated mean daily fluoride released at steady-state, data interpolation suggests that the US Environmental Protection Agency reference dose for fluoride would not be exceeded in most patients when administering MK-8507 at doses currently under clinical investigation (≤400 mg once weekly).

Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Consequently, the degree to which facial traits share a common genetic basis across diverse sets of humans remains largely unknown. We therefore investigated the genetic basis of facial morphology in an East African cohort. We applied an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children. This approach segments the face into hierarchically arranged, multivariate features that capture the shape variation after adjusting for age, sex, height, weight, facial size and population stratification. Genome scans of these multivariate shape phenotypes revealed significant (p < 2.5 × 10−8) signals at 20 loci, which were enriched for active chromatin elements in human cranial neural crest cells and embryonic craniofacial tissue, consistent with an early developmental origin of the facial variation. Two of these associations were in highly conserved regions showing craniofacial-specific enhancer activity during embryological development (5q31.1 and 12q21.31). Six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance (p < 6.25 × 10−10). Cross-population comparisons indicated 10 association signals were shared with Europeans (seven sharing the same associated SNP), and facilitated fine-mapping of causal variants at previously reported loci. Taken together, these results may point to both shared and population-specific components to the genetic architecture of facial variation., Author summary Genetic factors play an important role in shaping human facial features. Over the last decade, studies have identified numerous genes associated with various facial traits. The vast majority of these studies have focused on European or Asian populations, while African populations have been underrepresented. Increasing the diversity of these analyses can reveal novel associations and cross-population analyses can help deepen our understanding of known genetic associations. We therefore performed a genome scan of 3D facial features in African children from Tanzania and then compared our results to Europeans. We found 20 regions of the genome associated with facial shape in Tanzanian children, 10 of which were also present in Europeans, indicating evidence for a partly shared genetic basis for human facial shape across populations. In addition, about half of the genetic associations observed in Tanzanians were not present in Europeans, and some of the shared signals differed between populations in the specific genetic variants associated or specific facial traits affected. These results shed light on the shared and population-specific genetic contributors to normal-range facial variation.

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.1668F is a founder variant among Ashkenazi Jews (allele frequency of -.2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

Background and aims Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by disease-associated variants in the alpha-galactosidase A gene (GLA). FD is a known cause of stroke in younger patients. There are limited data on prevalence of FD and stroke risk in unselected stroke patients. Methods A prospective nationwide study including 35 (78%) of all 45 stroke centers and all consecutive stroke patients admitted during three months. Clinical data were collected in the RES-Q database. FD was diagnosed using dried blood spots in a stepwise manner: in males—enzymatic activity, globotriaosylsphingosine (lyso-Gb3) quantification, if positive followed by GLA gene sequencing; and in females GLA sequencing followed by lyso-Gb3. Results 986 consecutive patients (54% men, mean age 70 years) were included. Observed stroke type was ischemic 79%, transient ischemic attack (TIA) 14%, intracerebral hemorrhage (ICH) 7%, subarachnoid hemorrhage 1% and cerebral venous thrombosis 0.1%. Two (0.2%, 95% CI 0.02–0.7) patients had a pathogenic variant associated with the classical FD phenotype (c.1235_1236delCT and p.G325S). Another fourteen (1.4%, 95% CI 0.08–2.4) patients had a variant of GLA gene considered benign (9 with p.D313Y, one p.A143T, one p.R118C, one p.V199A, one p.R30K and one p.R38G). The index stroke in two carriers of disease-associated variant was ischemic lacunar. In 14 carriers of GLA gene variants 11 strokes were ischemic, two TIA, and one ICH. Patients with positive as compared to negative GLA gene screening were younger (mean 60±SD, min, max, vs 70±SD, min, max, P = 0.02), otherwise there were no differences in other baseline variables. Conclusions The prevalence of FD in unselected adult patients with acute stroke is 0.2%. Both patients who had a pathogenic GLA gene variant were younger than 50 years. Our results support FD screening in patients that had a stroke event before 50 years of age.

Introduction: There are growing concerns among European health authorities regarding increasing prices for new cancer medicines, prices not necessarily linked to health gain and the implications for the sustainability of their healthcare systems. Areas covered: Narrative discussion principally among payers and their advisers regarding potential approaches to the pricing of new cancer medicines. Expert opinion: A number of potential pricing approaches are discussed including minimum effectiveness levels for new cancer medicines, managed entry agreements, multicriteria decision analyses (MCDAs), differential/tiered pricing, fair pricing models, amortization models as well as de-linkage models. We are likely to see a growth in alternative pricing deliberations in view of ongoing challenges. These include the considerable number of new oncology medicines in development including new gene therapies, new oncology medicines being launched with uncertainty regarding their value, and continued high prices coupled with the extent of confidential discounts for reimbursement. However, balanced against the need for new cancer medicines. This will lead to greater scrutiny over the prices of patent oncology medicines as more standard medicines lose their patent, calls for greater transparency as well as new models including amortization models. We will be monitoring these developments., peer-reviewed

The aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed., Graphical abstract

Blockade of the immunosuppressive tryptophan catabolism mediated by indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) holds enormous promise for sensitising cancer patients to immune checkpoint blockade. Yet, only IDO1 inhibitors had entered clinical trials so far, and those agents have generated disappointing clinical results. Improved understanding of molecular mechanisms involved in the immune-regulatory function of the tryptophan catabolism is likely to optimise therapeutic strategies to block this pathway. The immunosuppressive role of tryptophan metabolite kynurenine is becoming increasingly clear, but it remains a mystery if tryptophan exerts functions beyond serving as a precursor for kynurenine. Here we hypothesise that tryptophan acts as a rheostat of kynurenine-mediated immunosuppression by competing with kynurenine for entry into immune T-cells through the amino acid transporter called System L. This hypothesis stems from the observations that elevated tryptophan levels in TDO-knockout mice relieve immunosuppression instigated by IDO1, and that the vacancy of System L transporter modulates kynurenine entry into CD4+ T-cells. This hypothesis has two potential therapeutic implications. Firstly, potent TDO inhibitors are expected to indirectly inhibit IDO1 hence development of TDO-selective inhibitors appears advantageous compared to IDO1-selective and dual IDO1/TDO inhibitors. Secondly, oral supplementation with System L substrates such as leucine represents a novel potential therapeutic modality to restrain the immunosuppressive kynurenine and restore anti-tumour immunity.

Summary Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation., Graphical Abstract, Highlights • Extreme long-range enhancer clusters overlap PRS patient mutations at the SOX9 locus • PRS enhancers drive stage-specific SOX9 expression in the cranial neural crest • Mandible development has heightened sensitivity to perturbation of SOX9 gene dosage • Deletion of mouse EC1.45 leads to quantitative changes in mandible morphology, Non-coding mutations over a megabase from SOX9 cause the craniofacial disorder Pierre Robin sequence (PRS). Long et al. leverage a human neural crest model to demonstrate that PRS is caused by loss of extreme long-range enhancers active during a restricted developmental window and explore mechanisms underlying the specificity of disease manifestations.

Cardiac arrhythmias are among the leading causes of mortality. They often arise from alterations in the electrophysiological properties of cardiac cells and their underlying ionic mechanisms. It is therefore critical to further unravel the pathophysiology of the ionic basis of human cardiac electrophysiology in health and disease. In the first part of this review, current knowledge on the differences in ion channel expression and properties of the ionic processes that determine the morphology and properties of cardiac action potentials and calcium dynamics from cardiomyocytes in different regions of the heart are described. Then the cellular mechanisms promoting arrhythmias in congenital or acquired conditions of ion channel function (electrical remodeling) are discussed. The focus is on human-relevant findings obtained with clinical, experimental, and computational studies, given that interspecies differences make the extrapolation from animal experiments to human clinical settings difficult. Deepening the understanding of the diverse pathophysiology of human cellular electrophysiology will help in developing novel and effective antiarrhythmic strategies for specific subpopulations and disease conditions.

The FaceBase Consortium was established by the National Institute of Dental and Craniofacial Research in 2009 as a ‘big data’ resource for the craniofacial research community. Over the past decade, researchers have deposited hundreds of annotated and curated datasets on both normal and disordered craniofacial development in FaceBase, all freely available to the research community on the FaceBase Hub website. The Hub has developed numerous visualization and analysis tools designed to promote integration of multidisciplinary data while remaining dedicated to the FAIR principles of data management (findability, accessibility, interoperability and reusability) and providing a faceted search infrastructure for locating desired data efficiently. Summaries of the datasets generated by the FaceBase projects from 2014 to 2019 are provided here. FaceBase 3 now welcomes contributions of data on craniofacial and dental development in humans, model organisms and cell lines. Collectively, the FaceBase Consortium, along with other NIH-supported data resources, provide a continuously growing, dynamic and current resource for the scientific community while improving data reproducibility and fulfilling data sharing requirements.

Objectives We reviewed a spectrum of congenital heart defects assessed in our center between 1/2010 and 4/2020, evaluated their gross anatomy, assessed the age distribution, evaluated performed surgical procedures, and correlated gross and ultrasound findings. Methods All necroptic cases and explanted hearts that underwent specialized cardiac autopsy were included in this study. Autopsy findings including gross description of congenital heart defects together with echocardiographic findings were retrospectively assessed. In surgically corrected hearts, the operation records were included as well. All congenital heart defects and surgical procedures were subclassified into main and additional category. Results The study included 92 necroptic cases of live-born children, 7 stillbirths, 2 cases of young adults, 50 induced abortions, and 5 explanted hearts, with median age 36 weeks. The most frequently encountered leading congenital heart defects were hypoplastic left heart syndrome, aortic stenosis, septal defects, or persistent arterial trunk. Fifty-one patients underwent surgical repair represented mainly by valvuloplasties, aortoplasty, and procedures leading to univentricular circulation. In the native hearts, 4 postnatal and 16 abortion/stillbirth cases showed discordance between gross and sonographic findings, mainly attributed to missed ventricular septal defect. Gestational age of the discordant group was significantly lower compared to the concordant group (P= .007). Conclusions Autopsy continues to provide essential information about the morphology of congenital heart defects. However, the encountered congenital heart defects were usually complex, often surgically corrected or evaluated as a result of induced abortion or still birth. Cardiac autopsy therefore places high demands on pathologists with regards to proper gross heart assessment. It is also an invaluable part of quality control in prenatal cardiology.

Objectives To examine the relationship of clinical, biochemical and imaging parameters to maximum oxygen uptake in patients after atrial correction of transposition of great arteries. Background Exercise tolerance is a key determinant of quality of life in patients with adult congenital heart disease. It is determined by a large scale of factors often different from general cardiology. Methods 86 consecutive patients after Senning correction of TGA were subjected to clinical and echocardiographic examination, Holter monitoring, blood tests of NT-proBNP, MRI of the heart and exercise test. Parameters of these examinations were correlated to VO2 max. Results The average age of patients was 28±3.5 years. The average systemic right ventricular function determined by MRI was 51.9±7.9 %. The average NT-proBPN was 124.3±23.6 ng/l, VO2 max. 31.7±6.5 ml/kg/min and the heart rate reserve 106±24 /min. Neither systemic right ventricular systolic function nor NT-proBPN predicted VO2 max., whereas the heart rate reserve did (p=0.003). Conclusion An inability to increase heart rate during exercise noted in a considerable number of patients after atrial switch of TGA caused a decreased exercise tolerance. It is not solely the global systolic function of either ventricle that influences the exercise performance, rather it is the ability to increase heart rate and overall cardiac output appropriately (Tab. 3, Fig. 6, Ref. 28).

This article describes policy processes that have led to the re-organisation of stroke care in the Czech Republic since 2011, which has been part of a broader process of care concentration in several medical fields. Currently, stroke care is provided by 13 Comprehensive and 32 Primary Stroke Centres. The paper explains factors that supported the reform implementation, reviews implications, and discusses future challenges. Mandatory reporting of quality indicators, the introduction of a benchmarking system, integration with pre-hospital emergency care, and the introduction of countrywide patient triage have supported more timely treatment for stroke patients and better quality of care. Data from the Stroke Care Quality Indicators of the Czech Stroke Society show positive trends in many areas: the number of patients treated with intravenous thrombolysis quadrupled in eight years, with 26.4 % of all acute stroke patients receiving thrombolysis in 2018. Czech Republic now ranks third in Europe in the number of thrombolysis per population and second in the number of mechanical thrombectomies per population. The Czech experience provides an example of positive outcomes of concentrated stroke care, while highlighting the importance of proper implementation processes. In particular, it is essential to involve stakeholders and to provide reputational incentives through continuous benchmarking.

R-loops are dynamic, co-transcriptional nucleic acid structures that facilitate physiological processes but can also cause DNA damage in certain contexts. Perturbations of transcription or R-loop resolution are expected to change their genomic distribution. Next-generation sequencing approaches to map RNA–DNA hybrids, a component of R-loops, have so far not allowed quantitative comparisons between such conditions. Here, we describe quantitative differential DNA–RNA immunoprecipitation (qDRIP), a method combining synthetic RNA–DNA-hybrid internal standards with high-resolution, strand-specific sequencing. We show that qDRIP avoids biases inherent to read-count normalization by accurately profiling signal in regions unaffected by transcription inhibition in human cells, and by facilitating accurate differential peak calling between conditions. We also use these quantitative comparisons to make the first estimates of the absolute count of RNA–DNA hybrids per cell and their half-lives genome-wide. Finally, we identify a subset of RNA–DNA hybrids with high GC skew which are partially resistant to RNase H. Overall, qDRIP allows for accurate normalization in conditions where R-loops are perturbed and for quantitative measurements that provide previously unattainable biological insights.

The objectives of this study were to characterize the concentration‐time profiles of total radioactivity equivalent and unchanged cefiderocol, the route(s) of elimination and mass balance, and safety of cefiderocol after intravenous administration of a single 1000‐mg (100 μCi) dose of [14C]‐cefiderocol as a 1‐hour infusion in healthy adult male subjects. Unchanged cefiderocol accounted for the majority of total radioactivity in plasma, and the partitioning of total radioactivity into red blood cells was negligible. The recovery of total radioactivity was complete in all subjects within 120 hours after initiation of the infusion (101.5% of the administered dose). Cefiderocol‐related material was primarily excreted into urine, with 98.7% of the administered dose of [14C]‐cefiderocol excreted as total radioactivity into urine and negligible excretion into feces. Based on the results of metabolite profiling, cefiderocol accounted for 92.3% of area under the concentration‐time curve of total radioactivity in plasma and accounted for 90.6% of the administered dose excreted into urine. Metabolism was a minor route of elimination for cefiderocol. Cefiderocol was generally safe and well tolerated in healthy adult male subjects. In conclusion, unchanged cefiderocol represents the majority of total radioactivity in plasma. Cefiderocol is primarily excreted as unchanged drug into urine. This study indicates that cefiderocol and drug‐related material did not remain in the body.

Introduction: There are positive aspects regarding the prescribing of fixed-dose combinations (FDCs) versus prescribing the medicines separately. However, these have to be balanced against concerns including increased costs and their irrationality in some cases. Consequently, there is a need to review their value among lower and middle income countries (LMICs) which have the greatest prevalence of both infectious and non-infectious diseases and issues of affordability. Areas covered: Review of potential advantages, disadvantages, cost-effectiveness and availability of FDCs in high priority disease areas in LMICs and possible initiatives to enhance the prescribing of valued FDCs and limit their use where concerns with their value. Expert commentary: FDCs are valued across LMICs. Advantages include potentially improved response rates, reduced adverse reactions, increased adherence rates and reduced costs. Concerns include increased chances of drug:drug interactions, reduced effectiveness, potential for imprecise diagnoses and higher unjustified prices. Overall certain FDCs including those for malaria, tuberculosis and hypertension are valued and listed in country’s essential medicine lists, with initiatives needed to enhance their prescribing where currently low prescribing rates. Proposed initiatives include robust clinical and economic data to address the current paucity of pharmacoeconomic data. Irrational FDCs persists in some countries which is being addressed.

Background Intravenous thrombolysis (IVT) is contraindicated in patients with acute ischemic stroke (AIS) using oral anticoagulants. A specific human monoclonal antibody was introduced to reverse immediately the anticoagulation effect of the direct inhibitor of thrombin, dabigatran. Until now, mostly individual cases presenting with successful IVT after a reversal of dabigatran anticoagulation in patients with AIS were published. Thus, we aimed to report real-world data from clinical practice. Methods Patients with AIS on dabigatran treated with IVT after antidote reversal were enrolled in the retrospective nationwide study. Neurological deficit was scored using the National Institutes of Health Stroke Scale (NIHSS) and 90-day clinical outcome using modified Rankin scale (mRS) with a score 0-2 for a good outcome. Intracerebral hemorrhage (ICH) was defined as a presence of any sign of bleeding on control imaging after IVT, and symptomatic intracerebral hemorrhage (SICH) was assessed according to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria. Results In total, 13 patients (7 men, mean age 70.0 ± 9.1 years) with a median NIHSS admission score of 7 points were analyzed. Of these patients, 61.5% used 2 × 150 mg of dabigatran daily. Antidote was administrated 427 ± 235 minutes after the last intake of dabigatran, with a mean activated prothrombin time of 38.1 ± 27.8 seconds and a mean thrombin time of 72.2 ± 56.1 seconds. Of the 13 patients, 2 had ICH and 1 had SICH, and no other bleeding complications were observed after IVT. Of the total number of patients, 76.9% had a good 3-month clinical outcome and 3 patients (23.1%) died. Recurrent ischemic stroke occurred in 2 patients (15.4%). Conclusion The data presented in the study support the safety and efficacy of IVT after the reversal of the anticoagulation effect of dabigatran with antidote in a real-world clinical practice.