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A screen for compounds with antigiardial activity in the Compounds Australia Scaffolds library identified SN00797640 (supplied structure being 8-acylaminodibenzoxazepinone 1) as a hit compound with potent anti-parasitic activity (concentration for 50% growth inhibition of Giardia duodenalis, IC50 0.18 μM). To further explore the structure–activity relationships in this series, compound 1 and analogues, including its 7-acylaminodibenzoxazepinone regioisomer (2), were synthesized and assessed for anti-Giardia activity. While regioisomer 2 demonstrated antigiardial activity, resynthesized 1 and other 8-acylaminodibenzoxazepinone analogues were inactive. Comparison of spectroscopic and physical properties demonstrated the correct structure of SN00797640 to be 7-acylamino regioisomer 2. These results highlight the importance of independent synthesis in verifying the structure and activity of screening hits.

The National Severe Storm Laboratory’s Warn-on-Forecast System (WoFS) is a convection-allowing ensemble with rapidly cycled data assimilation (DA) of various satellite and radar datasets designed for prediction at 0–6-h lead time of hazardous weather. With the focus on short lead times, WoFS predictive accuracy is strongly dependent on its ability to accurately initialize and depict the evolution of ongoing storms. Since it takes multiple DA cycles to fully “spin up” ongoing storms, predictive skill is likely a function of storm age at the time of model initialization, meaning that older storms that have been through several DA cycles will be forecast with greater accuracy than newer storms that initiate just before model initialization or at any point after. To quantify this relationship, we apply an object-based spatial tracking and verification approach to map differences in the probability of detection (POD), in space–time, of predicted storm objects from WoFS with respect to Multi-Radar Multi-Sensor (MRMS) reflectivity objects. Object-tracking/matching statistics are computed for all suitable and available WoFS cases from 2017 to 2021. Our results indicate sharply increasing POD with increasing storm age for lead times within 3 h. PODs were about 0.3 for storm objects that emerge 2–3 h after model initialization, while for storm objects that were at least an hour old at the time of model initialization by DA, PODs ranged from around 0.7 to 0.9 depending on the lead time. These results should aid in forecaster interpretation of WoFS, as well as guide WoFS developers on improving the model and DA system. Significance Statement The Warn-on-Forecast System (WoFS) is a collection of weather models designed to predict individual thunderstorms. Before the models can predict storms, they must ingest radar and satellite observations to put existing storms into the models. Because storms develop at different times, more observations will exist for some storms in the model domain than others, which results in WoFS forecasts with different accuracy for different storms. This paper estimates the differences in accuracy for storms that have existed for a long time and those that have not by tracking observed and predicted storms. We find that the likelihood of WoFS accurately predicting a thunderstorm nearly doubles if the storm has existed for over an hour prior to the forecast. Understanding this relationship between storm age and forecast accuracy will help forecasters better use WoFS predictions and guide future research to improve WoFS forecasts.

Observational data collection is extremely hazardous in supercell storm environments, which makes for a scarcity of data used for evaluating the storm-scale guidance from convection allowing models (CAMs) like the National Oceanic and Atmospheric Administration (NOAA) Warn-on-Forecast System (WoFS). The Targeted Observations with UAS and Radar of Supercells (TORUS) 2019 field mission provided a rare opportunity to not only collect these observations, but to do so with advanced technology: vertically pointing Doppler lidar. One standing question for WoFS is how the system forecasts the feedback between supercells and their near-storm environment. The lidar can observe vertical profiles of wind over time, creating unique datasets to compare to WoFS kinematic predictions in rapidly evolving severe weather environments. Mobile radiosonde data are also presented to provide a thermodynamic comparison. The five lidar deployments (three of which observed tornadic supercells) analyzed show WoFS accurately predicted general kinematic trends in the inflow environment; however, the predicted feedback between the supercell and its environment, which resulted in enhanced inflow and larger storm-relative helicity (SRH), were muted relative to observations. The radiosonde observations reveal an overprediction of CAPE in WoFS forecasts, both in the near and far field, with an inverse relationship between the CAPE errors and distance from the storm. Significance Statement It is difficult to evaluate the accuracy of weather prediction model forecasts of severe thunderstorms because observations are rarely available near the storms. However, the TORUS 2019 field experiment collected multiple specialized observations in the near-storm environment of supercells, which are compared to the same near-storm environments predicted by the National Oceanic and Atmospheric Administration (NOAA) Warn-on-Forecast System (WoFS) to gauge its performance. Unique to this study is the use of mobile Doppler lidar observations in the evaluation; lidar can retrieve the horizontal winds in the few kilometers above ground on time scales of a few minutes. Using lidar and radiosonde observations in the near-storm environment of three tornadic supercells, we find that WoFS generally predicts the expected trends in the evolution of the near-storm wind profile, but the response is muted compared to observations. We also find an inverse relationship of errors in instability to distance from the storm. These results can aid model developers in refining model physics to better predict severe storms.

Many tornadoes are unreported because of lack of observers or are underrated in intensity, width, or track length because of lack of damage indicators. These reporting biases substantially degrade estimates of tornado frequency and thereby undermine important endeavors such as studies of climate impacts on tornadoes and cost–benefit analyses of tornado damage mitigation. Building on previous studies, we use a Bayesian hierarchical modeling framework to estimate and correct for tornado reporting biases over the central United States during 1975–2018. The reporting biases are treated as a univariate function of population density. We assess how these biases vary with tornado intensity, width, and track length and over the analysis period. We find that the frequencies of tornadoes of all kinds, but especially stronger or wider tornadoes, have been substantially underestimated. Most strikingly, the Bayesian model estimates that there have been approximately 3 times as many tornadoes capable of (E)F2+ damage as have been recorded as (E)F2+ [(E)F indicates a rating on the (enhanced) Fujita scale]. The model estimates that total tornado frequency changed little over the analysis period. Statistically significant trends in frequency are found for tornadoes within certain ranges of intensity, pathlength, and width, but it is unclear what proportion of these trends arise from changes in damage survey practices. Simple analyses of the tornado database corroborate many of the inferences from the Bayesian model. Significance Statement Prior studies have shown that the probabilities of a tornado being reported and of its intensity, track length, and width being accurately estimated are strongly correlated with the local population density. We have developed a sophisticated statistical model that accounts for these population-dependent tornado reporting biases to improve estimates of tornado frequency in the central United States. The bias-corrected tornado frequency estimates differ markedly from the official tornado climatology and have important implications for tornado risk assessment, damage mitigation, and studies of climate change impacts on tornado activity.

Thunderstorm mode strongly impacts the likelihood and predictability of tornadoes and other hazards, and thus is of great interest to severe weather forecasters and researchers. It is often impossible for a forecaster to manually classify all the storms within convection-allowing model (CAM) output during a severe weather outbreak, or for a scientist to manually classify all storms in a large CAM or radar dataset in a timely manner. Automated storm classification techniques facilitate these tasks and provide objective inputs to operational tools, including machine learning models for predicting thunderstorm hazards. Accurate storm classification, however, requires accurate storm segmentation. Many storm segmentation techniques fail to distinguish between clustered storms, thereby missing intense cells, or to identify cells embedded within quasi-linear convective systems that can produce tornadoes and damaging winds. Therefore, we have developed an iterative technique that identifies these constituent storms in addition to traditionally identified storms. Identified storms are classified according to a seven-mode scheme designed for severe weather operations and research. The classification model is a hand-developed decision tree that operates on storm properties computed from composite reflectivity and midlevel rotation fields. These properties include geometrical attributes, whether the storm contains smaller storms or resides within a larger-scale complex, and whether strong rotation exists near the storm centroid. We evaluate the classification algorithm using expert labels of 400 storms simulated by the NSSL Warn-on-Forecast System or analyzed by the NSSL Multi-Radar/Multi-Sensor product suite. The classification algorithm emulates expert opinion reasonably well (e.g., 76% accuracy for supercells), and therefore could facilitate a wide range of operational and research applications. Significance Statement We have developed a new technique for automatically identifying intense thunderstorms in model and radar data and classifying storm mode, which informs forecasters about the risks of tornadoes and other high-impact weather. The technique identifies storms that are often missed by other methods, including cells embedded within storm clusters, and successfully classifies important storm modes that are generally not included in other schemes, such as rotating cells embedded within quasi-linear convective systems. We hope the technique will facilitate a variety of forecasting and research efforts.

Acute thrombotic thrombocytopenic purpura (TTP) is a life-threatening emergency and plasma exchange (PEX) is the initial treatment shown to reduce acute mortality.To compare current practice in the United Kingdom (UK) against the standards set out in the 2012 British Society of Haematology guideline, and to better understand the issues affecting prompt initiation of PEX.The trainee research network HaemSTAR conducted a retrospective nationwide review of adults presenting to UK hospitals with a first episode of acute TTP.Data on 148 patients treated at 80 UK hospitals between 2014 and 2019 demonstrated that 64.8% of patients received PEX within 24 h. Diagnostic uncertainty was the most commonly cited reason for delayed treatment. Conversely, a shorter time to PEX occurred in patients who had red cell fragments or severe thrombocytopenia identified on their first complete blood count. Availability of on-site PEX was associated with a greater proportion of patients receiving PEX within 8 h compared to patients transferred, but by 24 h there was no difference between the two groups and two-thirds of all patients had received their first PEX. The mortality rate for patients that received PEX was 9.2%, with 27.8% of deaths linked to delayed treatment initiation.This is the first multi-center evaluation of treatment delays in acute TTP and it will inform targeted pathways to improve prompt access to life-saving intervention.

A multiscale analysis of the significant nocturnal tornado outbreak in Tennessee on 2–3 March 2020 is presented. This outbreak included several significant tornadoes and resulted in the second most fatalities (25) and most injuries (309) of all nocturnal tornado events in Tennessee in 1950–2020. The two deadliest tornadoes struck Nashville (EF3 intensity) and Cookeville (EF4) resulting in 5 and 19 fatalities, respectively. The supercell responsible for the tornado outbreak initiated at 0330 UTC 3 March within a region of warm frontogenesis in western Tennessee. Throughout its life cycle, the supercell was located in a region of convective available potential energy near 1000 J kg−1 and 0–1-km storm-relative helicity over 350 m2 s−2. Retrospective 3-h forecasts from the experimental Warn-on-Forecast System (WoFS) convection-allowing ensemble initialized after the parent supercell initiated indicated a high probability, high severity scenario for tornadoes across Tennessee and into Nashville through 0700 UTC. Earlier WoFS forecasts indicated a low probability, high severity scenario owing to uncertainty in the initiation of supercells. The presence of these supercells was sensitive to the upstream thermodynamic conditions and warm frontogenesis regions that were inherited from the lateral boundary conditions. In all, this study highlights the potential of the WoFS ensemble to contribute useful probabilistic severe weather information to the short-term forecast process during a nocturnal significant tornado outbreak.

Single-phase Hf2Al4C5 ternary carbide was fabricated from Hf/Al/C powder mixtures by pressure assisted sintering techniques such as hot pressing and spark plasma sintering at 1900 °C for 3 h and 10 min, respectively. XRD confirmed that the ternary carbide started to form at temperatures as low as 1500 °C and with total formation of Hf2Al4C5 after reactive sintering for 1 h at 1900 °C. It is evident from HRTEM that two Hf-C layers were sandwiched with 4 Al-C layers (Al4C3) in the Hf2Al4C5 ternary carbide. Tight interlocking of grains, faceted grains and stacking faults were occasionally observed. Thermal conductivity of Hf2Al4C5 is measured to be 14 w m−1k−1 from room temperature to 1300 °C. The oxidation studies carried out at 1300 °C for 3 h reveal that the oxidation layer thickness is around 220 μm and it contains microcracks closer to sample surface whereas the interface looks seamless without any cracking or spallation of the oxide layer.

This study sought to assess the comparative effectiveness of cardiac resynchronization therapy with defibrillator (CRT-D) over implantable cardioverter-defibrillator (ICD) alone in older Medicare patients with heart failure with reduced ejection fraction (HFrEF).Despite growing numbers of older patients with HFrEF, the benefits of cardiac resynchronization therapy (CRT) in this group are largely unknown.A cohort of fee-for-service Medicare beneficiaries ≥65 years of age with HFrEF and enrolled in Medicare Part D who underwent CRT-D or ICD implantation from January 2008 to August 2015 was identified. Beneficiaries were divided by age (65-74, 75-84, and 85+ years), and outcomes were compared between the CRT-D and ICD groups after inverse probability weighting.Compared with the ICD group, the CRT-D group was older and more likely to be White, be female, and have left bundle branch block. After weighting, overall complications were high across age and device groups (14%-20%). The 1-year mortality was high across all groups. In the 2 oldest age strata, the hazard of death was lower in the CRT-D group (HR: 0.90; 95% CI: 0.86-0.95 and HR: 0.81; 95% CI: 0.72-0.90, respectively; P 0.001); the hazard of heart failure hospitalization was lower for CRT-D vs ICD in the 85+ years age group (HR: 0.82; 95% CI: 0.74-0.92; P 0.001).In older Medicare beneficiaries undergoing ICD with or without CRT, complications and 1-year mortality were high. Compared with ICD alone, CRT-D was associated with a lower hazard of mortality in patients ≥74 years of age and lower hazard of HF hospitalization in those ≥85 years of age. These findings support the use of CRT in eligible older patients undergoing ICD implantation.

The National Severe Storms Laboratory (NSSL) Warn-on-Forecast System (WoFS) is an experimental real-time rapidly updating convection-allowing ensemble that provides probabilistic short-term thunderstorm forecasts. This study evaluates the impacts of reducing the forecast model horizontal grid spacing Δx from 3 to 1.5 km on the WoFS deterministic and probabilistic forecast skill, using 11 case days selected from the 2020 NOAA Hazardous Weather Testbed (HWT) Spring Forecasting Experiment (SFE). Verification methods include (i) subjective forecaster impressions; (ii) a deterministic object-based technique that identifies forecast reflectivity and rotation track storm objects as contiguous local maxima in the composite reflectivity and updraft helicity fields, respectively, and matches them to observed storm objects; and (iii) a recently developed algorithm that matches observed mesocyclones to mesocyclone probability swath objects constructed from the full ensemble of rotation track objects. Reducing Δx fails to systematically improve deterministic skill in forecasting reflectivity object occurrence, as measured by critical success index (CSIDET), a metric that incorporates both probability of detection (PODDET) and false alarm ratio (FARDET). However, compared to the Δx = 3 km configuration, the Δx = 1.5 km WoFS shows improved midlevel mesocyclone detection, as evidenced by its statistically significant (i) higher CSIDET for deterministic midlevel rotation track objects and (ii) higher normalized area under the performance diagram curve (NAUPDC) score for probability swath objects. Comparison between Δx = 3 km and Δx = 1.5 km reflectivity object properties reveals that the latter have 30% stronger mean updraft speeds, 17% stronger median 80-m winds, 67% larger median hail diameter, and 28% higher median near-storm-maximum 0–3-km storm-relative helicity.

To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-actionin vitroactivity againstPlasmodium falciparum. This work identifiedN,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplas-modial chemotype (e.g.,196 h IC50550 nM) with a different action to delayed-death slow-action drugs. Structure activity relationship analysis of analogues identified multiple compounds with potent and selectivein vitroactivity against drug-sensitive and multi-drug resistantPlasmodiumparasites (e.g.,31and3296 h IC502,500). However subsequent studies in mice with lead compound1, which had the best microsomal stability of the compounds assessed, demonstrated rapid clearance (T1/2<1.6 h) and poor oralin vivoefficacy. This indicates that improvements in the pharmacokinetic profile ofN,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines would be needed for the development of this chemotype for malaria chemoprophylaxis.

Malaria is caused by infection with Plasmodium parasites and results in significant health and economic impacts. Malaria eradication is hampered by parasite resistance to current drugs and the lack of a widely effective vaccine. Compounds that target epigenetic regulatory proteins, such as histone deacetylases (HDACs), may lead to new therapeutic agents with a different mechanism of action, thereby avoiding resistance mechanisms to current antimalarial drugs. The anticancer HDAC inhibitor AR-42, as its racemate (rac-AR-42), and 36 analogues were investigated for in vitro activity against P. falciparum. Rac-AR-42 and selected compounds were assessed for cytotoxicity against human cells, histone hyperacetylation, human HDAC1 inhibition and oral activity in a murine malaria model. Rac-AR-42 was tested for ex vivo asexual and in vitro exoerythrocytic stage activity against P. berghei murine malaria parasites. Rac-AR-42 and 13 achiral analogues were potent inhibitors of asexual intraerythrocytic stage P. falciparum 3D7 growth in vitro (IC50 5–50 nM), with four of these compounds having >50-fold selectivity for P. falciparum versus human cells (selectivity index 56–118). Rac-AR-42 induced in situ hyperacetylation of P. falciparum histone H4, consistent with PfHDAC(s) inhibition. Furthermore, rac-AR-42 potently inhibited P. berghei infected erythrocyte growth ex vivo (IC50 40 nM) and P. berghei exoerythrocytic forms in hepatocytes (IC50 1 nM). Oral administration of rac-AR-42 and two achiral analogues inhibited P. berghei growth in mice, with rac-AR-42 (50 mg/kg/day single dose for four days) curing all infections. These findings demonstrate curative properties for HDAC inhibitors in the oral treatment of experimental mouse malaria., Graphical abstract Image 1, Highlights • HDAC inhibitors rac-AR-42 and 13 analogues inhibit P. falciparum growth in vitro. • Rac-AR-42 inhibits P. berghei exoerythrocytic forms in hepatocytes (IC50 1 nM). • Rac-AR-42 causes in situ hyperacetylation of P. falciparum histone H4. • Rac-AR-42 cures P. berghei infected mice with oral dosing.

In 2018, the US Preventive Services Task Force endorsed primary human papillomavirus testing (pHPV) for cervical cancer screening. We aimed to describe providers’ beliefs about pHPV testing effectiveness and which screening approach they regularly recommend. We invited providers who performed 10 or more cervical cancer screens in 2019 in 3 healthcare systems that had not adopted pHPV testing: Kaiser Permanente Washington, Mass General Brigham, and Parkland Health; 53.7% (501/933) completed the survey between October and December 2020. Response distributions varied across modalities (P

Tornadoes have Lorenzian predictability horizons O(10) min, and convection-allowing ensemble prediction systems (EPSs) often provide probabilistic guidance of such events to forecasters. Given the O(0.1)-km length scale of tornadoes and O(1)-km scale of mesocyclones, operational models running at horizontal grid spacings (Δx) of 3 km may not capture narrower mesocyclones (typical of the southeastern United States) and certainly do not resolve most tornadoes per se. In any case, it requires O(50) times more computer power to reduce Δx by a factor of 3. Herein, to determine value in such an investment, we compare two EPSs, differing only in Δx (3 vs 1 km), for four low-CAPE, high-shear cases. Verification was grouped as 1) deterministic, traditional methods using pointwise evaluation, 2) a scale-aware probabilistic metric, and 3) a novel method via object identification and information theory. Results suggest 1-km forecasts better detect storms and any associated rapid low- and midlevel rotation, but at the cost of weak–moderate reflectivity forecast skill. The nature of improvement was sensitive to the case, variable, forecast lead time, and magnitude, precluding a straightforward aggregation of results. However, the distribution of object-specific information gain over all cases consistently shows greater average benefit from the 1-km EPS. We also reiterate the importance of verification methodology appropriate for the hazard of interest.

HIV/HCV prevention among people who inject drugs (PWID) is of key public health importance. We aimed to assess the impact of COVID-19 and associated response measures on HIV/HCV prevention services and socio-economic status of PWID in high-HIV-risk sites. Sites with recent (2011-2019) HIV outbreaks among PWID in Europe North America and Israel, that had been previously identified, were contacted early May 2020. Out of 17 sites invited to participate, 13 accepted. Semi-structured qualitative site reports were prepared covering data from March to May 2020, analyzed/coded and confirmed with a structured questionnaire, in which all sites explicitly responded to all 103 issues reported in the qualitative reports. Opioid maintenance treatment, needle/syringe programs and antiretroviral treatment /hepatitis C treatment continued, but with important reductions and operational changes. Increases in overdoses, widespread difficulties with food and hygiene needs, disruptions in drug supply, and increased homelessness were reported. Service programs rapidly reformed long established, and politically entrenched, restrictive service delivery policies. Future epidemic control measures should include mitigation of negative side-effects on service provision and socio-economic determinants in PWID.La prevención del VIH/VHC entre las personas que se inyectan drogas (PWID) es de vital importancia para la salud pública. Nuestro objetivo fue evaluar el impacto de COVID-19 y las medidas de respuesta asociadas en los servicios de prevención del VIH/VHC y el estado socioeconómico de las PWID en sitios de alto riesgo de VIH. Se contactó con sitios con brotes recientes (2011–2019) de VIH entre PWID en Europa, América del Norte e Israel, que habían sido previamente identificados, a principios de mayo de 2020. De los 17 sitios invitados a participar, 13 aceptaron. Se prepararon informes cualitativos semiestructurados del sitio que cubrían los datos de marzo a mayo de 2020, analizados/codificados y confirmados con un cuestionario estructurado, en el que todos los sitios respondieron explícitamente a los 103 asuntos reportados en los informes cualitativos. El tratamiento de mantenimiento con opiáceos, los programas de agujas/jeringas y el tratamiento antirretroviral/tratamiento de la hepatitis C continuaron, pero con importantes reducciones y cambios operativos. Se reportaron aumentos en las sobredosis, dificultades generalizadas con las necesidades alimentarias y de higiene, interrupciones en el suministro de medicamentos y aumento de personas sin hogar. Los programas de servicios reformaron rápidamente las políticas restrictivas de prestación de servicios, establecidas desde hace mucho tiempo y políticamente arraigadas. Las futuras medidas de control de epidemias deben incluir la mitigación de los efectos secundarios negativos en la prestación de servicios y los determinantes socioeconómicos en las PWID.

This study aimed to assess if, during incremental exercise, considering individual characteristics can make the relationship between the percentages of heart rate (HRR) and oxygen uptake (

ObjectivesWe investigated whether high responsiveness or low responsiveness to exercise training aggregates in the same individuals across seven cardiometabolic traits.MethodsA total of 564 adults (29.2% black, 53.7% female) from the HERITAGE family study completed a 20-week endurance training programme (at 55%–75% of participants’ maximal oxygen uptake (VO2max)) with VO2max, per cent body fat, visceral adipose tissue, fasting levels of insulin, high-density lipoprotein cholesterol, small low-density lipoprotein particles and inflammatory marker GlycA measured before and after training. For each exercise response trait, we created ethnicity-specific, sex-specific and generation-specific quintiles. High responses were defined as those within the 20th percentile representing the favourable end of the response trait distribution, low responses were defined as the 20th percentile from the least favourable end, and the remaining were labelled as average responses.ResultsOnly one individual had universally high or low responses for all seven cardiometabolic traits. Almost half (49%) of the cohort had at least one high response and one low response across the seven traits. About 24% had at least one high response but no low responses, 24% had one or more low responses but no high responses, and 2.5% had average responses across all traits.ConclusionsInterindividual variation in exercise responses was evident in all the traits we investigated, and responsiveness did not aggregate consistently in the same individuals. While adherence to an exercise prescription is known to produce health benefits, targeted risk factors may not improve.