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Vaccines and monoclonal antibody treatments to prevent severe coronavirus disease 2019 (COVID-19) illness were available within a year of the pandemic being declared but there remained an urgent need for therapeutics to treat patients who were not vaccinated, were immunocompromised or whose vaccine immunity had waned. Initial results for investigational therapies were mixed. AT-527, a repurposed nucleoside inhibitor for hepatitis C virus, enabled viral load reduction in a hospitalized cohort but did not reduce viral load in outpatients. The nucleoside inhibitor molnupiravir prevented death but failed to prevent hospitalization. Nirmatrelvir, an inhibitor of the main protease (Mpro), co-dosed with the pharmacokinetic booster ritonavir, reduced hospitalization and death. Nirmatrelvir–ritonavir and molnupiravir received an Emergency Use Authorization in the United States at the end of 2021. Immunomodulatory drugs such as baricitinib, tocilizumab and corticosteroid, which target host-driven COVID-19 symptoms, are also in use. We highlight the development of COVID-19 therapies and the challenges that remain for anticoronavirals. Therapeutics for COVID-19 and their development during a pandemic are reviewed, including future prospects for anticoronavirals.

The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has substantially impacted healthcare utilization worldwide. The objective of this retrospective analysis of a large hospital discharge database was to compare all-cause and cause-specific hospitalizations during the first six months of the pandemic in the United States with the same months in the previous four years. Data were collected from all hospitals in the Premier Healthcare Database (PHD) and PHD Special Release reporting hospitalizations from January through July for each year from 2016 through 2020. Hospitalization trends were analyzed stratified by age group, major diagnostic categories (MDCs), and geographic region. The analysis included 286 hospitals from all 9 US Census divisions. The number of all-cause hospitalizations per month was relatively stable from 2016 through 2019 and then fell by 21% (57,281 fewer hospitalizations) between March and April 2020, particularly in hospitalizations for non-respiratory illnesses. From April onward there was a rise in the number of monthly hospitalizations per month. Hospitalizations per month, nationally and in each Census division, decreased for 20 of 25 MDCs between March and April 2020. There was also a decrease in hospitalizations per month for all age groups between March and April 2020 with the greatest decreases in hospitalizations observed for patients 50-64 and ≥65 years of age. Rates of hospitalization declined substantially during the first months of the COVID-19 pandemic, suggesting delayed routine, elective, and emergency care in the United States. These lapses in care for illnesses not related to COVID-19 may lead to increases in morbidity and mortality for other conditions. Thus, in the current stage of the pandemic, clinicians and public-health officials should work, not only to prevent SARS-CoV-2 transmission, but also to ensure that care for non-COVID-19 conditions is not delayed.

Nirmatrelvir–ritonavir is approved for adults with mild-to-moderate COVID-19 who are at risk of severe disease. There are little clinical data to guide the duration of therapy in patients who are immunocompromised. We aimed to compare the approved 5-day regimen of nirmatrelvir–ritonavir with 10-day and 15-day regimens. This placebo-controlled, randomised, double-blind, phase 2 trial enrolled non-hospitalised, immunocompromised individuals aged 12 years or older with symptomatic COVID-19 from 73 sites across nine countries. Participants were randomly assigned (1:1:1) to receive 300 mg nirmatrelvir and 100 mg ritonavir orally twice per day for 5, 10, or 15 days. Randomisation was stratified according to whether participants were considered immunocompromised due to use of corticosteroids or tumour necrosis factor blockers. Investigators, participants, and caregivers were masked to the assigned study group. The primary endpoint was proportion of randomly assigned and dosed participants with sustained nasopharyngeal SARS-CoV-2 RNA concentrations below the lower limit of quantification (2·0 log10 copies per mL) from days 15 to 44. Secondary endpoints included the incidence of viral rebound after the end of treatment up to day 44. Safety, a secondary endpoint, was assessed in all randomly assigned participants who received at least one dose of nirmatrelvir–ritonavir. This trial was registered with ClinicalTrials.gov (NCT05438602) and is completed. Among 156 participants (84 female, 72 male) randomly assigned from Aug 3, 2022 to July 17, 2023, 150 comprised the analysis population. The primary endpoint was reached in 32 (61·5%, 95% CI 48·3–74·8) of 52 participants in the 5-day treatment group, 34 (70·8%, 58·0–83·7) of 48 participants in the 10-day treatment group, and 33 (66·0%, 52·9–79·1) of 50 participants in the 15-day treatment group. Viral rebound occurred in 17·3% (95% CI 8·2–30·3) of participants in the 5-day group, 2·1% (0·1–11·1) in the 10-day group, and 2·0% (0·1–10·6) in the 15-day group. Adverse events occurred in 28 (52·8%) of 53, 34 (66·7%) of 51, and 31 (60·8%) of 51 participants across the 5-day, 10-day, and 15-day groups, respectively. Two COVID-19-related hospitalisations were reported, both in the 5-day treatment group. No difference was observed between the three treatment durations in the primary endpoint. Extending nirmatrelvir–ritonavir treatment beyond 5 days resulted in a nominal improvement in the frequency of viral rebound and was generally well tolerated. Pfizer.

Background Whilst it is recognised that a capacity to manage uncertainty is an essential aspect of working as a healthcare professional, there is little clear guidance on how to facilitate student learning in this domain. A lack of faculty development opportunities also suggests that health professions’ educators may feel ill-equipped to assist students in developing effective approaches to uncertainty. The purpose of this study was to explore a faculty development intervention designed to help educators unpack students’ experiences of uncertainty, and identify attributes which may help students to manage uncertain situations. Methods This qualitative study was informed by a constructivist methodological approach, where participants were encouraged to share meaning around the nature of uncertainty in health professions’ education. Two 90-min faculty development sessions were held. These sessions invited participants to apply Han et al .’s taxonomy of uncertainty to role-played scenarios of student uncertainty within a focus group setting. Focus group data were collected, and examined using a two-stage, hybrid approach of deductive and inductive thematic analysis. Results Han et al. ’s taxonomy helped participants to identify multiple sources and issues of uncertainty in the role played scenarios, thus unveiling the extent of uncertainties encountered by health professions’ learners. Data analysis revealed four themes overall: “Sources of uncertainty”, “Issues of uncertainty”, “Uncertainty attributes”, and “Learning environment.” Participants also contributed to a list of attributes which they considered helpful to undergraduate health professions’ students in managing uncertain situations. These included an awareness of the nature of uncertainty within healthcare practice, an ability to recognise uncertainty, and adopting attitudes of adaptability, positivity, and resilience. Conclusions This study highlights the successful use of Han et al. ’s taxonomy of uncertainty within a faculty development setting. Our findings suggest that the taxonomy is a practical and versatile tool that health professions’ educators can use in shared reflections and conversations around uncertainty with students or colleagues.

Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the likelihood of receiving a diagnosis when fetal structural anomalies are identified. However, some parents will receive uncertain results such as variants of uncertain significance and secondary findings. We aimed to develop a set of attributes and associated levels for a discrete-choice experiment (DCE) that will examine parents’ preferences for tests that may reveal uncertain test results. A two phase mixed-methods approach was used to develop attributes for the DCE. In Phase 1, a “long list” of candidate attributes were identified via two approaches: 1) a systematic review of the literature around parental experiences of uncertainty following prenatal testing; 2) 16 semi-structured interviews with parents who had experienced uncertainty during pregnancy and 25 health professionals who return uncertain prenatal results. In Phase 2, a quantitative scoring exercise with parents prioritised the candidate attributes. Clinically appropriate levels for each attribute were then developed. A final set of five attributes and levels were identified: likelihood of getting a result, reporting of variants of uncertain significance, reporting of secondary findings, time taken to receive results, and who tells you about your result. These attributes will be used in an international DCE study to investigate preferences and differences across countries. This research will inform best practice for professionals supporting parents to manage uncertainty in the prenatal setting.

Background and Objective Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia results in substantial morbidity and mortality. As current treatments often lead to unsatisfactory outcomes, evidence guiding alternative treatment options is needed. This study evaluated real-world clinical outcomes of ceftaroline fosamil for the treatment of MRSA bacteremia. Methods This retrospective study included adults hospitalized with MRSA bacteremia between 2011 and 2019. Patients were classified according to treatment with ceftaroline fosamil (ceftaroline), vancomycin, or daptomycin: Group 1, ceftaroline; Group 2, vancomycin or daptomycin (without ceftaroline); Group 3, combination therapy with ≥ 2 of these three agents. Clinical outcomes were compared using propensity-score-adjusted odds ratios (ORs) from logistic regression models. Results Overall, 24,479 patients were included (Group 1, n  = 532; Group 2, n  = 21,555; Group 3, n  = 2392). Mean age was 59.6, 60.8, and 57.4 years in Groups 1, 2, and 3, respectively. Mean post-index treatment length of stay was 8.8, 8.8, and 8.0 days, respectively. The most frequent line of therapy was ceftaroline first-line (42.1%), vancomycin or daptomycin first-line (95.4%), and combination therapy third-line or later (67.8%) in Groups 1, 2, and 3, respectively. Compared with Group 2, Groups 1 and 3 had similar favorable clinical responses {odds ratio [OR] = 1.18 [95% confidence interval (CI) 0.98–1.44], p  = 0.08; OR = 1.20 [95% CI 0.97–1.47], p  = 0.09, respectively} and were less likely to switch treatment (both p  < 0.001). Compared with Group 2, Group 1 was more likely to undergo 30-day all-cause readmission [OR = 1.38 (95% CI 1.06–1.80), p  = 0.02], whereas this was less likely for Group 3 [OR = 0.77 (95% CI 0.58–1.00), p  = 0.05]. Conclusions Patients receiving ceftaroline more often had favorable clinical responses than those receiving vancomycin or daptomycin monotherapy. In the absence of large-scale randomized controlled trials, these real-world data provide insights into the potential role of ceftaroline for treating MRSA bacteremia.

Vaccinia virus is the prototypic orthopoxvirus and was the vaccine used to eradicate smallpox, yet the expression profiles of many of its genes remain unknown. Using a genome tiling array approach, we simultaneously measured the expression levels of all 223 annotated vaccinia virus genes during infection and determined their kinetics. For 95% of these genes, significant transcript levels were detected. Most remarkably, classification of the genes by their expression profiles revealed 35 genes exhibiting immediate-early expression. Although a similar kinetic class has been described for other virus families, to our knowledge, this is the first demonstration of its existence in orthopoxviruses. Despite expression levels higher than for genes in the other three kinetic classes, the functions of more than half of these remain unknown. Additionally, genes within each kinetic class were spatially grouped together in the genome. This genome-wide picture of transcription alters our understanding of how orthopoxviruses regulate gene expression.

A feminist/queer/crip close textual reading of Disney's The Little Mermaid and its straight-to-DVD sequel, The Little Mermaid II: Return to the Sea, uncovers contrasting cultural narratives of disability. The first film, and mermaid Ariel's story line, represent conservative ideologies of compulsory able-bodiedness and the need for overcoming disability, as well as a strongly reinforced binary of merfolk versus humans. Conversely, the sequel, and (Ariel's and Prince Eric's daughter) Melody's narrative, imagine more progressive desirably disabled futurities and welcome hybrid embodiments through the process of shifting societal perspectives and deconstructing binaries that work to other those with nonnormative bodies.

Some individuals engage in both mild and severe forms of problem behavior. Research has shown that when mild behaviors precede severe behaviors (i.e., the mild behaviors serve as precursors), they can (a) be maintained by the same source of reinforcement as severe behavior and (b) reduce rates of severe behavior observed during assessment. In Study 1, we developed an objective checklist to identify precursors via videotaped trials for 16 subjects who engaged in problem behavior and identified at least 1 precursor for every subject. In Study 2, we conducted separate functional analyses of precursor and severe problem behaviors for 8 subjects, and obtained correspondence between outcomes in 7 cases. In Study 3, we evaluated noncontingent reinforcement schedule thinning plus differential reinforcement of alternative behavior to reduce precursors, increase appropriate behavior, and maintain low rates of severe behavior during 3 treatment analyses for 2 subjects. Results showed that this treatment strategy was effective for behaviors maintained by positive and negative reinforcement.

Most animals have predators, and therefore must balance the needs of foraging and mating with those of shelter and safety. Many species rely on chemosensory cues to identify predators and organize defenses specific to particular types of predators. A large body of research in this area has focused on lizards and snakes because they have heightened chemical senses and have been shown to identify predators using chemical cues alone. We designed an experiment to examine the antipredator behavior of a common desert-dwelling nocturnal lizard, the Banded Gecko (Coleonyx variegatus), towards snake predators that use different hunting techniques: active-hunting Glossy Snakes (Arizona elegans) and ambush-hunting rattlesnakes (Crotalus cerastes). We exposed Banded Geckos to chemical cues from these two predators and measured a series of behavioral responses including tail displays, time spent investigating chemical cues while actively moving, and time spent in refugia. Geckos exhibited clear antipredator behaviors toward both snakes but spent more time actively moving in response to glossy snake cues. Because rattlesnakes use ambush strategies to capture prey whereas glossy snakes are active searchers, remaining in place while assessing rattlesnake cues is probably less risky than when assessing glossy snake cues. Our findings indicate that Banded Geckos can not only discriminate among different predatory snake species based on chemical cues alone, but they also appear to adjust their antipredator responses in a predator-specific manner.