Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19.

BACKGROUND: Nirmatrelvir in combination with ritonavir is an antiviral treatment for mild-to-moderate coronavirus disease 2019 (Covid-19). The efficacy of this treatment in patients who are at standard risk for severe Covid-19 or who are fully vaccinated and have at least one risk factor for severe Covid-19 has not been established. METHODS: In this phase 2-3 trial, we randomly assigned adults who had confirmed Covid-19 with symptom onset within the past 5 days in a 1:1 ratio to receive nirmatrelvir-ritonavir or placebo every 12 hours for 5 days. Patients who were fully vaccinated against Covid-19 and who had at least one risk factor for severe disease, as well as patients without such risk factors who had never been vaccinated against Covid-19 or had not been vaccinated within the previous year, were eligible for participation. Participants logged the presence and severity of prespecified Covid-19 signs and symptoms daily from day 1 through day 28. The primary end point was the time to sustained alleviation of all targeted Covid-19 signs and symptoms. Covid-19-related hospitalization and death from any cause were also assessed through day 28. RESULTS: Among the 1296 participants who underwent randomization and were included in the full analysis population, 1288 received at least one dose of nirmatrelvir-ritonavir (654 participants) or placebo (634 participants) and had at least one postbaseline visit. The median time to sustained alleviation of all targeted signs and symptoms of Covid-19 was 12 days in the nirmatrelvir-ritonavir group and 13 days in the placebo group (P = 0.60). Five participants (0.8%) in the nirmatrelvir-ritonavir group and 10 (1.6%) in the placebo group were hospitalized for Covid-19 or died from any cause (difference, -0.8 percentage points; 95% confidence interval, -2.0 to 0.4). The percentages of participants with adverse events were similar in the two groups (25.8% with nirmatrelvir-ritonavir and 24.1% with placebo). In the nirmatrelvir-ritonavir group, the most commonly reported treatment-related adverse events were dysgeusia (in 5.8% of the participants) and diarrhea (in 2.1%). CONCLUSIONS: The time to sustained alleviation of all signs and symptoms of Covid-19 did not differ significantly between participants who received nirmatrelvir-ritonavir and those who received placebo. (Supported by Pfizer; EPIC-SR ClinicalTrials.gov number, NCT05011513.).

Ceftaroline Fosamil for the Treatment of Methicillin-Resistant Staphylococcus Aureus Bacteremia: A Real-World Comparative Clinical Outcomes Study.

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.

Knowledge, attitudes and decision regret: a longitudinal survey study of participants offered genome sequencing in the 100,000 Genomes Project.

We used cross-sectional surveys to compare the knowledge, attitudes, and decision regret of participants who had consented for genome sequencing (GS) for rare disease diagnosis in the 100,000 Genomes Project (100kGP) across two timepoints (at the time of consenting for GS (T1) and 12-18 months later (T2)). At T1, participants (n = 504) completed a survey that included measures of general knowledge of GS ("Knowledge of Genome Sequencing" (KOGS)), specific knowledge of GS and attitudes towards GS ("General attitudes" and "Specific attitudes"). At T2, participants (n = 296) completed these same assessments (apart from the specific knowledge scale) together with an assessment of decision regret towards GS ("Decisional Regret Scale"). At 12-18 months after consenting for GS, participants' basic knowledge of GS had remained stable. General knowledge of GS varied across topics; concepts underlying more general information about genetics were better understood than the technical details of genomic testing. Attitudes towards GS at T2 were generally positive, and feelings towards GS (both positive and negative) remained unchanged. However, those who were more positive about the test at the outset had greater specific knowledge (as opposed to general knowledge) of GS. Finally, although the majority of participants indicated feeling little regret towards undergoing GS, those with low positive attitude and high negative attitude about GS at T1 reported greater decision regret at T2. Careful assessment of patient knowledge about and attitudes towards GS at the time of offering testing is crucial for supporting informed decision making and mitigating later regret.

Therapeutics for COVID-19.

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.

Women's experiences of premature ovarian insufficiency: a thematic synthesis.

OBJECTIVE: Receiving a diagnosis of premature ovarian insufficiency (POI) can be an emotional and distressing experience for women. The aim of this meta-synthesis was to examine women's experiences of POI both before and after diagnosis to provide new understandings of those experiences. DESIGN: A systematic review of ten studies examining women's experiences of POI. RESULTS: Using thematic synthesis, three analytical themes were identified, demonstrating the complexity of experiences of women diagnosed with POI: 'What is happening to me?', 'Who am I?' and 'Who can help me?'. Women experience profound changes and losses associated with their identity that they must adjust to. Women also experience an incongruence between their identity as a young woman and that of a menopausal woman. Difficulty was also experienced accessing support pre-and post-diagnosis of POI, which could hinder coping with and adjustment to the diagnosis. CONCLUSION: Women require adequate access to support following diagnosis of POI. Further training should be provided to health care professionals not only on POI but including the importance of psychological support for women with POI and the resources available to provide the much needed emotional and social support.

Successful Treatment of Prolonged, Severe Coronavirus Disease 2019 Lower Respiratory Tract Disease in a B cell Acute Lymphoblastic Leukemia Patient With an Extended Course of Remdesivir and Nirmatrelvir/Ritonavir.

A patient with B-cell acute lymphoblastic leukemia (ALL) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had persistent, progressive pneumonia with viremia after 5 months of infection despite monoclonal antibodies, intravenous (IV) remdesivir and prolonged oral steroids. Twenty days of nirmatrelvir/ritonavir and 10 days of IV remdesivir led to full recovery.

Third Trimester Fetuses Demonstrate Priming, a Form of Implicit Memory, In Utero.

Research examinations of changes in fetal heart rate (HR) to operationalize fetal memory suggests that human memory capacities emerge in utero. However, there is little evidence for a form of implicit memory or priming. The present aim was to determine if priming is evident in utero. Fetal HR, maternal HR and maternal respiratory rate (RR) were examined in 105 women during the third trimester of pregnancy. Women experienced two counterbalanced laboratory tasks, the Stroop task and the paced breathing task, and their cardiorespiratory activity functioned as a stimulus for fetuses. Repeated measures ANOVAs revealed maternal HR increased during the Stroop task but only when the Stroop task was presented first (89.64 bpm to 92.39 bpm) (p = 0.04). Maternal RR increased during the Stroop task, regardless of task order (17.72 bpm to 21.11 bpm; 18.50 bpm to 22.60 bpm) (p < 0.01). Fetal HR increased during the paced breathing task, but only when it followed maternal exposure to the Stroop task (141.13 bpm to 143.97 bpm) (p < 0.01). Fetuses registered maternal HR and RR reactivity to the Stroop task, which influenced their response during maternal engagement with a related task, suggesting priming. Further study of fetal memory may suggest another pathway by which prenatal exposures impact future development.

Factors that impact on women's decision-making around prenatal genomic tests: An international discrete choice survey.

OBJECTIVE: We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. METHODS: Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. RESULTS: Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. CONCLUSION: Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable.

Ceftaroline Fosamil for the Empiric Treatment of Hospitalized Adults with cSSTI: An Economic Analysis from the Perspective of the Spanish National Health System.

Purpose: Complicated skin and soft tissue infections (cSSTI) are associated with high healthcare resource use and costs. The emergency nature of cSSTI hospitalizations requires starting immediate empiric intravenous (IV) antibiotic treatment, making the appropriate choice of initial antibiotic therapy crucial. Patients and Methods: The use of ceftaroline fosamil (CFT) as an alternative to other IV antibiotic therapies for the empiric treatment of hospitalized adults with cSSTI (vancomycin, linezolid, daptomycin, cloxacillin, tedizolid) was evaluated through cost consequences analysis. The model structure was a decision tree accounting for four different pathways: patients demonstrating early response (ER) either discharged early (with oral antibiotic) or remaining in hospital to continue the initial therapy; non-responders either remaining on the initial IV therapy or switching to a second-line antibiotic. The model perspective was the Spanish National Health System. Results: CFT resulted in average percentage of patients discharged early (PDE) of 24.6% (CI 19.49-30.2%) with average total cost per patient of €6763 (€6268-€7219). Vancomycin, linezolid, daptomycin and tedizolid resulted in average PDE of 22% (17.34-27.09%), 26.4% (20.5-32.32%), 28.6% (22.08-35.79%) and 26.5% (20.39-33.25%), respectively, for a total cost per patient of €6,619 (€5,902-€6,929), €6,394 (€5,881-€6,904), €6,855 (€5,800-€7,410) and €7,173 (€6,608-€7,763), respectively. Key model drivers were ER and antibiotic treatment duration, with hospital costs accounting for over 83% of the total expenditures. Conclusion: Given its clinical and safety profile, CFT is an acceptable choice for cSSTI empiric therapy providing comparable ER and costs to other relevant antibiotic options.

"It's okay to not know " a qualitative exploration of faculty approaches to working with uncertainty.

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.

Participant experiences of genome sequencing for rare diseases in the 100,000 Genomes Project: a mixed methods study.

In this mixed methods study, a survey and in-depth interviews were used to explore whether decision regret and the psychological impact of receiving genome sequencing (GS) results differed between parents and patients, and between those who received a genetic diagnosis and those who did not. Participants (n = 77) completed a survey that included the Decisional Regret Scale (DRS) and an adaptation of the Multidimensional Impact of Cancer Risk Assessment (MICRA) at least 12 months after consenting for GS for rare disease diagnosis in the 100,000 Genomes Project. Survey participants were invited to take part in an interview and 39 agreed; 12 with a diagnosis, 5 with variants of uncertain significance, and 19 with no pathogenic findings identified. Both survey and interview findings indicated that decision regret was low. DRS scores revealed no differences in levels of regret between parents and patients, or between those with a diagnosis and those without. Though MICRA scores indicated minimal evidence of negative psychological impacts of receiving GS results, subscale analysis revealed greater distress and uncertainty for parents compared to patients. Receiving a diagnosis was found not to influence MICRA scores, supporting interview findings of both positive and negative emotional and psychological impacts irrespective of a genetic diagnosis. Our findings have implications for policy and practice as GS is integrated into the UK and worldwide; notably, that expectation-setting is critical when offering GS, and that post-test counselling is important regardless of the GS result received, with parents perhaps needing additional emotional support.

Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.

BACKGROUND: Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro. METHODS: We conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. RESULTS: A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of -5.81 percentage points (95% CI, -7.78 to -3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. CONCLUSIONS: Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).

Pandemic-related declines in hospitalization for non-COVID-19-related illness in the United States from January through July 2020.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clinical and Pregnancy Outcomes of Coronavirus Disease 2019 Among Hospitalized Pregnant Women in the United States.

BACKGROUND: Pregnant women with coronavirus disease 2019 (COVID-19) may be at greater risk of poor maternal and pregnancy outcomes. This retrospective analysis reports clinical and pregnancy outcomes among hospitalized pregnant women with COVID-19 in the United States. METHODS: The Premier Healthcare Database-Special Release was used to examine the impact of COVID-19 among pregnant women aged 15-44 years who were hospitalized and who delivered compared with pregnant women without COVID-19. Outcomes evaluated were COVID-19 clinical progression, including the use of supplemental oxygen therapy, intensive care unit admission, critical illness, receipt of invasive mechanical ventilation/extracorporeal membrane oxygenation, maternal death, and pregnancy outcomes, including preterm delivery and stillbirth. RESULTS: Overall, 473 902 hospitalized pregnant women were included, 8584 (1.8%) of whom had a COVID-19 diagnosis (mean age = 28.4 [standard deviation = 6.1] years; 40% Hispanic). The risk of poor clinical and pregnancy outcomes was greater among pregnant women with COVID-19 compared with pregnant women without a COVID-19 diagnosis in 2020; the risk of poor clinical and pregnancy outcomes increased with increasing age. Hispanic and Black non-Hispanic women were consistently observed to have the highest relative risk of experiencing poor clinical or pregnancy outcomes across all age groups. CONCLUSIONS: Overall, COVID-19 had a significant negative impact on maternal health and pregnancy outcomes. These data help inform clinical practice and counseling to pregnant women regarding the risks of COVID-19. Clinical studies evaluating the safety and efficacy of vaccines against severe acute respiratory syndrome coronavirus 2 in pregnant women are urgently needed.

Assessing women's preferences towards tests that may reveal uncertain results from prenatal genomic testing: Development of attributes for a discrete choice experiment, using a mixed-methods design.

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.

Living with osteogenesis imperfecta: A qualitative study exploring experiences and psychosocial impact from the perspective of patients, parents and professionals.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic condition characterised by increased bone fragility. Recurrent fractures, pain and fatigue have a considerable impact on many aspects of the life of a person affected with OI and their families. OBJECTIVE: To improve our understanding of the impact of OI on the daily lives of individuals and families and consider how the condition is managed so that support needs can be better addressed. METHODS: Semi-structured qualitative interviews (n = 56) were conducted with adults affected with OI, with (n = 9) and without children (n = 8), parents of children affected with OI (n = 8), health professionals (n = 29) and patient advocates (n = 2). Interviews were digitally recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: Three overarching themes are described: OI is not just a physical condition, parenting and family functioning and managing the condition. Fractures, chronic pain and tiredness impact on daily life and emotional well-being. For parents with OI, pain, tiredness and mobility issues can limit interactions and activities with their children. Specialist paediatric health services for OI were highly valued. The need for more emotional support and improved coordination of adult health services was highlighted. CONCLUSIONS: Our findings allow a better understanding of the day-to-day experiences of individuals and families affected with OI. Supporting emotional well-being needs greater attention from policy makers and researchers. Improvements to the coordination of health services for adults with OI are needed and an in-depth exploration of young people's support needs is warranted with research focused on support through the teenage years.

The interaction between diet and neurobehavior in very low birth weight infants.

BACKGROUND: Modulation of behavior and physiology by dietary perturbations early in life can provide clues to the pathogenesis of adult diseases. We tested the hypothesis that a period of early protein supplementation modulates sympathetic nervous system activity demonstrated indirectly by an increase in active sleep state distribution in very low birth weight (VLBW) infants. METHODS: VLBW infants (n = 71) were randomized to a total parenteral nutritional regimen providing 18% of the energy intake as amino acids (AA) or a conventional regimen providing 12.5% to achieve targeted AA intakes of 4 g/kg/day (0.004 kcal/kg/day) and 3 g/kg/day (0.003 kcal/kg/day), respectively. Both groups were weaned to enteral feeding and advanced to provide similar AA intake of 4 g/kg/day (0.004 kcal/kg/day). Six-hour daytime, behavioral sleep studies were performed when the infants reached full enteral intake (165 ml/kg/day). RESULTS: Infants in the high protein group spent more time in active sleep (77.2 ± 10.5% vs. 70.7 ± 11.8%), p < 0.01 and less time in quiet sleep (12.9 ± 3.4% vs. 17.7 ± 7.0%, p < 0.01) as compared to the conventional group. No group differences were observed for indeterminate sleep, awake, or crying states. CONCLUSIONS: These results suggest that dietary intake may indirectly influence sympathetic nervous system activity. IMPACT: Infants randomized to an early, high protein nutritional regimen spent an increased percentage of time in active sleep, supporting the hypothesis that nutrition and behavior are interactive. Furthermore, sleep states are an indirect measure of sympathetic nervous system activity, suggesting that dietary intake may influence sympathetic nervous system activity. This study highlights the importance of considering the impact of nutrition during critical periods of development in order to further understand and improve the long-term outcomes of very low birth weight infants.

Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.