Revisiting COVID-19 policies: 10 evidence-based recommendations for where to go from here.

BACKGROUND: Strategies to control coronavirus 2019 disease (COVID-19) have often been based on preliminary and limited data and have tended to be slow to evolve as new evidence emerges. Yet knowledge about COVID-19 has grown exponentially, and the expanding rollout of vaccines presents further opportunity to reassess the response to the pandemic more broadly. MAIN TEXT: We review the latest evidence concerning 10 key COVID-19 policy and strategic areas, specifically addressing: 1) the expansion of equitable vaccine distribution, 2) the need to ease restrictions as hospitalization and mortality rates eventually fall, 3) the advantages of emphasizing educational and harm reduction approaches over coercive and punitive measures, 4) the need to encourage outdoor activities, 5) the imperative to reopen schools, 6) the far-reaching and long-term economic and psychosocial consequences of sustained lockdowns, 7) the excessive focus on surface disinfection and other ineffective measures, 8) the importance of reassessing testing policies and practices, 9) the need for increasing access to outpatient therapies and prophylactics, and 10) the necessity to better prepare for future pandemics. CONCLUSIONS: While remarkably effective vaccines have engendered great hope, some widely held assumptions underlying current policy approaches call for an evidence-based reassessment. COVID-19 will require ongoing mitigation for the foreseeable future as it transforms from a pandemic into an endemic infection, but maintaining a constant state of emergency is not viable. A more realistic public health approach is to adjust current mitigation goals to be more data-driven and to minimize unintended harms associated with unfocused or ineffective control efforts. Based on the latest evidence, we therefore present recommendations for refining 10 key policy areas, and for applying lessons learned from COVID-19 to prevent and prepare for future pandemics.

Efficacy and safety of AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, in patients with asthma: a phase 2a randomized, double blind, placebo-controlled crossover trial.

BACKGROUND: Inhaled corticosteroids reduce inflammation in asthma but chronic use may cause adverse effects. AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, has the potential of an improved risk-benefit profile. We investigated the safety and efficacy of AZD7594 in asthma. METHODS: This phase 2a multi-center, randomized, double-blind, placebo-controlled crossover study enrolled adults with asthma aged 18 to 75 years. Patients were treated with budesonide 200 µg twice daily for 2-3 3 weeks (run in part one). If controlled, as demonstrated by an asthma control questionnaire-5 score of < 1.5, patients entered a three-week run-in (part two) where they received a short acting bronchodilator alone. Thereafter, patients with a fractional exhaled nitric oxide (FENO) ≥25 ppb and pre-dose FEV1 40 to 90% predicted were randomized to one of nine treatment sequences. Each patient received placebo and two of three dose levels of AZD7594 (58, 250, 800 µg) once daily via inhalation, in 14-day treatment periods, separated by three-week washout periods. The primary endpoint was the change from baseline in morning trough FEV1 versus placebo on day 15. Secondary endpoints included measures of airway inflammation and asthma control. RESULTS: Fifty-four patients were randomized and received at least 1 dose of treatment, 48 patients completed the study. Overall 52 patients received placebo, 34 received AZD7594 58 µg, 34 received AZD7594 250 µg, and 34 received AZD7594 800 µg. AZD7594 800 µg demonstrated a significant improvement in Day 15 morning trough FEV1versus placebo (LS means difference 0.148 L 95% CI 0.035-0.261, p = 0.011), with a dose-dependent response seen in the 250 µg (0.076 L -0·036-0·188, p = 0.183) and 58 µg (0·027 L -0·086-0·140, p = 0.683). All secondary endpoints showed statistically significant improvement at the 800 µg dose. All doses demonstrated a significant reduction in FENO at day 15 p < 0.01. No statistically significant difference in plasma cortisol level was observed between AZD7594 and placebo at any dose. AZD7594 was considered safe and well tolerated. CONCLUSIONS: Two-week treatment with AZD7594 demonstrated a favorable risk-benefit profile in patients with mild to moderate asthma. Further clinical studies are needed to fully characterize AZD7594. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02479412 .

School education to increase organ donation and awareness of issues in transplantation in the UK.

BACKGROUND: Over 6000 people are on the United Kingdom organ transplant waiting list, and approximately three people die each day due to a lack of donors. Social deprivation status has been shown to affect registration. The aim of this study was to evaluate the effectiveness of school level education at increasing awareness of the issues surrounding organ donation and organ donor registration, and the effect of socioeconomic deprivation and age has on these outcomes. METHODS: A 15-minute presentation about organ donation and the issues in transplantation was given to secondary school students from the United Kingdom. An optional questionnaire was then distributed. RESULTS: 1155 paper questionnaires were completed from nine schools. The average age was 15.5 (SD = 0.5) years. Before the presentation, 10% of students were on the ODR. Following the presentation, the number of students who were on the ODR or planned to join significantly increased to 56%, independent of age (P < 0.0001). Similarly, there was a significant increase in Likert scores for awareness of the issues in transplantation, independent of age (P < 0.0001). CONCLUSIONS: This early educational presentation significantly increased awareness of the issues in transplantation and planned organ donor registration, independent of age and deprivation.

The role of excitation-pattern, temporal-fine-structure, and envelope cues in the discrimination of complex tones.

The discrimination of bandpass-filtered harmonic (H) from inharmonic (I) tones (produced by shifting all components of the H tones upwards by a fixed amount in Hz) could be based on shifts in the pattern of ripples in the excitation pattern (EP) or on changes in the temporal fine structure evoked by the tones. The predictions of two computational EP models were compared with measured performance. One model used auditory filters with bandwidth values specified by Glasberg and Moore [(1990). Hear. Res. 47, 103-138] and one used filters that were twice as sharp. Stimulus variables were passband width, fundamental frequency, harmonic rank (N) of the lowest component within the passband, component phase (cosine or random), signal-to-noise ratio (SNR), and random perturbation in level of each component in the tones. While the EP models correctly predicted the lack of an effect of phase and some of the trends in the data as a function of fundamental frequency and N, neither model predicted the worsening in performance with increasing passband width or the lack of effect of SNR and level perturbation. It is concluded that discrimination of the H and I tones is not based solely on the use of EP cues.

Redefining the Role of Nutrition in Infant Food Allergy Prevention: A Narrative Review.

Pediatric food allergy remains commonplace, despite the advancement in our understanding of risk factors and prevention modalities for the condition. Early allergen introduction, a dietary intervention, has been endorsed by professional societies globally as an effective primary preventive measure, yet awareness among medical professionals and parents is lacking. Alongside food allergen introduction, overall nutrition, such as diet diversity, also plays an important role in allergy prevention. To address both food allergen introduction and overall nutrition, dietitians play a pivotal role in the dissemination and education of current guidelines to caregivers. This review addresses the particular role of the dietitian in food allergy prevention consultations, providing up-to-date information on food allergies, their development and prevalence, risk factors, dietary factors and an overview of the current guidelines in the United States. This has not been addressed in any of the current food allergy or nutrition guidelines.

Contribution of temporal fine structure information and fundamental frequency separation to intelligibility in a competing-speaker paradigm.

The speech reception threshold (SRT) for identifying a target speaker in a background speaker was measured as a function of the difference (F0sep) in fundamental frequency (F0) between the two speakers. The amount of original temporal fine structure (TFS) information in the mixed signals was manipulated by tone vocoding channels above a certain cutoff channel (CO). When the natural variations in F0 of both speakers were preserved, the SRT did not decrease with increasing F0sep, indicating that short-term differences in F0 can allow perceptual segregation of two speakers even when their F0s cross. When F0 variations were removed from both speakers, increasing F0sep led to decreased (better) SRTs. The decrease was greater for unprocessed signals than for fully tone-vocoded signals. However, the decrease was similar for unprocessed signals and for signals with original TFS below 1600 Hz, suggesting that most of the benefit from increasing F0 difference depends on the use of TFS information at lower frequencies. Adding original TFS information to channels centered above 1600 Hz produced roughly the same decrease in SRT as adding original TFS information to channels centered below 1600 Hz, suggesting a benefit from original TFS information apart from that related to differences in F0.

The dominant region for the pitch of complex tones with low fundamental frequencies.

The dominant region for pitch for complex tones with low fundamental frequency (F0) was investigated. Thresholds for detection of a change in F0 (F0DLs) were measured for a group of harmonics (group B) embedded in a group of fixed non-overlapping harmonics (group A) with the same mean F0. It was assumed that F0DLs would be smallest when the harmonics in group B fell in the dominant region. The rank of the lowest harmonic in group B, N, was varied from 1 to 15. When all components had the same level, F0DLs increased with increasing N, but the increase started at a lower value of N for F0 = 200 Hz than for F0 = 50 or 100 Hz, the opposite of what would be expected if the dominant region corresponds to resolved harmonics. When the component levels followed an equal-loudness contour, F0DLs for F0 = 50 Hz were lowest for N = 1, but overall performance was much worse than for equal-level components, suggesting that the lowest harmonics were masking information from the higher harmonics.

Motivational interviewing and HIV drug adherence.

Despite advances in HIV treatment, adherence rates remain low, with only around 50-70% of those who should be taking antiretroviral therapy fully concordant with the treatment regimen. This article explores why this might be. It analyses the literature on motivational interviewing, and its effectiveness in improving patient adherence to antiretroviral therapy in the treatment of HIV.

Metabolic consequences of antipsychotic therapy: preclinical and clinical perspectives on diabetes, diabetic ketoacidosis, and obesity.

Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs. Hence, there is an urgent need for a new generation of antipsychotic drugs that provide efficacy equal to the best of the SGAs without their liability to cause weight gain or type 2 diabetes. In the absence of such safe and effective alternatives to the SGAs, there is a substantial clinical need for the introduction of new antipsychotics without adverse metabolic effects and new antiobesity drugs to combat these metabolic side effects. We discuss the adverse metabolic consequences of schizophrenia, its exacerbation by a lack of social care, and the additional burden placed on patients by their medication. A critical evaluation of the animal models of antipsychotic-induced metabolic disturbances is provided with observations on their strengths and limitations. Finally, we discuss novel antipsychotic drugs with a lower propensity to increase metabolic risk and adjunctive medications to mitigate the adverse metabolic actions of the current generation of antipsychotics.

Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.

The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.

Characterization of a novel deletion causing beta-thalassemia major in an Afghan family.

We have identified and characterized a novel beta-globin gene deletion mutation in a family of Afghan ancestry. The proband was a 10-year-old transfusion-dependent female with the phenotype of beta-thalassemia major (beta-TM). DNA sequencing of the beta-globin gene showed no abnormalities. Multiplex ligation-dependent probe amplification (MLPA) showed reduced/absent probe height of the probe covering the 5' end of the beta-globin gene indicating a possible deletion. Gap-polymerase chain reaction (gap-PCR) produced junctional fragments and direct sequencing of the product revealed that the 5' breakpoint was 478 nucleotides upstream of the Cap site and the 3' breakpoint was in the second exon of the beta-globin gene, giving a deletion size of 909 bp. The proband was homozygous and the parents were heterozygous for the deletion. This is the first report of a large beta-thalassemia (beta-thal) deletion mutation in this ethnic group.

Budget Impact Analysis of the Introduction of Injectable Prolonged-Release Buprenorphine on Opioid Use Disorder Care Resource Requirements.

OBJECTIVE: To assess budget impact of the introduction of prolonged-release buprenorphine (PRB) for care of opioid use disorder (OUD) over 1 year in a defined population. MATERIALS AND METHODS: A healthcare perspective, decision-tree model analysis of the cost of OUD care for a standard population was prepared to compare two scenarios: treatment of a population under the existing standard of care, or with the addition of PRB. The model assessed OUD-related direct costs (medication, delivery, psychosocial treatment), other services costs (harm reduction, general healthcare, social and justice services) and the impact of behaviors such as engaging with treatment and electing to use additional opioids "on top" of treatment regimens, and "dropping out" from treatment. RESULTS: Standard population definition (persons offered OUD care services) is based on a typical administrative region in England with general population of 400,000 citizens, 1,777 high-risk opioid users requiring treatment and 909 patients initiating treatment in a year. The cost to provide OUD care for 1 year under the current scenario (70% treated with methadone, 30% sublingual buprenorphine) is £19.7M. In scenarios with increased PRB adoption/reduced sublingual buprenorphine or oral methadone use, the cost reduction ranges from £0.2M to 0.7M. CONCLUSION: The assessment showed a reduction of overall costs after introduction of PRB.

Zvandiri-Bringing a Differentiated Service Delivery Program to Scale for Children, Adolescents, and Young People in Zimbabwe.

Since 2004, there has been a dramatic shift in the HIV response for children, adolescents, and young people in low resource settings. Previous programs and services were largely orientated to adults. This is now changing, but there is limited evidence on how to take services for children, adolescents, and young people living with HIV (CAYPLHIV) to scale. Zvandiri is a theoretically grounded, multicomponent-differentiated service delivery model for children, adolescents, and young people in Zimbabwe that integrates peer-led, community interventions within government health services. Africaid analyzed routine program and other data from November 2004 to October 2017 to document Zvandiri scale-up, framed by the World Health Organization framework for scaling up interventions. Since 2004, Zvandiri has evolved from one support group in Harare into a comprehensive model, combining community- and clinic-based health services and psychosocial support for CAYPLHIV. Zvandiri was scaled up across Zimbabwe through phased expansion into 51 of 63 districts, reaching 40,213 CAYPLHIV. Evidence indicates that this approach improved uptake of HIV testing services, adherence, and retention in care. The environment and strategic choices were critical when taking the model to scale, particularly nesting the program within existing services, and capacity strengthening of service providers working jointly with trained, mentored CAYPLHIV. The results provide a firm foundation for programming and from which to build evidence of sustainable impact. Formal impact evaluation is needed and underway. These program data contribute to the essential evidence base on strategic approaches to assist in planning services for this relatively neglected group.

Management of cold agglutinin immune hemolytic anemia in pregnancy.

BACKGROUND: Cold hemagglutinin disease is an acquired autoimmune hemolytic anemia caused by an immunoglobulin M autoantibody directed against the polysaccharide antigens on the red blood cell surface. This case presents the challenges surrounding the management of cold hemagglutinin disease in pregnancy. CASE: A pregnant woman in her thirties with type-2 diabetes, reporting shortness of breath and productive cough, was found to have anemia, reticulocytosis, bilirubinemia, positive direct Coombs test result, positive cold agglutinin antibody, and raised lactate dehydrogenase levels. As the infection screen and autoimmune serology results were negative, she was diagnosed as having idiopathic cold hemagglutinin disease. The management included keeping the patient warm and hydrated and treating the anemia with warm packed red blood cell transfusion. CONCLUSION: Cold hemagglutinin disease is a rare condition. Investigations to rule out infections help determine the diagnosis of cold hemagglutinin disease of unknown origin.

Service-learning across an accelerated curriculum.

In support of the community-based education philosophy, nursing faculty at a small health careers college in the midwestern United States incorporated a service-learning experience involving Sudanese refugee families and Latino community members into its accelerated community-based nursing program (ACE) curriculum. The purpose of the service-learning experience is to allow students the opportunity develop relationships through which they may gain an understanding of unique needs within a community. This article describes the development and benefits of the service-learning experience across the ACE curriculum. Through reflection, students broaden and deepen their understanding about the health of individuals in the community and acquire a more sophisticated understanding of risk

Screening for hereditary haemochromatosis within families and beyond.

Screening programmes for haemochromatosis that include follow-up identification of relatives are claimed to be cost effective. We assessed uptake of screening by first-degree relatives of two groups of index cases: people homozygous for the C282Y mutation ascertained by genetic screening of blood donors; and patients presenting clinically with haemochro matosis. Only 40 (24%) of 165 relatives of blood donors had been tested. By contrast, testing uptake in 121 relatives of patients diagnosed clinically was more than double that (53%), despite unstructured provision of genetic information. A substantial number of untested relatives had undiagnosed iron overload. Overall efficacy of population screening for haemochromatosis is undermined by these observations.

Changes in erythropoiesis in hereditary hemochromatosis are not mediated by HFE expression in nucleated red cells.

BACKGROUND AND OBJECTIVES: The HFE protein interacts with the transferrin receptor (TfR) to regulate cellular iron uptake. Nucleated erythroid cells have the highest number of TfR and the greatest iron uptake. The aim of this study was to investigate whether erythroid iron uptake is directly affected by HFE mutations. DESIGN AND METHODS: Iron status and erythropoiesis was investigated in sixty, asymptomatic HFE C282Y homozygotes. Reverse transcription-polymerase chain reaction, flow cytometry and immunocytochemistry were employed to investigate the HFE expression profile of normal peripheral blood, nucleated erythroid cells and several cultured cell lines. RESULTS: The HFE C282Y homozygous subjects showed subtle erythropoietic changes with raised transferrin saturation and reticulocyte counts and low-normal serum transferrin receptor levels, but normal erythrocyte count and mean cell volume. HFE mRNA was detected in macrophages and monocytes and HFE protein was detected in granulocytes and at low levels in monocytes. Cultured primary human erythroid colonies did not express HFE mRNA or protein. INTERPRETATION AND CONCLUSIONS: There is evidence that HFE C282Y homozygotes display increased plasma iron turnover and increased erythropoiesis, despite there being no evidence that HFE is expressed in erythroid colonies with a normal HFE genotype. It is likely that HFE mutations do not directly alter erythroid iron handling, but alter the supply of iron to the erythroid tissues.

The uptake of a fluorescently labelled antisense oligonucleotide in vitro and in vivo.

Antisense oligonucleotides have been used to target a range of different gene products in the CNS including neurotransmitter receptors. Previous studies using antisense oligonucleotides to target the rat alpha(2A/D)-adrenoceptor revealed changes in receptor expression in specific brain areas following i.c.v. administration but no reduction was observed following antisense treatment in primary cortical neurones. In order to resolve these discrepant results, the uptake and distribution of the antisense sequence has been determined. In vivo, the fluorescent signal was detected close to the site of injection (2-3 mm) and on the same side of the brain as the injection. Although the oligonucleotides (ODN) were distributed throughout the CSF, the ODN was not widely distributed within the mid or hindbrain parenchyma. In vitro uptake studies revealed the antisense was poorly taken up into primary cortical neurones but a higher level of fluorescence was detected in a small sub-population of cells. These studies demonstrate that antisense is rapidly taken up into cells in vivo but poorly taken up into primary cortical neurones in culture. These data provide further evidence for the uptake and distribution of antisense oligonucleotides in neuronal tissue in vivo.

The utility of animal models to evaluate novel anti-obesity agents.

The global incidence of obesity continues to rise and is a major driver of morbidity and mortality through cardiovascular and cerebrovascular diseases. Animal models used in the discovery of novel treatments for obesity range from straightforward measures of food intake in lean rodents to long-term studies in animals exhibiting obesity due to the continuous access to diets high in fat. The utility of these animal models can be extended to determine, for example, that weight loss is due to fat loss and/or assess whether beneficial changes in key plasma parameters (e.g. insulin) are evident. In addition, behavioural models such as the behavioural satiety sequence can be used to confirm that a drug treatment has a selective effect on food intake. Typically, animal models have excellent predictive validity whereby drug-induced weight loss in rodents subsequently translates to weight loss in man. However, despite this, at the time of writing orlistat (Europe; USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events. While the utility of rodent models in predicting clinical weight loss is detailed, the review also discusses whether animals can be used to predict adverse events such as those seen with recent anti-obesity drugs in the clinic.