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Abstract The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Control (CMC) Community hosted a virtual panel discussion on July 15, 2022, to provide a forum to discuss industry and regulator CMC challenges associated with emergency use authorizations.

Background: The implementation of Big Data analytics in healthcare has an incredible chance of improving the quality of care, minimizing waste and error, and also decreasing the cost of care. Purpose: This systematic comment of literature objectives to discover the assortment of Big Data analytics in healthcare, including its applications and challenges in the adoption of its in healthcare. Furthermore, it intends to figure out the strategies to overcome the challenges. Data sources: An organized search of the articles was carried out on five primary scientific databases: ScienceDirect, Taylor, Francis and Emerald. The information articles on Big Data analytics in healthcare published from January 2017 to January 2022 are deemed. Data extraction: two reviewers independently extracted information on definitions of Big Data analytics; sources and applications of Big Data analytics in the healthcare field; challenges and strategies to overcome the issues in healthcare. Results: A complete of fifty eight articles are selected as per the inclusion needs and examined. The analyses of these posts placed that scientists do not have consensus about the useful definition of Big Data in serious healthcare. Big Data analytics finds the application for healthcare option support, optimization of healthcare operations, and reduction of treatment cost. The chief fight in serious adoption of Big Data analytics is non accessibility of evidence of its in healthcare. Conclusion: This review analysis unveils that there is a paucity of information on evidence of world utilization that is real of Big Data analytics in healthcare. Keywords: Big data, healthcare analytics.

Background: Effective therapeutics given early to high-risk ambulatory patients with coronavirus disease 2019 (COVID-19) could improve outcomes and reduce overall healthcare burden. However, conducting site visits in non-hospitalised patients, who should remain isolated, is problematic. Aim: To evaluate the feasibility of a purely remote (virtual) study in non-hospitalised patients with COVID-19; and the efficacy and safety of nebulised recombinant interferon-β1a (SNG001) in this setting. Design & setting: Randomised, double-blind, parallel-group study, which was conducted remotely. Method: Eligible patients aged ≥65 years (or ≥50 years with risk factors) with COVID-19 and not requiring hospital admission were recruited remotely. They were randomised to SNG001 or placebo once-daily via nebuliser for 14 days. The main outcomes were assessments of feasibility and safety, which were all conducted remotely. Results: Of 114 patients treated, 111 (97.4%) completed 28 days of follow-up. Overall compliance to study medication was high, with ≥13 doses taken by 89.7% and 92.9% of treated patients in the placebo and SNG001 groups, respectively. Over the course of the study, only two patients were hospitalised, both in the placebo group; otherwise there were no notable differences between treatments for the efficacy parameters. No patients withdrew owing to an adverse event, and a similar proportion of patients experienced on-treatment adverse events in the two treatment groups (64.3% and 67.2% with SNG001 and placebo, respectively); most were mild or moderate and not treatment-related. Conclusion: This study demonstrated that it is feasible to conduct a purely virtual study in community-based patients with COVID-19, when the study included detailed daily assessments and with medication administered via nebuliser.

Freshwater wetlands and their biodiversity have suffered substantial losses globally, mainly due to the drainage of wetlands for agriculture. Recent studies suggest that small drainage and/or irrigation canals established in lowland areas can function both as partial replacement of wetlands lost and as biodiversity hotspots in agricultural landscapes. However, small canals are usually not protected or managed for biodiversity. We studied whether and how the timing of reed management (removal in winter, in spring, no removal) on small canals affects nest site selection and breeding success in Great Reed Warblers, Acrocephalus arundinaceus, a flagship species of small canals in an intensive agricultural landscape in a five-year quasi-experiment. We found significantly more nests in winter-managed than in non-managed canal sections and hardly any in spring-managed sections. The number of nests also increased with the proportion of reed removed and with reed density. Breeding success measured as the probability of fledging chicks was positively influenced by reed density only and was not affected by management type, nesting height, water depth and water level fluctuation. Reed density had a central role as it mediated the effect of management both on nest site selection and breeding success, likely through better concealment of the nests from predators. Our results suggest that winter management should be favored as much as possible in the conservation of Great Reed Warblers and other reed-nesting passerines, whereas spring management should be avoided as it results in a complete lack of reed or poorly grown reed unsuitable for nest-building by the start of the breeding season. Our study draws attention to the importance of proper management of small canals that can serve as local hotspots of biodiversity in heavily human-modified landscapes, and which thus deserve more conservation attention than they currently have.

Abstract The reproductive period in animals is a demanding part in their life history. In birds, environmental factors, such as adverse weather, predation, or brood parasitism; and/or anthropogenic disturbance, can limit breeding success, resulting in failure of clutches. The nest loss in open‐cup nesting passerines is usually replaced with a new nest with a new clutch, however, in some cases the clutch replacement may occur in unusual forms. In this study, we report on three cases of within‐season nest reuse in the Great Reed Warbler. In the first case, a nest was reused for two times in the same season after unsuccessful nesting attempts (two‐time nest reuse). After the nest was depredated the first time, the female laid new eggs that were depredated again, then again the female laid new eggs that produced four fledglings. In the second case, the first clutch was depredated, after which the female laid a new clutch in the same nest that was again depredated. In the third case, the female laid new eggs among the eggs that failed to hatch previously. Our observations tend not to be consistent with the predator avoidance hypothesis because the depredated nests were reused by the parents. The time/energy saving hypothesis or possible deterrence of nest parasitism could explain nest reuse in this study, but because of low number of nests reused compared to the total number of nests found, this phenomenon needs further clarification.

Abstract Background Malaria remains the top infectious disease threat facing the U.S. military in many forward operating environments. Compliance with malaria chemoprophylaxis remains a critical component in preventing malaria in the deployed Service Member. Studies of previous military operations show that compliance is consistently higher with weekly versus daily dosing regimens. Current FDA approved weekly chemoprophylaxis options have contraindications that can limit prescribing. The combination of chloroquine (CQ) with azithromycin (AZ) has previously been shown to be an efficacious treatment option for malaria, has pharmacokinetics compatible with weekly dosing, and has shown synergy when combined in vitro. Methods In this open label study, 18 healthy volunteers, aged 18–50 years (inclusive), were randomly assigned to receive either 300 mg CQ or 300 mg CQ and 2 gm azithromycin (CQAZ) of directly observed therapy, weekly for 3 weeks prior to undergoing mosquito bite challenge with chloroquine-resistant Plasmodium falciparum. Volunteers that remained asymptomatic and had no evidence of parasitaemia continued to receive weekly post-exposure chemoprophylaxis for 3 weeks following malaria challenge. The primary endpoint was the number of volunteers that remained asymptomatic and had no evidence of parasitaemia 28 days after the malaria challenge. Results All 6 (100%) volunteers randomized to the CQ control group became symptomatic with parasitaemia during the 28-day post-challenge period. Only 1/12 (8.3%) of volunteers in the CQAZ group developed symptoms and parasitaemia during the 28-day post-challenge period. However, after chemoprophylaxis was discontinued an additional 6 volunteers developed parasitaemia between days 28–41 after challenge, with 4 of 6 experiencing symptoms. 80% of subjects in the CQAZ group experienced treatment related gastrointestinal adverse events (including 13% that experienced severe nausea) compared to 38% in the CQ group. A comparison of the pharmacokinetics in the CQAZ group demonstrated higher azithromycin Cmax (p = 0.03) and AUC (p = 0.044) levels in those volunteers who never became parasitaemic compared to those who did. Conclusion Given the high rate of side effects and poor efficacy when administered for 3 weeks before and after challenge, the combination of weekly chloroquine and azithromycin is a suboptimal regimen combination for weekly malaria chemoprophylaxis. Trial registration ClinicalTrials.gov NCT03278808

National Oceanic and Atmospheric Administration’s Coral Reef Conservation Program supports the National Coral Reef Monitoring Program (NCRMP) in the United States Pacific, Atlantic, Caribbean, and Gulf of Mexico. NCRMP conducts standardized observations of biological, climatic, and socioeconomic indicators across American Samoa, Guam, the Main Hawaiian Islands, the Northwestern Hawaiian Islands, the Northern Mariana Islands, the Pacific Remote Islands, Florida, the Flower Garden Banks, Puerto Rico, and the United States Virgin Islands. NCRMP provides periodic, national-level assessments of the status of United States coral reef ecosystems and communities connected to them. In 2014, NCRMP partnered with the University of Maryland Center for Environmental Science on an unprecedented collaboration between federal and jurisdictional/state agencies, academia, and non-governmental organizations to synthesize NCRMP data into a reporting format designed to be accessible and relevant to the public and policy makers. The process involved multi-year data analyses of key benthic, fish, and climate indicators. In populated jurisdictions, socioeconomic data were integrated to assess public support for management actions, participation in pro-environmental behaviors, and awareness of threats to coral reefs. Jurisdictions were scored using a report-card scale (0–100%) by establishing references for each indicator using best-available historical data or expert opinion where historical data did not exist or were not statistically comparable. Despite overall ecosystem scores of Fair for all combined Atlantic (70%) and Pacific (74%) jurisdictions, the current trend is downward with a majority of United States coral reefs declining and vulnerable to further degradation. Remote, uninhabited reefs had an advantage with respect to reef fish population scores, i.e., Flower Garden Banks (85%) and Pacific Remote Islands (93%), when compared to populated location scores, i.e., Puerto Rico (63%) and Main Hawaiian Islands (66%). All coral reefs are highly impacted by climate change, and climate impacts were more pronounced than expected on remote reefs, i.e., the Northwestern Hawaiian Islands (58%). Presenting results in a report-card style facilitates communication to the public and policy makers, and provides a useful mechanism to garner support for management actions such as expanding protected areas; enforcing existing regulations; increasing climate change education; reducing land-based sources of pollution; and other actions to improve the trajectory of coral reef ecosystem conditions.

The COVID-19 pandemic has far reaching potential public mental health impacts and is linked to higher levels of depression and anxiety. To address these in part, online information resources acted as mass interventions. It is vital to explore the content of these interventions, to consider the framing of the pandemic and to examine the extent to which their content is relevant. In March 2020, a qualitative content analysis was undertaken of 39 easily accessible online resources that offered advice, tips or guidance relating to mental health or mental wellbeing and COVID-19. Their content was compared to subsequent reports of the mental health impact of the pandemic. Resources frequently focused on anxiety. The content of intervention was typically of a cognitive-behavioral nature, with a significant focus on maintaining social contact. Typically, distress related to the situation was normalized and stigmatizing language was not seen. Data revealed a significant impact of the pandemic on depression as well as anxiety measures in the general UK population. A key recommendation is to ensure both depression and anxiety are addressed in these public mental health resources.

The Hawaiian Archipelago experienced a moderate bleaching event in 2019-the third major bleaching event over a 6-year period to impact the islands. In response, the Hawai'i Coral Bleaching Collaborative (HCBC) conducted 2,177 coral bleaching surveys across the Hawaiian Archipelago. The HCBC was established to coordinate bleaching monitoring efforts across the state between academic institutions, non-governmental organizations, and governmental agencies to facilitate data sharing and provide management recommendations. In 2019, the goals of this unique partnership were to: 1) assess the spatial and temporal patterns of thermal stress; 2) examine taxa-level patterns in bleaching susceptibility; 3) quantify spatial variation in bleaching extent; 4) compare 2019 patterns to those of prior bleaching events; 5) identify predictors of bleaching in 2019; and 6) explore site-specific management strategies to mitigate future bleaching events. Both acute thermal stress and bleaching in 2019 were less severe overall compared to the last major marine heatwave events in 2014 and 2015. Bleaching observed was highly site- and taxon-specific, driven by the susceptibility of remaining coral assemblages whose structure was likely shaped by previous bleaching and subsequent mortality. A suite of environmental and anthropogenic predictors was significantly correlated with observed bleaching in 2019. Acute environmental stressors, such as temperature and surface light, were equally important as previous conditions (e.g. historical thermal stress and historical bleaching) in accounting for variation in bleaching during the 2019 event. We found little evidence for acclimation by reefs to thermal stress in the main Hawaiian Islands. Moreover, our findings illustrate how detrimental effects of local anthropogenic stressors, such as tourism and urban run-off, may be exacerbated under high thermal stress. In light of the forecasted increase in severity and frequency of bleaching events, future mitigation of both local and global stressors is a high priority for the future of corals in Hawai'i.

Activation of skeletal muscle contractions require that action potentials can be excited and propagated along the muscle fibers. Recent studies have revealed that muscle fiber excitability is regulated during repeated firing of action potentials by cellular signaling systems that control the function of ion channel that determine the resting membrane conductance (Gm). In fast-twitch muscle, prolonged firing of action potentials triggers a marked increase in Gm, reducing muscle fiber excitability and causing action potential failure. Both ClC-1 and KATP ion channels contribute to this Gm rise, but the exact molecular regulation underlying their activation remains unclear. Studies in expression systems have revealed that ClC-1 is able to bind adenosine nucleotides, and that low adenosine nucleotide levels result in ClC-1 activation. In three series of experiments, this study aimed to explore whether ClC-1 is also regulated by adenosine nucleotides in native skeletal muscle fibers, and whether the adenosine nucleotide sensitivity of ClC-1 could explain the rise in Gm muscle fibers during prolonged action potential firing. First, whole cell patch clamping of mouse muscle fibers demonstrated that ClC-1 activation shifted in the hyperpolarized direction when clamping pipette solution contained 0 mM ATP compared with 5 mM ATP. Second, three-electrode Gm measurement during muscle fiber stimulation showed that glycolysis inhibition, with 2-deoxy-glucose or iodoacetate, resulted in an accelerated and rapid >400% Gm rise during short periods of repeated action potential firing in both fast-twitch and slow-twitch rat, and in human muscle fibers. Moreover, ClC-1 inhibition with 9-anthracenecarboxylic acid resulted in either an absence or blunted Gm rise during action potential firing in human muscle fibers. Third, Gm measurement during repeated action potential firing in muscle fibers from a murine McArdle disease model suggest that the rise in Gm was accelerated in a subset of fibers. Together, these results are compatible with ClC-1 function being regulated by the level of adenosine nucleotides in native tissue, and that the channel operates as a sensor of skeletal muscle metabolic state, limiting muscle excitability when energy status is low.

Passenger motor vehicle transport is a significant and growing emissions source contributing to climate change. Switching from internal combustion engines to electric vehicles (EV) would significantly reduce most countries’ emissions, but for many consumers perceived barriers deter EV adoption. Consequently, government policies designed to incentivise a transition to EVs could benefit from consideration of the utility of communication channels such as print media for influencing consumer behaviour. This research explores the role that media and other communication channels writing about EVs play in consumer perceptions and awareness of government-initiated programs and policies to incentivise EV market transition. Using mixed methods of a media review and New Zealand car buyer surveys (questionnaires, interviews) (n = 893), we identified car buyers’ media use to update knowledge about cars, perceptions about EVs, and likelihood to buy, and tested awareness and popularity of incentives. We derive recommendations for policy improvements to accelerate EV uptake, including a significant role for the print media to disseminate relevant information, increase awareness of policies, and shift perceptions about EVs. We argue that social marketing programs should be enhanced to overcome lack of knowledge and misinformation, focusing on the market segment next most likely to buy EVs.

Actions to reduce greenhouse gas emissions are required from all actors. Adopting plug-in electric vehicles (EV) would reduce light motor vehicle travel emissions, a significant and rising emissions source. To encourage EV uptake, many governments have implemented policies which may be less effective than desired. Using New Zealand as a case study, we surveyed private motorists. The results show that consumers are heterogeneous, with varying car-buying motivations, perceptions, attitudes to EVs and awareness of policies. Uniquely, we segmented motorists into four attitudinal groups to ascertain characteristics potentially affecting EV readiness to provide evidence to improve policies and aid social marketing. Our results show the next-most-ready to buy EVs are early mainstream consumers—designated the EV Positives—who were most concerned about vehicle range, perceptions of EV expense, charging-related inconvenience and the unknown value proposition of batteries, and were relatively unaware of incentives compared to EV Owners. The EV Positives favored incentives designed to effect purchase price reductions and increase nation-wide fast-charger deployment. To increase awareness of EVs and shift perceptions of EV expense and inconvenience, we suggest policies that potentially increase EV adoption rates and suggest reframing the language to appeal to EV Positives through information programs. Increasing EV procurement by organizations could increase opportunities for positive information dissemination via employees.

Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease.

Circadian clocks are fundamental physiological regulators of energy homeostasis, but direct transcriptional targets of the muscle clock machinery are unknown. To understand how the muscle clock directs rhythmic metabolism, we determined genome-wide binding of the master clock regulators brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα in murine muscles. Integrating occupancy with 24-hr gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERBα, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERBα targets using luciferase assays and in vivo rescue, we demonstrate how a major role of the muscle clock is to promote diurnal cycles of neutral lipid storage while coordinately inhibiting lipid and protein catabolism prior to awakening. This occurs by BMAL1-dependent activation of Dgat2 and REV-ERBα-dependent repression of major targets involved in lipid metabolism and protein turnover (MuRF-1, Atrogin-1). Accordingly, muscle-specific loss of BMAL1 is associated with metabolic inefficiency, impaired muscle triglyceride biosynthesis, and accumulation of bioactive lipids and amino acids. Taken together, our data provide a comprehensive overview of how genomic binding of BMAL1 and REV-ERBα is related to temporal changes in gene expression and metabolite fluctuations.

In an observer blind, phase 2 trial, 55 adults were randomized to receive one dose of Ad35.CS.01 vaccine followed by two doses of RTS,S/AS01 (ARR-group) or three doses of RTS,S/AS01 (RRR-group) at months 0, 1, 2 followed by controlled human malaria infection.ARR and RRR vaccine regimens were well tolerated. Efficacy of ARR and RRR groups after controlled human malaria infection was 44% (95% confidence interval 21%-60%) and 52% (25%-70%), respectively. The RRR-group had greater anti-CS specific IgG titers than did the ARR-group. There were higher numbers of CS-specific CD4 T-cells expressing > 2 cytokine/activation markers and more ex vivo IFN-γ enzyme-linked immunospots in the ARR-group than the RRR-group. Protected subjects had higher CS-specific IgG titers than non-protected subjects (geometric mean titer, 120.8 vs 51.8 EU/ml, respectively; P = .001).An increase in vaccine efficacy of ARR-group over RRR-group was not achieved. Future strategies to improve upon RTS,S-induced protection may need to utilize alternative highly immunogenic prime-boost regimens and/or additional target antigens.ClinicalTrials.gov NCT01366534.

Entrepreneurship is considered a critical factor in stimulating economic growth and creating employment. Entrepreneurship education is viewed as one of the key instruments for increasing entrepreneurial intention and activities. However, it remains unclear which elements of entrepreneurship education are most influential in shaping a participant's intention to start a venture. This study aims to fill this gap by examining the impact of entrepreneurship education and the mediating role of alertness, inspiration, social networks and the acquisition of knowledge and skills (the rational "learning" component of entrepreneurship education) in a participant's intention to start a venture. Drawing on entrepreneurship education theory, the author proposes that entrepreneurship education increases entrepreneurial intention if it induces a perceived increase in alertness, inspiration, social networks or knowledge and skills among participants. The empirical results of the multiple hierarchical regression analysis provide support for a full mediation effect of inspiration, social networks and knowledge and skills on the relationship between entrepreneurship education and entrepreneurial intention. These findings contribute to research in entrepreneurship education, enhance understanding of the main success factors in entrepreneurship education and offer useful insights for practitioners when developing effective entrepreneurship programs.