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Abstract Background The COVID-19 pandemic severely impacted care for non-COVID patients. Performance indicators to monitor acute care, timely reported and internationally accepted, lacked during the pandemic in OECD countries. This study aims to summarize the performance indicators available in the literature to monitor changes in the quality of acute care in OECD countries during the first year and a half of the pandemic (2020-July 2021) and to assess their trends. Methods Scoping review. Search in Embase and MEDLINE (07-07-2022). Acute care performance indicators and indicators related to acute general surgery were collected and collated following a care pathway approach. Indicators assessing identical clinical measures were grouped under a common indicator title. The trends from each group of indicators were collated (increase/decrease/stable). Results A total of 152 studies were included. 2354 indicators regarding general acute care and 301 indicators related to acute general surgery were included. Indicators focusing on pre-hospital services reported a decreasing trend in the volume of patients: from 225 indicators, 110 (49%) reported a decrease. An increasing trend in pre-hospital treatment times was reported by most of the indicators (n = 41;70%) and a decreasing trend in survival rates of out-of-hospital cardiac arrest (n = 61;75%). Concerning care provided in the emergency department, most of the indicators (n = 752;71%) showed a decreasing trend in admissions across all levels of urgency. Concerning the mortality rate after admission, most of the indicators (n = 23;53%) reported an increasing trend. The subset of indicators assessing acute general surgery showed a decreasing trend in the volume of patients (n = 50;49%), stability in clinical severity at admission (n = 36;53%), and in the volume of surgeries (n = 14;47%). Most of the indicators (n = 28;65%) reported no change in treatment approach and stable mortality rate (n = 11,69%). Conclusion This review signals relevant disruptions across the acute care pathway. A subset of general surgery performance indicators showed stability in most of the phases of the care pathway. These results highlight the relevance of assessing this care pathway more regularly and systematically across different clinical entities to monitor disruptions and to improve the resilience of emergency services during a crisis.

Abstract Background International mobility of health workforce affects the performance of health systems and has major relevance in human resources for health policy and planning. To date, there has been little research exploring the reasons why general practitioners (GPs) migrate. This mixed methods study aimed to investigate the reasons why Spain-trained GPs migrate and develop GP retention and recruitment health policy recommendations relevant to Spanish primary care. Methods The study followed an explanatory sequential mixed methods study design combining surveys with semi-structured interviews and focus groups with GPs who qualified in Spain and were living overseas at the time of the study. The survey data examined the reasons why GPs left Spain and their intention to return and were analysed using quantitative methods. The transcripts from interviews and focus groups centred on GPs’ insights to enhance retention and recruitment in Spain and were analysed thematically. Results The survey had 158 respondents with an estimated 25.4% response rate. Insufficient salary (75.3%), job insecurity and temporality (67.7%), excessive workload (67.7%), poor primary care governance (55.7%), lack of flexibility in the workplace (43.7%) and personal circumstances (43.7%) were the main reasons for leaving Spain. Almost half of the respondents (48.7%) would consider returning to Spanish general practice if their working conditions improved. Interviews and focus groups with respondents (n = 24) pointed towards the need to improve the quality of employment contracts, working conditions, opportunities for professional development, and governance in primary care for effective retention and recruitment. Conclusion Efforts to improve GP retention and recruitment in Spain should focus on salary, job security, flexibility, protected workload, professional development, and governance. We draw ten GP retention and recruitment recommendations expected to inform urgent policy action to tackle existing and predicted GP shortages in Spanish primary care.

Abstract Background In insurance-based healthcare systems, healthcare insurers are interested in engaging citizens in care procurement to contract healthcare services that matter to people. In the Netherlands, an amendment to the Health Insurance Act was set forth in 2021 to formalize and strengthen the engagement of the insured population with healthcare insurers’ procurement cycles. This study explores the role of Dutch healthcare insurers in operationalizing citizen engagement in procurement cycles before changes occur linked to the amendment to the Health Insurance Act. Methods A phenomenological qualitative design was employed in two phases: (1) we consulted academics and policy experts on the role of healthcare insurers regarding citizen engagement; (2) we conducted focus groups with representatives of healthcare insurers to understand how citizens’ engagement is being operationalized. Transcripts of the interviews with experts and detailed notes of focus group meetings were analysed using a qualitative inductive approach. Selected excerpts were analysed on discourse and content and organized by a coding scheme following a rigorous and accelerated data reduction technique. Results We identified four strategies used by healthcare insurers to operationalize citizen engagement: (1) broadening their population health orientation; (2) developing and improving mechanisms for engaging citizens; (3) strengthening features of data governance for effective use of value-driven data; (4) implementing financial and incentive mechanisms among healthcare providers in support of value-based healthcare. However, regulated market mechanisms and low institutional trust in healthcare insurers undermine their transition from merely funding healthcare towards becoming people-centred value-based healthcare purchasers. Conclusion Dutch healthcare insurers seem to be strengthening the community orientation of their functioning while enhancing the end-to-end experience of the insured. The expected practical effects of the amendment to the Health Insurance Act include broadening the role of the council of insurees in decision-making processes and systematically documenting the efforts set forth by healthcare insurers in engaging citizens. Further research is needed to better understand how the regulated competitive market could be hampering the engagement of citizens in healthcare procurement decision-making and value creation from the citizens’ perspective.

Abstract Background Between 2019 and 2021, the first Irish health system performance assessment (HSPA) framework was developed. As routinely collected health data are necessary to continuously populate indicators of an HSPA framework, a purpose-driven assessment of the health information system (HIS) in Ireland and its fitness to support the implementation of an HSPA framework was conducted. This study reports on the status of the Irish HIS through a multimethod assessment based on continuous broad stakeholder involvement. Methods Between May and November 2020, over 50 informants were engaged in individual and group interviews and stakeholder consultation workshops as part of the HIS assessment process. Descriptive themes and high-level data availability heatmaps were derived from interview and workshop data using thematic analysis. Indicator “passports” for the HSPA framework were populated during stakeholder consultation workshops and analysed using univariate descriptive statistics. Results The HIS in Ireland was able to provide administrative, survey and registry-based data for public sector acute care services, focusing on structure, process and output metrics. Significant data availability gaps, most notably from primary care, private hospitals and community care, were reported, with little availability of electronic health record and people-reported data. Data on outcome metrics were mostly missing, as were linkage possibilities across datasets for care pathway monitoring. The COVID-19 pandemic highlighted the national HIS’s shortcomings but also the capacity for rapid development and improvement. Conclusions A tailor-made assessment of the HIS in Ireland, involving a broad set of relevant stakeholders, revealed strengths, weaknesses and areas for improvement in the Irish health data landscape. It also contributed to the development of a national HSPA framework and momentum to further strengthen data infrastructure and governance, while working towards a more data-driven and person-centred healthcare system. This work demonstrates the utility of an inclusive HIS assessment process and is applicable beyond Ireland, where this case study was conducted.

Abstract Background Cancer comprises a high burden on health systems. Performance indicators monitoring cancer outcomes are routinely used in OECD countries. However, the development of process and cancer-pathway based information is essential to guide health care delivery, allowing for better monitoring of changes in the quality of care provided. Assessing the changes in the quality of cancer care during the COVID-19 pandemic requires a structured approach considering the high volume of publications. This study aims to summarize performance indicators used in the literature to evaluate the impact of the COVID-19 pandemic on cancer care (January-June 2020) in OECD countries and to assess changes in the quality of care as reported via selected indicators. Methods Search conducted in MEDLINE and Embase databases. Performance indicators and their trends were collated according to the cancer care pathway. Results This study included 135 articles, from which 1013 indicators were retrieved. Indicators assessing the diagnostic process showed a decreasing trend: from 33 indicators reporting on screening, 30 (91%) signalled a decrease during the pandemic (n = 30 indicators, 91%). A reduction was also observed in the number of diagnostic procedures (n = 64, 58%) and diagnoses (n = 130, 89%). The proportion of diagnoses in the emergency setting and waiting times showed increasing trends (n = 8, 89% and n = 14, 56%, respectively). A decreasing trend in the proportion of earliest stage cancers was reported by 63% of indicators (n = 9), and 70% (n = 43) of indicators showed an increasing trend in the proportion of advanced-stage cancers. Indicators reflecting the treatment process signalled a reduction in the number of procedures: 79%(n = 82) of indicators concerning surgeries, 72%(n = 41) of indicators assessing radiotherapy, and 93%(n = 40) of indicators related to systemic therapies. Modifications in cancer treatment were frequently reported: 64%(n = 195) of indicators revealed changes in treatment. Conclusions This study provides a summary of performance indicators used in the literature to assess the cancer care pathway from January 2020 to June 2020 in OECD countries, and the changes in the quality of care signalled by these indicators. The trends reported inform on potential bottlenecks of the cancer care pathway. Monitoring this information closely could contribute to identifying moments for intervention during crises.

Abstract Background In complex critical neonatal and paediatric clinical practice, little is known about long-term patient outcomes and what follow-up care is most valuable for patients. Emma Children’s Hospital, Amsterdam UMC (Netherlands), implemented a follow-up programme called Follow Me for neonatal and paediatric patient groups, to gain more insight into long-term outcomes and to use such outcomes to implement a learning cycle for clinical practice, improve follow-up care and facilitate research. Three departments initiated re-engineering and change processes. Each introduced multidisciplinary approaches to long-term follow-up, including regular standardised check-ups for defined age groups, based on medical indicators, developmental progress, and psychosocial outcomes in patients and their families. This research evaluates the implementation of the three follow-up programmes, comparing predefined procedures (work-as-imagined) with how the programmes were implemented in practice (work-as-done). Methods This study was conducted in 2019–2020 in the outpatient settings of the neonatal intensive care, paediatric intensive care and paediatric surgery departments of Emma Children’s Hospital. It focused on the organisational structure of the follow-up care. The functional resonance analysis method (FRAM) was applied, using documentary analysis, semi-structured interviews, observations and feedback sessions. Results One work-as-imagined model and four work-as-done models were described. The results showed vast data collection on medical, developmental and psychosocial indicators in all work-as-done models; however, process indicators for programme effectiveness and performance were missing. In practice there was a diverse allocation of roles and responsibilities and their interrelations to create a multidisciplinary team; there was no one-size-fits-all across the different departments. Although control and feedback loops for long-term outcomes were specified with respect to the follow-up groups within the programmes, they were found to overlap and misalign with other internal and external long-term outcome monitoring practices. Conclusion Implementing structured long-term follow-up may provide insights for improving daily practice and follow-up care, with the precondition of standardised measurements. Lessons learned from practice are (1) to address fragmentation in data collection and storage, (2) to incorporate the diverse ways to create a multidisciplinary team in practice, and (3) to include timely actionable indicators on programme effectiveness and performance, alongside medical, developmental and psychosocial indicators.

Objectives Regulatory oversight organisations play an important role in quality stewardship in long-term care (LTC) facilities. Performance indicators are a key tool for any quality-related work. Our aim was to better understand how and what performance indicators are used by regulatory oversight organisations for long-term care facilities oversight and which features are affecting their fitness for use.Design Qualitative descriptive.Setting and participants We explored the use of LTC facility performance indicators by 10 regulatory oversight organisations from England, Ireland, Malta, New Zealand, Norway, Scotland, Singapore, Slovenia, Sweden and the Netherlands. We collected information by means of a questionnaire, 13 follow-up interviews with 20 experts from these organisations and document review.Results Performance indicators are used by participating oversight organisations to choose priority topics for audits, prioritise facilities to be audited and to identify areas within an audited facility, that require more attention. The indicators of most interest to oversight organisations are related to the dimensions of care articulated in the preset requirements on which audits are based. When the purpose of using indicators is to design a risk assessment model, the fitness for use of indicators ultimately depends on their ability to predict non-compliances on subsequent audits. When indicators are used directly by auditors, the ease of access, clear guidance to evaluate the data and the provision of contextual information are used by oversight organisations to increase fitness for use.Conclusions Oversight organisations do not use LTC facility performance indicators to assess quality, but rather to assess the risk of lower quality or of non-compliance with requirements. This risk-related purpose has to be considered when the indicators used in oversight are chosen and when other aspects of fitness for use, such as data analysis and displaying findings, are developed.

Introduction: Data and digital infrastructure drive collaboration and help develop integrated healthcare systems and services. COVID-19 induced changes to collaboration between healthcare organisations, which previously often happened in fragmented and competitive ways. New collaborative practices relied on data and were crucial in managing coordinated responses to the pandemic. In this study, we explored data-driven collaboration between European hospitals and other healthcare organisations in 2021 by identifying common themes, lessons learned and implications going forward. Methods: Study participants were recruited from an existing Europe-wide community of mid-level hospital managers. For data collection, we ran an online survey, conducted multi-case study interviews and organised webinars. Data were analysed using descriptive statistics, thematic analysis and cross-case synthesis. Results: Mid-level hospital managers from 18 European countries reported an increase in data exchange between healthcare organisations during the COVID-19 pandemic. Data-driven collaborative practices were goal-oriented and focused on the optimisation of hospitals’ governance functions, innovation in organisational models and improvements to data infrastructure. This was often made possible by temporarily overcoming system complexities, which would otherwise hinder collaboration and innovation. Sustainability of these developments remains a challenge. Discussion: Mid-level hospital managers form a huge potential of reacting and collaborating when needed, including rapidly setting up novel partnerships and redefining established processes. Major post-COVID unmet medical needs are linked to hospital care provision, including diagnostic and therapeutic backlogs. Tackling these will require rethinking of the position of hospitals within healthcare systems, including their role in care integration. Conclusion: Learning from COVID-19-induced developments in data-driven collaboration between hospitals and other healthcare organisations is important to address systemic barriers, sustain resilience and further build transformative capacity to help build better integrated healthcare systems.

Background Governments across the World Health Organization (WHO) European Region have prioritised dashboards for reporting COVID-19 data. The ubiquitous use of dashboards for public reporting is a novel phenomenon. Objective This study explores the development of COVID-19 dashboards during the first year of the pandemic and identifies common barriers, enablers and lessons from the experiences of teams responsible for their development. Methods We applied multiple methods to identify and recruit COVID-19 dashboard teams, using a purposive, quota sampling approach. Semi-structured group interviews were conducted from April to June 2021. Using elaborative coding and thematic analysis, we derived descriptive and explanatory themes from the interview data. A validation workshop was held with study participants in June 2021. Results Eighty informants participated, representing 33 national COVID-19 dashboard teams across the WHO European Region. Most dashboards were launched swiftly during the first months of the pandemic, February to May 2020. The urgency, intense workload, limited human resources, data and privacy constraints and public scrutiny were common challenges in the initial development stage. Themes related to barriers or enablers were identified, pertaining to the pre-pandemic context, pandemic itself, people and processes and software, data and users. Lessons emerged around the themes of simplicity, trust, partnership, software and data and change. Conclusions COVID-19 dashboards were developed in a learning-by-doing approach. The experiences of teams reveal that initial underpreparedness was offset by high-level political endorsement, the professionalism of teams, accelerated data improvements and immediate support with commercial software solutions. To leverage the full potential of dashboards for health data reporting, investments are needed at the team, national and pan-European levels.

Objectives To explore available data sources, secondary uses and key considerations for optimising the actionability of primary care prescribing data to improve quality of care in the Dutch context.Design An exploratory qualitative study was undertaken based on semi-structured interviews. We anchored our investigation around three tracer prescription types: antibiotics; benzodiazepines and opioids. Descriptive and explanatory themes were derived from interview data using thematic analysis.Setting Stakeholders were sampled from across the micro (clinical), meso (organisational) and macro (policy) contexts of the Dutch primary care system.Participants The study involved 28 informants representing general practitioners (GPs), community pharmacists, regional chronic care networks (care groups), academia and research institutes, insurers, professional associations, electronic health record (EHR) vendors and national authorities.Results In the Netherlands, three main sources of data for improving prescribing in primary care are in use: clinical data in the EHRs of GP practices; pharmacy data in community pharmacy databases and claims data of insurers. While the secondary use of pharmacy and claims data is well-established across levels, the use of these data together with EHR data is limited. Important differences in the types of prescribing information needed by micro-meso-macro context are found, though the extent to which current indicators address these varies by prescription type. Five main themes were identified as areas for optimising data use: (1) measuring what matters, (2) increasing data linkages, (3) improving data quality, (4) facilitating data sharing and (5) optimising fit for use analysis.Conclusions To make primary care prescribing data useful for improving quality, consolidated patient-specific data on the indication for a prescription and dispensed medicine, over time, is needed. In the Netherlands, the selection of indicators requires further prioritisation to better signal the appropriateness and long-term use of prescription drugs. Prioritising data linkages is critical towards more actionable use.

The majority of naturally elicited antibodies against the HIV-1 envelope glycoproteins (Env) are non-neutralizing (nnAbs) because they are unable to recognize the Env trimer in its native "closed" conformation. Nevertheless, it has been shown that nnAbs have the potential to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC) provided that Env is present on the cell surface in its "open" conformation. This is because most nnAbs recognize epitopes that become accessible only after Env interaction with CD4 and the exposure of epitopes that are normally occluded in the closed trimer. HIV-1 limits this vulnerability by downregulating CD4 from the surface of infected cells, thus preventing a premature encounter of Env with CD4. Small CD4-mimetics (CD4mc) sensitize HIV-1-infected cells to ADCC by opening the Env glycoprotein and exposing CD4-induced (CD4i) epitopes. There are two families of CD4i nnAbs, termed anti-cluster A and anti-CoRBS Abs, which are known to mediate ADCC in the presence of CD4mc. Here, we performed Fab competition experiments and found that anti-gp41 cluster I antibodies comprise a major fraction of the plasma ADCC activity in people living with HIV (PLWH). Moreover, addition of gp41 cluster I antibodies to cluster A and CoRBS antibodies greatly enhanced ADCC-mediated cell killing in the presence of a potent indoline CD4mc, CJF-III-288. This cocktail outperformed broadly neutralizing antibodies and even showed activity against HIV-1-infected monocyte-derived macrophages. Thus, combining CD4i antibodies with different specificities achieves maximal ADCC activity, which may be of utility in HIV cure strategies.IMPORTANCEThe elimination of HIV-1-infected cells remains an important medical goal. Although current antiretroviral therapy decreases viral loads below detection levels, it does not eliminate latently infected cells that form the viral reservoir. Here, we developed a cocktail of non-neutralizing antibodies targeting highly conserved Env regions and combined it with a potent indoline CD4mc. This combination exhibited potent ADCC activity against HIV-1-infected primary CD4 + T cells as well as monocyte-derived macrophages, suggesting its potential utility in decreasing the size of the viral reservoir., Competing Interests: The authors declare no conflict of interest.

HIV-1 envelope glycoproteins (Env) from primary HIV-1 isolates typically adopt a pretriggered "closed" conformation that resists to CD4-induced (CD4i) non-neutralizing antibodies (nnAbs) mediating antibody-dependent cellular cytotoxicity (ADCC). CD4-mimetic compounds (CD4mcs) "open-up" Env allowing binding of CD4i nnAbs, thereby sensitizing HIV-1-infected cells to ADCC. Two families of CD4i nnAbs, the anti-cluster A and anti-coreceptor binding site (CoRBS) Abs, are required to mediate ADCC in combination with the indane CD4mc BNM-III-170. Recently, new indoline CD4mcs with improved potency and breadth have been described. Here, we show that the lead indoline CD4mc, CJF-III-288, sensitizes HIV-1-infected cells to ADCC mediated by anti-CoRBS Abs alone, contributing to improved ADCC activity. Structural and conformational analyses reveal that CJF-III-288, in combination with anti-CoRBS Abs, potently stabilizes an asymmetric "open" State-3 Env conformation, This Env conformation orients the anti-CoRBS Ab to improve ADCC activity and therapeutic potential.

Natural Killer (NK) cells have the potential to eliminate HIV-1-infected cells by antibody-dependent cellular cytotoxicity (ADCC). NK cell activation is tightly regulated by the engagement of its inhibitory and activating receptors. The activating receptor CD16 drives ADCC upon binding to the Fc portion of antibodies; NK cell activation is further sustained by the co-engagement of activating receptors NTB-A and 2B4. During HIV-1 infection, Nef and Vpu accessory proteins contribute to ADCC escape by downregulating the ligands of NTB-A and 2B4. HIV-1 also evades ADCC by keeping its envelope glycoproteins (Env) in a "closed" conformation which effectively masks epitopes recognized by non-neutralizing antibodies (nnAbs) which are abundant in the plasma of people living with HIV. To achieve this, the virus uses its accessory proteins Nef and Vpu to downregulate the CD4 receptor, which otherwise interacts with Env and exposes the epitopes recognized by nnAbs. Small CD4-mimetic compounds (CD4mc) have the capacity to expose these epitopes, thus sensitizing infected cells to ADCC. Given the central role of NK cell co-activating receptors NTB-A and 2B4 in Fc-effector functions, we studied their contribution to CD4mc-mediated ADCC. Despite the fact that their ligands are partially downregulated by HIV-1, we found that both co-activating receptors significantly contribute to CD4mc sensitization of HIV-1-infected cells to ADCC.

We describe an approach for designing high-affinity small molecule-binding proteins poised for downstream sensing. We use deep learning-generated pseudocycles with repeating structural units surrounding central binding pockets with widely varying shapes that depend on the geometry and number of the repeat units. We dock small molecules of interest into the most shape complementary of these pseudocycles, design the interaction surfaces for high binding affinity, and experimentally screen to identify designs with the highest affinity. We obtain binders to four diverse molecules, including the polar and flexible methotrexate and thyroxine. Taking advantage of the modular repeat structure and central binding pockets, we construct chemically induced dimerization systems and low-noise nanopore sensors by splitting designs into domains that reassemble upon ligand addition.

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified 1-4 , the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Since the beginning of the SARS-CoV-2 pandemic, several variants of concern (VOCs), such as the Alpha, Beta, Gamma, Delta and Omicron variants, have arisen and spread worldwide. Today, the predominant circulating subvariants are sublineages of the Omicron variant, which have more than 30 mutations in their Spike glycoprotein compared to the ancestral strain. The Omicron subvariants were significantly less recognized and neutralized by antibodies from vaccinated individuals. This resulted in a surge in the number of infections, and booster shots were recommended to improve responses against these variants. While most studies mainly measured the neutralizing activity against variants, we and others previously reported that Fc-effector functions, including antibody-dependent cellular cytotoxicity (ADCC), play an important role in humoral responses against SARS-CoV-2. In this study, we analyzed Spike recognition and ADCC activity against several Omicron subvariants by generating cell lines expressing different Omicron subvariant Spikes. We tested these responses in a cohort of donors, who were recently infected or not, before and after a fourth dose of mRNA vaccine. We showed that ADCC activity is less affected than neutralization by the antigenic shift of the tested Omicron subvariant Spikes. Moreover, we found that individuals with a history of recent infection have higher antibody binding and ADCC activity against all Omicron subvariants than people who were not recently infected. With an increase in the number of reinfections, this study helps better understand Fc-effector responses in the context of hybrid immunity.

Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants have recently emerged, becoming the dominant circulating strains in many countries. These variants contain a large number of mutations in their spike glycoprotein, raising concerns about vaccine efficacy. In this study, we evaluate the ability of plasma from a cohort of individuals that received three doses of mRNA vaccine to recognize and neutralize these Omicron subvariant spikes. We observed that BA.4/5 and BQ.1.1 spikes are markedly less recognized and neutralized compared with the D614G and other Omicron subvariant spikes tested. Also, individuals who have been infected before or after vaccination present better humoral responses than SARS-CoV-2-naive vaccinated individuals, thus indicating that hybrid immunity generates better humoral responses against these subvariants., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

COVID-19 convalescent plasmas (CCPs) are chosen for plasma therapy based on neutralizing titers and anti-Spike immunoglobulin levels. However, CCP characteristics that promote SARS-CoV-2 control are complex and incompletely defined. Using an in vivo imaging approach, we demonstrate that CCPs with low neutralizing (ID 50  ≤ 1:250), but moderate to high Fc-effector activity, in contrast to those with poor Fc function, delay mortality and/or improve survival of SARS-CoV-2-challenged K18-hACE2 mice. The impact of innate immune cells on CCP efficacy depended on their residual neutralizing activity. Fractionation of a selected CCP revealed that IgG and Ig(M + A) were required during therapy, but the IgG fraction alone sufficed during prophylaxis. Finally, despite reduced neutralization, ancestral SARS-CoV-2-elicited CCPs significantly delayed Delta and Beta-induced mortality suggesting that Fc-effector functions contribute to immunity against VOCs. Thus, Fc activity of CCPs provide a second line of defense when neutralization is compromised and can serve as an important criterion for CCP selection., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ethanol is a known vertebrate teratogen that causes craniofacial defects as a component of fetal alcohol syndrome (FAS). Our results show that sea urchin embryos treated with ethanol similarly show broad skeletal patterning defects, potentially analogous to the defects associated with FAS. The sea urchin larval skeleton is a simple patterning system that involves only two cell types: the primary mesenchymal cells (PMCs) that secrete the calcium carbonate skeleton and the ectodermal cells that provide migratory, positional, and differentiation cues for the PMCs. Perturbations in RA biosynthesis and Hh signaling pathways are thought to be causal for the FAS phenotype in vertebrates. Surprisingly, our results indicate that these pathways are not functionally relevant for the teratogenic effects of ethanol in developing sea urchins. We found that developmental morphology as well as the expression of some ectodermal and PMC genes was delayed by ethanol exposure. Temporal transcriptome analysis revealed significant impacts of ethanol on signaling and metabolic gene expression, and a disruption in the timing of GRN gene expression that includes both delayed and precocious gene expression throughout the specification network. We conclude that the skeletal patterning perturbations in ethanol-treated embryos likely arise from a loss of temporal synchrony within and between the instructive and responsive tissues., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Emerging data highlight the interactions of preadmission glycemia, reflected by admission HbA1c levels, glycemic control during critical illness, and mortality. The association of preadmission insulin treatment with outcomes is unknown., Methods: This observational cohort study includes 5245 patients admitted to the medical-surgical intensive care unit of a university-affiliated teaching hospital. Three groups were analyzed: patients with diabetes with prior insulin treatment (DM-INS, n  = 538); patients with diabetes with no prior insulin treatment (DM-No-INS, n  = 986); no history of diabetes (NO-DM, n  = 3721). Groups were stratified by HbA1c level: <6.5%; 6.5%-7.9% and >8.0%., Results: Among the three strata of HbA1c, mean blood glucose (BG), coefficient of variation (CV), and hypoglycemia increased with increasing HbA1c, and were higher for DM-INS than for DM-No-INS. Among patients with HbA1c < 6.5%, mean BG ≥ 180 mg/dL and CV > 30% were associated with lower severity-adjusted mortality in DM-INS compared to patients with mean BG 80-140 mg/dL and CV < 15%, ( P  = .0058 and < .0001, respectively), but higher severity-adjusted mortality among DM-No-INS ( P  = .0001 and < .0001, respectively) and NON-DM ( P  < .0001 and < .0001, respectively). Among patients with HbA1c ≥ 8.0%, mean BG ≥ 180 mg/dL was associated with lower severity-adjusted mortality for both DM-INS and DM-No-INS than was mean BG 80-140 mg/dL ( p  < 0.0001 for both comparisons)., Conclusions: Significant differences in mortality were found among patients with diabetes based on insulin treatment and HbA1c at home and post-admission glycemic control. Prospective studies need to confirm an individualized approach to glycemic control in the critically ill.

Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)