Macrophage senescence in health and diseases.

Macrophage senescence, manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype, has long been considered harmful. Persistent senescence of macrophages may lead to maladaptation, immune dysfunction, and finally the development of age-related diseases, infections, autoimmune diseases, and malignancies. However, it is a ubiquitous, multi-factorial, and dynamic complex phenomenon that also plays roles in remodeled processes, including wound repair and embryogenesis. In this review, we summarize some general molecular changes and several specific biomarkers during macrophage senescence, which may bring new sight to recognize senescent macrophages in different conditions. Also, we take an in-depth look at the functional changes in senescent macrophages, including metabolism, autophagy, polarization, phagocytosis, antigen presentation, and infiltration or recruitment. Furthermore, some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated, not only emphasizing the possibility of regulating macrophage senescence to benefit age-associated diseases but also has an implication on the finding of potential targets or drugs clinically.

Proteomic Assessment of SKBR3/HER2+ Breast Cancer Cellular Response to Lapatinib and Investigational Ipatasertib Kinase Inhibitors.

Modern cancer treatment approaches aim at achieving cancer remission by using targeted and personalized therapies, as well as harnessing the power of the immune system to recognize and eliminate the cancer cells. To overcome a relatively short-lived response due to the development of resistance to the administered drugs, combination therapies have been pursued, as well. To expand the outlook of combination therapies, the objective of this study was to use high-throughput data generation technologies such as mass spectrometry and proteomics to investigate the response of HER2+ breast cancer cells to a mixture of two kinase inhibitors that has not been adopted yet as a standard treatment regime. The broader landscape of biological processes that are affected by inhibiting two major pathways that sustain the growth and survival of cancer cells, i.e., EGFR and PI3K/AKT, was investigated by treating SKBR3/HER2+ breast cancer cells with Lapatinib or a mixture of Lapatinib/Ipatasertib small molecule drugs. Changes in protein expression and/or activity in response to the drug treatments were assessed by using two complementary quantitative proteomic approaches based on peak area and peptide spectrum match measurements. Over 900 proteins matched by three unique peptide sequences (FDR<0.05) were affected by the exposure of cells to the drugs. The work corroborated the anti-proliferative activity of Lapatinib and Ipatasertib, and, in addition to cell cycle and growth arrest processes enabled the identification of several multi-functional proteins with roles in cancer-supportive hallmark processes. Among these, immune response, adhesion and migration emerged as particularly relevant to the ability to effectively suppress the proliferation and dissemination of cancer cells. The supplementation of Lapatinib with Ipatasertib further affected the expression or activity of additional transcription factors and proteins involved in gene expression, trafficking, DNA repair, and development of multidrug resistance. Furthermore, over fifty of the affected proteins represented approved or investigational targets in the DrugBank database, which through their protein-protein interaction networks can inform the selection of effective therapeutic partners. Altogether, our findings exposed a broad plethora of yet untapped opportunities that can be further explored for enhancing the anti-cancer effects of each drug as well as of many other multi-drug therapies that target the EGFR/ERBB2 and PI3K/AKT pathways. The data are available via ProteomeXchange with identifier PXD051094.

Effects of Anti-Seizure Medication on Neuregulin-1 Gene and Protein in Patients with First-Episode Focal Epilepsy.

Introduction: Neuregulin-1 (NRG-1) appears to play a role in the pathogenesis of several neuropsychiatric disorders, including epilepsy. We conducted a study to investigate the effect of anti-seizure medication on NRG-1 mRNA and NRG-1 protein levels in patients with first-episode focal epilepsy. Methods: The levels of NRG-1 mRNA isoforms (type I, II, III, and IV) in peripheral blood mononuclear cells (PBMCs) of 39 healthy controls, 39 first-episode focal epilepsy patients before anti-seizure medication (ASM) therapy and four weeks after administration of ASM were measured by RT-qPCR, and the levels of NRG-1 protein in the serum of samples of each group were determined using ELISA. In addition the relationship between efficacy, NRG-1 mRNA expression, and NRG-1 protein expression was analyzed. Results: The levels of NRG-1 mRNA progressively increased in patients with first-episode focal epilepsy treated with ASM and were distinctly different from those before medication, but remained lower than in healthy controls (all P < 0.001). Before and after drug administration, NRG-1 protein levels were substantially higher in epileptic patients than in healthy controls, and no significant changes were detected with prolonged follow-up (P < 0.001). Patients with epilepsy who utilized ASM were able to control seizures with an overall efficacy of 97.4%. There was a negative correlation between NRG-1 mRNA levels and efficacy: as NRG-1 mRNA levels increased, seizures reduced (all P < 0.05). Conclusion: Our research indicated that NRG-1 may play a role in the pathophysiology of epilepsy. NRG-1 mRNA may provide ideas for the discovery of novel epilepsy therapeutic markers and therapeutic targets for novel ASM.

Computational model for drug research.

This special issue focuses on computational model for drug research regarding drug bioactivity prediction, drug-related interaction prediction, modelling for immunotherapy and modelling for treatment of a specific disease, as conveyed by the following six research and four review articles. Notably, these 10 papers described a wide variety of in-depth drug research from the computational perspective and may represent a snapshot of the wide research landscape.

DNA methylation heterogeneity attributable to a complex tumor immune microenvironment prompts prognostic risk in glioma.

Gliomas are malignant tumours of the human nervous system with different World Health Organization (WHO) classifications, glioblastoma (GBM) with higher grade and are more malignant than lower-grade glioma (LGG). To dissect how the DNA methylation heterogeneity in gliomas is influenced by the complex cellular composition of the tumour immune microenvironment, we first compared the DNA methylation profiles of purified human immune cells and bulk glioma tissue, stratifying three tumour immune microenvironmental subtypes for GBM and LGG samples from The Cancer Genome Atlas (TCGA). We found that more intermediate methylation sites were enriched in glioma tumour tissues, and used the Proportion of sites with Intermediate Methylation (PIM) to compare intertumoral DNA methylation heterogeneity. A larger PIM score reflected stronger DNA methylation heterogeneity. Enhanced DNA methylation heterogeneity was associated with stronger immune cell infiltration, better survival rates, and slower tumour progression in glioma patients. We then created a Cell-type-associated DNA Methylation Heterogeneity Contribution (CMHC) score to explore the impact of different immune cell types on heterogeneous CpG site (CpGct) in glioma tissues. We identified eight prognosis-related CpGct to construct a risk score: the Cell-type-associated DNA Methylation Heterogeneity Risk (CMHR) score. CMHR was positively correlated with cytotoxic T-lymphocyte infiltration (CTL), and showed better predictive performance for IDH status (AUC = 0.96) and glioma histological phenotype (AUC = 0.81). Furthermore, DNA methylation alterations of eight CpGct might be related to drug treatments of gliomas. In conclusion, we indicated that DNA methylation heterogeneity is associated with a complex tumour immune microenvironment, glioma phenotype, and patient's prognosis.

Punitive legal responses to prenatal drug use in the United States: A survey of state policies and systematic review of their public health impacts.

BACKGROUND: Punitive legal responses to prenatal drug use may be associated with unintended adverse health consequences. However, in a rapidly shifting policy climate, current information has not been summarized. We conducted a survey of U.S. state policies that utilize criminal or civil legal system penalties to address prenatal drug use. We then systematically identified empirical studies evaluating these policies and summarized their potential public health impacts. METHODS: Using existing databases and original statutory research, we surveyed current U.S. state-level prenatal drug use policies authorizing explicit criminalization, involuntary commitment, civil child abuse substantiation, and parental rights termination. Next, we systematically identified quantitative associations between these policies and health outcomes, restricting to U.S.-based peer-reviewed research, published January 2000-December 2022. Results described study characteristics and synthesized the evidence on health-related harms and benefits associated with punitive policies. Validity threats were described narratively. RESULTS: By 2022, two states had adopted policies explicitly authorizing criminal prosecution, and five states allowed pregnancy-specific and drug use-related involuntary civil commitment. Prenatal drug use was grounds for substantiating civil child abuse and terminating parental rights in 22 and five states, respectively. Of the 16 review-identified articles, most evaluated associations between punitive policies generally (k = 12), or civil child abuse policies specifically (k = 2), and multiple outcomes, including drug treatment utilization (k = 6), maltreatment reporting and foster care entry (k = 5), neonatal drug withdrawal syndrome (NDWS, k = 4) and other pregnancy and birth-related outcomes (k = 3). Most included studies reported null associations or suggested increases in adverse outcome following punitive policy adoption. CONCLUSIONS: Nearly half of U.S. states have adopted policies that respond to prenatal drug use with legal system penalties. While additional research is needed to clarify whether such approaches engender overt health harms, current evidence indicates that punitive policies are not associated with public health benefits, and therefore constitute ineffective policy.

Co-located Heroin Assisted Treatment within primary care: A preliminary analysis of the implications for healthcare access, cost, and treatment delivery in the UK.

BACKGROUND: The UK is experiencing its highest rate of drug related deaths in 25 years. Poor and inconsistent access to healthcare negatively impacts health outcomes for people who use drugs. Innovation in models of care which promote access and availability of physical treatment is fundamental. Heroin Assisted Treatment (HAT) is a treatment modality targeted at the most marginalised people who use drugs, at high risk of mortality and morbidity. The first service-provider initiated HAT service in the UK ran between October 2019 and November 2022 in Middlesbrough, England. The service was co-located within a specialist primary care facility offering acute healthcare treatment alongside injectable diamorphine. METHODS: Analysis of anonymised health records for healthcare costs (not including drug treatment) took place using descriptive statistics prior and during engagement with HAT, at both three (n=15) and six (n=12) months. Primary outcome measures were incidents of wound care, skin and soft tissue infections (SSTIs), overdose (OD) events, unplanned overnight stays in hospital, treatment engagement (general and within hospital care settings) and ambulance incidents. Secondary outcome measures were costs associated with these events. RESULTS: A shift in healthcare access for participants during HAT engagement was observed. HAT service attendance appeared to support health promoting preventative care, and reduce reactive reliance on emergency healthcare systems. At three and six months, engagement for preventative wound care and treatment for SSTIs increased at the practice. Unplanned emergency healthcare interactions for ODs, overnight hospital stays, serious SSTIs, and ambulance incidents reduced, and there was an increase in treatment engagement (i.e. a reduction in appointments which were not engaged with). There was a decrease in treatment engagement in hospital settings. Changes in healthcare utilisation during HAT translated to a reduction in healthcare costs of 58% within six months compared to the same timeframe from the period directly prior to commencing HAT. CONCLUSION: This exploratory study highlights the potential for innovative harm reduction interventions such as HAT, co-located with primary care services, to improve healthcare access and engagement for a high-risk population. Increased uptake of primary healthcare services translated to reductions in emergency healthcare use and associated costs. Although costs of HAT provision are substantial, the notable cost-savings in health care should be an important consideration in service implementation planning.

New pharmacotherapies to tackle the unmet needs in bipolar disorder: a focus on acute suicidality.

INTRODUCTION: Suicidal behavior is relatively frequent in patients with bipolar disorder (BD) and constitutes their most frequent cause of death. Suicide rates remain high in patients with BD despite adherence to guidelines recommending lithium as first line, and/or antidepressants, antipsychotics, psychotherapy, psychosocial interventions, and electroconvulsive therapy. Hence the need to identify more effective and rapid anti-suicide interventions. AREAS COVERED: To tackle the unmet needs of pharmacotherapy, we investigated the PubMed database on 24-25 January 2024 using strategies like ('acute suicid*'[ti] OR 'suicide crisis syndrome' OR 'acute suicidal affective disturbance') AND (lithium[ti] OR clozapine[ti]), which obtained 3 results, and ('acute suicid*'[ti] OR 'suicide crisis syndrome' OR 'acute suicidal affective disturbance') AND (ketamine[ti] OR esketamine[ti] OR NMDA[ti] OR glutamat*[ti]), which yielded 14 results. We explored glutamatergic abnormalities in BD and suicide and found alterations in both. The noncompetitive NMDS antagonist ketamine and its S-enantiomer esketamine reportedly decrease acute suicidality. EXPERT OPINION: Intranasal esketamine or subcutaneous ketamine, single-bolus or intravenous, and possibly other glutamate receptor modulators may improve suicidal behavior in patients with unipolar and bipolar depression. This may be achieved through prompt remodulation of glutamate activity. The correct use of glutamatergic modulators could reduce acute suicidality and mortality in patients with BD.

What features of drug treatment programs help, or not, with access? a qualitative study of the perspectives of family members and community-based organization staff in Atlantic Canada.

BACKGROUND: Withdrawal management and opioid agonist treatment (OAT) programs help to reduce some of the harms experienced by people who use substances (PWUS). There is literature on how features of drug treatment programs (e.g., policies and practices) are helpful, or not helpful, to PWUS when seeking access to, or in, treatment. There is, however, relatively little literature based on the perspectives of family members/family of choice of PWUS and community-based organization staff within the context of Atlantic Canada. This paper explored the perspectives of these two groups on what was helpful, or not, about drug treatment programs in Atlantic Canada in terms of supporting access to, and retention in, treatment. METHODS: One-on-one qualitative telephone interviews were conducted in 2020 with the two groups. Interviews focused on government-funded withdrawal management and OAT programs. Data were coded using a qualitative data management program (ATLAS.ti) and analyzed inductively for key themes/subthemes using grounded theory techniques. RESULTS: Fifteen family members/family of choice and 16 community-based organization staff members participated (n = 31). Participants spoke about features of drug treatment programs in various places, and noted features that were perceived as helpful (e.g., quick access), as well as not helpful (e.g., wait times, programs located far from where PWUS live). Some participants provided their perceptions of how PWUS felt when seeking or accessing treatment. A number of participants reported taking various actions to help support access to treatment, including providing transportation to programs. A few participants also provided suggestions for change to help support access and retention such as better alignment of mental health and addiction systems. CONCLUSIONS: Participants highlighted several helpful and not helpful features of drug treatment programs in terms of supporting treatment access and retention. Previous studies with PWUS and in other places have reported similar features, some of which (e.g., wait times) have been reported for many years. Changes are needed to reduce barriers to access and retention including the changes recommended by study participants. It is critical that the voices of key groups, (including PWUS) are heard to ensure treatment programs in all places support access and retention.

Impact of COVID-19 Treatment on Real-World Outcomes in Inflammatory Bowel Disease.

BACKGROUND: While there are multiple safe and effective agents for COVID-19 treatment, their impact in inflammatory bowel disease (IBD) remains uncertain. AIMS: Our objective was to assess the effects of these therapies on both IBD and COVID outcomes. METHODS: A single-center retrospective study of adult patients with IBD who contracted COVID-19 between 12/2020 and 11/2022 was performed. Patients were stratified by COVID-19 treatment (antivirals and/or intravenous antibodies) vs no therapy. The primary outcome was the development of severe COVID-19 infection, defined by need for supplemental oxygen, corticosteroids and/or antibiotics, or hospitalization. Secondary outcomes included rates of withholding advanced IBD therapy (defined as biologic agents or small molecules) and of post-COVID-19 IBD flare. RESULTS: Of 127 patients with COVID-19 infection, 70% were on advanced therapies, 35% received COVID-19 treatment, and 15% developed severe COVID-19. Those treated for COVID-19 were more likely to be on corticosteroids [odds ratio (OR) 4.61, 95% confidence interval (CI) 1.72-12.39, p = 0.002] or advanced IBD therapies (OR 2.78, 95% CI 1.04-7.43, p = 0.041). After adjusting for age, race, sex, corticosteroid use, obesity, COVID-19 vaccination status, and severe COVID-19 infection, those treated for COVID-19 were more likely to have IBD therapy held (OR 6.95, 95% CI 1.72-28.15, p = 0.007). There was no significant difference in rates of post-COVID-19 IBD flares or severe COVID-19 infection. There were no COVID-related deaths. CONCLUSIONS: Patients with IBD on advanced therapies were frequently treated for acute COVID-19. Although COVID-19 treatment was associated with temporary withholding of IBD therapy, it did not result in increased IBD flares.

[Health alerts for substandard, falsified, and unregistered medical products at the onset of the COVID-19 pandemic in the AmericasAlertas de saúde para produtos médicos abaixo do padrão, falsificados e não registrados no início da pandemia de COVID-19 nas Américas]. / Alertas sanitarias de productos médicos subestándares, falsificados y no registrados al inicio de la pandemia de COVID-19 en las Américas.

Objective: Identify and analyze incidents of substandard, falsified, unregistered, and stolen medical products at the onset of the COVID-19 pandemic. Methods: Detailed search of the websites of regulatory authorities in the Americas. Identification of incidents of substandard, falsified, unregistered, and stolen medicines and medical devices (including in vitro diagnostics). The types of products were determined, as were the stages in the supply chain where they were detected, and the actions taken by authorities. Results: A total of 1 273 incidents were identified in 15 countries (1 087 substandard, 44 falsified, 123 unregistered, and 19 stolen products). The largest number of incidents involved medical devices, disinfectants, and antiseptics. The most frequently reported point in the supply chain was online purchasing. The principal measures taken by the regulatory authorities were: alerts, prohibition of use, prohibition of advertising and manufacture, recall, and monitoring of adverse events. Conclusions: A substantial number of incidents involving substandard, falsified, unregistered, and stolen medical products at the onset of the COVID-19 pandemic were identified. Shortages of supplies, easing of regulatory requirements, and increased demand are factors that may have led to an increase in the number of incidents. The national regulatory authorities of reference reported more frequent detection of incidents and more frequent application of health measures. A regulatory strategy is needed in order to address online sales and ensure the safe distribution of medical products.

Objetivo: Identificar e analisar incidentes de produtos médicos abaixo do padrão, falsificados, não registrados e roubados no início da pandemia de COVID-19. Métodos: Foi realizada uma busca detalhada nos sites das autoridades reguladoras das Américas. Foram identificados incidentes envolvendo medicamentos e dispositivos médicos (incluindo para diagnóstico in vitro) abaixo do padrão, falsificados, não registrados e roubados. Foram determinados os tipos de produtos, os estágios da cadeia de abastecimento em que foram detectados e as medidas tomadas pelas autoridades. Resultados: Foram identificados 1 273 incidentes em 15 países (1 087 produtos abaixo do padrão, 44 falsificados, 123 não registrados e 19 roubados). O maior número de incidentes estava relacionado a dispositivos médicos, desinfetantes e antissépticos. O ponto na cadeia de abastecimento com a maior frequência de relatos foi a de aquisição pela internet. As medidas tomadas pelas autoridades reguladoras foram principalmente alertas, proibições de uso, proibições de publicidade e fabricação, recolhimento de produtos do mercado e monitoramento de eventos adversos. Conclusões: Houve um número significativo de incidentes envolvendo produtos médicos abaixo do padrão falsificados, não registrados e roubados no início da pandemia de COVID-19. A escassez de insumos, a flexibilização das exigências regulatórias e o aumento da demanda são fatores que podem levar a um maior número de incidentes. As autoridades reguladoras nacionais de referência informaram um aumento na frequência de detecção de incidentes e implementação de medidas sanitárias. O canal de vendas pela internet precisa ser abordado com alguma estratégia regulatória para garantir a distribuição segura de produtos médicos.

Comparative responses to 17 different antidepressants in major depressive disorder: Results from a 2-year long-term nation-wide population-based study emulating a randomized trial.

BACKGROUND: Long-term studies comparing nonresponse to antidepressants for major depressive disorder (MDD) are lacking. AIMS: To present systematic population-based nation-wide register data on comparative 2-year non-response within six antidepressant drug classes and 17 different antidepressants in patients with MDD. METHOD: The study included all 106,920 patients in Denmark with a first main index diagnosis of MDD at a psychiatric hospital inpatient or outpatient contact and who subsequently had a purchase of an antidepressant in the period from 1995 to 2018. Non-response to first antidepressant within a 2-year study period was defined as switch to or add-on of another antidepressant, antipsychotic medication, lithium, or hospitalization. Analyses emulated a targeted trial in populations standardized according to age, sex, socioeconomic status, and comorbidity with psychiatric and physical disorders. RESULTS: Compared with sertraline, there was no difference for citalopram (RR: 1.00 [95% CI: 0.98-1.02]) but fluoxetine (1.13 [95% CI: 1.10-1.17]), paroxetine (1.06 [95% CI: 1.01-1.10]) and escitalopram (1.22 [95% CI: 1.18-1.25]) were associated with higher risk ratio of non-responses. Within selective noradrenaline reuptake inhibitors, sertraline outperformed reboxetine; within serotonin-norepinephrine reuptake inhibitors, venlafaxine outperformed duloxetine; within noradrenergic and specific serotonergic antidepressants, mirtazapine outperformed mianserin and within the class of other antidepressants, sertraline outperformed agomelatine and vortioxetine. Within tricyclic antidepressants, compared to amitriptyline, nortriptyline, dosulepin, and clomipramine had higher non-response, whereas there was no difference for imipramine. CONCLUSIONS: These analyses emulating a randomized trial of "real world" observational register-based data show that 2-year long-term non-responses to some antidepressants within six different drug classes are increased over others.

Real world drug treatment models for pregnancy complicated with urinary tract infection in China from 2018 to 2022: a cross-section analysis.

Objective: Urinary tract infection (UTI) is common in pregnant women. The selection of anti-infection plans during pregnancy must take into account the dual factors of patient pregnancy status and urinary tract infection anti-infection treatment, as well as the efficacy, cost, risk, and potential adverse reactions associated with each method applied to individual patients. Consequently, there are numerous drugs from which to choose; presently, there is no unified conclusion regarding the choice of drug therapy, and there is a lack of long-term drug treatment for UTI during pregnancy. Our objective is to investigate the actual drug treatment patterns of UTI patients during pregnancy in China over the past 5 years, with a particular emphasis on the trend and rationality of antibiotic use in these patients over the past 5 years. Method: We conducted a cross-sectional analysis of data from a China Medical Association-supervised hospital prescription analysis cooperation initiative. From January 2018 to December 2022, the information is extracted from prescriptions/medical orders of patients with UTI during pregnancy. Using a primary anatomical therapeutic chemistry (ATC) classification code and the US Food and Drug Administration (FDA) classification, we quantified the frequency of drug use and drug types. We also calculated the prevalence of the most frequently prescribed antibacterial medications and assessed the efficacy of anti-infection plans based on drug labels and guidelines. Results: Among the 563 patients included in this research, Chengdu (36.59%), Guangzhou (27.72%), and Shanghai (8.70%) were the top three cities. Over the course of 5 years, the average age was 29.60% ± 6.59 years, with approximately 60.21% of women between the ages of 25 and 34. Each patient's primary anti-infection medications were statistically analyzed. Cephalosporins (403, 71.58%), enzyme inhibitors (66, 11.72%), and penicillins (34, 6.04%) were the first few categories, followed by the most commonly used cephalosporins. Cefuroxime, ceftriaxone, and cefdinib, rounded out the top five. Cefoxitin and cefaclor. According to the 5-year change in dosage, cephalosporins have always ranked first. Three of the top five most expensive drugs are cephalosporins, carbapenems, and enzyme inhibitors. Teicoplanin, tigecycline, nifurtel, linezolid, and quinolones ranked among the top five in terms of per-patient drug costs for patients receiving comprehensive treatment drugs. Conclusion: In the 5 years of research, the average age of patients who visit a doctor has not increased substantially, but the opportunity cost of female fertility has increased, which has severely impeded the fulfillment of fertility desires. The selection of medications is generally reasonable, and the dosage of the first-line cephalosporins recommended by the guidelines is relatively high in this study. The dosage of furantoin and fosfomycin, which are more prevalent in urinary tract infections, is however relatively low. In addition, some expensive pharmaceuticals may increase patients' financial burden. On the premise of meeting clinical needs, future research will focus on how to further improve the level of rational drug use in outpatient clinics, attain economical, safe, and effective drug use, and thus reduce the economic burden on patients.

Determining and Comparing the Real-World Effectiveness of Molnupiravir and Nirmatrelvir-Ritonavir in Patients Hospitalized With COVID-19.

BACKGROUND: Current guidelines recommend using nirmatrelvir-ritonavir for coronavirus disease 2019 (COVID-19) treatment, but its potential drug interactions and contraindications limit its applicability in certain categories of patients. The aim of the study was to evaluate the real-world effectiveness of molnupiravir and nirmatrelvir-ritonavir in managing COVID-19 among hospitalized patients. METHODS: We conducted a retrospective cohort study among hospitalized COVID-19 patients who received molnupiravir or nirmatrelvir-ritonavir and did not require baseline supplemental oxygen from February 2022 to January 2023. We compared the effectiveness of molnupiravir and nirmatrelvir-ritonavir with a focus on disease progression. RESULTS: The study included 401 high-risk, hospitalized adult COVID-19 patients who received molnupiravir or nirmatrelvir-ritonavir. No significant difference was found in disease progression, the composite outcome of disease progression (4.0% vs. 1.4%, P = 0.782), and O2 supplementation via nasal prong (21.8% vs. 14.8%, P = 0.115) between the patients treated with molnupiravir and those treated with nirmatrelvir-ritonavir. This finding was similar after 1:1 propensity-score matching. In the multivariate analysis, molnupiravir treatment was not significantly associated with progression to severe disease. CONCLUSION: In conclusion, our findings suggest that similar to nirmatrelvir-ritonavir, molnupiravir has a distinct potential role in COVID-19 treatment, transcending its current perceived status as only a secondary option.

Perceptions of prospective pharmaceutical stimulant substitution treatments among people who use illicit stimulants in Vancouver, Canada.

BACKGROUND: Stimulant-involved overdose deaths are increasing, driven by polysubstance use and adulteration of the illicit drug supply. While emerging evidence for prescription stimulant substitution is promising, there are no approved treatment options for stimulant use disorder that address the realities of an unpredictable drug supply. This study explores treatment experiences of people who use illicit stimulants (PWUS) to identify gaps and perceptions of prospective pharmaceutical stimulant substitution treatments (SST). METHODS: In-depth qualitative interviews were conducted with 86 PWUS in Vancouver, Canada. Thematic analysis focused on experiences of available treatment options for stimulant use and perceptions of prospective SST. RESULTS: Participants identified how primarily behavioral treatment approaches do not meet the unique needs of PWUS, in contrast with the range of medical treatments available for opioid use disorder. Participants anticipated health and social benefits if they were able to access SST, including avoiding the toxic illicit stimulant supply, reduced engagement in criminalized activities, and greater economic security. Perceptions of prospective SST were informed by knowledge of existing opioid treatments. This led some participants to be unsupportive of SST, citing concerns around agency and highly regulated operational contexts that do not align with the lived realities of stimulant use. CONCLUSION: Findings demonstrate the need for SST pilot programs in real-world settings and underscore the health and social advantages SST may offer; although drawing on existing opioid treatment models to implement SST pilots may limit success. Thus, any novel treatments for stimulant use must centre the lived realities of PWUS.

Pharmacogenetic and pharmacogenomic treatment of rheumatoid arthritis: a review of Pharmacogenomics Knowledge Base scientific evidence.

Tweetable abstract Update on the genetic variants with the highest level of Pharmacogenomics Knowledge Base evidence for their association with toxicity and efficacy in response to the most commonly used disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis.

Evaluating in vivo effectiveness of sotrovimab for the treatment of Omicron subvariant BA.2 versus BA.1: a multicentre, retrospective cohort study.

BACKGROUND: In vitro data suggested reduced neutralizing capacity of sotrovimab, a monoclonal antibody, against Omicron BA.2 subvariant. However, limited in vivo data exist regarding clinical effectiveness of sotrovimab for coronavirus disease 2019 (COVID-19) due to Omicron BA.2. METHODS: A multicentre, retrospective cohort study was conducted at three Canadian academic tertiary centres. Electronic medical records were reviewed for patients ≥ 18 years with mild COVID-19 (sequencing-confirmed Omicron BA.1 or BA.2) treated with sotrovimab between February 1 to April 1, 2022. Thirty-day co-primary outcomes included hospitalization due to moderate or severe COVID-19; all-cause intensive care unit (ICU) admission, and all-cause mortality. Risk differences (BA.2 minus BA.1 group) for co-primary outcomes were adjusted with propensity score matching (e.g., age, sex, vaccination, immunocompromised status). RESULTS: Eighty-five patients were included (15 BA.2, 70 BA.1) with similar baseline characteristics between groups. Adjusted risk differences were non-statistically significant between groups for 30-day hospitalization (- 14.3%; 95% confidence interval (CI): - 32.6 to 4.0%), ICU admission (- 7.1%; 95%CI: - 20.6 to 6.3%), and mortality (- 7.1%; 95%CI: - 20.6 to 6.3%). CONCLUSIONS: No differences were demonstrated in hospitalization, ICU admission, or mortality rates within 30 days between sotrovimab-treated patients with BA.1 versus BA.2 infection. More real-world data may be helpful to properly assess sotrovimab's effectiveness against infections due to specific emerging COVID-19 variants.

Identification of MDK as a Hypoxia- and Epithelial-Mesenchymal Transition-Related Gene Biomarker of Glioblastoma Based on a Novel Risk Model and In Vitro Experiments.

BACKGROUND: Tumor cells are commonly exposed to a hypoxic environment, which can easily induce the epithelial-mesenchymal transition (EMT) of tumor cells, further affecting tumor proliferation, invasion, metastasis, and drug resistance. However, the predictive role of hypoxia and EMT-related genes in glioblastoma (GBM) has not been investigated. METHODS: Intersection genes were identified by weighted correlation network analysis (WGCNA) and differential expression analyses, and a risk model was further constructed by LASSO and Cox analyses. Clinical, immune infiltration, tumor mutation, drug treatment, and enrichment profiles were analyzed based on the risk model. The expression level of the MDK gene was tested using RT-PCR, immunohistochemistry, and immunofluorescence. CCK8 and EdU were employed to determine the GBM cells' capacity for proliferation while the migration and invasion ability were detected by a wound healing assay and transwell assay, respectively. RESULTS: Based on the GBM data of the TCGA and GTEx databases, 58 intersection genes were identified, and a risk model was constructed. The model was verified in the CGGA cohort, and its accuracy was confirmed by the ROC curve (AUC = 0.807). After combining clinical subgroups, univariate and multivariate Cox regression analyses showed that risk score and age were independent risk factors for GBM patients. Furthermore, our subsequent analysis of immune infiltration, tumor mutation, and drug treatment showed that risk score and high- and low-risk groups were associated with multiple immune cells, mutated genes, and drugs. Enrichment analysis indicated that the differences between high- and low-risk groups were manifested in tumor-related pathways, including the PI3K-AKT and JAK-STAT pathways. Finally, in vivo experiments proved that the hypoxia environment promoted the expression of MDK, and MDK knockdown reduced the proliferation, migration, and EMT of GBM cells induced by hypoxia. CONCLUSIONS: Our novel prognostic correlation model provided more potential treatment strategies for GBM patients.

How Real-World Data Can Facilitate the Development of Precision Medicine Treatment in Psychiatry.

Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification and holds great potential for the treatment of mental disorders. However, several important factors are needed to transform current practice into a precision psychiatry framework. Most important are 1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, 2) the development and validation of advanced analytical tools for stratification and prediction, and 3) the development of clinically useful management platforms for patient monitoring that can be integrated into health care systems in real-life settings. This narrative review summarizes strategies for obtaining the key elements-well-powered samples from large biobanks integrated with electronic health records and health registry data using novel artificial intelligence algorithms-to predict outcomes in severe mental disorders and translate these models into clinical management and treatment approaches. Key elements are massive mental health data and novel artificial intelligence algorithms. For the clinical translation of these strategies, we discuss a precision medicine platform for improved management of mental disorders. We use cases to illustrate how precision medicine interventions could be brought into psychiatry to improve the clinical outcomes of mental disorders.