Impact of Antimicrobial Stewardship Program Intervention Acceptance on Hospital Length of Stay.

Background: Inappropriate antibiotic use is a major public health concern. Excessive exposure to antibiotics results in the proliferation of multidrug-resistant bacteria, increase in potentially avoidable adverse drug reactions, healthcare utilization, and cost. Currently, systematic reviews and controlled trials assessing the effects of antimicrobial stewardship programs (ASP) on hospital length of stay (LOS), mortality, and cost-savings are conflicting. Some studies reported a significant cost-savings driven by shorter hospital LOS while the others found no effect and, in some cases, prolonged LOS. Shortening the time to appropriate therapy and reducing unnecessary days of therapy have been shown to reduce hospital LOS. Objective: The purpose of this study was to evaluate the effects of prescriber acceptance to ASP interventions on hospital LOS. Methods: Between January 2018 and December 2019, 764 charts were retrospectively reviewed for patients who received antimicrobial treatment and in whom an ASP intervention was performed. Patients were allocated into 2 groups: those whose ASP interventions were accepted and those whose were rejected. Provider responses were then documented within 24 hours of being communicated. The primary outcome was hospital LOS. Secondary outcomes included 30-day readmission rates and inpatient antimicrobial duration of therapy (DOT). Results: There were 384 patients with an accepted ASP intervention and 380 with a denied intervention. Baseline characteristics were similar between both groups, except for a difference in the types of intervention performed (P < 0.001). The median hospital LOS for patients in the accepted intervention group was 6.5 days compared to 7 days in the rejected intervention group (P = 0.009). Antimicrobial DOT was also shorter in the accepted intervention group (5 vs 7 days; P < 0.001). There was no difference in 30-day readmission rates (P = 0.98). Conclusion: Prescriber acceptance to ASP interventions decreases hospital LOS and antimicrobial DOT without affecting 30-day readmission rates.

Medical students and the response to COVID-19: Educational preparedness and psychological impact of their involvement in communicating with patients' relatives.

OBJECTIVES: The COVID-19 pandemic has challenged without precedent both healthcare and educational systems worldwide. How medical students could and should be engaged in the response remains unclear. Medical students were asked to help with communicating with patients' relatives in our institution. Authors aimed: to (i) present the rapid implementation and assessment of a teaching/e-teaching lesson in the COVID-19 era; (ii) report an early evaluation of preparedness, mental health and well-being of students involved. METHODS: The lesson was elaborated at lockdown in France. The clinical guidance consisted of a voluntary lesson entitled: "How to communicate with relatives of hospitalized COVID-19 patients?". Students received an anonymous online questionnaire after two weeks. RESULTS: Sixty-six medical students were trained (32% face-to-face). The response rate was 64%. Most students informed relatives about the routine care of the patient (95%). Concerning the lesson, students assured to have had one (95%), considered it relevant (86%), and had used the educational content (81%). 33% were charged with unexpected missions (only 36% felt prepared). Most of them did not report any psychological impact, but some reported anxiety or sleep disorders with no difference between face-to-face/distance training. CONCLUSIONS: This pandemic may last. Communication ability is a key competence in medical curriculum and is more than ever essential. Distance learning technologies may provide a useful and accepted tool for medical students. We report on a rapid feedback on what can be expected or not from students in terms of mission and short-term psychological consequences.

Controlled growth of ultrasmall Cu2O clusters on TiO2nanoparticles by atmospheric-pressure atomic layer deposition for enhanced photocatalytic activity.

This work presents a gas-phase approach for the synthesis of Cu2O/TiO2powder-based photocatalysts using atomic layer deposition (ALD). The process is carried out in a fluidized bed reactor working at atmospheric pressure using (trimethylvinylsilyl)-hexafluoroacetulacetonate copper(I) as the Cu-precursor and H2O vapor as the oxidizer. The saturating regime of the chemical reactions and the linear growth of ALD are achieved. In combination with the unsaturated regime, the ALD approach enables the deposition of ultrasmall Cu2O clusters with average diameters in the range of 1.3-2.0 nm, narrow particle size distributions and tunable Cu2O loadings on P25 TiO2nanoparticles. The photocatalytic performance of Cu2O/TiO2photocatalysts is investigated by the degradation of organic dyes, including Rhodamine B (RhB), methyl orange, and methylene blue; the results demonstrate that the surface modification of TiO2nanoparticles by Cu2O nanoclusters significantly enhances the photocatalytic activity of TiO2. This is attributed to the efficient charge transfer between Cu2O and TiO2that reduces the charge recombination. The photocatalytic reaction mechanism is further investigated for the degradation of RhB, revealing the dominating role of holes, which contribute to both direct hole oxidation and indirect oxidation (i.e. via the formation of hydroxyl radicals). Our approach provides a fast, scalable and efficient process to deposit ultrasmall Cu2O clusters in a controllable fashion for surface engineering and modification.

XPG-related nucleases are hierarchically recruited for double-stranded rDNA break resection.

dsDNA breaks (DSBs) are resected in a 5'→3' direction, generating single-stranded DNA (ssDNA). This promotes DNA repair by homologous recombination and also assembly of signaling complexes that activate the DNA damage checkpoint effector kinase Chk1. In fission yeast (Schizosaccharomyces pombe), genetic screens have previously uncovered a family of three xeroderma pigmentosum G (XPG)-related nucleases (XRNs), known as Ast1, Exo1, and Rad2. Collectively, these XRNs are recruited to a euchromatic DSB and are required for ssDNA production and end resection across the genome. Here, we studied why there are three related but distinct XRN enzymes that are all conserved across a range of species, including humans, whereas all other DSB response proteins are present as single species. Using S. pombe as a model, ChIP and DSB resection analysis assays, and highly efficient I-PpoI-induced DSBs in the 28S rDNA gene, we observed a hierarchy of recruitment for each XRN, with a progressive compensatory recruitment of the other XRNs as the responding enzymes are deleted. Importantly, we found that this hierarchy reflects the requirement for different XRNs to effect efficient DSB resection in the rDNA, demonstrating that the presence of three XRN enzymes is not a simple division of labor. Furthermore, we uncovered a specificity of XRN function with regard to the direction of transcription. We conclude that the DSB-resection machinery is complex, is nonuniform across the genome, and has built-in fail-safe mechanisms, features that are in keeping with the highly pathological nature of DSB lesions.

Identification and Characterization of a Poliovirus Capsid Mutant with Enhanced Thermal Stability.

Enteric viruses, including poliovirus, are spread by the fecal-oral route. In order to persist and transmit to a new host, enteric virus particles must remain stable once they are in the environment. Environmental stressors such as heat and disinfectants can inactivate virus particles and prevent viral transmission. It has been previously demonstrated that bacteria or bacterial surface glycans can enhance poliovirus virion stability and limit inactivation from heat or bleach. While investigating the mechanisms underlying bacterially enhanced virion thermal stability, we identified and characterized a poliovirus (PV) mutant with increased resistance to heat inactivation. The M132V mutant harbors a single amino acid change in the VP1 capsid coding that is sufficient to confer heat resistance but not bleach resistance. Although the M132V virus was stable in the absence of bacteria or feces at most temperatures, M132V virus was stabilized by feces at very high temperatures. M132V PV had reduced specific infectivity and RNA uncoating compared with those of wild-type (WT) PV, but viral yields in HeLa cells were similar. In orally inoculated mice, M132V had a slight fitness cost since fecal titers were lower and 12.5% of fecal viruses reverted to the WT. Overall, this work sheds light on factors that influence virion stability and fitness.IMPORTANCE Viruses spread by the fecal-oral route need to maintain viability in the environment to ensure transmission. Previous work indicated that bacteria and bacterial surface polysaccharides can stabilize viral particles and enhance transmission. To explore factors that influence viral particle stability, we isolated a mutant poliovirus that is heat resistant. This mutant virus does not require feces for stability at most temperatures but can be stabilized by feces at very high temperatures. Even though the mutant virus is heat resistant, it is susceptible to inactivation by treatment with bleach. This work provides insight into how viral particles maintain infectivity in the environment.

Efficacy of cefoxitin versus carbapenem in febrile male urinary tract infections caused by extended spectrum beta-lactamase-producing Escherichia coli: a multicenter retrospective cohort study with propensity score analysis.

Cefoxitin has demonstrated good in vitro activity against extended spectrum beta-lactamase (ESBL)-producing Escherichia coli (ESBL-Ec) and is regarded as a carbapenem-sparing beta-lactam alternative in urinary tract infections. Its efficacy has never been compared to carbapenems in male UTIs. Our study aimed to compare the clinical and microbiological efficacy of cefoxitin (FOX) and carbapenems (CP) in febrile M-UTI due to ESBL-Ec (F-M-UTI). We conducted a multicenter retrospective cohort study of patients with F-M-UTI treated with FOX or CP as definitive therapy, between January 2013 and June 2015, in six French acute care teaching hospitals. The clinical and microbiological efficacies of FOX and CP were compared using multivariable logistic regression models, adjusting for propensity scores. Of the 66 patients included, 23 patients in FOX group and 27 in CP group had clinical assessment at follow-up. Median follow-up after end of treatment was 63 days (interquartile range 26-114). Clinical success was observed for 17/23 (73.9%) and 22/27 (81.5%) patients and microbiological success for 11/19 (57.9%) and for 6/12 (50.0%) patients in FOX and CP groups respectively. We did not find any significant difference for clinical (OR = 0.90, 95% CI [0.12; 6.70]) neither microbiological (OR = 0.85, 95% CI [0.05; 14.00]) success between CP and FOX groups in univariate and multivariable models. In the FOX group, high dose with use of continuous infusion was associated with clinical success. These results add evidence that FOX is an effective alternative treatment to carbapenems for M-UTI caused by ESBL-Ec, particularly when high doses and continuous infusion are used.

Effectiveness of an education health programme about Middle East respiratory syndrome coronavirus tested during travel consultations.

OBJECTIVE: We aimed to evaluate the level of knowledge of Middle East respiratory syndrome coronavirus (MERS-CoV) among Hajj pilgrims before and after an education health programme during international vaccine consultations in France. STUDY DESIGN: A cross-sectional study was performed in the consultation for travel medicine and international vaccination in Reims University Hospital between July 2014 and October 2015. METHODS: Consecutive adults (>18 years old) who attended for pre-Hajj meningococcal vaccination were eligible to complete an anonymous questionnaire with closed answers to evaluate their level of knowledge about MERS-CoV. To evaluate the effectiveness of the information given during the consultation, the same questionnaire was completed by the Hajj pilgrim before and after the consultation, where the information about MERS-CoV was provided. RESULTS: Among 82 Hajj pilgrim adults enrolled in the study, less than 25% were aware of the routes of transmission, symptoms and preventive behaviours to adopt abroad or in case of fever. Pilgrims had a higher rate of correct responses on each question at the time they completed the second questionnaire, as compared with the first, with 11 of 13 questions answered significantly better after delivery of educational information about MERS-CoV. However, although the rate of correct answers to the questions about routes of transmission, symptoms, preventive behaviours to adopt in case of fever and time delay between return and potential MERS-CoV occurrence increased significantly after receiving the information, the rates remained below 50%. CONCLUSION: Information given during travel consultations significantly increases the general level of knowledge, but not enough to achieve epidemic control.

Usefulness of temporal bone prototype for drilling training: A prospective study.

OBJECTIVES: Dissection of cadaveric temporal bones (TBs) is considered the gold standard for surgical training in otology. For many reasons, access to the anatomical laboratory and cadaveric TBs is difficult for some facilities. The aim of this prospective and comparative study was to evaluate the usefulness of a physical TB prototype for drilling training in residency. DESIGN: Prospective study. SETTING: Tertiary referral centre. PARTICIPANTS: Thirty-four residents were included. Seventeen residents (mean age 26.7±1.6) drilled on only cadaveric TBs ("traditional" group), in the traditional training method, while seventeen residents (mean age 26.5±1.7) drilled first on a prototype and then on a cadaveric TB ("prototype" group). MAIN OUTCOME MEASURES: Drilling performance was assessed using a validated scale. Residents completed a mastoid image before and after each drilling to enable evaluation of mental representations of the mastoidectomy. RESULTS: No differences were observed between the groups with respect to age, drilling experience and level of residency. Regarding drilling performance, we found a significant difference across the groups, with a better score in the prototype group (P=.0007). For mental representation, the score was statistically improved (P=.0003) after drilling in both groups, suggesting that TB drilling improves the mental representation of the mastoidectomy whether prototype or cadaveric TB is used. CONCLUSION: The TB prototype improves the drilling performance and mental representation of the mastoidectomy in the young resident population. A drilling simulation with virtual or physical systems seems to be a beneficial tool to improve TB drilling.

Anatomical, functional and quality-of-life results for mastoid and epitympanic obliteration with bioactive glass s53p4: a prospective clinical study.

OBJECTIVE: To analyse the anatomical, functional and quality-of-life results when using bioactive glass in mastoid and epitympanic obliteration. DESIGN: Prospective clinical study. SETTING: Tertiary referral centre. PARTICIPANTS: Forty-one cases (39 patients) operated between May 2013 and January 2015. MAIN OUTCOME MEASURES: Anatomical results were evaluated by otomicroscopy 1 year after surgery and using imaging to detect residual disease. Functional results were studied by postoperative hearing gain. Quality of life was assessed with the Glasgow Benefit Inventory questionnaire and the success of surgery by a surgery-specific questionnaire. RESULTS: At 1 year, all patients presented a well-healed external auditory canal, with an intact tympanic membrane. In cases with cholesteatoma (n = 23), no recurrent retraction pockets or residual disease were observed on imaging studies. The overall air-bone gap closure was 7.7 ± 1.84 dB (mean ± se of the mean, P < 0.001, paired t-test). No significant differences were found on hearing results when comparing primary versus revision surgery, canal-wall-up versus canal-wall-down obliterations, type of tympanoplasty and presence of cholesteatoma (multifactor anova). The Glasgow Benefit Inventory improved with an average score of 28 and the success of surgery questionnaire showed a significant improvement in ear discharge and a moderate improvement in hearing and equilibrium. CONCLUSIONS: The use of bioactive glass for mastoid and epitympanic obliteration in canal-wall-down or canal-wall-up tympanoplasties is an effective procedure in both primary and revision surgery. The anatomical and functional results appear to be well correlated with patient experience and to the improvement in quality of life.

The Volume of the Spleen and Its Correlates after Acute Stroke.

BACKGROUND: Animal studies describe changes in the spleen following a stroke, with an immediate reduction in volume associated with changes in the counts of specific blood white blood cell (WBCs). This brain-spleen cell cycling after stroke affects systemic inflammation and the brain inflammatory milieu and may be a target for emerging therapeutic studies. This study aimed to evaluate features of this brain-spleen model in human patients admitted for acute stroke. METHODS: Medical and imaging records were retrospectively reviewed for 82 consecutive patients admitted for acute stroke in whom an abdominal computed tomography scan was performed. RESULTS: Mean ± SD splenic volume was 224.5 ± 135.5 cc. Splenic volume varied according to gender (P = .014) but not stroke subtype (ischemic versus hemorrhagic, P = .76). The change in splenic volume over time was biphasic (P = .04), with splenic volumes initially decreasing over time, reaching a nadir 48 hours after stroke onset, then increasing thereafter. Splenic volume was related inversely to percent blood lymphocytes (r = -.36, P = .001) and positively to percent blood neutrophils (r = .30, P = .006). CONCLUSIONS: Current results support that several features of brain-spleen cell cycling after stroke described in preclinical studies extend to human subjects, including the immediate contraction of splenic volume associated with proportionate changes in blood WBC counts. Splenic volume may be useful as a biomarker of systemic inflammatory events in clinical trials of interventions targeting the immune system after stroke.

Twenty-year trends in benzodiazepine dispensing in the Australian population.

AIM: Considerable concern has been expressed about overprescribing of benzodiazepines and related harms. Past analyses have relied on World Health Organization-defined daily doses (DDD) which are sometimes out of keeping with clinical usage. This study examines 20-year (1992-2011) trends of benzodiazepine dispensing in Australia using both DDD and Ashton equivalent dose. METHODS: Data from the Drug Utilisation Sub-Committee and the Pharmaceutical Benefits Scheme (PBS) website were analysed. Trends in number of prescriptions, DDD/1000 people/day and DDD/prescription were examined over time, and between states/territories. RESULTS: In the 20-year period, 174 080 904 scripts were recorded, with temazepam the most dispensed benzodiazepine (35% of scripts), followed by diazepam (23%). Overall recorded utilisation fell from 27.7 DDD/1000 people/day in 1992 to 20.8 in 2011 (24.9% decrease). There were striking changes in use of individual benzodiazepines over time, with reductions in oxazepam and flunitrazepam and dramatic increases in alprazolam. Since 1998, there has been a steady increase, albeit modest, in per script DDD. The DDD/1000 people/day for items dispensed through PBS/Repatriaton-PBS was highest in Tasmania and lowest in Northern Territory. CONCLUSION: Despite a modest overall decline in the amount of benzodiazepine dispensed, the level of use is still likely to reflect relative over-prescribing given the paucity of accepted indications for long-term use. Since 1998, there was a polynomial increase in quantity dispensed per script. The WHO-defined DDD for clonazepam seems inappropriate and could impede monitoring of its abuse. Other problems include lack of national data for medications not subsidised on PBS/Repatriation PBS. A broad policy approach is required, not one which targets only one particular benzodiazepine.

A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression.

Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8+ T cell activation and suppressed melanoma progression. CD63+ mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63+ mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.

Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Signaling.

Therapeutic resistance to immune checkpoint blockade has been commonly linked to the process of mesenchymal transformation (MT) and remains a prevalent obstacle across many cancer types. An improved mechanistic understanding for MT-mediated immune evasion promises to lead to more effective combination therapeutic regimens. Herein, we identify the Hedgehog transcription factor, Gli2, as a key node of tumor-mediated immune evasion and immunotherapy resistance during MT. Mechanistic studies reveal that Gli2 generates an immunotolerant tumor microenvironment through the upregulation of Wnt ligand production and increased prostaglandin synthesis. This pathway drives the recruitment, viability, and function of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) while also impairing type I conventional dendritic cell, CD8 + T cell, and NK cell functionality. Pharmacologic EP2/EP4 prostaglandin receptor inhibition and Wnt ligand inhibition each reverses a subset of these effects, while preventing primary and adaptive resistance to anti-PD-1 immunotherapy, respectively. A transcriptional Gli2 signature correlates with resistance to anti-PD-1 immunotherapy in stage IV melanoma patients, providing a translational roadmap to direct combination immunotherapeutics in the clinic. SIGNIFICANCE: Gli2-induced EMT promotes immune evasion and immunotherapeutic resistance via coordinated prostaglandin and Wnt signaling.

SdiA aids enterohemorrhagic Escherichia coli carriage by cattle fed a forage or grain diet.

Enterohemorrhagic Escherichia coli (EHEC) causes hemorrhagic colitis and life-threatening complications. The main reservoirs for EHEC are healthy ruminants. We reported that SdiA senses acyl homoserine lactones (AHLs) in the bovine rumen to activate expression of the glutamate acid resistance (gad) genes priming EHEC's acid resistance before they pass into the acidic abomasum. Conversely, SdiA represses expression of the locus of enterocyte effacement (LEE) genes, whose expression is not required for bacterial survival in the rumen but is necessary for efficient colonization at the rectoanal junction (RAJ) mucosa. Our previous studies show that SdiA-dependent regulation was necessary for efficient EHEC colonization of cattle fed a grain diet. Here, we compared the SdiA role in EHEC colonization of cattle fed a forage hay diet. We detected AHLs in the rumen of cattle fed a hay diet, and these AHLs activated gad gene expression in an SdiA-dependent manner. The rumen fluid and fecal samples from hay-fed cattle were near neutrality, while the same digesta samples from grain-fed animals were acidic. Cattle fed either grain or hay and challenged with EHEC orally carried the bacteria similarly. EHEC was cleared from the rumen within days and from the RAJ mucosa after approximately one month. In competition trials, where animals were challenged with both wild-type and SdiA deletion mutant bacteria, diet did not affect the outcome that the wild-type strain was better able to persist and colonize. However, the wild-type strain had a greater advantage over the SdiA deletion mutant at the RAJ mucosa among cattle fed the grain diet.

The acyl-homoserine lactone synthase YenI from Yersinia enterocolitica modulates virulence gene expression in enterohemorrhagic Escherichia coli O157:H7.

The human pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7 colonizes the rectoanal junction (RAJ) in cattle, its natural reservoir. Colonization at the RAJ poses a serious risk for fecal shedding and contamination of the environment. We previously demonstrated that EHEC senses acyl-homoserine lactones (AHLs) produced by the microbiota in the rumen to activate the gad acid resistance genes necessary for survival through the acidic stomachs in cattle and to repress the locus of enterocyte effacement (LEE) genes important for colonization of the RAJ, but unnecessary in the rumen. Devoid of AHLs, the RAJ is the prominent site of colonization of EHEC in cattle. To determine if the presence of AHLs in the RAJ could repress colonization at this site, we engineered EHEC to express the Yersinia enterocolitica AHL synthase gene yenI, which constitutively produces AHLs, to mimic a constant exposure of AHLs in the environment. The yenI(+) EHEC produces oxo-C6-homoserine lactone (oxo-C6-HSL) and had a significant reduction in LEE expression, effector protein secretion, and attaching and effacing (A/E) lesion formation in vitro compared to the wild type (WT). The yenI(+) EHEC also activated expression of the gad genes. To assess whether AHL production, which decreases LEE expression, would decrease RAJ colonization by EHEC, cattle were challenged at the RAJ with WT or yenI(+) EHEC. Although the yenI(+) EHEC colonized the RAJ with efficiency equal to that of the WT, there was a trend for the cattle to shed the WT strain longer than the yenI(+) EHEC.

[Artificial intelligence and internal medicine: The example of hydroxychloroquine according to ChatGPT]. / Les intelligences artificielles conversationnelles en médecine interne : l'exemple de l'hydroxychloroquine selon ChatGPT.

Artificial intelligence (AI) using deep learning is revolutionizing several fields, including medicine, with a wide range of applications. Available since the end of 2022, ChatGPT is a conversational AI or "chatbot", using artificial intelligence to dialogue with its users in all fields. Through the example of hydroxychloroquine (HCQ), we discuss its use for patients, clinicians, or researchers, and discuss its performance and limitations, particularly in relation to algorithmic bias. If AI tools using deep learning do not dispense with the expertise and experience of a clinician (at least, for the moment), they have a potential to improve or simplify our daily practice.

SARS-CoV-2 Reinfection and Severity of the Disease: A Systematic Review and Meta-Analysis.

Since the discovery of SARS-CoV-2, changes in genotype and reinfection with different variants have been observed in COVID-19-recovered patients, raising questions around the clinical pattern and severity of primary infection and reinfection. In this systematic review, we summarize the results of 23 studies addressing SARS-CoV-2 reinfections. A total of 23,231 reinfected patients were included, with pooled estimated reinfection rates ranging from 0.1 to 6.8%. Reinfections were more prevalent during the Omicron variant period. The mean age of reinfected patients was 38.0 ± 6. years and females were predominant among reinfected patients (M/F = 0.8). The most common symptoms during the first and second infection were fever (41.1%), cough (35.7% and 44.6%), myalgia (34.5% and 33.3%), fatigue (23.8% and 25.6%), and headaches (24.4% and 21.4%). No significant differences of clinical pattern were observed between primary infection and reinfection. No significant differences in the severity of infection were observed between primary infection and reinfection. Being female, being a patient with comorbidities, lacking anti-nucleocapsid IgG after the first infection, being infected during the Delta and Omicron wave, and being unvaccinated were associated with a higher risk of reinfection. Conflicting age-related findings were found in two studies. Reinfection with SARS-CoV-2 suggests that natural immunity is not long-lasting in COVID-19 patients.

COVID-19: A Review of Potential Treatments (Corticosteroids, Remdesivir, Tocilizumab, Bamlanivimab/Etesevimab, and Casirivimab/Imdevimab) and Pharmacological Considerations.

Objectives: In light of the ongoing global pandemic, this paper reviews data on a number of potential and approved agents for COVID-19 disease management, including corticosteroids, remdesivir, tocilizumab, and monoclonal antibody combinations. Dose considerations, potential drug-drug interactions, and access issues are discussed. Key findings: Remdesivir is the first antiviral agent approved for the treatment of COVID-19, based on results from large clinical trials showing reduction in recovery time, faster clinical improvement, and decrease in time to discharge with remdesivir. Dexamethasone and tocilizumab have demonstrated mortality benefits in large, randomized controlled trials. Consequently, the use of corticosteroids has become the standard of care for hospitalized patients with severe or critical COVID-19, while tocilizumab is recommended for use in combination with a corticosteroid in certain hospitalized patients. Recently, monoclonal antibody combinations bamlanivimab/etesevimab and casirivimab/imdevimab received emergency use authorizations for use in non-hospitalized patients with mild-to-moderate COVID-19 at high risk of disease progression. Summary: As data from large clinical trials emerge, the paradigm of COVID-19 treatments has shifted significantly. The use of corticosteroids, remdesivir, and tocilizumab depend on disease severity. Emerging data on monoclonal antibody combinations are promising, but further data are required. Pharmacists can play a role in ensuring appropriate access, correct administration, and safe use of COVID-19 treatments and are encouraged to stay abreast of new developments.

A SREBF2-dependent gene program drives an immunotolerant dendritic cell population during cancer progression.

Dendritic cells (cDCs) are essential mediators of anti-tumor immunity. Cancers have developed mechanisms to render DCs dysfunctional within the tumor microenvironment. Utilizing CD63 as a unique surface marker, we demonstrate that mature regulatory DCs (mregDCs) suppress DC antigen cross-presentation while driving T H 2 and regulatory T cell differentiation within tumor-draining lymph node tissues. Transcriptional and metabolic studies show that mregDC functionality is dependent upon the mevalonate biosynthetic pathway and the master transcription factor, SREBP2. Melanoma-derived lactate activates DC SREBP2 in the tumor microenvironment (TME) and drives mregDC development from conventional DCs. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promotes anti-tumor CD8 + T cell activation and suppresses melanoma progression. CD63 + mregDCs reside within the sentinel lymph nodes of melanoma patients. Collectively, this work describes a tumor-driven SREBP2-dependent program that promotes CD63 + mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME. One Sentence Summary: The metabolic transcription factor, SREBF2, regulates the development and tolerogenic function of the mregDC population within the tumor microenvironment.

Usage of RePlay as a Take-Home System to Support High-Repetition Motor Rehabilitation After Neurological Injury.

Stroke is a leading cause of chronic motor disability. While physical rehabilitation can promote functional recovery, several barriers prevent patients from receiving optimal rehabilitative care. Easy access to at-home rehabilitative tools could increase patients' ability to participate in rehabilitative exercises, which may lead to improved outcomes. Toward achieving this goal, we developed RePlay: a novel system that facilitates unsupervised rehabilitative exercises at home. RePlay leverages available consumer technology to provide a simple tool that allows users to perform common rehabilitative exercises in a gameplay environment. RePlay collects quantitative time series force and movement data from handheld devices, which provide therapists the ability to quantify gains and individualize rehabilitative regimens. RePlay was developed in C# using Visual Studio. In this feasibility study, we assessed whether participants with neurological injury are capable of using the RePlay system in both a supervised in-office setting and an unsupervised at-home setting, and we assessed their adherence to the unsupervised at-home rehabilitation assignment. All participants were assigned a set of 18 games and exercises to play each day. Participants produced on average 698 ± 36 discrete movements during the initial 1 hour in-office visit. A subset of participants who used the system at home produced 1593 ± 197 discrete movements per day. Participants demonstrated a high degree of engagement while using the system at home, typically completing nearly double the number of assigned exercises per day. These findings indicate that the open-source RePlay system may be a feasible tool to facilitate access to rehabilitative exercises and potentially improve overall patient outcomes.