International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics: Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists: An executive summary.

Intravenous ß-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. ß-lactams are well established to display time-dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PI) can be applied during the administration of intravenous ß-lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of ß-lactam PI developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug monitoring considerations, and the use of PI ß-lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of ß-lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP).

International consensus recommendations for the use of prolonged-infusion beta-lactam antibiotics: Endorsed by the American College of Clinical Pharmacy, British Society for Antimicrobial Chemotherapy, Cystic Fibrosis Foundation, European Society of Clinical Microbiology and Infectious Diseases, Infectious Diseases Society of America, Society of Critical Care Medicine, and Society of Infectious Diseases Pharmacists.

Intravenous ß-lactam antibiotics remain a cornerstone in the management of bacterial infections due to their broad spectrum of activity and excellent tolerability. ß-lactams are well established to display time-dependent bactericidal activity, where reductions in bacterial burden are directly associated with the time that free drug concentrations remain above the minimum inhibitory concentration (MIC) of the pathogen during the dosing interval. In an effort to take advantage of these bactericidal characteristics, prolonged (extended and continuous) infusions (PIs) can be applied during the administration of intravenous ß-lactams to increase time above the MIC. PI dosing regimens have been implemented worldwide, but implementation is inconsistent. We report consensus therapeutic recommendations for the use of PI ß-lactams developed by an expert international panel with representation from clinical pharmacy and medicine. This consensus guideline provides recommendations regarding pharmacokinetic and pharmacodynamic targets, therapeutic drug-monitoring considerations, and the use of PI ß-lactam therapy in the following patient populations: severely ill and nonseverely ill adult patients, pediatric patients, and obese patients. These recommendations provide the first consensus guidance for the use of ß-lactam therapy administered as PIs and have been reviewed and endorsed by the American College of Clinical Pharmacy (ACCP), the British Society for Antimicrobial Chemotherapy (BSAC), the Cystic Fibrosis Foundation (CFF), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Infectious Diseases Society of America (IDSA), the Society of Critical Care Medicine (SCCM), and the Society of Infectious Diseases Pharmacists (SIDP).

Transition Regret and Detransition: Meanings and Uncertainties.

Gender transition is undertaken to improve the well-being of people suffering from gender dysphoria. However, some have argued that the evidence supporting medical interventions for gender transition (e.g., hormonal therapies and surgery) is weak and inconclusive, and an increasing number of people have come forward recently to share their experiences of transition regret and detransition. In this essay, I discuss emerging clinical and research issues related to transition regret and detransition with the aim of arming clinicians with the latest information so they can support patients navigating the challenges of regret and detransition. I begin by describing recent changes in the epidemiology of gender dysphoria, conceptualization of transgender identification, and models of care. I then discuss the potential impact of these changes on regret and detransition; the prevalence of desistance, regret, and detransition; reasons for detransition; and medical and mental healthcare needs of detransitioners. Although recent data have shed light on a complex range of experiences that lead people to detransition, research remains very much in its infancy. Little is known about the medical and mental healthcare needs of these patients, and there is currently no guidance on best practices for clinicians involved in their care. Moreover, the term detransition can hold a wide array of possible meanings for transgender-identifying people, detransitioners, and researchers, leading to inconsistences in its usage. Moving forward, minimizing harm will require conducting robust research, challenging fundamental assumptions, scrutinizing of practice patterns, and embracing debate.

Inclusion of pregnant and breastfeeding women in nonobstetrical randomized controlled trials.

BACKGROUND: There is an urgent need to prioritize and expedite the inclusion of pregnant and breastfeeding women in research. Characterizing trials that have successfully included these populations could inform the design and execution of future studies. In addition, up-to-date data on their inclusion in clinical research could assist in setting benchmarks, establishing targets, and monitoring progress toward more equitable inclusion. OBJECTIVE: This study aimed to characterize the eligibility and enrollment of pregnant and breastfeeding women in randomized controlled trials evaluating interventions for nonobstetrical conditions experienced by, but not limited to, these populations. STUDY DESIGN: We developed a literature search in collaboration with an information specialist. We included randomized controlled trials published between 2017 and 2019 in the 5 highest-impact general medicine journals and the 3 highest-impact specialty journals in cardiovascular disease, critical care, general infectious diseases, HIV, and psychiatry. We included randomized controlled trials that evaluated screening, diagnosis, prevention, or treatment of nonobstetrical medical conditions. We excluded randomized controlled trials exclusively focused on males, pediatrics, geriatrics, oncology, or postmenopausal women, and publications reporting subgroup, pooled, or follow-up analyses of previously published randomized controlled trials. We screened titles and abstracts independently and in duplicate, with discrepancies resolved by a third reviewer. We entered data into a standardized electronic case report form. We reviewed study protocols, appendices, and trial registries for additional data. RESULTS: Of the 1333 randomized controlled trials, pregnant and breastfeeding women were eligible for 13 (1.0%) and 6 (0.5%), respectively. Pregnancy and breastfeeding eligibility criteria were not addressed in 383 of 1333 (28.7%) and 710 of 1333 (53.3%) randomized controlled trials, respectively. In total, 102 of 937 (10.9%) and 33 of 617 (5.3%) randomized controlled trials that explicitly excluded pregnant and breastfeeding women documented the rationale. Most studies excluding pregnant women (542/937; 57.8%) required at least 1 method of contraception and/or pregnancy testing as part of trial participation for women with reproductive capacity. Among the 13 randomized controlled trials that allowed inclusion of pregnant women, 3 restricted eligibility to specific trimesters. Two randomized controlled trials enrolled pregnant women after the first year of the study following interim review of safety results in nonpregnant participants. Four randomized controlled trials reported the number of pregnant women enrolled, which ranged from 0.7% to 3.4% of the study population. None of the studies reported on pregnancy or perinatal outcomes. Compared with randomized controlled trials that excluded pregnant women, those including them more commonly had an infectious disease focus (12/13 [92.3%] vs 270/937 [28.8%]; p<.0001), including HIV (5/13 [38.5%] vs 96/937 [10.2%]; p=.0079), enrolled participants in sub-Saharan Africa (5/13 [38.5%] vs 111/937 [11.8%]; p=.0143), and had exclusively nonindustry sponsorship (13/13 [100%] vs 559/937 [59.7%]; p=.0025); inclusion varied by study phase, randomization level, and intervention type. CONCLUSION: This study illustrates a major inequity in research involving pregnant and breastfeeding women. As new health challenges arise, including novel pandemics, and the research community mobilizes to develop therapies and innovate in patient care, it is crucial that pregnant and breastfeeding women not be left behind. Greater regulatory support, in the form of explicit requirements and incentives, will be needed to ensure these populations are integrated into the research agenda.

Production and Characterization of Peptide Antibodies to the C-Terminal of Frameshifted Calreticulin Associated with Myeloproliferative Diseases.

Myeloproliferative Neoplasms (MPNs) constitute a group of rare blood cancers that are characterized by mutations in bone marrow stem cells leading to the overproduction of erythrocytes, leukocytes, and thrombocytes. Mutations in calreticulin (CRT) genes may initiate MPNs, causing a novel variable polybasic stretch terminating in a common C-terminal sequence in the frameshifted CRT (CRTfs) proteins. Peptide antibodies to the mutated C-terminal are important reagents for research in the molecular mechanisms of MPNs and for the development of new diagnostic assays and therapies. In this study, eight peptide antibodies targeting the C-terminal of CRTfs were produced and characterised by modified enzyme-linked immunosorbent assays using resin-bound peptides. The antibodies reacted to two epitopes: CREACLQGWTE for SSI-HYB 385-01, 385-02, 385-03, 385-04, 385-07, 385-08, and 385-09 and CLQGWT for SSI-HYB 385-06. For the majority of antibodies, the residues Cys1, Trp9, and Glu11 were essential for reactivity. SSI-HYB 385-06, with the highest affinity, recognised recombinant CRTfs produced in yeast and the MARIMO cell line expressing CRTfs when examined in Western immunoblotting. Moreover, SSI-HYB 385-06 occasionally reacted to CRTfs from MPN patients when analysed by flow cytometry. The characterized antibodies may be used to understand the role of CRTfs in the pathogenesis of MPNs and to design and develop new diagnostic assays and therapeutic targets.

A review of remdesivir for COVID-19 in pregnancy and lactation.

Mounting evidence suggests that pregnant people have an elevated risk of severe COVID-19-related complications compared with their non-pregnant counterparts, underscoring the need for effective prevention and treatment strategies. However, despite progress in innovative and flexible trial designs during the COVID-19 pandemic, regressive policies excluding pregnant and breastfeeding people from biomedical research persist. Remdesivir, a broad-spectrum antiviral, was the first drug licensed for the treatment of COVID-19, based on data showing it reduced the time to recovery in hospitalized patients. Pregnant and breastfeeding people were specifically excluded from all clinical trials of remdesivir in COVID-19, but data are accumulating from post-marketing registries, compassionate use programmes and case series/reports. In this review we synthesize these data and highlight key knowledge gaps to help inform clinical decision-making about its use in pregnancy and lactation.

Remdesivir: Review of Pharmacology, Pre-clinical Data, and Emerging Clinical Experience for COVID-19.

The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an urgent need for effective antivirals. Remdesivir (formerly GS-5734) is a nucleoside analogue pro-drug currently being evaluated in COVID-19 clinical trials. Its unique structural features allow high concentrations of the active triphosphate metabolite to be delivered intracellularly and it evades proofreading to successfully inhibit viral RNA synthesis. In pre-clinical models, remdesivir has demonstrated potent antiviral activity against diverse human and zoonotic ß-coronaviruses, including SARS-CoV-2. In this article, we critically review available data on remdesivir with an emphasis on biochemistry, pharmacology, pharmacokinetics, and in vitro activity against coronaviruses as well as clinical experience and current progress in COVID-19 clinical trials.