Search

Background Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase (BTK) that is FDA-approved for several lymphoproliferative disorders and chronic GVHD. Objective To characterize cutaneous eruptions arising from ibrutinib and highlight overlap with epidermal growth factor receptor inhibitor (EGFRi)-induced dermatologic adverse events (dAEs). Methods Single-center retrospective cohort of patients referred to the Skin Toxicities Program for management of cutaneous eruptions while taking ibrutinib. Results Among 19 patients, cutaneous eruptions manifested as facial-predominant papulopustular eruptions, petechiae or ecchymoses, photosensitivity, panniculitis, xerosis, and clinical staphylococcal overgrowth. The majority of patients were able to continue ibrutinib therapy with focused management of their cutaneous toxicities. Limitations This study represents cases at a single tertiary care center and is limited to patients referred for toxicity. Conclusions With the exception of petechiae, the cutaneous toxicities of ibrutinib overlap with those associated with selective EGFR inhibitors. We observed that these reactions can be successfully managed using approaches for EGFR inhibitor-induced cutaneous adverse events.

Objective Multiple system atrophy (MSA) is characterized by urinary dysfunction, yet the influence of sex and gender on urinary symptoms and treatment is unclear. We sought to characterize sex and gender differences in the symptomatology, evaluation, and management of urinary dysfunction in patients with MSA.Methods Patients with MSA evaluated at our institution were reviewed and stratified by sex.Results While the prevalence of urinary symptoms was similar in male and female patients, incontinence was more common in females. Despite this, males and females underwent postvoid residual (PVR) measurement at similar rates. While catheterization rates were similar when PVR was measured, males were more than twice as likely to be catheterized than females in the absence of PVR measurement.Conclusion Urinary symptoms are common in MSA, but their presentation differs between males and females. The difference in catheterization rates may be driven by a gender disparity in referrals for PVR, which can guide treatment.

Interferons (IFNs) are cytokines with potent antineoplastic and antiviral properties. IFNα has significant clinical activity in the treatment of myeloproliferative neoplasms (MPN), but the precise mechanisms by which it acts are not well understood. Here, we demonstrate that chromatin assembly factor 1 subunit B (CHAF1B), an Unc-51-like kinase 1 (ULK1)-interactive protein in the nuclear compartment of malignant cells, is overexpressed in patients with MPN. Remarkably, targeted silencing of CHAF1B enhances transcription of IFNα-stimulated genes and promotes IFNα-dependent antineoplastic responses in primary MPN progenitor cells. Taken together, our findings indicate that CHAF1B is a promising newly identified therapeutic target in MPN and that CHAF1B inhibition in combination with IFNα therapy might offer a novel strategy for treating patients with MPN. Significance: Our findings raise the potential for clinical development of drugs targeting CHAF1B to enhance IFN antitumor responses in the treatment of patients with MPN and should have important clinical translational implications for the treatment of MPN and possibly in other malignancies.

This paper examines global data on unbanked and underbanked consumers to highlight the role improved financial literacy and capability could play in motivating and enabling the safe and beneficial use of financial services. The paper uses Global Findex data, a demand-side survey on ownership and use of accounts at formal financial institutions, such as a bank or similar financial institution, or a mobile money service provider. The paper reviews the self-reported barriers to account ownership and use cited by unbanked adults and identifies the challenges faced by account owners who could not use an account without help. Together, these issues point to the importance of financial education to improve digital and financial literacy skills, in addition to product design that considers customer abilities, and strong consumer safeguards to ensure that customers benefit from financial access.

Sepsis is a dysregulated host response to infection that results in life-threatening organ dysfunction. Virtually every body system can be affected by this syndrome to greater or lesser extents. Gene transcription and downstream pathways are either up- or downregulated, albeit with considerable fluctuation over the course of the patient’s illness. This multi-system complexity contributes to a pathophysiology that remains to be fully elucidated. Consequentially, little progress has been made to date in developing new outcome-improving therapeutics. Endocrine alterations are well characterised in sepsis with variations in circulating blood levels and/or receptor resistance. However, little attention has been paid to an integrated view of how these hormonal changes impact upon the development of organ dysfunction and recovery. Here, we present a narrative review describing the impact of the altered endocrine system on mitochondrial dysfunction and immune suppression, two interlinked and key aspects of sepsis pathophysiology.

Background and ObjectivesAbaloparatide (ABL) significantly increases bone mineral density in men with osteoporosis similar to what was reported in postmenopausal women with osteoporosis. The cost effectiveness of sequential treatment with ABL followed by alendronate (ALN) in men at high fracture risk was compared to relevant alternative treatments.MethodsA Markov-based microsimulation model based on a lifetime US healthcare decision maker perspective was developed to evaluate the cost (expressed in US$2021) per quality-adjusted life-years (QALYs) gained of sequential ABL/ALN. Comparators were sequential treatment unbranded teriparatide (TPTD)/ALN, generic ALN monotherapy, and no treatment. Discount rates of 3% were used. Consistent with practice guidelines, patients received 18 months of ABL or TPTD followed by ALN for 5 years, or 5 years of ALN monotherapy. Analyses were conducted in high-risk men aged over 50 years defined as having a bone mineral density T-score = 60 years.ConclusionsSequential therapy using ABL/ALN may be cost effective compared with generic ALN monotherapy in US men aged >= 50 years at high fracture risk, especially in those aged >= 60 years. Unbranded TPTD/ALN and no treatment were dominated interventions (less QALY, more costs) compared with ABL/ALN or ALN monotherapy.

ZusammenfassungFrauen weisen ein erhöhtes Risiko für unerwünschte Arzneimittelwirkungen auf. Die Ergebnisse von Untersuchungen zu geschlechtsspezifischen Unterschieden sind dabei z. T. noch lückenhaft und widersprüchlich. Durch das komplexe Zusammenspiel exogener und endogener, geschlechtsspezifischer und individueller Einflüsse können unerwartete Effekte eintreten. Die Auswahl einer Medikation sollte nach individuellen Gegebenheiten und gemeinsamer Nutzen-Risiko-Abwägung mit der zu behandelnden Frau erfolgen. Dies ist insbesondere in der Forensik von hoher Bedeutung, da Frauen hier häufig eine Langzeitbehandlung benötigen.Aufgrund vielfältiger Einflüsse, wie z. B. auch Schwankungen von Medikamentenspiegeln im Rahmen des Zyklus, sind neben der spiegelkontrollierten Behandlung v. a. immer eine klinische Kontrolle und Befragung der behandelten Frau wichtigste Instrumente bei der Beurteilung erwünschter und unerwünschter Effekte. So kann im Idealfall gute klinische Verträglichkeit bei effektiver Wirkung Behandlungssicherheit und Zufriedenheit erhöhen.

Based on a study of U.S.-tagged items in a global database of fact-checked statements about the novel coronavirus throughout the first year of the pandemic, this article explores the nature of fact-checkers’ “retroactive gatekeeping.” This term is introduced here to describe the process of assessing the veracity of information after it has entered the public domain rather than before. Although an overwhelming majority of statements across 16 thematic categories were deemed false and debunked, often repeatedly, misinformation continued to circulate freely and widely.

The timing of the onset of magnetochron M0r and its duration are disputed, reflecting both a limited set of radioisotopic dates and uncertain magnetostratigraphic correlations. We present a chronostratigraphic framework for a reversed polarity interval based on two chronometers (40Ar/39Ar, U-Pb) and newly published paleomagnetic data from the Qingshan Group, Jiaolai Basin, China. Bayesian modeling of U-Pb zircon and 40Ar/39Ar sanidine dates suggests a minimum duration of 540 ± 37 k.y. (95% credible interval) for the reversed polarity interval. These findings are compatible with an astrochronologic age model for M-sequence seafloor magnetic anomalies, indicating that the reversely magnetized sediments correspond to magnetochron M0r rather than the shorter chron “M-1r.” Integration of U-Pb and 40Ar/39Ar ages constrains the onset of M0r to 120.29 ± 0.09 Ma, which is ~1 m.y. younger than that inferred in the current geologic time scale (GTS 2020). This finding also implies that the Cretaceous normal superchron (CNS) began at 119.70 ± 0.12 Ma and that the average seafloor spreading rate during the CNS was ~3.5% higher than that inferred from GTS 2020. It also suggests that oceanic anoxic event 1a began at 119.40 ± 0.12 Ma, thereby providing an updated chronologic basis for exploring the primary trigger of this carbon cycle perturbation.

Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI).The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEVFrom Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEVIn individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment.

OBJECTIVE: To support family physicians in preventing atrial fibrillation (AF) in patients at risk and in identifying and managing those with established AF; and to summarize key recommendations for ideal screening and care of patients. SOURCES OF INFORMATION: The 2020 Canadian Cardiovascular Society and Canadian Heart Rhythm Society comprehensive guidelines for the management of AF, based on current evidence and clinical experience related to AF. MAIN MESSAGE: Atrial fibrillation, which is estimated to affect at least 500,000 Canadians, is associated with high risks of stroke, heart failure, and death. Primary care clinicians occupy a central role in the management of this chronic condition, focusing on the challenges of preventing AF and identifying, diagnosing, treating, and following patients with AF. Evidence-based guidelines that provide optimal management strategies have been published by the Canadian Cardiovascular Society and Canadian Heart Rhythm Society to assist in these tasks. Messages critical to primary care are offered to support effective knowledge translation. CONCLUSION: Most patients with AF can be managed effectively in primary care. Family physicians not only play an important role in ensuring patients with AF receive timely diagnoses, but they are also key to providing initial and ongoing care, especially in patients with comorbid conditions.

Menopause is a high-risk period for osteoporosis, which may be exacerbated by HIV and/or antiretroviral therapy (ART).To study the impact of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) on bone mineral density (BMD) in peri and early post-menopausal women living with HIV.A randomized, international, multicenter study of an early vs delayed (48-week) switch. BMD measured by DXA scan.Thirty-four women enrolled; 19 in the immediate and 15 in the delayed switch arm Sept 2017 to April 2019; 30 completed the 96-week protocol. The study closed for futility during the COVID pandemic. The median (IQR) age was 51 years (47, 53), with a median (IQR) of 16.5 years (14, 23) since HIV diagnosis, median (IQR) 14 years (11, 20) of ART, and mean 8.6 years TDF. At enrollment, TDF was used in combination with a boosted protease inhibitor (n=7), a non-nucleoside reverse transcriptase inhibitor (n=13), an integrase inhibitor (n= 11) or more than one ART class (n=3). The median (95% CI) % change in BMD at the lumbar spine from 0-48 weeks in the immediate switch group was 1.97% (-1.15, 5.49) compared to a median (95% CI) decrease of 2.32% (- 5.11, 0.19) in the delayed arm. The median (95% CI) % change in BMD from 0-96 weeks was 2.33% (0, 4.51) in the immediate arm compared to 0.70% (-3.19, 2.47) in the delayed arm.We demonstrated a trend to increased BMD at the lumbar spine following a switch from TDF to TAF in peri-and early post menopausal women living with HIV.