Cardiovascular complications of modern multiple myeloma therapy: A pharmacovigilance study.

AIMS: Multiple myeloma accounts for over 10-15% of haematological malignancies. Continued molecular advances have resulted in the development of new drugs for treatment of multiple myeloma. Four drugs were approved by the Food and Drug Administration (FDA) in 2015, but their safety is not well defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs. METHODS: We reviewed the adverse cardiac events of newly approved FDA drugs since 2015 using the US FDA Adverse Events Reporting System (FAERS) database. We calculated the reporting odds ratio (ROR) with 95% confidence interval (CIs) for the drugs that have the highest incidence of cardiovascular adverse events. RESULTS: Among the medications that have approved for multiple myeloma between 2015 and 2020, 4 novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, ixazomib, daratumumab and panobinostat compared to other FAERS drugs was 5.8 (4.4-7.7), 1.9 (1.5-2.3), 4.8 (4.2-5.6) and 5.7 (4.1-8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7) and 5.6 (3.8-8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2.3 (1.9-2.8) and 4.6 (3.2-6.6) due to elotuzumab, ixazomib, daratumumab and panobinostat compared to all other drugs in FAERS. CONCLUSION: Our results demonstrated that certain newly approved antimyeloma therapies are significantly associated with previously unknown cardiotoxicity. These results warrant further studies and highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.

Recurrence after stopping anticoagulants in women with combined oral contraceptive-associated venous thromboembolism: A systematic review and meta-analysis.

The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY [95% confidence interval (CI) 0.92-1.62, I2  = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I2  = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I2  = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE.

Health-care workers' occupational exposures to body fluids in 21 countries in Africa: systematic review and meta-analysis.

OBJECTIVE: To estimate the lifetime and 12-month prevalence of occupational exposure to body fluids among health-care workers in Africa. METHODS: Embase®, PubMed® and CINAHL databases were systematically searched for studies published between January 2000 and August 2017 that reported the prevalence of occupational exposure to blood or other body fluids among health-care workers in Africa. The continent-wide prevalence of exposure was estimated using random-effects meta-analysis. FINDINGS: Of the 904 articles identified, 65 studies from 21 African countries were included. The estimated pooled lifetime and 12-month prevalence of occupational exposure to body fluids were 65.7% (95% confidence interval, CI: 59.7-71.6) and 48.0% (95% CI: 40.7-55.3), respectively. Exposure was largely due to percutaneous injury, which had an estimated 12-month prevalence of 36.0% (95% CI: 31.2-40.8). The pooled 12-month prevalence of occupational exposure among medical doctors (excluding surgeons), nurses (including midwives and nursing assistants) and laboratory staff (including laboratory technicians) was 46.6% (95% CI: 33.5-59.7), 44.6% (95% CI: 34.1-55.0) and 34.3% (95% CI: 21.8-46.7), respectively. The risk of exposure was higher among health-care workers with no training on infection prevention and those who worked more than 40 hours per week. CONCLUSION: The evidence available suggests that almost one half of health-care workers in Africa were occupationally exposed to body fluids annually. However, a lack of data from some countries was a major limitation. National governments and health-care institutions across Africa should prioritize efforts to minimize occupational exposure among health-care workers.

Prolonged disynaptic inhibition in the cortex mediated by slow, non-α7 nicotinic excitation of a specific subset of cortical interneurons.

Cholinergic activation of nicotinic receptors in the cortex plays a critical role in arousal, attention, and learning. Here we demonstrate that cholinergic axons from the basal forebrain of mice excite a specific subset of cortical interneurons via a remarkably slow, non-α7 nicotinic receptor-mediated conductance. In turn, these inhibitory cells generate a delayed and prolonged wave of disynaptic inhibition in neighboring cortical neurons, altering the spatiotemporal pattern of inhibition in cortical circuits.

Management of recurrent focal segmental glomerulosclerosis (FSGS) post renal transplantation.

BACKGROUND: One of the common GN causing ESKD is focal segmental glomerulosclerosis (FSGS). Recurrence of FSGS post-transplantation can lead to graft loss. Data on management either prophylactically or once recurrence occurs are limited. This review article aims to assess the effective management of patients with FSGS recurrence post-transplantation, looking mainly at recurrence post prophylactic treatment and remission in case of treatment post recurrence. METHODS: Twenty-three studies were included using the search MeSH terms "FSGS" "recurrence" "adults" "transplantation" "treatment". Search engines used were Pubmed, clinical key, Scopus and Cochrane library. Inclusion criteria were articles covered adult patients with recurrent FSGS post renal transplantation, treatment with rituximab and plasmapheresis, and articles published from 2000 tt2021. Excluded articles were paediatric population, studies with no reported outcomes of the treatment of FSGS, and Patients who received stem cell transplantation or galactose therapy. RESULTS: Prophylactic PP did not show a reduction in recurrence of FSGS in 2/3 studies. Prophylactic rituximab was shown to reduce recurrence of FSGS in one-study and case reports. Treatment of recurrent FSGS with PP showed responses ranging from 41% to 100%. Only one study did not show improvement with PP use as treatment having a 27% remission. Treatment with rituximab showed variable results, with reports showing remission ranging from 57% to 100%. Whereas other reports showing no response at all. PP prescription reporting was variable. One study suggested intensified PP regimen while in most other studies PP was guided by the response reflected by the reduction of proteinuria. DISCUSSION: Reviewing the treatment of recurrent FSGS is crucial, as there no consensus on treating FSGS as the disease is not very common in the adult population. The evidence of different modalities is based on small cohort studies. This paper supports the use of PP and RTX as treatment of recurrent FSGS. CONCLUSIONS: In conclusion, PP and RTX are the main modalities to treat recurrent FSGS with varying response rates. Prophylactic PP does not play a role in preventing recurrent FSGS. Prophylactic rituximab might play a role in preventing FSGS post-transplantation. PP and RTX, when used as a treatment, show variable response rates. Larger RCTs are needed to have a strong level of evidence to base our clinical management on.

Association of Nephrectomy of the Failed Renal Allograft With Outcome of the Future Transplant: A Systematic Review.

Kidney allograft failure is a significant complication in kidney transplant recipients, and the surgical decision to perform allograft nephrectomy poses a strong dilemma because it is associated with significant morbidity and mortality. There is a debate over the effect of allograft nephrectomy on the development of allosensitization and the impact on potential retransplantation. Moreover, the use of immunosuppression may contribute to antibody allosensitization as allograft nephrectomy and immunosuppression act jointly and interdependently toward antibody formation. Because more and more patients with kidney allograft failure are entering wait lists for repeat transplant procedures, a review of available evidence on the field is required. Here, we performed a literature search using multiple medical databases to identify relevant studies that assessed the effects of allograft nephrectomy on important retransplant endpoints such as allograft and patient survival; furthermore, secondary outcomes such as alloantibody sensitization were also evaluated. A total of 15 studies were identified; all were retrospective, single-center studies. The rate of allograft nephrectomy in patients with retransplant varied widely (from 20% to 80%). The average allograft nephrectomy rate in included studies was 43% (allograft nephrectomy number/number of repeat transplantations: 2351/5431). Most studies did not observe an allograft survival benefit after retransplant for patients with allograft nephrectomy with the exception of 4 studies that found worse allograft survival after allograft nephrectomy. Interestingly, 1 study found that, in the patient subgroup with early kidney allograft failure (<12 months posttransplant), allograft nephrectomy may be associated with better allograft survival. Available data suggested that allograft nephrectomy may be associated with a higher risk of increasing anti-HLA antibody levels. The quality of the included studies suffered from nonrandomized design, potential confounding, and small sample size. To conclude, further randomized controlled trials are required to delineate the role of allograft nephrectomy on retransplant outcomes.

Long-term risk of recurrent venous thromboembolism after a first contraceptive-related event: Data from REVERSE cohort study.

INTRODUCTION: The risk of recurrent venous thromboembolism (VTE) after combined oral contraceptive (COC) use is variably reported. We assessed the long-term risk of recurrent VTE in women on COC at the time of a first VTE, in comparison to women without COC use. Our secondary aim assessed the impact of COC use on the recurrent VTE risk in high-risk and low-risk hyperpigmentation, edema, or redness in either leg; D-dimer level ≥250 µg/L; obesity with body mass index ≥30; or older age, ≥65 years (HERDOO2) subgroups. METHODS: The REVERSE cohort study derived the HERDOO2 clinical decision rule to predict recurrent VTE in patients who discontinued anticoagulation after 5-7 months for a first unprovoked VTE. Incidence rates of recurrent VTE among women with and without COC exposure were calculated as the number of recurrent VTE over the number of person-years of follow-up, and Cox proportional hazards model was used to compare risks between groups. RESULTS: The risk of recurrent VTE among COC users was 1.1% (95% confidence interval [CI] 0.3-2.9) per patient-year as compared with 3.2% per patient-year (95% CI 2.4-4.3) among nonusers (hazard ratio 0.37; 95% CI 0.1-1.0). Women who were COC users and high risk by HERDOO2 score had a recurrence rate of 3.5% (95% CI 0.4-12.5) compared with 6.1% (95% CI 4.3-8.5) among women who were non-COC users and at high risk by HERDOO2 score (HR 0.6, 95% CI 0.1-2.5). CONCLUSIONS: Women who were COC users at the time of an otherwise unprovoked VTE event had a lower VTE recurrence rate during long-term follow-up, compared with nonusers. The use of HERDOO2 rule may help identify higher risk women with COC use.

Motivation and Engagement during Visually Guided Behavior.

Animal behavior is motivated by internal drives, such as thirst and hunger, generated in hypothalamic neurons that project widely to many brain areas. We find that water-restricted mice maintain stable, high-level contrast sensitivity and brief reaction time while performing a visual task, but then abruptly stop and become disengaged. Mice consume a significant amount of water when freely provided in their home cage immediately after the task, indicating that disengagement does not reflect cessation of thirst. Neuronal responses of V1 neurons are reduced in the disengaged state, but pupil diameter does not decrease, suggesting that animals' reduced level of arousal does not drive the transition to disengagement. Our findings indicate that satiation level alone does not have an instructive role in visually guided behavior and suggest that animals' behavior is governed by cost-benefit analysis that can override thirst signals.

From 'fixed dose combinations' to 'a dynamic dose combiner': 3D printed bi-layer antihypertensive tablets.

There is an increased evidence for treating hypertension by a combination of two or more drugs. Increasing the number of daily intake of tablets has been reported to negatively affect the compliance of patients. Therefore, numerous fixed dose combinations (FDCs) have been introduced to the market. However, the inherent rigid nature of FDCs does not allow the titration of the dose of each single component for an individual patient's needs. In this work, flexible dose combinations of two anti-hypertensive drugs in a single bilayer tablet with a range of doses were fabricated using dual fused deposition modelling (FDM) 3D printer. Enalapril maleate (EM) and hydrochlorothiazide (HCT) loaded filaments were produced via hot-melt extrusion (HME). Computer software was utilised to design sets of oval bi-layer tablets of individualised doses. Thermal analysis and x-ray diffractometer (XRD) indicated that HCT remained crystalline in the polymeric matrix whilst EM appeared to be in an amorphous form. The interaction between anionic EM and cationic methacrylate polymer may have contributed to a drop in the glass transition temperature (Tg) of the filament and obviated the need for a plasticiser. Across all tablet sets, the methacrylate polymeric matrix provided immediate drug release profiles. This dynamic dosing system maintained the advantages of FDCs while providing a superior flexibility of dosing range, hence offering an optimal clinical solution to hypertension therapy in a patient-centric healthcare service.

Mental health service recipients and prison work release: how do the mentally ill fare compared to other inmates in prison work release programs?

The objective of this study was to compare the success rate of the mentally ill and other inmates on prison work release within gender groups. Mentally ill (MI) men (n = 42) had a higher success rate (79%) than other men (NMI) (61%) (n = 49), but this difference only approached statistical significance (p = 0.07), and mental illness did not distinguish male success/failures in regression analyses. Mentally ill women (n = 51) had a statistically significant lower success rate (58%) than other women inmates (n = 49) (83%) on work release. The difference in rates, however, only occurred in the group of women who were currently in prison due to a parole violation, not new court commitments. Regression analysis confirmed the importance of mental illness and current commitment as a parole violator. A greater number of MI men should be allowed to participate in work release. Women with mental health issues who had prior trouble on parole may need enhanced services.