Registries of clinical trials exist in part to standardize data for the scientific community. Studies in the United States demonstrated gaps in reporting on ClinicalTrials.gov. The purpose of this ...cross-sectional study was to evaluate clinical trial participation among global registries.
This study identified registries with results reported and assessed available results for physical and rehabilitation medicine (PRM) diagnosis, intervention, primary outcome, and the International Classification of Functioning, Disability and Health (ICF) categories. Participant characteristics including sex, age, and race/ethnicity were assessed.
A total of 93 rehabilitation trials from eight registries met inclusion criteria. Most trials included persons with musculoskeletal disorders (50.5%), technology such as robotics (25.8%) and outcomes in ICF category of body functions and structures (54.7%). Sex was reported in 61.3% of trials and varied among registries (0 to 100%). Participation of women in trials showed variability from 0 to 75%. Reporting of age of the participants was not uniform and six registries did not include age in all trials. Information about race/ethnicity was absent in most trials and registries.
Based on trials registered with accessible results, these findings may reveal either a gap in reporting results or a lack of trials investigating important PRM diagnoses, interventions, and outcomes.
Implications for Rehabilitation
This study contributes to the growing body of evidence that there are gaps in standardization of rehabilitation results reported on clinical trials registries.
The uniform reporting of results is an important component of advancing rehabilitation science and may be a factor in high-quality study design and improved transparency.
COVID-19 has led many countries to dismiss globalization and reassert sovereignty through 'Vaccine Nationalism', a process whereby high-income countries race to secure vaccine doses for their own ...populations. This nationalist behaviour has severe consequences for low-income countries lacking vaccine manufacturing capacity or the funds to buy doses, by limiting their access to the pool of available vaccines. Despite calls for vaccine sharing by international organizations, this nationalist behaviour has continued for two years by many countries, including typical multilateral actors such as Canada. To understand this trend, this paper argues that the pursuit of vaccine nationalism by wealthy nations is both a rational by-product of realpolitik, and justified through securitization discourse. In looking back at Canada's active engagement in vaccine nationalism throughout the pandemic, this paper concludes that as a long-time multilateral leader, Canada's nationalist actions to secure COVID-19 vaccines were uncalled for.
Contemporary data on infections after intensive chemotherapy for acute myeloid leukemia (AML) are scarce. Cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone ("CLAG-M") may ...result in higher remission rates than standard-dose cytarabine plus anthracycline ("7 + 3") but may result in more infections. We compared moderate to severe infections occurring up to 90 days after the first induction cycle for AML or other high-grade myeloid neoplasms in patients receiving CLAG-M for newly diagnosed (n = 196) or relapsed/refractory disease (n = 131) or 7 + 3 for newly diagnosed disease (n = 115). For newly diagnosed disease, microbiologically documented infections were more frequent after CLAG-M compared to 7 + 3 (adjusted rate ratio, 1.65 95% CI, 1.06-2.58; P = 0.03), with a cumulative incidence of 27.8% and 16.5% by day 90, respectively. Patients receiving CLAG-M for relapsed/refractory disease had the highest cumulative incidence of 50.7%. Bacterial bloodstream infections were the most frequent followed by respiratory tract infections. Among 29 patients (7%) who died, infection was a primary or contributing cause of death in 59%. These data indicate that infections continue to cause substantial morbidity in patients treated for AML, especially those treated for relapsed/refractory disease, and are more common with newer, more myelosuppressive regimens such as CLAG-M. Improved strategies for infection prevention are needed.
Typical and atypical dopamine uptake inhibitors (DUIs) prefer distinct conformations of the dopamine transporter (DAT) to form ligand-transporter complexes, resulting in markedly different effects on ...behavior, neurochemistry, and potential for addiction. Here we show that cocaine and cocaine-like typical psychostimulants elicit changes in DA dynamics distinct from those elicited by atypical DUIs, as measured via voltammetry procedures. While both classes of DUIs reduced DA clearance rate, an effect significantly related to their DAT affinity, only typical DUIs elicited a significant stimulation of evoked DA release, an effect unrelated to their DAT affinity, which suggests a mechanism of action other than or in addition to DAT blockade. When given in combination, typical DUIs enhance the stimulatory effects of cocaine on evoked DA release while atypical DUIs blunt them. Pretreatments with an inhibitor of CaMKIIα, a kinase that interacts with DAT and that regulates synapsin phosphorylation and mobilization of reserve pools of DA vesicles, blunted the effects of cocaine on evoked DA release. Our results suggest a role for CaMKIIα in modulating the effects of cocaine on evoked DA release without affecting cocaine inhibition of DA reuptake. This effect is related to a specific DAT conformation stabilized by cocaine. Moreover, atypical DUIs, which prefer a distinct DAT conformation, blunt cocaine's neurochemical and behavioral effects, indicating a unique mechanism underlying their potential as medications for treating psychostimulant use disorder.
Many therapeutic monoclonal antibodies require binding to Fc γ receptors (FcγRs) for full effect and increasing the binding affinity increases efficacy. Preeminent among the five activating human ...FcγRs is FcγRIIIa/CD16a expressed by natural killer (NK) cells. CD16a is heavily processed, and recent reports indicate that the composition of the five CD16a asparagine(N)-linked carbohydrates (glycans) impacts affinity. These observations indicate that specific manipulation of CD16a N-glycan composition in CD16a-expressing effector cells including NK cells may improve treatment efficacy. However, it is unclear if modifying the expression of select genes that encode processing enzymes in CD16a-expressing effector cells is sufficient to affect N-glycan composition. We identified substantial processing differences using a glycoproteomics approach by comparing CD16a isolated from two NK cell lines, NK92 and YTS, with CD16a expressed by HEK293F cells and previous reports of CD16a from primary NK cells. Gene expression profiling by RNA-Seq and qRT-PCR revealed expression levels for glycan-modifying genes that correlated with CD16a glycan composition. These results identified a high degree of variability between the processing of the same human protein by different human cell types. N-glycan processing correlated with the expression of glycan-modifying genes and thus explained the substantial differences in CD16a processing by NK cells of different origins.
Abstract Objective Preclinical evidence suggests that metformin exhibits anti-tumorigenic effects in endometrial cancer. We sought to investigate the association of metformin on endometrial cancer ...outcomes. Methods A multi-institutional IRB-approved retrospective cohort analysis was conducted comparing endometrial cancer patients with diabetes mellitus who used metformin (based on medication review at the time of diagnosis) to those who did not use metformin from 2005 to 2010. Metformin use on treatment related outcomes (TTR: time to recurrence; RFS: recurrence free survival; OS: overall survival) were evaluated using univariate and multivariate modeling. Results 24% (363/1495) endometrial cancer patients were diabetic, of whom 54% used metformin. Metformin users were younger and heavier than non-users, though nearly all were postmenopausal and obese. 75% of both groups had endometrioid histology. Stage, grade, and adjuvant therapy distributions were similar. Metformin users had improved RFS and OS. Non-metformin users had 1.8 times worse RFS (95% CI: 1.1–2.9, p = 0.02) and 2.3 times worse OS (95% CI: 1.3–4.2, p = 0.005) after adjusting for age, stage, grade, histology and adjuvant treatment. Metformin use was not associated with TTR. Conclusion Metformin use was associated with improved RFS and OS but not TTR, most likely due to improving all-cause mortality. Its role in modifying cancer recurrence remains unclear. Prospective studies that capture metformin exposure prior to, during and post endometrial cancer treatment may help define the role of metformin upon cancer specific and overall health outcomes.
Tristetraprolin (TTP), encoded by the Zfp36 gene, is a zinc-finger protein that regulates RNA stability primarily through association with 3' untranslated regions (3' UTRs) of target mRNAs. While TTP ...is expressed abundantly in the intestines, its function in intestinal epithelial cells (IECs) is unknown. Here we used a cre-lox system to remove Zfp36 in the mouse epithelium to uncover a role for TTP in IECs and to identify target genes in these cells. While TTP was largely dispensable for establishment and maintenance of the colonic epithelium, we found an expansion of the proliferative zone and an increase in goblet cell numbers in the colon crypts of Zfp36
mice. Furthermore, through RNA-sequencing of transcripts isolated from the colons of Zfp36
and Zfp36
mice, we found that expression of inducible nitric oxide synthase (iNos or Nos2) was elevated in TTP-knockout IECs. We demonstrate that TTP interacts with AU-rich elements in the Nos2 3' UTR and suppresses Nos2 expression. In comparison to control Zfp36
mice, Zfp36
mice were less susceptible to dextran sodium sulfate (DSS)-induced acute colitis. Together, these results demonstrate that TTP in IECs targets Nos2 expression and aggravates acute colitis.
Outcomes with "7 + 3" are often unsatisfactory in acute myeloid leukemia (AML). Trials demonstrating improved outcomes with high-dose cytarabine, addition of cladribine, or escalated anthracycline ...doses prompted a phase 1/2 study (NCT02044796) of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms. One hundred and twenty-one patients, median age 60 (range 21-81) years, were enrolled. In phase 1, cohorts of 6-12 patients were assigned to 12-18 mg/m
/day of mitoxantrone as part of GCLAM. Because all dose levels were well-tolerated, mitoxantrone at 18 mg/m
was declared the recommended phase 2 dose (RP2D). 74/94 (79%) patients treated at the RP2D achieved a complete remission (CR; 67/74 without measureable residual disease MRD) for an overall MRD
CR rate of 71% (primary phase 2 endpoint). Seven patients achieved a CR with incomplete blood count recovery (CRi; 7%, 5 MRD
) for a CR/CRi rate of 81/94 (86%). Four-week mortality was 2%. After adjustment, the MRD
CR and CR/CRi rates compared favorably to 100 matched controls treated with 7 + 3 at our center and 245 matched patients treated with 7 + 3 on a cooperative group trial. Our data indicate GCLAM with mitoxantrone at 18 mg/m
/day is safe and induces high-quality remissions in adults with newly-diagnosed AML.
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