We present a structured matrix factorization approach to analyzing calciumimaging recordings of large neuronal ensembles. Our goal is to simultaneouslyidentify the locations of the neurons, demix spatially overlapping components,and denoise and deconvolve

Background

Data on the association between subclinical thyroid dysfunction and fractures conflict.

Purpose

To assess the risk for hip and nonspine fractures associated with subclinical thyroid dysfunction among prospective cohorts.

Data sources

Search of MEDLINE and EMBASE (1946 to 16 March 2014) and reference lists of retrieved articles without language restriction.

Study selection

Two physicians screened and identified prospective cohorts that measured thyroid function and followed participants to assess fracture outcomes.

Data extraction

One reviewer extracted data using a standardized protocol, and another verified data. Both reviewers independently assessed methodological quality of the studies.

Data synthesis

The 7 population-based cohorts of heterogeneous quality included 50,245 participants with 1966 hip and 3281 nonspine fractures. In random-effects models that included the 5 higher-quality studies, the pooled adjusted hazard ratios (HRs) of participants with subclinical hyperthyroidism versus euthyrodism were 1.38 (95% CI, 0.92 to 2.07) for hip fractures and 1.20 (CI, 0.83 to 1.72) for nonspine fractures without statistical heterogeneity (P = 0.82 and 0.52, respectively; I2= 0%). Pooled estimates for the 7 cohorts were 1.26 (CI, 0.96 to 1.65) for hip fractures and 1.16 (CI, 0.95 to 1.42) for nonspine fractures. When thyroxine recipients were excluded, the HRs for participants with subclinical hyperthyroidism were 2.16 (CI, 0.87 to 5.37) for hip fractures and 1.43 (CI, 0.73 to 2.78) for nonspine fractures. For participants with subclinical hypothyroidism, HRs from higher-quality studies were 1.12 (CI, 0.83 to 1.51) for hip fractures and 1.04 (CI, 0.76 to 1.42) for nonspine fractures (P for heterogeneity = 0.69 and 0.88, respectively; I2 = 0%).

Limitations

Selective reporting cannot be excluded. Adjustment for potential common confounders varied and was not adequately done across all studies.

Conclusion

Subclinical hyperthyroidism might be associated with an increased risk for hip and nonspine fractures, but additional large, high-quality studies are needed.

Primary funding source

Swiss National Science Foundation.

Objective

Data on the association between subclinical thyroid dysfunction and dementia are limited and conflicting. We aimed to determine whether subclinical thyroid dysfunction was associated with dementia and cognitive decline.

Design

Population-based prospective cohort study.

Patients

Adults aged 70-79 years with measured thyroid function, but no dementia at baseline, and Modified Mini-Mental State (3MS) at baseline and follow-up.

Measurements

Primary outcome was incident-adjudicated dementia, based on 3MS, hospital records and dementia drugs. Secondary outcome was change in 3MS. Models were adjusted for age, sex, race, education and baseline 3MS, and then further for cardiovascular risk factors.

Results

Among 2558 adults, 85% were euthyroid (TSH 0.45-4.49mIU/L), 2% had subclinical hyperthyroidism with mildly decreased TSH (TSH 0.10-0.44 mIU/L), 1% subclinical hyperthyroidism with suppressed TSH (TSH < 0.10 mIU/L with normal free thyroxine [FT4]) and 12% subclinical hypothyroidism (TSH 4.50-19.99 mIU/L with normal FT4). Over 9 years, 22% developed dementia. Compared to euthyroidism, risk of dementia was higher in participants with subclinical hyperthyroidism with suppressed TSH (HR 2.38, 95% CI = 1.13;5.04), while we found no significant association in those with mildly decreased TSH (HR 0.79, 95% CI = 0.45;1.38) or with subclinical hypothyroidism (HR 0.91, 95% CI = 0.70;1.19). Participants with subclinical hyperthyroidism with suppressed TSH had a larger decline in 3MS (-3.89, 95% CI = -7.62; -0.15).

Conclusions

Among older adults, subclinical hyperthyroidism with a TSH < 0.10 mIU/L was associated with a higher risk of dementia and a larger cognitive decline, while subclinical hyperthyroidism with mildly decreased TSH or subclinical hypothyroidism were not.

Background A cointervention in a randomized clinical trial (RCT) is medical care given in addition to the tested intervention. If cointerventions are unbalanced between trial arms, the results may be biased. We hypothesized that cointerventions would be more adequately reported in RCTs without full blinding or at risk of bias. Methods and Results To describe the reporting of cointerventions and to evaluate the factors associated with their reporting, we did a systematic search of all RCTs evaluating pharmacological interventions on cardiovascular outcomes published in 5 high-impact journals. The reporting of cointerventions, blinding, and risk of bias were extracted and evaluated independently by 2 reviewers (E.M., L.A.). Cointerventions were inadequately reported in 87 of 123 RCTs (70.7%), with 56 (45.5%) providing no information on cointerventions and 31 (25.2%) providing only partial information. Of the RCTs, 52 (42.3%) had inadequate blinding of participants and/or personnel and 63 (51.2%) of the RCTs were judged at risk of bias. In univariable analysis, the reporting of cointerventions was not associated with blinding of participants and/or personnel (odds ratio [OR], 1.04; 95% CI, 0.47-2.27 for adequately versus inadequately blinded trials) or with risk of bias (OR, 1.47; 95% CI, 0.67-3.21 for at low risk of bias versus trials at risk of bias). In multivariable analysis, only a follow-up of <1 month was associated with the adequate reporting of cointerventions (OR, 3.63; 95% CI, 1.21-10.91). Conclusions More than two-thirds of recent major cardiovascular trials did not adequately report cointerventions. The quality of reporting was not better among trials that were not fully blinded or at risk for bias. Registration URL: https://www.crd.york.ac.uk/PROSP​ERO/. Unique identifier: CRD42018106771.

Objective

To assess how inadequate reporting of cointerventions influences estimated treatment effects in recent cardiovascular trials.

Methods

Medline/Embase were systematically searched from January 1, 2011 to July 1, 2021 for trials evaluating pharmacologic interventions on clinical cardiovascular outcomes published in 5 high-impact journals. Information on adequate vs inadequate reporting of cointerventions, blinding, risk of bias due to deviations of intended interventions (low vs high/some concerns), funding (nonindustry vs industry), design (superiority vs noninferiority), and results were assessed by 2 reviewers. The association with effect sizes was assessed using meta-regression random-effect analysis, expressed as ratios of odds ratios (ROR). RORs of >1.0 indicated that trials with the methodological factor pointing to lower quality report larger treatment estimates.

Results

In total, 164 trials were included. Of the 164 trials, 124 (74%) did not adequately report cointerventions; 89 of the 164 trials (54%) provided no information regarding cointerventions, and 70 of the 164 (43%) were at risk of bias due to inadequate blinding. Moreover, 86 of the 164 (53%) were at risk of bias due to deviation of intended interventions. Of the 164 trials, 144 (88%) were funded by the industries. Trials with inadequate reporting of cointerventions had larger treatment estimates for the primary end point (ROR, 1.08; 95% CI, 1.01-1.15; I²=0%). No significant association with results for blinding (ROR, 0.97; 95% CI, 0.91-1.03; I²=66%), deviation of intended interventions (ROR, 0.98; 95% CI, 0.92-1.04; I²=0%), or funding (ROR, 1.01; 95% CI, 0.93-1.09; I²=0%) was found.

Conclusion

We conclude that trials with inadequate reporting of cointerventions showed larger treatment effect estimates, potentially indicating overestimation of therapeutic benefit.

Trial registration

Prospero Identifier: CRD42017072522.

Purpose

The surface receptor MET is highly expressed on primary uveal melanoma; MET inhibitors demonstrated early clinical signals of efficacy in slowing uveal melanoma growth. The primary objective of our study was to compare the progression-free survival rate at 4 months (PFS4) of patients with uveal melanoma treated with cabozantinib or chemotherapy.

Patients and methods

Patients with metastatic uveal melanoma and RECIST measurable disease were randomized 2:1 to receive either cabozantinib (arm 1) versus temozolomide or dacarbazine (arm 2) with restaging imaging every two cycles. Cross-over from arm 2 to cabozantinib after progression was allowed (arm 2X). Available tumor specimens were analyzed by whole-exome sequencing (WES) and results were correlated with outcome.

Results

Forty-six eligible patients were accrued with 31, 15, and 9 in arms 1, 2, and 2X, respectively. Median lines of prior therapy, including hepatic embolization, were two. Rates of PFS4 in arm 1 and arm 2 were 32.3% and 26.7% (P = 0.35), respectively, with median PFS time of 60 and 59 days (P = 0.964; HR = 0.99). Median overall survival (OS) was 6.4 months and 7.3 months (P = 0.580; HR = 1.21), respectively. Grade 3-4 Common Terminology Criteria for Adverse Events were present in 61.3%, 46.7%, and 37.5% in arms 1, 2, and 2X, respectively. WES demonstrated a mean tumor mutational burden of 1.53 mutations/Mb and did not separate OS ≤ or >1 year (P = 0.14). Known mutations were identified by WES and novel mutations were nominated.

Conclusions

MET/VEGFR blockade with cabozantinib demonstrated no improvement in PFS but an increase in toxicity relative to temozolomide/dacarbazine in metastatic uveal melanoma.

Studies in persons of European descent have suggested that mitochondrial DNA (mtDNA) haplogroups influence antiretroviral therapy (ART) toxicity. We explored associations between mtDNA variants and changes in endothelial function and biomarkers among non-Hispanic white, ART-naive subjects starting ART. A5152s was a substudy of A5142, a randomized trial of initial class-sparing ART regimens that included efavirenz or lopinavir/ritonavir with nucleoside reverse transcriptase inhibitors (NRTIs), or both without NRTIs. Brachial artery flow-mediated dilation (FMD) and cardiovascular biomarker assessments were performed at baseline and at weeks 4 and 24. Ten haplogroup-defining mtDNA polymorphisms were determined. FMD and biomarker changes from baseline to week 24 by mtDNA variant were assessed using Wilcoxon rank-sum tests. Thirty-nine non-Hispanic white participants had DNA and 24-week data. The nonsynonymous m.10398A>G mtDNA polymorphism (N=8) was associated with higher median baseline adiponectin (5.0 vs. 4.2 μg/ml; p=0.003), greater absolute (-1.9 vs. -0.2 μg/ml) and relative (-33% vs. -3%) adiponectin decreases (p<0.001 for both), and lower week 24 brachial artery FMD (3.6% vs. 5.4%; p=0.04). Individual mtDNA haplogroups, including haplogroups H (N=13) and U (N=6), were not associated with adiponectin or FMD changes. In this small pilot study, adiponectin and brachial artery FMD on ART differed in non-Hispanic whites with a nonsynonymous mtDNA variant associated with several human diseases. These preliminary findings support the hypothesis that mtDNA variation influences metabolic ART effects. Validation studies in larger populations and in different racial/ethnic groups that include m.10398G carriers are needed.

Uveal melanoma is a rare form of melanoma with particularly poor outcomes in the metastatic setting. In contrast with cutaneous melanoma, uveal melanoma lacks BRAF mutations and demonstrates very low response rates to immune-checkpoint blockade. Our objectives were to study the transcriptomics of metastatic uveal melanoma with the intent of assessing gene pathways and potential molecular characteristics that might be nominated for further exploration as therapeutic targets. We initially analyzed transcriptional data from The Cancer Genome Atlas suggesting PI3K/mTOR and glycolysis as well as IL6 associating with poor survival. From tumor samples collected in a prospective phase II trial (A091201), we performed a transcriptional analysis of human metastatic uveal melanoma observing a novel role for epithelial-mesenchymal transition associating with survival. Specifically, we nominate and describe initial functional validation of neuropillin-1 from uveal melanoma cells as associated with poor survival and as a mediator of proliferation and migration for uveal melanoma in vitro. These results immediately nominate potential next steps in clinical research for patients with metastatic uveal melanoma.

Background

Among critically ill patients with acute kidney injury (AKI), earlier initiation of renal replacement therapy (RRT) may mitigate fluid accumulation and confer better outcomes among individuals with greater fluid overload at randomization.

Methods

We conducted a pre-planned post hoc analysis of the STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial. We evaluated the effect of accelerated RRT initiation on cumulative fluid balance over the course of 14 days following randomization using mixed models after censoring for death and ICU discharge. We assessed the modifying effect of baseline fluid balance on the impact of RRT initiation strategy on key clinical outcomes. Patients were categorized in quartiles of baseline fluid balance, and the effect of accelerated versus standard RRT initiation on clinical outcomes was assessed in each quartile using risk ratios (95% CI) for categorical variables and mean differences (95% CI) for continuous variables.

Results

Among 2927 patients in the modified intention-to-treat analysis, 2738 had available data on baseline fluid balance and 2716 (92.8%) had at least one day of fluid balance data following randomization. Over the subsequent 14 days, participants allocated to the accelerated strategy had a lower cumulative fluid balance compared to those in the standard strategy (4509 (- 728 to 11,698) versus 5646 (0 to 13,151) mL, p = 0.03). Accelerated RRT initiation did not confer greater 90-day survival in any of the baseline fluid balance quartiles (quartile 1: RR 1.11 (95% CI 0.92 to 1.34), quartile 2: RR 1.03 (0.87 to 1.21); quartile 3: RR 1.08 (95% CI 0.91 to 1.27) and quartile 4: RR 0.87 (95% CI 0.73 to 1.03), p value for trend 0.08).

Conclusions

Earlier RRT initiation in critically ill patients with AKI conferred a modest attenuation of cumulative fluid balance. Nonetheless, among patients with greater fluid accumulation at randomization, accelerated RRT initiation did not have an impact on all-cause mortality.

Trial registration

ClinicalTrials.gov number, https://clinicaltrials.gov/ct2/show/NCT02568722 , registered October 6, 2015.