The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is ...unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling.
Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI). Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041).
In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects.
clinicaltrials.gov Identifier: NCT01342029.
Potential cardiovascular (CV) risks of testosterone replacement therapy (TRT) are currently a topic of intense interest. However, no studies have addressed CV risk as a function of the route of ...administration of TRT.
Two meta-analyses were conducted, one of CV adverse events (AEs) in 35 randomized controlled trials (RCTs) of TRT lasting 12 weeks or more, and one of 32 studies reporting the effect of TRT on serum testosterone and dihydrotestosterone (DHT).
CV risks of TRT: Of 2,313 studies identified, 35 were eligible and included 3,703 mostly older men who experienced 218 CV-related AEs. No significant risk for CV AEs was present when all TRT administration routes were grouped (relative risk (RR) = 1.28, 95% confidence interval (CI): 0.76 to 2.13, P = 0.34). When analyzed separately, oral TRT produced significant CV risk (RR = 2.20, 95% CI: 1.45 to 3.55, P = 0.015), while neither intramuscular (RR = 0.66, 95% CI: 0.28 to 1.56, P = 0.32) nor transdermal (gel or patch) TRT (RR = 1.27, 95% CI: 0.62 to 2.62, P = 0.48) significantly altered CV risk. Serum testosterone/DHT following TRT: Of 419 studies identified, 32 were eligible which included 1,152 men receiving TRT. No significant difference in the elevation of serum testosterone was present between intramuscular or transdermal TRT. However, transdermal TRT elevated serum DHT (5.46-fold, 95% CI: 4.51 to 6.60) to a greater magnitude than intramuscular TRT (2.20-fold, 95% CI: 1.74 to 2.77).
Oral TRT produces significant CV risk. While no significant effects on CV risk were observed with either injected or transdermal TRT, the point estimates suggest that further research is needed to establish whether administration by these routes is protective or detrimental, respectively. Differences in the degree to which serum DHT is elevated may underlie the varying CV risk by TRT administration route, as elevated serum dihydrotestosterone has been shown to be associated with CV risk in observational studies.
Aims/hypothesis
Previous studies of pancreases obtained at autopsy or by radiography note reduced pancreas weight (PW) and size, respectively, in type 1 diabetes; this finding is widely considered to ...be the result of chronic insulinopenia. This literature is, however, limited with respect to the influence of age, sex, anthropometric factors and disease duration on these observations. Moreover, data are sparse for young children, a group of particular interest for type 1 diabetes. We hypothesised that the pancreas-to-body weight ratio would normalise confounding inter-subject factors, thereby permitting better characterisation of PW in type 1 diabetes.
Methods
Transplant-grade pancreases were recovered from 216 organ donors with type 1 diabetes (
n
= 90), type 2 diabetes (
n
= 40) and no diabetes (
n
= 86). Whole-organ and head, body and tail weights were determined. The relative PW (RPW; PW g / body weight kg) was calculated and tested for normalisation of potential differences due to age, sex and BMI.
Results
PW significantly correlated with body weight in control donors (
R
2
= 0.76,
p
< 0.001) while RPW (1.03 ± 0.36, mean ± SD) did not significantly differ across ages (0–58 years). Donors with type 1 diabetes (0.57 ± 0.18,
p
< 0.001), but not those with type 2 diabetes (0.93 ± 0.30), had significantly lower RPW. The relative weights of each pancreatic region from donors with type 1 diabetes were significantly smaller than those of regions from control donors and donors with type 2 diabetes (
p
< 0.001). Perhaps most interestingly, the RPW was not significantly associated with duration of type 1 diabetes or type 2 diabetes.
Conclusions/interpretation
RPW allows for comparisons across a wide range of donor ages by eliminating confounding variables. These data validate an interesting feature of the type 1 diabetes pancreas and underscore the need for additional studies to identify the mechanistic basis for this finding, including those beyond the chronic loss of endogenous insulin secretion.
Clinical studies have shown that sensory input improves motor function when added to active training after neurological injuries in the spinal cord.
We aimed to determine the effect on motor function ...of extremities of adding an electrical sensory modality without motor recruitment before or with routine rehabilitation for hemiparesis after stroke by a comprehensive systematic review and meta-analysis.
We searched databases including MEDLINE via PubMed and the Cochrane Central Register of Controlled Trials from 1978 to the end of November 2017 for reports of randomized controlled trials or controlled studies of patients with a clinical diagnosis of stroke who underwent 1) transcutaneous electrical nerve stimulation (TENS) or peripheral electromyography-triggered sensory stimulation over a peripheral nerve and associated muscles or 2) acupuncture to areas that produced sensory effects, without motor recruitment, along with routine rehabilitation. Outcome measures were motor impairment, activity, and participation outcomes defined by the International Classification of Functioning, Disability and Health.
The search yielded 11studies with data that could be included in a meta-analysis. Electrical sensory inputs, when paired with routine therapy, improved peak torque dorsiflexion (mean difference MD 2.44 Nm, 95% confidence interval CI 0.26–4.63). On subgroup analysis, the combined therapy yielded a significant difference in terms of sensory stimulation without motor recruitment only on the Timed Up and Go test in the chronic phase of stroke (MD 3.51sec, 95% CI 3.05–3.98). The spasticity score was reduced but not significantly (MD−0.83 points, 95% CI -1.77−0.10).
Electrical sensory input can contribute to routine rehabilitation to improve early post-stroke lower-extremity impairment and late motor function, with no change in spasticity. Prolonged periods of sensory stimulation such as TENS combined with activity can have beneficial effects on impairment and function after stroke.
A peer-reviewed meta-analysis methods article mathematically proved that mainstream random-effects methods, "weights inversely proportional to the estimated variance," are flawed and can lead to ...faulty public health recommendations. Because the arguments causing this off-label (unproven) use of mainstream practices were subtle, changing these practices will require much clearer explanations that can be grasped by clinical and translational scientists. There are five assumptions underlying the mainstream's derivation of its statistical properties. This paper will demonstrate that if the first is true, it follows that the last two are false. Ratio estimation, borrowed from classical survey sampling, provides a rigorous alternative. Papers reporting results rarely fully disclose these assumptions. This is analogous to watching TV ads with the sound muted. You see high quality of life and do not hear about the complications. This article is a poster child for translational science, as it takes a theoretical discovery from the biostatistical world, translates it into language clinical scientists can understand, and thereby can change their research practice.
This article is aimed at future applications of meta-analysis of complete collections of randomized clinical trials. It leaves it to past authors as to whether to reanalyze their data. No blame for past use is assessed.
By treating the individual completed studies in the meta-analysis as a random sample from a conceptual universe of completed studies, we use ratio estimation to obtain estimates of relative risk (ratio of failure rates treatment: control) and mean differences, projecting our sample value to estimate the universe's value.
Two examples demonstrate that the mainstream methods likely adversely impacted major treatment options. A third example shows that the key mainstream presumption of independence between the study weights and study estimates cannot be supported.
There is no rationale for ever using the mainstream for meta-analysis of randomized clinical trials.
Future meta-analysis of clinical trials should never employ mainstream methods. Doing so could lead to potentially harmful public health policy recommendations. Clinical researchers need to play a primary role to assure good research practices in meta-analysis.
Before learning anything about statistical inference in beginning service courses in biostatistics, students learn how to calculate the mean and variance of linear combinations of random variables. ...Practical precalculus examples of the importance of these exercises can be helpful for instructors, the target audience of this paper. We shall present applications to the “1‐sample” and “2‐sample” methods for randomized short‐term 2‐treatment crossover studies, where patients experience both treatments in random order with a “washout” between the active treatment periods. First, we show that the 2‐sample method is preferred as it eliminates “conditional bias” when sample sizes by order differ and produces a smaller variance. We also demonstrate that it is usually advisable to use the differences in posttests (ignoring baseline and post washout values) rather than the differences between the changes in treatment from the start of the period to the end of the period (“delta of delta”). Although the intent is not to provide a definitive discussion of crossover designs, we provide a section and references to excellent alternative methods, where instructors can provide motivation to students to explore the topic in greater detail in future readings or courses.
Nutritional phases in Prader-Willi syndrome Miller, Jennifer L; Lynn, Christy H; Driscoll, Danielle C ...
American journal of medical genetics. Part A,
20/May , Letnik:
155A, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Prader-Willi syndrome (PWS) is a complex neurobehavioral condition which has been classically described as having two nutritional stages: poor feeding, frequently with failure to thrive (FTT) in ...infancy (Stage 1), followed by hyperphagia leading to obesity in later childhood (Stage 2). We have longitudinally followed the feeding behaviors of individuals with PWS and found a much more gradual and complex progression of the nutritional phases than the traditional two stages described in the literature. Therefore, this study characterizes the growth, metabolic, and laboratory changes associated with the various nutritional phases of PWS in a large cohort of subjects. We have identified a total of seven different nutritional phases, with five main phases and sub-phases in phases 1 and 2. Phase 0 occurs in utero, with decreased fetal movements and growth restriction compared to unaffected siblings. In phase 1 the infant is hypotonic and not obese, with sub-phase 1a characterized by difficulty feeding with or without FTT (ages birth-15 months; median age at completion: 9 months). This phase is followed by sub-phase 1b when the infant grows steadily along a growth curve and weight is increasing at a normal rate (median age of onset: 9 months; age quartiles 5-15 months). Phase 2 is associated with weight gain-in sub-phase 2a the weight increases without a significant change in appetite or caloric intake (median age of onset 2.08 years; age quartiles 20-31 months;), while in sub-phase 2b the weight gain is associated with a concomitant increased interest in food (median age of onset: 4.5 years; quartiles 3-5.25 years). Phase 3 is characterized by hyperphagia, typically accompanied by food-seeking and lack of satiety (median age of onset: 8 years; quartiles 5-13 years). Some adults progress to phase 4 which is when an individual who was previously in phase 3 no longer has an insatiable appetite and is able to feel full. Therefore, the progression of the nutritional phases in PWS is much more complex than previously recognized. Awareness of the various phases will aid researchers in unraveling the pathophysiology of each phase and provide a foundation for developing rational therapies. Counseling parents of newly diagnosed infants with PWS as to what to expect with regard to these nutritional phases may help prevent or slow the early-onset of obesity in this syndrome.
Withdrawal: Shuster, JJ, Handler, M. How to investigate an accused serial sexual harasser. Statistics in Medicine. 2019; 1–4. https://doi.org/10.1002/sim.8145. The above article from Statistics in ...Medicine, published online on 21 March 2019 in Wiley Online Library (http://wileyonlinelibrary.com) has been withdrawn by agreement of the authors, the Journal Editors (Ralph D'Agostino, Simon Day, Els Goetghebeur and Joel Greenhouse) and John Wiley & Sons Ltd. The editors acknowledge that the original manuscript did not undergo the rigorous peer‐review process that is customarily expected of a scholarly journal.
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