Disseminating Justified, Well-Designed, and Well-Executed Studies Despite Nonsignificant Tests

Disseminating Justified, Well-Designed, and Well-Executed Studies Despite Nonsignificant Tests

To the Editor

In her editorial1 published in JAMA Psychiatry, Dr Kraemer gives important insights into using covariates, thereby adding to her large body of highly valuable publications…

 

Gunther Meinlschmidt, PhD; Jan K. Woike, PhD; Marion Tegethoff, PhD
JAMA Psychiatry. 2016;73(1):88-89. doi:10.1001/jamapsychiatry.2015.2259.
Posted in February, Hot Topics in Research, Research Commentary

Disseminating Justified, Well-Designed, and Well-Executed Studies With Nonsignificant Tests—Reply

Disseminating Justified, Well-Designed, and Well-Executed Studies With Nonsignificant Tests—Reply

In Reply I wholeheartedly agree with the main point made by Meinlschmidt et al that well-justified, well-designed, and well-executed (non–poorly justified, designed, or executed [PJDE]) randomized clinical trials warrant dissemination—statistically significant or not. Crucial is whether a randomized clinical trial advances knowledge…

 

Helena Chmura Kraemer, PhD1

JAMA Psychiatry. 2016;73(1):89-90. doi:10.1001/jamapsychiatry.2015.2301.

Posted in February, Hot Topics in Research, Research Commentary

Paradoxical Motor Recovery From a First Stroke After Induction of a Second Stroke: Reopening a Postischemic Sensitive Period

Paradoxical Motor Recovery From a First Stroke After Induction of a Second Stroke: Reopening a Postischemic Sensitive Period

Abstract Background and objective. Prior studies have suggested that after stroke there is a time-limited period of increased responsiveness to training as a result of heightened plasticity—a sensitive period thought to be induced by ischemia itself. Using a mouse model, we have previously shown that most training-associated recovery after a caudal forelimb area (CFA) stroke occurs in the first week and is attributable to reorganization in a medial premotor area (AGm). The existence of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and promote full recovery from the first stroke. To test this prediction, we induced a second stroke in the AGm of mice with incomplete recovery after a first stroke in CFA. Methods. Mice were trained to perform a skilled prehension (reachto-grasp) task to an asymptotic level of performance, after which they underwent photocoagulation-induced stroke in CFA. After a 7-day poststroke delay, the mice were then retrained to asymptote. We then induced a second stroke in the AGm, and after only a 1-day delay, retrained the mice. Results. Recovery of prehension was incomplete when training was started after a 7-day poststroke delay and continued for 19 days. However, a second focal stroke in the AGm led to a dramatic response to 9 days of training, with full recovery to normal levels of performance. Conclusions. New ischemia can reopen a sensitive period of heightened responsiveness to training and mediate full recovery from a previous stroke.

 

Steven R. Zeiler, MD, PhD , Robert Hubbard , Ellen M. Gibson , Tony Zheng , Kwan Ng, MD, PhD , Richard O’Brien, MD, PhD , and John W. Krakauer, MD

Posted in Brain, Cardiology, February, Hot Topics in Research Tagged with: , ,

Schizophrenia risk from complex variation of complement component 4

Schizophrenia risk from complex variation of complement component 4

Abstract

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.

Corresponding Author: McCarroll, Steven A.

Nature (2016), doi:10.1038/nature16549, Published online 27 January 2016

Posted in Dementia, February, Hot Topics in Research, Memory Impairment

Association between sleeping difficulty and type 2 diabetes in women

Association between sleeping difficulty and type 2 diabetes in women

Abstract

Aims/hypothesis

Sleeping difficulty has been associated with type 2 diabetes in some prior studies. Whether the observed associations are independent of health behaviours, other cardiovascular risk factors or other sleep disorders is unclear.

Methods

We analysed data from 133,353 women without diabetes, cardiovascular disease and cancer at baseline in the Nurses’ Health Study (NHS, 2000–2010) and the NHSII (2001–2011). Sleeping difficulty was assessed as having difficulty falling or staying asleep ‘all of the time’ or ‘most of the time’ at baseline (2000 in NHS and 2001 in NHSII).

Results

We documented 6,407 incident cases of type 2 diabetes during up to 10 years of follow-up. After adjustment for lifestyle factors at baseline, comparing women with and without sleeping difficulty, the multivariate-adjusted HR (95% CI) for type 2 diabetes was 1.45 (95% CI 1.33, 1.58), which changed to 1.22 (95% CI 1.12, 1.34) after further adjustment for hypertension, depression and BMI based on the updated repeated measurements. Women who reported all four sleep conditions (sleeping difficulty, frequent snoring, sleep duration ≤6 h and sleep apnoea in NHS or rotating shift work in NHSII) had more than a fourfold increased likelihood of type 2 diabetes (HR 4.17, 95% CI 2.93, 5.91).

Conclusions/interpretation

Sleeping difficulty was significantly associated with type 2 diabetes. This association was partially explained by associations with hypertension, BMI and depression symptoms, and was particularly strong when combined with other sleep disorders. Our findings highlight the importance of sleep disturbance in the development and prevention of type 2 diabetes.

Yanping Li,  Xiang Gao, John W. Winkelman, Elizabeth M. Cespedes, Chandra L. Jackson, Arthur S. Walters, Eva Schernhammer, Susan Redline, Frank B. Hu

© Springer-Verlag Berlin Heidelberg 2016

Posted in Diabetes, February, Hot Topics in Research

Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study

Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study

Background

Compared with traditional photon radiotherapy, proton radiotherapy irradiates less normal tissue and might improve health outcomes associated with photon radiotherapy by reducing toxic effects to normal tissue. We did a trial to assess late complications, acute side-effects, and survival associated with proton radiotherapy in children with medulloblastoma.

Methods

In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients aged 3–21 years who had medulloblastoma. Patients had craniospinal irradiation of 18–36 Gy radiobiological equivalents (GyRBE) delivered at 1·8 GyRBE per fraction followed by a boost dose. The primary outcome was cumulative incidence of ototoxicity at 3 years, graded with the Pediatric Oncology Group ototoxicity scale (0–4), in the intention-to-treat population. Secondary outcomes were neuroendocrine toxic effects and neurocognitive toxic effects, assessed by intention-to-treat. This study is registered at ClinicalTrials.gov, number NCT00105560.

Findings

We enrolled 59 patients from May 20, 2003, to Dec 10, 2009: 39 with standard-risk disease, six with intermediate-risk disease, and 14 with high-risk disease. 59 patients received chemotherapy. Median follow-up of survivors was 7·0 years (IQR 5·2–8·6). All patients received the intended doses of proton radiotherapy. The median craniospinal irradiation dose was 23·4 GyRBE (IQR 23·4–27·0) and median boost dose was 54·0 GyRBE (IQR 54·0–54·0). Four (9%) of 45 evaluable patients had grade 3–4 ototoxicity according to Pediatric Oncology Group ototoxicity scale in both ears at follow-up, and three (7%) of 45 patients developed grade 3–4 ototoxicity in one ear, although one later reverted to grade 2. The cumulative incidence of grade 3–4 hearing loss at 3 years was 12% (95% CI 4–25). At 5 years, it was 16% (95% CI 6–29). Pediatric Oncology Group hearing ototoxicity score at a follow-up of 5·0 years (IQR 2·9–6·4) was the same as at baseline or improved by 1 point in 34 (35%) of 98 ears, worsened by 1 point in 21 (21%), worsened by 2 points in 35 (36%), worsened by 3 points in six (6%), and worsened by 4 points in two (2%). Full Scale Intelligence Quotient decreased by 1·5 points (95% CI 0·9–2·1) per year after median follow-up up of 5·2 years (IQR 2·6–6·4), driven by decrements in processing speed and verbal comprehension index. Perceptual reasoning index and working memory did not change significantly. Cumulative incidence of any neuroendocrine deficit at 5 years was 55% (95% CI 41–67), with growth hormone deficit being most common. We recorded no cardiac, pulmonary, or gastrointestinal late toxic effects. 3-year progression-free survival was 83% (95% CI 71–90) for all patients. In post-hoc analyses, 5-year progression-free survival was 80% (95% CI 67–88) and 5-year overall survival was 83% (95% CI 70–90).

Interpretation

Proton radiotherapy resulted in acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments.

Torunn I Yock, Beow Y Yeap, David H Ebb, Elizabeth Weyman, Bree R Eaton, Nicole A Sherry, Robin M Jones, Shannon M MacDonald, Margaret B Pulsifer, Beverly Lavally, Annah N Abrams, Mary S Huang, Karen J Marcus, Nancy J Tarbell

The Lancet Oncology

Posted in Brain, February, Hot Topics in Research, Oncology, Pediatrics Tagged with: , ,

eNeurosurgery Trial – Feedback Requested

Trial access to Thieme eNeurosurgery available until February 29th

URL: http://eneurosurgery.thieme.com

Thieme eNeurosurgery is the world’s most comprehensive resource for neurological and spine surgery online, providing access to:

  • Thieme’s entire neurosurgical E-Book library of 161 books including CORE TEXTS for residency programs and board exam preparation
  • Over 410 illustrated surgical procedures, original to Thieme eNeurosurgery, providing step-by-step instruction on core techniques and approaches
  • 225 cases with associated Q&A
  • Author-narrated videos, embedded into the text and available to search independently
  • More than 50,000 images for download and use in other applications, with legends and links to original sources
  • Simultaneous search across the neurosurgery titles in Thieme’s E-Journal platform, as well as across all journals indexed in PubMed, with results given to the abstract level

Did you find this resource useful? Please send comments to library@pcom.edu.

Posted in Front Page, Library News, New Resources

Scheduled Refworks Downtime 1/18/2016

On Saturday, January 16, 2016, ProQuest will be upgrading its systems infrastructure. ProQuest (including Refworks and Digital Dissertations) platforms will be unavailable beginning at at 10:00 PM Eastern Standard Time and will last for 8 hours.

Posted in Service Disruptions

Hot Topics in Research

The PCOM Library announces a new information service focused on very recent trends in medical research. The new service kicks-off this month featuring radiology, brain/neurosurgery,cardiology, dementia/memory impairment and cancers of the breast, lung and prostate.

The collection of hot topic articles is accessible directly at http://library.pcom.edu/category/hot-topics/ or by linking from the “Hot Topics in Research” button on the Library’s homepage.
hot topics home page screenshot

Articles are presented in abstract form, with easy links to the full-text versions for detailed research information.

If readers have other suggestions for future monthly hot topics in medical research, please send an email to PJ Grier, associate director at: perskogr@pcom.edu.

Posted in Front Page, Library News

Prostate cancer discovery may make it easier to kill cancer cells

Checkpoint Kinase 2 Negatively Regulates Androgen Sensitivity and Prostate Cancer Cell Growth

Abstract:

Prostate cancer is the second leading cause of cancer death in American men, and curing metastatic disease remains a significant challenge. Nearly all patients with disseminated prostate cancer initially respond to androgen deprivation therapy (ADT), but virtually all patients will relapse and develop incurable castrationresistant prostate cancer (CRPC). A high-throughput RNAi screen to identify signaling pathways regulating prostate cancer cell growth led to our discovery that checkpoint kinase 2 (CHK2) knockdown dramatically increased prostate cancer growth and hypersensitized cells to low androgen levels. Mechanistic investigations revealed that the effects of CHK2 were dependent on the downstream signaling proteins CDC25C and CDK1. Moreover, CHK2depletion increased androgen receptor (AR) transcriptional activity on androgen-regulated genes, substantiating the finding that CHK2 affects prostate cancer proliferation, partly, through the AR. Remarkably, we further show that CHK2 is a novel ARrepressed gene, suggestive of a negative feedback loop between CHK2 and AR. In addition, we provide evidence that CHK2 physically associates with the AR and that cell-cycle inhibition increased this association. Finally, IHC analysis of CHK2 in prostate cancer patient samples demonstrated a decrease in CHK2 expression in high-grade tumors. In conclusion, we propose that CHK2 is a negative regulator of androgen sensitivity and prostate cancer growth, and that CHK2 signaling is lost during prostate cancer progression to castration resistance. Thus, perturbing CHK2 signaling may offer a new therapeutic approach for sensitizing CRPC to ADT and radiation.

 

Cancer Research. 12/1/2015, Vol. 75 Issue 23, p5093-5105. 13p.

Posted in Hot Topics in Research, Oncology, Prostate, Uncategorized

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