Androgen Deprivation Therapy Differentially Impacts Bone and Muscle in the Short Term in Physically Active Men With Prostate Cancer.

Androgen deprivation therapy (ADT) is a cornerstone of advanced prostate cancer (PCa) therapy. Its use is associated with a loss of bone mineral density (BMD) and a greater risk of falls and osteoporotic fractures. In this prospective cohort study, we examined the impact of ADT on muscle and bone strength in men initiating ADT for PCa. Participants were evaluated at three time points: immediately before (week 0), and 6 and 24 weeks after ADT initiation. Study measures included fasting blood levels (for markers of muscle and bone metabolic activity), MRI and QCT imaging (for muscle fat content, and bone density and architecture), and validated clinical tests of muscle strength and gait. Sixteen men completed all study visits. At baseline and throughout the study, participants exercised a median of four times/week, but still experienced weight gain (+2.0 kg at week 24 versus week 0, p = 0.004). Biochemically, all men sustained dramatic early and persistent reductions in sex hormones post-ADT, along with a progressive and significant increase in serum C-telopeptide of type I collagen (CTX, +84% at week 24 versus week 0). There was a trend for rise in serum sclerostin (p = 0.09) and interleukin 6 (IL-6) (p = 0.08), but no significant change in serum myostatin (p = 0.99). Volumetric BMD by QCT declined significantly at the femoral neck (-3.7% at week 24 versus week 0), particularly at the trabecular compartment. On MRI, there were no significant changes in thigh muscle fat fraction. On physical testing, men developed weaker grip strength, but experienced no worsening in lower extremity and lumbar spine muscle strength, or on functional tests of gait. In conclusion, in physically active men, ADT for 24 weeks results in a significant increase in bone resorption and reduction in BMD, but nonsignificant changes in thigh muscle quality (on imaging) or strength and gait (on functional testing). © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Pelvic muscle size and myosteatosis: Relationship with age, gender, and obesity.

PURPOSE: To evaluate interreader performance in the measurement of the cross-sectional area and myosteatosis of pelvic skeletal muscles using fat quantification magnetic resonance imaging (MRI) and correlate with patient anthropomorphic characteristics. MATERIALS AND METHODS: A Health Insurance Portability and Accountability Act-compliant retrospective cross-sectional study was performed. Between January and April 2016, 61 patients (26 males and 35 females) underwent a lumbosacral plexus 3T MRI with a modified three-dimensional spoiled gradient echo sequence dedicated to fat quantification (mDixon Quant; Philips Healthcare). Two independent reviewers outlined muscle cross-sectional area on axial images using a freehand region of interest tool and documented proton-density fat fraction (FF) and muscle area (cm2) of the psoas, gluteus medius, gluteus maximus, and rectus femoris muscles on each side. Interreader agreement was assessed by intraclass correlation coefficient (ICC), and correlation between the measurements and subject's age, gender, and body mass index (BMI) was assessed using multiple linear regression analysis. RESULTS: Excellent interreader agreement was obtained (ICC ≥0.74) for all muscle groups except for the left gluteus medius area and right psoas FF which showed good agreement (0.65 and 0.61, respectively). Statistically significant (P ≤ 0.05) positive correlation was seen between the gluteal muscle FF and area with BMI, and rectus muscle FF with age and BMI. Statistically significant negative correlation between the rectus femoris area and age was also observed. CONCLUSION: Fat quantification MRI is a highly reproducible imaging technique for the assessment of myosteatosis and muscle size. Intramuscular FF and cross-sectional area were correlated with age and BMI across multiple muscle groups.

A Team Disclosure of Error Educational Activity: Objective Outcomes.

Medical errors can involve multiple team members. Few curricula are being developed to provide instruction on disclosing medical errors that include simulation training with interprofessional team disclosure. To explore more objective evidence for the value of an educational activity on team disclosure of errors, faculty developed and assessed the effectiveness of a multimodal educational activity for learning team-based disclosure of a medical error. This study employed a methodological triangulation research design. Participants (N = 458) included students enrolled in academic programs at three separate institutions. The activity allowed students to practice team communication while: (1) discussing a medical error within the team; (2) planning for the disclosure of the error; and (3) conducting the disclosure. Faculty assessed individual student's change in knowledge and, using a rubric, rated the performance of the student teams during a simulation with a standardized family member (SFM). Students had a high level of preexisting knowledge and demonstrated the greatest knowledge gains in questions regarding the approach to disclosure (P < .001) and timing of an apology (P < .001). Both SFMs and individual students rated the team error disclosure behavior highly (rho = 0.54; P < .001). Most participants (more than 80%) felt the activity was worth their time and that they were more comfortable with disclosing a medical error as a result of having completed the activity. This activity for interprofessional simulation of team-based disclosure of a medical error was effective for teaching students about and how to perform this type of important disclosure.

Detrimental effect of systemic vascular risk factors on brain hemodynamic function assessed with MRI.

Background and purpose Vascular risk factors have been associated with decreased cerebral blood flow (CBF) but this is etiologically nonspecific and may result from vascular insufficiency or a response to decreased brain metabolic activity. We apply new MRI techniques to measure oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO2), hypothesizing that decreased CBF related to these vascular risk factors will be associated with increased OEF, confirming a primary vascular insufficiency. Methods 3T MRI was obtained on 70 community-based participants in this IRB-approved study with informed consent, with previous assessment of systolic blood pressure, hypertension medication, elevated serum triglycerides, low serum HDL, and diabetes mellitus. CBF was measured using phase contrast adjusted for brain volume (ml/100 g/min), OEF (%) was obtained from T2-Relaxation-Under-Spin-Tagging (TRUST), and CMRO2 (µmol/100 g/min) was derived using the Fick principle. Stepwise linear regression identified optimal predictors of CBF with age, sex, and hematocrit included for adjustment. This predictive model was then evaluated against OEF and CMRO2. Results Hypertriglyceridemia was associated with low CBF and high OEF. High systolic blood pressure was associated with high CBF and low OEF, which was primarily attributable to those with pressures above 160 mmHg. Neither risk factor was associated with significant differences in cerebral metabolic rate. Conclusion Low CBF related to hypertriglyceridemia was accompanied by high OEF with no significant difference in CMRO2, confirming subclinical vascular insufficiency. High CBF related to high systolic blood pressure likely reflected limitations of autoregulation at higher blood pressures.

How Common Are Pulmonary and Hepatic Adverse Effects in Older Adults Prescribed Nitrofurantoin?

OBJECTIVES: To determine the frequency of serious pulmonary and hepatic adverse events (AEs) in persons aged 65 and older prescribed nitrofurantoin. DESIGN: Retrospective electronic health record (EHR) audit of nitrofurantoin prescriptions and associated AEs. SETTING: Urban academic medical center. PARTICIPANTS: All inpatients and outpatients aged 65 and older prescribed nitrofurantoin from January 1, 2010, to December 31, 2014. MEASUREMENTS: The number of nitrofurantoin prescriptions and pulmonary and hepatic AEs associated with nitrofurantoin use was acquired by data extraction from EHRs. RESULTS: Of 3,400 individuals aged 65 and older prescribed nitrofurantoin during the study period, 641 were identified as possibly having one of five targeted symptoms or disease complications (pulmonary and hepatic) associated with nitrofurantoin. After a detailed chart audit, 89% were deemed to have no adverse reaction, 7% had a minor side effect or allergy, and 3.9% met criteria for suspicion of a nitrofurantoin-induced AE, five of whom were rated as being highly suspicious for nitrofurantoin toxicity; four of the five were identified with pulmonary toxicity and one with hepatotoxicity. Four of five of these individuals used nitrofurantoin chronically. CONCLUSION: Nitrofurantoin was prescribed for 3,400 individuals aged 65 and older during the 5-year study period. Serious side effects appeared to be uncommon, but chronic use appeared to be at greater risk.

AGS Position Statement: Making Medical Treatment Decisions for Unbefriended Older Adults.

In this position statement, we define unbefriended older adults as patients who: (1) lack decisional capacity to provide informed consent to the medical treatment at hand; (2) have not executed an advance directive that addresses the medical treatment at hand and lack capacity to do so; and (3) lack family, friends or a legally authorized surrogate to assist in the medical decision-making process. Given the vulnerable nature of this population, clinicians, health care teams, ethics committees and other stakeholders working with unbefriended older adults must be diligent when formulating treatment decisions on their behalf. The process of arriving at a treatment decision for an unbefriended older adult should be conducted according to standards of procedural fairness and include capacity assessment, a search for potentially unidentified surrogate decision makers (including non-traditional surrogates) and a team-based effort to ascertain the unbefriended older adult's preferences by synthesizing all available evidence. A concerted national effort is needed to help reduce the significant state-to-state variability in legal approaches to unbefriended patients. Proactive efforts are also needed to identify older adults, including "adult orphans," at risk for becoming unbefriended and to develop alternative approaches to medical decision making for unbefriended older adults. This document updates the 1996 AGS position statement on unbefriended older adults.

Donepezil effects on hippocampal and prefrontal functional connectivity in Alzheimer's disease: preliminary report.

We used functional connectivity magnetic resonance imaging (fcMRI) to investigate changes in interhemispheric brain connectivity in 11 patients with mild Alzheimer's disease (AD) following eight weeks of treatment with the cholinesterase inhibitor donepezil. We examined functional connectivity between four homologous temporal, frontal, and occipital regions. These regions were selected to represent sites of AD neuropathology, sites of donepezil-related brain activation change in prior studies, and sites that are minimally affected by the pathologic changes of AD. Based on previous findings of selective, localized frontal responses to donepezil, we predicted that frontal connectivity would be most strongly impacted by treatment. Of the areas examined, we found that treatment had a significant effect only on functional connectivity between right and left dorsolateral prefrontal cortices. Implications for understanding the impact of donepezil treatment on brain functioning and behavior in patients with AD are discussed. This preliminary report suggests that fcMRI may provide a useful index of treatment outcome in diseases affecting brain connectivity. Future research should investigate these treatment-related changes in larger samples of patients and age-matched controls.

Reduced hippocampal functional connectivity in Alzheimer disease.

OBJECTIVE: To determine if functional connectivity of the hippocampus is reduced in patients with Alzheimer disease. DESIGN: Functional connectivity magnetic resonance imaging was used to investigate coherence in the magnetic resonance signal between the hippocampus and all other regions of the brain. PARTICIPANTS: Eight patients with probable Alzheimer disease and 8 healthy volunteers. RESULTS: Control subjects showed hippocampal functional connectivity with diffuse cortical, subcortical, and cerebellar sites, while patients demonstrated markedly reduced functional connectivity, including an absence of connectivity with the frontal lobes. CONCLUSION: These findings suggest a functional disconnection between the hippocampus and other brain regions in patients with Alzheimer disease.

The primary care of Alzheimer disease.

Alzheimer disease is the most common cause of progressive irreversible intellectual loss in aging humans. The number of individuals and families affected by this disorder will continue to grow as society ages worldwide. Our understanding of the biology, underlying pathophysiology, and diagnosis of Alzheimer disease has greatly expanded over the past few years and much has been published in these areas. This review focuses on the primary care of this disorder and addresses the "now what" question. Topics examined include limiting excess disability, responding to commonly raised questions of family members, pharmacologic and nonpharmacologic therapeutic options, long-term planning, and caregiver issues.

The spectrum of WRN mutations in Werner syndrome patients.

The International Registry of Werner syndrome (www.wernersyndrome.org) has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators.

Emerging concepts in osteoporosis and bone strength.

OBJECTIVE: Osteoporosis is a systemic skeletal disorder characterized by compromised bone strength and increased fracture risk. The factors that contribute to bone strength include bone mineral density (BMD) and bone quality, which encompasses factors such as bone turnover, microarchitecture, mineralization, and geometry. The objective of this paper was to review the factors that contribute to bone strength and osteoporosis. RESEARCH DESIGN: A MEDLINE search of English language journals between 1 January 1995 and 1 March 2005 was conducted using the term 'osteoporosis' combined with 'bone strength' or 'bone quality'. Reference lists of pivotal studies and reviews were also examined. Studies were otherwise not excluded on the basis of quality or size, the aim being to present an overview of research conducted to date on osteoporosis and bone strength. RESULTS: While there is a relationship between BMD and fracture risk, evidence suggests that BMD measurements reflect only 1 component of bone strength. For example, small changes in BMD produced by osteoporosis treatments do not fully explain the reductions in fracture risk observed after initiation of therapy, and substantial fracture risk reduction is observed before peak increases in BMD are achieved. In addition to their effects on BMD, anti-resorptive therapies for osteoporosis (i.e., bisphosphonates, selective estrogen receptor modulators, calcitonin, and estrogen) produce positive effects on bone turnover, microarchitecture, and/or mineralization, all of which can contribute to the reductions in fracture risk observed with these agents. Anabolic agents such as teriparatide also appear to have beneficial effects on bone strength independent of bone mass. New, non-invasive, high-resolution imaging methods, such as magnetic resonance imaging and computed tomography, may offer a comprehensive assessment of bone quality in the future. CONCLUSIONS: The development of clinical tools that assess bone quality independent of BMD will be essential to advance our assessment of fracture risk and response to osteoporosis treatment.

Development of geriatrics-oriented faculty in general internal medicine.

The need for adequate geriatrics training for the physician workforce has been recognized for decades. However, there are not enough academic geriatricians to provide for the educational needs of trainees, and this situation is not expected to change in the future. General internists are often responsible for teaching medical students and internal medicine residents to care for elderly patients in inpatient and ambulatory settings. These academic general internists could play a pivotal role in providing geriatrics instruction. To characterize what is being done to develop geriatrics-oriented general internal medicine faculty, we identified current practices, "best practices," goals and targets, and barriers to achieving those goals and targets. We reviewed the literature on faculty-development programs for general internal medicine faculty, and we held focus groups and structured interviews with general internal medicine unit chiefs and directors of Geriatric Centers of Excellence at 46 medical schools throughout the United States. We found a need for programs to develop geriatrics-oriented academic general internists. Although general internal medicine faculties seem receptive to further geriatrics training, important obstacles exist. These include inadequate time and resources as well as motivational and attitudinal challenges. We discuss potential solutions for overcoming these barriers and the implications of these solutions for stakeholders.