Testicular tissue cryopreservation: 8 years of experience from a coordinated network of academic centers.

STUDY QUESTION: Is it feasible to disseminate testicular tissue cryopreservation with a standardized protocol through a coordinated network of centers and provide centralized processing/freezing for centers that do not have those capabilities? SUMMARY ANSWER: Centralized processing and freezing of testicular tissue from multiple sites is feasible and accelerates recruitment, providing the statistical power to make inferences that may inform fertility preservation practice. WHAT IS KNOWN ALREADY: Several centers in the USA and abroad are preserving testicular biopsies for patients who cannot preserve sperm in anticipation that cell- or tissue-based therapies can be used in the future to generate sperm and offspring. STUDY DESIGN, SIZE, DURATION: Testicular tissue samples from 189 patients were cryopreserved between January 2011 and November 2018. Medical diagnosis, previous chemotherapy exposure, tissue weight, and presence of germ cells were recorded. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human testicular tissue samples were obtained from patients undergoing treatments likely to cause infertility. Twenty five percent of the patient's tissue was donated to research and 75% was stored for patient's future use. The tissue was weighed, and research tissue was fixed for histological analysis with Periodic acid-Schiff hematoxylin staining and/or immunofluorescence staining for DEAD-box helicase 4, and/or undifferentiated embryonic cell transcription factor 1. MAIN RESULTS AND THE ROLE OF CHANCE: The average age of fertility preservation patients was 7.9 (SD = 5) years and ranged from 5 months to 34 years. The average amount of tissue collected was 411.3 (SD = 837.3) mg and ranged from 14.4 mg-6880.2 mg. Malignancies (n = 118) were the most common indication for testicular tissue freezing, followed by blood disorders (n = 45) and other conditions (n = 26). Thirty nine percent (n = 74) of patients had initiated their chemotherapy prior to undergoing testicular biopsy. Of the 189 patients recruited to date, 137 have been analyzed for the presence of germ cells and germ cells were confirmed in 132. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive study of testicular tissues obtained from patients who were at risk of infertility. The function of spermatogonia in those biopsies could not be tested by transplantation due limited sample size. WIDER IMPLICATIONS OF THE FINDINGS: Patients and/or guardians are willing to pursue an experimental fertility preservation procedure when no alternatives are available. Our coordinated network of centers found that many patients request fertility preservation after initiating gonadotoxic therapies. This study demonstrates that undifferentiated stem and progenitor spermatogonia may be recovered from the testicular tissues of patients who are in the early stages of their treatment and have not yet received an ablative dose of therapy. The function of those spermatogonia was not tested. STUDY FUNDING/COMPETING INTEREST(S): Support for the research was from the Eunice Kennedy Shriver National Institute for Child Health and Human Development grants HD061289 and HD092084, the Scaife Foundation, the Richard King Mellon Foundation, the Departments of Ob/Gyn & Reproductive Sciences and Urology of the University of Pittsburgh Medical Center, United States-Israel Binational Science Foundation (BSF), and the Kahn Foundation. The authors declare that they do not have competing financial interests.

Artifactual formylation of the secondary amine of duloxetine hydrochloride by acetonitrile in the presence of titanium dioxide: implications for HPLC method development.

Duloxetine hydrochloride, a secondary amine containing pharmaceutical, currently marketed as Cymbalta, is shown to undergo N-formylation as an artifact of sample preparation prior to HPLC analysis for impurities. The reaction was discovered as a result of an investigation into variability in the levels of N-formyl duloxetine observed upon HPLC analysis. The reaction is catalyzed by sonication and/or light in the presence of titanium dioxide and is proposed to occur via a radical-initiated mechanism. The mechanism is supported by controlled sample preparation studies with deuterium-labeled acetonitrile and LC/MS studies that showed incorporation of one deuterium into N-formyl duloxetine. This discovery is broadly relevant because sonication is commonly used to aid dissolution of pharmaceuticals in acetonitrile for HPLC analysis, titanium dioxide is a commonly used excipient, the amount of light found in modern analytical laboratories is sufficient to cause the reaction to occur, and secondary amines are present in the structures of many pharmaceuticals. The artifactual reaction was effectively eliminated by changing the sample solvent to methanol and replacing sonication with shaking to aid sample dissolution.

Getting the measure of spasticity in multiple sclerosis: the Multiple Sclerosis Spasticity Scale (MSSS-88).

Spasticity is most commonly defined as an inappropriate, velocity dependent, increase in muscle tonic stretch reflexes, due to the amplified reactivity of motor segments to sensory input. It forms one component of the upper motor neuron syndrome and often leads to muscle stiffness and disability. Spasticity can, therefore, be measured through electrophysiological, biomechanical and clinical evaluation, the last most commonly using the Ashworth scale. None of these techniques incorporate the patient experience of spasticity, nor how it affects people's daily lives. Consequently, we set out to construct a rating scale to quantify the perspectives of the impact of spasticity on people with multiple sclerosis. Qualitative methods (in-depth patient interviews and focus groups, expert opinion and literature review) were used to develop a conceptual framework of spasticity impact, and to generate a pool of items with the potential to convert this framework into a rating scale with multiple dimensions. This item pool was administered, in the form of a questionnaire, to a sample of people with multiple sclerosis and spasticity. Guided by Rasch analysis, we constructed and validated a rating scale for each component of the conceptual framework. Decisions regarding item selection were based on the integration and assimilation of seven specific analyses including clinical meaning, ordering of thresholds, fit statistics and differential item functioning. The qualitative phase (17 patient interviews, 3 focus groups) generated 144 potential scale items and a conceptual model with eight components addressing symptoms (muscle stiffness, pain and discomfort and muscle spasms,), physical impact (activities of daily living, walking and body movements) and psychosocial impact (emotional health, social functioning). The first postal survey was sent to 272 people with multiple sclerosis and had a response rate of 88%. Findings supported the development of scales for each component but demonstrated that five item response options were too many. The 144-item questionnaire, reformatted with four-item response options, was administered with four validating instruments to an independent sample of 259 people with multiple sclerosis (response rate 78%). From the responses, an 88-item instrument with eight subscales was developed that satisfied criteria for reliable and valid measurement. Correlations with other measures were consistent with predictions. The 88-item Multiple Sclerosis Spasticity Scale (MSSS-88) is a reliable and valid, patient-based, interval-level measure of the impact of spasticity in multiple sclerosis. It has the potential to advance outcomes measurement in clinical trials and clinical practice, and provides a new perspective in the clinical evaluation of spasticity.

Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up.

OBJECTIVE: To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. METHODS: In total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to 12 months in the follow up study reported here. RESULTS: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Delta(9)-THC mean reduction 1.82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI -0.99 to 1.19), placebo -0.23 (n = 176, 95% CI -1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Delta(9)-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. CONCLUSIONS: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

Health and long-term care for people with Alzheimer's disease and related dementias: policy research issues.

Policy research into the service needs of persons with dementia had its origin looking at challenges confronting caregivers--extended hours of instrumental task assistance, social isolation, fatigue, depression--and how public policy might support informal care-giving while saving public expenditures from nursing home care. This paper, drawing on the experience of the Medicare Alzheimer's Disease Demonstration and other work, provides suggestions for extending care and financing considerations to include health care use and the medical management of chronic health conditions. Basic research is needed to document current use and risk factors, as is experimentation with clinical and other interventions designed to achieve desired quality of care and cost outcomes. This section of the paper will be of direct interest to both US and international readers. The second half of the paper reviews the US state role in regulating and financing nursing homes, home and community-based care, and residential care. All these sectors have high rates of staff turnover, staff shortages, and concerns with quality of care. The international community and US states provide naturally occurring opportunities for delivery system experimentation and innovation. Research taking advantage of these opportunities could greatly inform public policy.

Estimating the costs of caring for people with Alzheimer disease in California: 2000-2040.

The costs of caring for people with Alzheimer disease (AD) in California are estimated using data from a study of the costs of caring for community-resident and institutionalized people with AD, combined will prevalence and population projections. Costs for community-resident patients will increase 83 percent in the period 2000 ($23.4 billion) to 2020 ($42.8 billion), and will grow an additional 59 percent from 2020 to 2040 ($68.1 billion). Costs for AD patients in institutions will increase 84 percent from 2000 ($2.5 billion) to 2020 ($4.6 billion), and will grow an additional 61 percent from 2020 to 2040 ($7.4 billion), assuming the supply of nursing home beds meets projected demand. Total costs of caring for AD patients will nearly triple between 2000 and 2040. The rapid aging of the U.S. population makes more aggressive societal action necessary if the personal and societal burden of Alzheimer's disease is to be reduced in the future.

Health and long-term care for people with Alzheimer's disease and related dementias: Policy research issues.

Policy research into the service needs of persons with dementia had its origin looking at challenges confronting caregivers-extended hours of instrumental task assistance, social isolation, fatigue, depression-and how public policy might support informal care-giving while saving public expenditures from nursing home care. This paper, drawing on the experience of the Medicare Alzheimer's Disease Demonstration and other work, provides suggestions for extending care and financing considerations to include health care use and the medical management of chronic health conditions. Basic research is needed to document current use and risk factors, as is experimentation with clinical and other interventions designed to achieve desired quality of care and cost outcomes. This section of the paper will be of direct interest to both US and international readers. The second half of the paper reviews the US state role in regulating and financing nursing homes, home and community-based care, and residential care. All these sectors have high rates of staff turnover, staff shortages, and concerns with quality of care. The international community and US states provide naturally occurring opportunities for delivery system experimentation and innovation. Research taking advantage of these opportunities could greatly inform public policy.

Defining dementia: social and historical background of Alzheimer disease.

Though Alzheimer disease (AD) has been recognized as a distinct entity since 1907, scientific understanding of, and public interest in, the disease remained very limited until the 1970s. The perception of AD as a significant problem has been substantially affected by cultural and demographic changes and by interest group and federal government initiatives. The recognition of AD has transformed senility from an expected stage of life into a "disease." It has also increased fear both of the individual effects of having AD and of the social consequences of AD in the population. Both the biotechnology industry and AD activist organizations will play a role in the social implications of genetic testing for AD.

Neurological and psychiatric predictors of mortality in patients with Alzheimer disease in California.

OBJECTIVE: To determine whether neurological and psychiatric symptoms predict survival time among patients with Alzheimer disease (AD) after adjusting for the influence of sociodemographic variables, health conditions, and dementia severity separately for men and women. DESIGN: The sample consisted of 936 men and women diagnosed as having probable or possible AD at 1 of 7 Alzheimer's Disease Diagnostic and Treatment Centers throughout California from 1986 through 1990. Data on dementia severity, comorbid conditions, and demographic characteristics were collected at the time of AD diagnosis. Data on vital status and dates of death were obtained by linking the patient file to several administrative databases maintained by the California State and federal governments. The mean length of follow-up was 31 months. Data were analyzed with Kaplan-Meier survival curves and Cox proportional hazards models. RESULTS: Men had shorter survival times than did women (log-rank test, 30.93, P < .001). Among men, but not women, survival times were negatively associated with selected neurological and psychiatric symptoms. Among women, but not men, a history of cardiovascular conditions was associated with poorer survival. CONCLUSIONS: Patterns of survival and predictors of survival time among patients with AD differ by sex. Future studies of survival and progression of AD need to examine men and women separately.

Effects of a health promotion program on sustaining health behaviors in older adults.

BACKGROUND: Controversy exists regarding the optimal way to provide health promotion education to the elderly. This prospective randomized study evaluated the effectiveness of individualized assessment and counseling coupled with the receipt of a written health plan on client adherence to health behavior recommendations. METHODS: Two hundred thirty-seven ethnically diverse and predominantly low-income adults 60 and older, participating for the first time in an established statewide public health prevention program delivered in both rural and urban clinics, were recruited and randomly assigned to treatment and control groups. All participants received a standardized assessment that included a health history, nutrition assessment, and limited physical exam from a public health nurse. The treatment group additionally received a written personal health plan and individualized counseling to support implementation of the plan. Both groups were interviewed after one year to determine their adherence to the original recommendations. RESULTS: Seventeen preventive services and health behaviors were evaluated. There were no statistically significant differences between the groups on health care use and previous health behaviors at baseline. Using logistic regression and controlling for socioeconomic and demographic variables, we found that the treatment group that received a personal health plan and counseling completed significantly more preventive referrals and health behavior changes (P < .001). CONCLUSIONS: A client-centered planning process with supportive counseling by public health nurses, combined with health plans provided to clients, can significantly increase the prevention measures taken by older adults.

Service use and cost outcomes for persons with Alzheimer disease.

Use of formal services and the associated costs of caring for people with Alzheimer disease and related disorders are expected increase into the next century. This will be driven primarily by general economic inflation, annual increases in health care costs exceeding the inflation rate, increasing numbers of people 85 years of age and older, increases in the expected life span of people at 65 years of age, increasing numbers of people in the nonelderly disabled population receiving Medicare benefits, and changes in the employment structure of the economy. Two sources of data that have been used to estimate formal health and social service utilization and costs are self-report and Medicare claims data. Self-report data are problematic in studies of people with Alzheimer disease because of the demented person's general inability to reliably report on service utilization and the necessary use of proxies to obtain information. Medicare claims are a source for both service utilization and cost data, but limitations in these data result from their use to document reimbursement claims as opposed to accurately reflecting service use histories. Given the lack of reliable and comprehensive service utilization and cost reporting systems, a variety of methods will be required to estimate service use and cost outcome data for people with dementia. These include self-reports of service use and cost, examination of claims records, and service use document abstraction, when feasible.

Correlates of Mini-Mental Status Examination scores among elderly demented patients: the influence of race-ethnicity.

Data on 1888 patients seen at Alzheimer's Disease Diagnostic and Treatment Centers in California were used to examine possible differences in Mini-Mental State Examination (MMSE) results for different racial-ethnic groups. White patients had scores less indicative of dementia than Black and Hispanic patients using the standard 23 cutting point on the MMSE. However, there were no differences among these groups in the percentages clinically diagnosed as demented. The difference in the percentage of Whites vs Blacks and Hispanics categorized as demented by the MMSE was not accounted for by education, occupation, age, sex, or other variables tested, even though these variables were correlated with MMSE scores. Our data suggest that clinicians should consider MMSE scores for Black and Hispanic patients an underestimate of their cognitive capabilities relative to that of White patients.

Professional allocations of counseling service to persons with Alzheimer's disease: an exploration.

Individual, family, and group counseling service recommendations made by California's diagnostic and treatment center staff to a clinical sample of Alzheimer's disease clients (N = 822) are examined using logistic regression. Predictors included the patients' enabling, need, and predisposing characteristics. Analysis shows that staff tend to consider fewer patient characteristics, and rely more on assessed family problems and payment source when deciding whether they recommend counseling to their patients.

The economic burden of Alzheimer's disease care.

This study examines total formal and informal care costs attributable to Alzheimer's disease for persons living in the community and in institutions. The total cost of caring for an Alzheimer's patient in northern California is approximately $47,000 per year whether the patient lives at home or in a nursing home, but the cost breakdown differs in the two settings. For community-resident patients, three-fourths of the total cost represents an imputed value for unpaid informal care compared with 12 percent for institutionalized patients. Formal services are financed primarily by individuals and their families. Over 60 percent of the services provided to patients in either care setting were paid out of pocket. With projected increases in the number of persons at risk of developing Alzheimer's disease, the economic impact of the disease on future long-term care costs will be significant.

Why home health services are provided to Alzheimer's disease patients in California's Alzheimer's disease program: an exploration.

Logistic regression is used to examine why formal home health service recommendations are made to Alzheimer's disease patients (N = 822) by staff at each of six Alzheimer's Disease Diagnostic and Treatment Centers (ADDTCs) in California. Patients are selected on the basis of their having Alzheimer's disease, and not having any physical co-morbid health problems noted at the time of their clinical assessment. Using Medicare Part A to pay for care, previous home health use, having regular access to and prior use of a primary care physician, prior hospitalization, client agitation and apathy, and family's social isolation were significant predictors of the latent propensity to recommend formal home health services to members of this sample.

The posthospital experience of elderly Medicare home health users.

This study describes the home health experience of 295 Medicare elderly persons following hospitalization. While a subset of persons improved medically and functionally during the home health service period, some declined on one or both dimensions and many showed not change. The most heavily utilized, non-Medicare, services were personal care and homemaker/chore, reflecting the functional needs of some posthospital elderly. One-fifth of Medicare home health users were reinstitutionalized or died during the service period. Those discharged to home had a range of continuing service needs, both medical and functional, after home health discharge.

Geriatric services: community mental health center boon or bane?

The fragmented and uncoordinated development of federal and state mental health policy for the aged, the lifting of federal mandates for CMHC service emphases on the aged, and the underutilization of CMHC services by the aged all raise the issue of the implications of CMHCs emphasis on services to elderly clients. We hypothesized that CMHCs with increases in aged clientele would fare worse in terms of budgets, services, and staffing than those that did not report increases in elderly clientele. The findings are more complex in that, compared to centers with no change in aged clientele, CMHCs fared better when they either had decreases in aged clientele (as expected) or increases in such clientele (in contradiction to the hypothesis), although the former relationship was stronger. These findings are interpreted in terms of the need for CMHCs to specialize either on the aged or on other client populations. Such specialization, and the stronger effect for de-emphasis on the aged, suggest greater barriers to access of the aged to community mental health care.

Thermoluminescence emission spectrometer.

A sensitive thermoluminescence (TL) emission spectrometer based on Fourier transform spectroscopy is described. It employs a modified scanning Twyman-Green interferometer with photomultiplier detection in a photon-counting mode. The etendue is 180pi mm(2), and it covers the 350-600-nm wavelength range. The output can be displayed either as a 3-D isometric plot of intensity vs temperature and wavelength, as a contour diagram, or as a conventional TL glow curve of intensity vs temperature. It is sufficiently sensitive to record thermoluminescence spectra of dosimeter phosphors and minerals for thermoluminescence dating at levels corresponding to those found during actual use as radiation monitors or in dating. Examples of actual spectra are given.