St. Louis VA Medical Center

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

The cardiovascular complications of acute coronavirus disease 2019 (COVID-19) are well described, but the post-acute cardiovascular manifestations of COVID-19 have not yet been comprehensively characterized. Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

This paper reports two studies of chronic pain patients (n = 444) relevant to the psychometric properties of the Pain Disability Index (PDI), a self-report instrument that has been used to assess the degree to which chronic pain interferes with various daily activities. In the first study, patients with high PDI scores reported more psychological distress (P less than 0.001), more severe pain characteristics (P less than 0.001), and more restriction of activities (P less than 0.001) than patients with low PDI scores, findings supportive of the construct validity of the measure. Further, a multiple regression showed that a linear combination of 9 variables predicted PDI scores (R = 0.74): time spent in bed, psychosomatic symptoms, stopping activities because of pain, work status, pain duration, usual pain intensity, quality of life, pain extent, and education. This study also showed differences for age and gender on disability. The second study involved 46 patients who had undergone inpatient treatment for their pain conditions. The study revealed modest test-retest reliability for the instrument. It also showed the PDI to be associated with the levels of pain behavior exhibited by these patients. The findings of both studies generally support the reliability and validity of the PDI as a brief measure of pain-related disability. Questions regarding its test-retest reliability and lack of association with certain pain behaviors are discussed, as are suggestions for future research.

OBJECTIVE: To determine the association of sarcopenic obesity with the onset of Instrumental Activities of Daily Living (IADL) disability in a cohort of 451 elderly men and women followed for up to 8 years. RESEARCH METHODS AND PROCEDURES: Sarcopenic obesity was defined at study baseline as appendicular skeletal muscle mass divided by stature squared <7.26 kg/m2 in men and 5.45 kg/m2 in women and percentage body fat greater than the 60th percentile of the study sample (28% body fat in men and 40% in women). Incident disability was defined as a loss of two or more points from baseline score on the IADL. Subjects with disability at baseline (scores < 8) were excluded. Cox proportional hazards analysis was used to determine the association of baseline sarcopenic obesity with onset of IADL disability, controlling for potential confounders. RESULTS: Subjects with sarcopenic obesity at baseline were two to three times more likely to report onset of IADL disability during follow-up than lean sarcopenic or nonsarcopenic obese subjects and those with normal body composition. The relative risk for incident disability in sarcopenic obese subjects was 2.63 (95% confidence interval, 1.19 to 5.85), adjusting for age, sex, physical activity level, length of follow-up, and prevalent morbidity. DISCUSSION: This is the first study, to our knowledge, to indicate that sarcopenic obesity is independently associated with and precedes the onset of IADL disability in the community-dwelling elderly. The etiology of sarcopenic obesity is unknown but may include a combination of decreases in anabolic signals and obesity-associated increases in catabolic signals in old age.

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-also referred to as Long COVID-have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.

C. Wang, E. Nieschlag, R. Swerdloff, H. M. Behre, W. J. Hellstrom, L. J. Gooren, J. M. Kaufman, J.-J. Legros, B. Lunenfeld, A. Morales, J. E. Morley, C. Schulman, I. M. Thompson, W. Weidner, and F. C. W. Wu

BACKGROUND AND METHODS: Chronic hepatitis B is a common and often progressive liver disorder for which there is no accepted therapy. To assess the efficacy of treatment with interferon, we randomly assigned patients with chronic hepatitis B to one of the following regimens: prednisone for 6 weeks followed by 5 million units of recombinant interferon alfa-2b daily for 16 weeks; placebo followed by 5 million units of interferon daily for 16 weeks; placebo followed by 1 million units of interferon daily for 16 weeks; or observation with no treatment. RESULTS: Hepatitis B e antigen and hepatitis B viral DNA disappeared from serum significantly more often in the patients given prednisone plus interferon (16 of 44 patients, or 36 percent) or 5 million units of interferon alone (15 of 41; 37 percent) than in the untreated controls (3 of 43; 7 percent; P less than 0.001); the difference between those given 1 million units of interferon (7 of 41; 17 percent) and the controls was not significant. The strongest independent predictor of a response to treatment was the amount of hepatitis B viral DNA in serum at entry (P less than 0.0001). Of the 38 patients who responded to interferon, 33 (87 percent) had normal serum aminotransferase levels after therapy; 11 patients who responded (29 percent), but no controls, lost the hepatitis B surface antigen. Blinded histologic assessment revealed a significant improvement in periportal necrosis in the treated patients (P = 0.03). CONCLUSIONS: In chronic hepatitis B, treatment with interferon alfa-2b (5 million units per day for 16 weeks) was effective in inducing a sustained loss of viral replication and achieving remission, assessed biochemically and histologically, in over a third of patients. Moreover, in about 10 percent of the patients treated with interferon, hepatitis B surface antigen disappeared from serum.

The objective of this study was to determine the relationship between prescribed daily dose frequency and patient medication compliance. The medication compliance of 105 patients receiving antihypertensive medications was monitored by analyzing data obtained from special pill containers that electronically record the date and time of medication removal. Inaccurate compliance estimates derived using the simple pill count method were thereby avoided. Compliance was defined as the percent of days during which the prescribed number of doses were removed. Compliance improved from 59.0% on a three-time daily regimen to 83.6% on a once-daily regimen. Thus, compliance improves dramatically as prescribed dose frequency decreases. Probably the single most important action that health care providers can take to improve compliance is to select medications that permit the lowest daily prescribed dose frequency.

Substances cross the blood-brain barrier (BBB) by a variety of mechanisms. These include transmembrane diffusion, saturable transporters, adsorptive endocytosis, and the extracellular pathways. Here, we focus on the chief characteristics of two mechanisms especially important in drug delivery: transmembrane diffusion and transporters. Transmembrane diffusion is non-saturable and depends, on first analysis, on the physicochemical characteristics of the substance. However, brain-to-blood efflux systems, enzymatic activity, plasma protein binding, and cerebral blood flow can greatly alter the amount of the substance crossing the BBB. Transport systems increase uptake of ligands by roughly 10-fold and are modified by physiological events and disease states. Most drugs in clinical use to date are small, lipid soluble molecules that cross the BBB by transmembrane diffusion. However, many drug delivery strategies in development target peptides, regulatory proteins, oligonucleotides, glycoproteins, and enzymes for which transporters have been described in recent years. We discuss two examples of drug delivery for newly discovered transporters: that for phosphorothioate oligonucleotides and for enzymes.

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs' national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93-2.45), hospitalization (HR = 3.32, 95% CI 3.13-3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

Are newer types of antihypertensive agents, which are currently more costly to purchase on average, as good or better than diuretics in reducing coronary heart disease incidence and progression? Will lowering LDL cholesterol in moderately hypercholesterolemic older individuals reduce the incidence of cardiovascular disease and total mortality? These important medical practice and public health questions are to be addressed by the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind trial in 40,000 high-risk hypertensive patients. ALLHAT is designed to determine whether the combined incidence of fatal coronary heart disease (CHD) and nonfatal myocardial infarction differs between persons randomized to diuretic (chlorthalidone) treatment and each of three alternative treatments--a calcium antagonist (amlodipine), an angiotensin converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). ALLHAT also contains a randomized, open-label, lipid-lowering trial designed to determine whether lowering LDL cholesterol in 20,000 moderately hypercholesterolemic patients (a subset of the 40,000) with a 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor, pravastatin, will reduce all-cause mortality compared to a control group receiving "usual care." ALLHAT's main eligibility criteria are: 1) age 55 or older; 2) systolic or diastolic hypertension; and 3) one or more additional risk factors for heart attack (eg, evidence of atherosclerotic disease or type II diabetes). For the lipid-lowering trial, participants must have an LDL cholesterol of 120 to 189 mg/dL (100 to 129 mg/dL for those with known CHD) and a triglyceride level below 350 mg/dL. The mean duration of treatment and follow-up is planned to be 6 years. Further features of the rationale, design, objectives, treatment program, and study organization of ALLHAT are described in this article.

BACKGROUND: Psychotherapy is the principal nonpharmacologic method for the management of depression, but its usefulness for depressed patients with diabetes remains unknown. OBJECTIVE: To assess the efficacy of cognitive behavior therapy (CBT) for depression in patients with diabetes. DESIGN: Randomized, controlled trial. SETTING: Referral-based academic medical center. PATIENTS: 51 patients with type 2 diabetes and major depression. INTERVENTION: Patients were assigned either to a group that received 10 weeks of individual CBT or to a control group that received no specific antidepressant treatment. All patients participated in a diabetes education program to control for the effects of supportive attention and the possible influence of enhanced diabetes control on mood. MEASUREMENTS: Degree of depression was measured by using the Beck Depression Inventory; glycemic control was measured by using glycosylated hemoglobin levels. Outcomes were assessed immediately after treatment and 6 months after treatment. RESULTS: The percentage of patients achieving remission of depression (Beck Depression Inventory score < or = 9) was greater in the CBT group than in the control group: posttreatment, 85.0% of patients in the CBT group (17 of 20) compared with 27.3% of controls (6 of 22) achieved remission (difference, 57.7 percentage points [95% CI, 33 to 82 percentage points]) (P < 0.001); at follow-up, 70.0% of patients in the CBT group (14 of 20) compared with 33.3% of controls (7 of 21) achieved remission (difference, 36.7 percentage points [CI, 9 to 65 percentage points]) (P = 0.03). Post-treatment glycosylated hemoglobin levels were not different in the two groups, but follow-up mean glycosylated hemoglobin levels were significantly better in the CBT group than in the control group (9.5% compared with 10.9%; P = 0.03). CONCLUSIONS: The combination of CBT and supportive diabetes education is an effective nonpharmacologic treatment for major depression in patients with type 2 diabetes. It may also be associated with improved glycemic control.

The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain-Barré syndrome, and encephalitis or encephalopathy. We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19.

Research and clinical experience indicate that drug use disorders tend to run in families. The objective of this study was to distinguish between the family environment and genetic factors as the source of this observed family resemblance. Data were collected by telephone interview from members of the Vietnam Era Twin Registry, comprising male twin pairs who served in the U.S. military between 1965 and 1975. There were 3,372 pairs in which both twins participated. Drug use disorder was defined as receiving a diagnosis of drug abuse or dependence according to DSM-III-R; 10.1% of the sample had abused or been dependent on at least one illicit drug. A significant difference between concordance rates for monozygotic (26.2%) vs. dizygotic (16.5%) twins indicated a genetic influence on drug use disorder. Biometrical modeling indicated that genetic factors (34% of the variance), the environment shared by twins (28% of the variance), and the nonshared environment (38% of the variance) had significant influences of similar magnitudes on the individual's risk of developing a drug use disorder. These results support the application of molecular genetic approaches to elucidate the genetic influence on drug use disorder, as well as the potential efficacy of environmental intervention to reduce risk.

BACKGROUND: Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. METHODS: A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. RESULTS: Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. CONCLUSION: The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.

Demographic data clearly demonstrate that the percentage of the population in the older age group is increasing. Androgen deficiency in the aging male has become a topic of increasing interest and debate throughout the world. Cross-sectional and longitudinal data indicate that testosterone falls progressively with age and that a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age, 20–30 years) men (Gray et al, 1991; Harman et al, 2001; Araujo et al, 2007; Wu et al, 2008). The principal questions raised by these observations are whether older hypogonadal men will benefit from testosterone treatment and what will be the risks associated with such intervention. The past decade has brought evidence of benefit of androgen treatment of hypogonadal men on multiple target organs, and recent studies show short-term beneficial effects of testosterone in older men that are similar to those in younger men. This has been comprehensively reviewed and summarized by the Institute of Medicine in Testosterone and Aging: Clinical Research Directions (Liverman and Blazer, 2004). Long-term data on the effects of testosterone treatment in the older population are limited mainly to effects on body composition and bone mass (Snyder et al, 1999a,b; Amory et al, 2004; Isidori et al, 2005a,b; Page et al, 2005). Key questions of the effects of testosterone on patient reported outcomes and functional benefits that may retard physical or mental frailty of the elderly or improve the quality of life are not yet available. Specific risk data on the prostate and cardiovascular systems are needed. Recent guidelines for the testosterone treatment of younger hypogonadal men are available from professional societies (AACE Hypogonadism Task Force, 2002; The Practice Committee of the American Society for Reproductive Medicine, 2004; Bhasin et al, 2006). Recommendations on the diagnosis, treatment, and monitoring of late-onset hypogonadism was published by the International Society for the Study of Aging Male (ISSAM) in 2002 (Morales and Lunenfeld, 2002). In 2005, a writing committee formed by the International Society of Andrology (ISA), the ISSAM, and the European Association of Urology (EAU) prepared a set of recommendations specifically on the “investigation, treatment, and monitoring of late onset hypogonadism.” In order to reach a large audience, these recommendations were published in the International Journal of Andrology, the Journal of Andrology, the Aging Male, and European Urology (Nieschlag et al, 2005a,b,c, 2006). In view of the growing interest from practitioners on the treatment of older men with testosterone, the ISA, ISSAM, EAU, European Academy of Andrology (EAA), and American Society of Andrology (ASA) convened meetings of the writing group with expert representatives from each of the societies. The writing group membership from 2005 was expanded to include additional urologists. Members of the writing group met in Berlin in 2007, Toronto in 2007, and Tampa in 2008 to revise these recommendations. There was no corporate funding or support for the development of these recommendations. The revised recommendations are supported by a selection of appropriate references and categorized by the level of evidence and grade of recommendation according to the US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research (1992:115–127; Table). To ensure broad outreach to multidisciplinary audiences, these recommendations are published in the European Journal of Endocrinology, European Urology, the International Journal of Andrology, the International Journal of Impotence Research, the Journal of Andrology, and The Aging Male simultaneously. Late-onset hypogonadism (LOH, also referred to as age-associated testosterone deficiency syndrome [TDS]) is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels (below the young healthy adult male reference range; Morales et al, 2006; Nieschlag et al, 2005a,b,c, 2006). This condition may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems. At present, the diagnosis of treatable hypogonadism requires the presence of symptoms and signs suggestive of testosterone deficiency (level 3, grade A; Bhasin et al, 2006; Nieschlag et al, 2005a,b,c, 2006). The symptom most associated with hypogonadism is low libido (level 3, grade A; Schiavi et al, 1991; Travison et al, 2006). Other manifestations of hypogonadism include: erectile dysfunction (ED), decreased muscle mass and strength, increased body fat, decreased bone mineral density and osteoporosis, decreased vitality, and depressed mood. None of these symptoms are specific to the low-androgen state, but may raise suspicion of testosterone deficiency. One or more of these symptoms must be corroborated with a low serum testosterone level (level 3, grade A; Kelleher et al, 2004; Zitzmann et al, 2006; Araujo et al, 2007; Morales et al, 2007). Questionnaires such as Aging Male Symptom Score (AMS; Heinemann et al, 2004; Moore et al, 2004) and Androgen Deficiency in Aging Men (ADAM; Morley et al, 2000) are not recommended for the diagnosis of hypogonadism because of low specificity (level 3, grade B; Tancredi et al, 2004; Beutel et al, 2005; Morales et al, 2007). In patients at risk or who are suspected of hypogonadism, a thorough physical and biochemical work-up is necessary (level 4, grade A). Transient decreases of serum testosterone levels, such as due to acute illnesses, should be excluded by careful clinical evaluations and repeated hormone measurement. Hypogonadism (primary or secondary) can occur at all ages, including in elderly men. Risk factors for hypogonadism in older men may include chronic illnesses (including diabetes mellitus, chronic obstructive lung disease, and inflammatory arthritic, renal, and HIV-related diseases), obesity, metabolic syndrome, and hemachromatosis (Bhasin et al, 2006). Such chronic diseases should be investigated and treated (level 4, grade A). A serum sample for total testosterone determination should be obtained between 0700 and 1100 hours (level 2a, grade A; Diver et al, 2003). The most widely accepted parameter to establish the presence of hypogonadism is the measurement of serum total testosterone. There are no generally accepted lower limits of normal. There is, however, general agreement that total testosterone level above 12 nmol/L (350 ng/dL) does not require substitution. Similarly, based on the data of younger men, there is consensus that patients with serum total testosterone levels below 8 nmol/L (230 ng/dL) will usually benefit from testosterone treatment. If the serum total testosterone level is between 8 and 12 nmol/L, repeating the measurement of total testosterone with sex hormone—binding globulin (SHBG) to calculate free testosterone or free testosterone by equilibrium dialysis may be helpful (see 3.5 and 3.7 below; level 2b, grade A). Measurements of serum luteinizing hormone will assist in differentiating between primary and secondary hypogonadism, and serum prolactin is indicated when the serum testosterone is lower than 5.2 nmol/L (150 ng/dL; Citron et al, 1996; Buvat and Lemaire, 1997; Bunch et al, 2002; Rhoden et al, 2003) or when secondary hypogonadism is suspected (level 3, grade B; Araujo et al, 2004; Vermeulen, 2005; Bhasin et al, 2006). Since there are known variations between assay methods, it is imperative that the practitioners utilize reliable laboratories and are acquainted with the reference ranges for testosterone from their local laboratory (level 2b, grade A; Taieb et al, 2003; Wang et al, 2004; Sikaris et al, 2005; Rosner et al, 2007). Current immunometric methods for measurement of testosterone can distinguish between hypogonadism and normal adult men. However, methods based on mass spectrometry (MS) are more accurate and precise (level 2b, grade A; Taieb et al, 2003; Wang et al, 2004; Sikaris et al, 2005) and are increasingly recognized as the method of choice for serum testosterone measurement. Measurement of free or bioavailable testosterone should be considered when the serum total testosterone concentration is not diagnostic of hypogonadism, particularly in obese men. There are no generally accepted lower limits of normal for free testosterone for the diagnosis of hypogonadism. However, a free testosterone level below 225 pmol/L (65 pg/mL) can provide supportive evidence for testosterone treatment (level 3, grade C; Vermeulen et al, 1999, 2005; Rosner et al, 2007). Threshold values for bioavailable testosterone depend on the method used and are not generally available (Rosner et al, 2007). Equilibrium dialysis is the gold standard for free testosterone measurement. Free testosterone assays based on analog displacement immunoassays are widely available but do not give an accurate measurement of free testosterone; thus, they should not be used (Rosner 1997; Swerdloff and Wang, 2008). Alternately, measuring serum SHBG levels together with reliable serum total testosterone levels provides the data necessary for calculating free testosterone levels (level 2b, grade A). Calculated free testosterone correlates well with free testosterone by equilibrium dialysis (Vermeulen et al, 1999; Rosner et al, 2007). 7) Efforts to create standardization of testosterone assays, agreement on standards for testosterone measurement and accurate reference ranges for testosterone by liquid chromatography-MS/MS are being developed. International reference standards, characterization of methodology, and population-based reference ranges for free testosterone by equilibrium dialysis are needed. Consensus on the equilibrium constants for testoseterone binding to SHBG and albumin will allow improved calculation of free testosterone (Rosner et al, 2007). Salivary testosterone has also been shown to be a reliable substitute for free testosterone measurements, but cannot be recommended for general use at this time since the methodology has not been standardized and adult male ranges are not available in most hospital or reference laboratories (level 3, grade B; Wang et al, 1981). Alterations in other endocrine systems occur in association with aging (ie, estradiol, growth hormone [GH], and dehydroepiandrosterone [DHEA]), but the significance of these changes is not well understood. Determinations of estradiol, thyroid hormones, cortisol, DHEA, dehydroepiandrosterone sulfate (DHEA-S), melatonin, GH, and insulinlike growth factor 1 are not indicated unless other endocrine disorders are suspected based on the clinical signs and symptoms of the patient (level 2, grade A; Bhasin et al, 2006). Improvement in signs and symptoms of testosterone deficiency should be sought. Failure to benefit clinical manifestations within a reasonable time interval (3 to 6 months is adequate for libido and sexual function, muscle function, and improved body fat; improvement in bone mineral density requires a longer interval to show improvement) should result in discontinuation of treatment. Further investigation for other causes of symptoms is then mandatory (level 1b, grade A). In men with hypogonadal values of testosterone, testosterone administration improves body composition (decrease of fat mass, increase of lean body mass; level 1b, grade A; Snyder et al, 1999b; Liverman and Blazer, 2004; Isidori et al, 2005b; Page et al, 2005; Allan et al, 2008). Secondary benefits of these changes of body composition on strength, muscle function, and metabolic and cardiovascular dysfunction are suggested by available data but require confirmation by large-scale studies. Osteopenia, osteoporosis, and fracture prevalence rates are greater in hypogonadal younger and older men (Meier et al, 2008). Bone density in hypogonadal men of all ages increases under testosterone substitution (level 1b, grade A; Snyder et al, 1999a; Kenny et al, 2000; Amory et al, 2004). Fracture data are not yet available, and thus the long-term benefit of testosterone requires further investigation. Assessment of bone density at 2-year intervals is advisable in hypogonadal men, and serum testosterone measurements should be obtained in all men with osteopenia (Schousboe et al, 2007; Freitas et al, 2008). The initial assessment of all men with ED and/or diminished libido should include determination of serum testosterone. These dysfunctions, with or without a testosterone deficiency, might be related to comorbidities (ie, diabetes mellitus, hyperprolactinemia, the metabolic syndrome, bladder outlet obstruction, peripheral vascular disease, or medications; level 2a, grade A; Morales et al, 2004). Men with ED and/or diminished libido and documented testosterone deficiency are candidates for testosterone therapy (level 2a, grade A). An inadequate response to testosterone treatment requires reassessment of the causal mechanisms responsible for the ED (see 7.4 below). In the presence of a clinical picture of testosterone deficiency and borderline serum testosterone levels, a short (eg, 3 months) therapeutic trial may be justified. An absence of response calls for discontinuation of testosterone administration. A satisfactory response might be placebo generated so that continued assessment is advisable before long-term treatment is recommended (level 2a, grade B; Black et al, 2004). There is evidence suggesting therapeutic synergism with combined use of testosterone and phosphodiesterase-5 inhibitors in hypogonadal or borderline eugonadal men (level 1b, grade B; Shabsigh et al, 2004; Greenstein et al, 2005). These observations are still preliminary and require additional study. However, the combination treatment should be considered in hypogonadal patients with ED failing to respond to either treatment alone. It is unclear whether men with hypogonadism and ED should be treated initially with phosphodiesterase-5-inhibitor, testosterone, or the combination of the two. Many of the components of the metabolic syndrome (obesity, hypertension, dyslipidemia, impaired glucose regulation, and insulin resistance) are also present in hypogonadal men. Numerous epidemiologic studies have established a close relationship between obesity and low serum testosterone levels in healthy men (Allen et al, 2002). Twenty percent to 64% of obese men have a low serum total or free testosterone levels (Kalyani and Dobs, 2007). The metabolic syndrome and type 2 diabetes mellitus are associated with low plasma testosterone (Allen et al, 2002; Laaksonen et al, 2004; Derby et al, 2006; Kupelian et al, 2006; Zitzmann et al, 2006; Kapoor et al, 2007; Rodriguez et al, 2007; Selvin et al, 2007). Serum testosterone should be measured in men with type 2 diabetes mellitus with symptoms suggestive of testosterone deficiency (level 2b, grade A). The effects of testosterone administration on glycemic control of men with diabetes mellitus are much less certain (Corrales et al, 2004; Kapoor et al, 2006; Basu et al, 2007). It is premature to recommend testosterone treatment for the metabolic syndrome or diabetes mellitus in the absence of laboratory and other clinical evidence of hypogonadism. In men with hypogonadism and diabetes and/or the metabolic syndrome, testosterone treatment for traditional hypogonadal symptoms may have other unproven benefits on their metabolic status (level 2a, grade B). At the present time, there is no conclusive evidence that testosterone therapy increases the risk of prostate cancer or benign prostatic hyperplasia (Carpenter et al, 2008; Roddam et al, 2008). There is also no evidence that testosterone treatment will convert subclinical prostate cancer to clinically detectable prostate cancer (level 4, grade C). However, there is unequivocal evidence that testosterone can stimulate growth and aggravate symptoms in men with locally advanced and metastatic prostate cancer (level 2a, grade A; Fowler and Whitmore, 1982; McConnell, 1995). Currently, adequately powered and optimally designed long-term prostate disease data are not available to determine whether there is any additional risk from testosterone replacement. Hypogonadal older (>45 years) men should be counseled on the potential risks and benefits of testosterone replacement before treatment and carefully monitored for prostate safety during treatment (level 3, grade A). Prior to therapy with testosterone, a man's risk of prostate cancer must be assessed using, as a minimum, digital rectal examination (DRE) and determination of serum prostate-specific antigen (PSA). However, the pretreatment assessment can be improved by incorporating other risk predictors such as age, family history, and ethnicity/race. Several tools have been developed to assist the clinician in assessing prostate cancer risk (eg, on-line prostate cancer risk calculator Parekh et al, 2006; Thompson et al, 2006a). These tools have not been validated for patients with LOH (TDS). If the patient and physician feel that the risk is sufficiently high, further assessment may be desirable (level 2a, grade B; Thompson et al, 2006a,b). However, pretreatment prostate ultrasound examinations or biopsies are not recommended as routine requirements. After initiation of testosterone treatment, patients should be monitored for prostate disease at 3 to 6 months, 12 months, and at least annually thereafter (level 3, grade C). Should the patient's prostate cancer risk be sufficiently high (suspicious finding on DRE, increased PSA, or as calculated using a combination of risk factors as noted above) transrectal ultrasound-guided biopsies of the prostate are indicated (level 2b, grade A; Meikle et al, 1997; Bhasin et al, 2003; Rhoden and Morgentaler, 2004; Marks et al, 2006). Severe symptoms of lower urinary tract symptoms (LUTS) evident by a high (>21) International Prostate Symptom Score due to benign prostate hyperplasia represent a relative contraindication (although there are no compelling data to suggest that testosterone treatment causes exacerbation of LUTS or promotes acute urinary retention [level 3, grade C]. After successful treatment of lower urinary tract obstruction, this contraindication is no longer applicable (level 4, grade C) Men successfully treated for prostate cancer and suffering from confirmed symptomatic hypogonadism are potential candidates for testosterone substitution after a prudent interval if there is no clinical or laboratory evidence of residual cancer (Kaufman and Graydon, 2004; Agarwal and Oefelein, 2005; Khera and Lipshultz, 2007; Sarosdy, 2007). As long-term outcome data are not available, clinicians must exercise good clinical judgment together with adequate knowledge of advantages and drawbacks of testosterone therapy in this situation (level 2b, grade C; Nieschlag and Behre, 2004; Nieschlag, 2006). The risk and benefits must be clearly discussed with and understood by the patient, and the follow-up must be particularly careful. Preparations of natural testosterone should be used for substitution therapy. Currently available intramuscular, subdermal, and of testosterone are and (level 1b, grade A). The physician should have knowledge and adequate of the as well as of the advantages and drawbacks of each The selection of the should be a of an patient and physician et al, 2005). Since the development of an during treatment or prostate et al, 2005) requires discontinuation of testosterone may be over in the initial treatment of patients with LOH (level 4, grade C). data are available to determine the serum testosterone level for and the present time, to lower young adult male serum testosterone levels appropriate as the therapeutic and Nieschlag, 2007). levels should be evidence for or the to the of serum testosterone levels (level 3, grade B). men are more to effects (level 2b, grade B; et al, 2005; Zitzmann and Nieschlag, 2007). The androgen such as testosterone, are because of their potential and should no longer be (level 2b, grade A). There is not evidence to recommend substitution of in aging other androgen such as DHEA, or are not recommended (level 1b, grade A). Human testosterone of at a lower in older than in younger men. Since the therapeutic and effects of treatment in older men and this treatment cannot be recommended in LOH when is an (level 1b, grade B). and inhibitors have been shown to increase testosterone levels (level 2b, grade B). evidence does not to recommend their androgen are under but are not yet clinically available. Many of these are and the risks of long-term use are Testosterone treatment is in men with prostate or cancer (level 3, grade A). Testosterone treatment is in men at high risk of prostate It is unclear whether 7) prostate cancer a relative or contraindication for treatment. for more level 4, C; et al, 2005; et al, 2006; Men with significant level 3, grade obstructive (level 3, grade (level 3, grade should not be on treatment with testosterone without of the condition et al, 2005; et al, 1995). can during testosterone treatment, in older men treated by testosterone assessment is indicated (ie, before treatment, then 3 to and 12 months in the of treatment, and annually it is not yet what is and/or may be necessary to below to (level 3, grade A; Bhasin et al, 2006; et al, 2005; Nieschlag, 2006). is not a contraindication to testosterone treatment. assessment of comorbidities causes of and potential risks benefits of testosterone treatment is particularly in elderly men (level 2a, grade A). The diagnosis of late-onset testosterone deficiency is based on the presence of symptoms or signs and low serum testosterone The benefits and risks of testosterone therapy must be clearly discussed with the patient and assessment of prostate and other risk factors considered before testosterone treatment. to testosterone treatment should be If there is no improvement of symptoms and treatment should be and the patient investigated for other causes of the clinical

There is a physiological decline in food intake with aging. The reasons for the decline in food intake are multifactorial and involve both peripheral and central mechanisms. Altered hedonic qualities of food occur due to alterations in taste and, more particularly, smell with aging. A decline in adaptive relaxation of the fundus of the stomach and an increased rate of antral filling appear to play a role in the early satiation seen in many older persons. Cholecystokinin levels are increased with aging and older persons are more sensitive to the satiating effects of this gut hormone. The decline in testosterone levels in older males leads to increased leptin levels and this may explain the greater decline in food intake with aging in the male. Within the hypothalamus, decreased activity of both the dynorphin (kappa opioid) and neuropeptide Y systems occurs in aging rodents. Cytokines are potent anorectic agents. Many older persons have mild inflammatory disorders that lead to anorexia. Exercise may increase food intake in older persons.

The inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine. The prevalence in the United States is greater than 200 cases per 100,000, with the total number of IBD patients between 1 and 1.5 million. CD may affect all parts of the gastrointestinal tract, from mouth to anus, but most commonly involves the distal part of the small intestine or ileum, and colon. UC results in colonic inflammation that can affect the rectum only, or can progress proximally to involve part of or the entire colon. Clinical symptoms include diarrhea, abdominal pain, gastrointestinal bleeding, and weight loss. A serious long-term complication of chronic inflammation is the development of colorectal cancer. A genetic basis for IBD had long been recognized based on the increased familial risk. However, significant discordance for CD in twins, and a much less robust phenotypic concordance for UC, suggested additional factors play a role in disease pathogenesis, including environmental factors. In the past several years, progress in understanding the molecular basis of IBD has accelerated, beginning with the generation of animal models of colitis and progressing to the identification of specific genetic markers from candidate gene, gene linkage, and genome-wide association analyses. Genetic studies have also resulted in the recognition of the importance of environmental factors, particularly the crucial role of the gut microbiota in CD and UC. Altered immune responses to the normal intestinal flora are key factors in IBD pathogenesis. In this research topic, the genetic basis of IBD, the genetic and cellular alterations associated with colitis-associated colon cancer, and the emerging role of the intestinal microbiota and other environmental factors will be reviewed.

BACKGROUND: Influenza-associated morbidity and mortality has not decreased in the last decade, despite increased receipt of vaccine. To improve the immunogenicity of influenza vaccine, a high-dose (HD) trivalent, inactivated influenza vaccine was developed. METHODS: A multicenter, randomized, double-blind controlled study was conducted to compare HD vaccine (which contains 60 microg of hemagglutinin per strain) with the licensed standard-dose (SD) vaccine (which contains 15 microg of hemagglutinin per strain) in adults > or = 65 years of age. RESULTS: HD vaccine was administered to 2575 subjects, and SD vaccine was administered to 1262 subjects. There was a statistically significant increase in the rates of seroconversion and mean hemagglutination inhibition titers at day 28 after vaccination among those who received HD vaccine, compared with those who received SD vaccine. Mean postvaccination titers for individuals who received HD vaccine were 116 for H1N1, 609 for H3N2, and 69 for B strain; for those who received SD vaccine, mean postvaccination titers were as 67 for H1N1, 333 for H3N2, and 52 for B strain. The HD vaccine met superiority criteria for both A strains, and the responses for B strain met non-inferiority criteria. Seroprotection rates were also higher for those who received HD vaccine than for those who received SD vaccine vaccine, for all strains. Local reactions were more frequent in individuals who received HD vaccine, but the reactions were mild to moderate. CONCLUSIONS: There was a statistically significant increase in the level of antibody response induced by HD influenza vaccine, compared with that induced by SD vaccine, without an attendant increase in the rate or severity of clinically relevant adverse reactions. These results suggest that the high-dose vaccine may provide improved protective benefits for older adults. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00391053 .