Banner - University Medical Center Tucson

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).

Within the past decade, clinical microbiology laboratories experienced revolutionary changes in the way in which microorganisms are identified, moving away from slow, traditional microbial identification algorithms toward rapid molecular methods and mass spectrometry (MS). Historically, MS was clinically utilized as a high-complexity method adapted for protein-centered analysis of samples in chemistry and hematology laboratories. Today, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS is adapted for use in microbiology laboratories, where it serves as a paradigm-shifting, rapid, and robust method for accurate microbial identification. Multiple instrument platforms, marketed by well-established manufacturers, are beginning to displace automated phenotypic identification instruments and in some cases genetic sequence-based identification practices. This review summarizes the current position of MALDI-TOF MS in clinical research and in diagnostic clinical microbiology laboratories and serves as a primer to examine the "nuts and bolts" of MALDI-TOF MS, highlighting research associated with sample preparation, spectral analysis, and accuracy. Currently available MALDI-TOF MS hardware and software platforms that support the use of MALDI-TOF with direct and precultured specimens and integration of the technology into the laboratory workflow are also discussed. Finally, this review closes with a prospective view of the future of MALDI-TOF MS in the clinical microbiology laboratory to accelerate diagnosis and microbial identification to improve patient care.

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

BACKGROUND: VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445-tezacaftor-ivacaftor). METHODS: ) from baseline. RESULTS: (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire-Revised. CONCLUSIONS: The use of VX-445-tezacaftor-ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471 ; and EudraCT number, 2017-000797-11 .).

Venoarterial extracorporeal membrane oxygenation (VA-ECMO)-also referred to as extracorporeal life support-is a form of temporary mechanical circulatory support and simultaneous extracorporeal gas exchange. The initiation of VA-ECMO has emerged as a salvage intervention in patients with cardiogenic shock, even cardiac arrest refractory to standard therapies. Analogous to veno-venous ECMO for acute respiratory failure, VA-ECMO provides circulatory support and allows time for other treatments to promote recovery or may be a bridge to a more durable mechanical solution in the setting of acute or acute on chronic cardiopulmonary failure. In this review, we provide a brief overview of VA-ECMO, the attendant physiological considerations of peripheral VA-ECMO, and its complications, namely that of left ventricular distention, bleeding, heightened systemic inflammatory response syndrome, thrombosis and thromboembolism, and extremity ischemia or necrosis.

IMPORTANCE: The Frailty Index (FI) is a known predictor of adverse outcomes in geriatric patients. The usefulness of the FI as an outcome measure in geriatric trauma patients is unknown. OBJECTIVE: To assess the usefulness of the FI as an effective assessment tool in predicting adverse outcomes in geriatric trauma patients. DESIGN, SETTING, AND PARTICIPANTS: A 2-year (June 2011 to February 2013) prospective cohort study at a level I trauma center at the University of Arizona. We prospectively measured frailty in all geriatric trauma patients. Geriatric patients were defined as those 65 years or older. The FI was calculated using 50 preadmission frailty variables. Frailty in patients was defined by an FI of 0.25 or higher. MAIN OUTCOMES AND MEASURES: The primary outcome measure was in-hospital complications. The secondary outcome measure was adverse discharge disposition. In-hospital complications were defined as cardiac, pulmonary, infectious, hematologic, renal, and reoperation. Adverse discharge disposition was defined as discharge to a skilled nursing facility or in-hospital mortality. Multivariate logistic regression was used to assess the relationship between the FI and outcomes. RESULTS: In total, 250 patients were enrolled, with a mean (SD) age of 77.9 (8.1) years, median Injury Severity Score of 15 (range, 9-18), median Glasgow Coma Scale score of 15 (range, 12-15), and mean (SD) FI of 0.21 (0.10). Forty-four percent (n = 110) of patients had frailty. Patients with frailty were more likely to have in-hospital complications (odds ratio, 2.5; 95% CI, 1.5-6.0; P = .001) and adverse discharge disposition (odds ratio, 1.6; 95% CI, 1.1-2.4; P = .001). The mortality rate was 2.0% (n = 5), and all patients who died had frailty. CONCLUSIONS AND RELEVANCE: The FI is an independent predictor of in-hospital complications and adverse discharge disposition in geriatric trauma patients. This index should be used as a clinical tool for risk stratification in this patient group.

PURPOSE: To determine the long-term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short-term double-blind trials have demonstrated its safety and efficacy, and one long-term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long-term study of VNS to date. METHODS: Patients with six or more complex partial or generalized tonic-clonic seizures enrolled in the pivotal EO5 study were prospectively evaluated for 12 months. The primary outcome variable was the percentage reduction in total seizure frequency at 3 and 12 months after completion of the acute EO5 trial, compared with the preimplantation baseline. Subjects originally randomized to low stimulation (active-control group) were crossed over to therapeutic stimulation settings for the first time. Subjects initially randomized to high settings were maintained on high settings throughout the 12-month study. RESULTS: The median reduction at 12 months after completion of the initial double-blind study was 45%. At 12 months, 35% of 195 subjects had a >50% reduction in seizures, and 20% of 195 had a >75% reduction in seizures. CONCLUSIONS: The efficacy of VNS improves during 12 months, and many subjects sustain >75% reductions in seizures.

BACKGROUND: Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS: A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS: Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION: Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.

Background: Endovascular treatment with mechanical thrombectomy (MT) is beneficial for patients with acute stroke suffering a large-vessel occlusion, although treatment efficacy is highly time-dependent. We hypothesized that interhospital transfer to endovascular-capable centers would result in treatment delays and worse clinical outcomes compared with direct presentation. Methods: STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) was a prospective, multicenter, observational, single-arm study of real-world MT for acute stroke because of anterior-circulation large-vessel occlusion performed at 55 sites over 2 years, including 1000 patients with severe stroke and treated within 8 hours. Patients underwent MT with or without intravenous tissue plasminogen activator and were admitted to endovascular-capable centers via either interhospital transfer or direct presentation. The primary clinical outcome was functional independence (modified Rankin Score 0–2) at 90 days. We assessed (1) real-world time metrics of stroke care delivery, (2) outcome differences between direct and transfer patients undergoing MT, and (3) the potential impact of local hospital bypass. Results: A total of 984 patients were analyzed. Median onset-to-revascularization time was 202.0 minutes for direct versus 311.5 minutes for transfer patients ( P &lt;0.001). Clinical outcomes were better in the direct group, with 60.0% (299/498) achieving functional independence compared with 52.2% (213/408) in the transfer group (odds ratio, 1.38; 95% confidence interval, 1.06–1.79; P =0.02). Likewise, excellent outcome (modified Rankin Score 0–1) was achieved in 47.4% (236/498) of direct patients versus 38.0% (155/408) of transfer patients (odds ratio, 1.47; 95% confidence interval, 1.13–1.92; P =0.005). Mortality did not differ between the 2 groups (15.1% for direct, 13.7% for transfer; P =0.55). Intravenous tissue plasminogen activator did not impact outcomes. Hypothetical bypass modeling for all transferred patients suggested that intravenous tissue plasminogen activator would be delayed by 12 minutes, but MT would be performed 91 minutes sooner if patients were routed directly to endovascular-capable centers. If bypass is limited to a 20-mile radius from onset, then intravenous tissue plasminogen activator would be delayed by 7 minutes and MT performed 94 minutes earlier. Conclusions: In this large, real-world study, interhospital transfer was associated with significant treatment delays and lower chance of good outcome. Strategies to facilitate more rapid identification of large-vessel occlusion and direct routing to endovascular-capable centers for patients with severe stroke may improve outcomes. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02239640.

Because patients treated with 60-90 mg/m2 every three to four weeks reach cardiotoxic doses of 550 mg/m2 within 36 weeks, prolonged treatment with Adriamycin is limited. The purpose of this study was to determine whether lower doses could be given over longer periods without loss of efficacy. Good risk patients treated with 75, 60, or 45 mg/m2 had remission rates of 25, 27, and 19%; poor risk patients treated with 50 and 25 mg/m2 had remission rates of 16 and 12% respectively. Although a dose response was identified, there were no statistically significant differences in remission rates, durations of remission, or toxicities in the dose schedules studied. Irreversible congestive heart failure occurred in five patients with cumulative doses of 240-390 mg/m2. Unless rapid remission induction is urgent, we recommend 60 mg/m2 X four doses and measurement of myocardial function if treatment is to continue.

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. MAESTRO-NAFLD-1 was a 52-week randomized, double-blind, placebo-controlled phase 3 trial evaluating the safety of resmetirom in adults with nonalcoholic fatty liver disease and presumed NASH. Patients were randomized to three double-blind arms (100 mg resmetirom (n = 325), 80 mg resmetirom (n = 327) or placebo (n = 320)) or open-label 100 mg resmetirom (n = 171). The primary end point was incidence of treatment-emergent adverse events (TEAEs) over 52 weeks and key secondary end points were LDL-C, apoB, triglycerides (over 24 weeks), hepatic fat (over 16 and 52 weeks) and liver stiffness (over 52 weeks). Resmetirom was safe and well tolerated. TEAEs occurred in 86.5% (open-label 100 mg resmetirom), 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom) and 81.8% (placebo) of patients. TEAEs in excess of placebo included diarrhea and nausea at the initiation of treatment. Key secondary end points included least square means difference from placebo at 80 mg, 100 mg resmetirom: LDL-C (-11.1%, -12.6%), apoB (-15.6%, -18.0%), triglycerides (-15.4%, -20.4%), 16-week hepatic fat (-34.9%, -38.6%), (P < 0.0001) and liver stiffness (-1.02, -1.70) and 52-week hepatic fat (-28.8, -33.9). These findings demonstrate resmetirom was safe and well tolerated in adults with presumed NASH, supporting a role for further clinical development. (ClinicalTrials.gov identifier NCT04197479 ).

The environment of southern Arizona with mild winters and hot, dry summers produces great variability in decay rates of human remains. Summer temperatures, which range well over 38 degrees C (100 degrees F), induce rapid bloating as a result of the accumulation of decompositional gases. However, in certain circumstances, the aridity can lead to extensive mummification, allowing preservation of remains for hundreds of years. A retrospective study of 189 cases, concentrating on remains found on the desert floor or in the surrounding mountains and on remains found within closed structures, outlines the time frame and sequences of the decay process. Remains can retain a fresh appearance for a considerable time in the winter, but the onset of marked decomposition is rapid in the summer months. Bloating of the body usually is present two to seven days following death. Following this, within structures, there is frequently rapid decomposition and skeletonization. With outdoor exposure, remains are more likely to pass through a long period of dehydration of outer tissues, mummification, and reduction of desiccated tissue. Exposure of large portions of the skeleton usually does not occur until four to six months after death. Bleaching and exfoliation of bone--the beginning stages of destruction of the skeletal elements--begins at about nine months' exposure. Insect activity, including that of maggot and beetle varieties, may accelerate decomposition, but this process is greatly affected by location of the body, seasonal weather, and accessibility of the soft tissues. Carnivores and other scavengers also are contributing factors, as are clothing or covering of the body, substrate, elevation, and latitude.

Mechanical circulatory assist devices (MCADs) are increasingly utilized independently of cardiac transplantation in the management of heart failure. Though MCAD use incorporates inherent mechanical risks, the inevitable onset of chronic anemia, with its associated morbidity and mortality, is also a significant concern. MCAD support has been correlated with elevated plasma levels of inflammatory cytokines TNF-alpha, IL-1beta, and IL-6, which have separately been found to inhibit erythropoietin (Epo)-induced erythrocyte (RBC) maturation. Previous analysis of hematological parameters for MCAD-supported patients concluded that an amplified inflammatory response impedes RBC proliferation and recovery from hemolytic anemia. Additional analysis may bolster this assertion. Hemoglobin concentration (HC), RBC distribution width (RDW), mean cell volume (MCV), and cardiac index were retrospectively analysed for 78 MCAD-supported patients implanted for greater than 30 days at the University of Arizona Health Sciences Center from 1996 to 2002. Analysis confirms that the HC, a conventional marker for anemia, declines with MCAD placement and remains below the clinically defined, minimum normal value. Inversely, the RDW rises above maximum normal measure, signifying an increased fraction of juvenile RBCs. The MCV remains unchanged and within normal limits, demonstrating adequate substrate for RBC formation. MCAD performance also stabilizes as adequate perfusion returns. These results further support our previously published conclusion that a sufficient response of erythropoiesis occurs in reaction to the onset of anemia by an increased production of immature RBCs. However, the cells never fully mature and join circulation. The patient's inflammatory cytokine response to the implanted device most likely mediates the chronic MCAD-induced anemia by inhibition of Epo effects.

Nerve growth factor (NGF) was originally discovered as a neurotrophic factor essential for the survival of sensory and sympathetic neurons during development. However, in the adult NGF has been found to play an important role in nociceptor sensitization after tissue injury. The authors outline mechanisms by which NGF activation of its cognate receptor, tropomyosin-related kinase A receptor, regulates a host of ion channels, receptors, and signaling molecules to enhance acute and chronic pain. The authors also document that peripherally restricted antagonism of NGF-tropomyosin-related kinase A receptor signaling is effective for controlling human pain while appearing to maintain normal nociceptor function. Understanding whether there are any unexpected adverse events and how humans may change their behavior and use of the injured/degenerating tissue after significant pain relief without sedation will be required to fully appreciate the patient populations that may benefit from these therapies targeting NGF.

There is growing recognition of the clinical importance of pulmonary haemodynamics during exercise, but several questions remain to be elucidated. The goal of this statement is to assess the scientific evidence in this field in order to provide a basis for future recommendations.Right heart catheterisation is the gold standard method to assess pulmonary haemodynamics at rest and during exercise. Exercise echocardiography and cardiopulmonary exercise testing represent non-invasive tools with evolving clinical applications. The term "exercise pulmonary hypertension" may be the most adequate to describe an abnormal pulmonary haemodynamic response characterised by an excessive pulmonary arterial pressure (PAP) increase in relation to flow during exercise. Exercise pulmonary hypertension may be defined as the presence of resting mean PAP <25 mmHg and mean PAP >30 mmHg during exercise with total pulmonary resistance >3 Wood units. Exercise pulmonary hypertension represents the haemodynamic appearance of early pulmonary vascular disease, left heart disease, lung disease or a combination of these conditions. Exercise pulmonary hypertension is associated with the presence of a modest elevation of resting mean PAP and requires clinical follow-up, particularly if risk factors for pulmonary hypertension are present. There is a lack of robust clinical evidence on targeted medical therapy for exercise pulmonary hypertension.

OBJECTIVES: To describe the prevalence of self-reported daytime sleepiness in older men and women and to describe their relationships with demographic factors, nocturnal complaints, health status, and cardiovascular diseases (CVD). DESIGN: Cross-sectional survey and clinical exam. SETTING: Participants in the Cardiovascular Health Study, 4578 adults aged 65 and older, recruited from a random sample of non-institutionalized Medicare enrollees in four U.S. communities. MEASURES: Daytime sleepiness measured by the Epworth Sleepiness Scale (ESS), magnetic resonance imaging of the brain (MRI), cognitive function tests, and standardized questionnaires for cardiopulmonary symptoms and diseases, depressive symptoms, social support, activities of daily living, physical activity, and current medications. RESULTS: Approximately 20% of the participants reported that they were "usually sleepy in the daytime". Although elderly black men were less likely to report frequent awakenings than those in the other three race and gender groups, they had significantly higher mean ESS scores. The following were independently associated with higher ESS scores in gender-specific models: non-white race, depression, loud snoring, awakening with dyspnea or snorting, frequent nocturnal awakenings, medications used to treat congestive heart failure, non-use of sleeping pills, a sedentary lifestyle, and limitation of activities of daily living in both men and women; additional correlates included hip circumference and current smoking in men, and hayfever in women. The following were not independently associated with ESS in the models: age, education, use of wine or beer to aid sleep, use of tricyclic antidepressants, long- or short-acting benzodiazepines, asthma, angina, myocardial infarction, congestive heart failure itself, forced vital capacity, social support, cognitive function, or MRI evidence of global brain atrophy or white matter abnormality. CONCLUSIONS: Daytime sleepiness is common in the elderly, probably due to nocturnal disturbances such as frequent awakenings and snoring. The occasional use of sleeping pills for insomnia is associated with reduced daytime sleepiness in the elderly, while the use of medications for congestive heart failure is associated with daytime sleepiness. Surprisingly, anatomic abnormalities such as evidence of previous strokes and brain atrophy (as seen on brain MRI scans) were not associated with daytime sleepiness in these non-institutionalized elderly persons.

Importance: Skin cancer is the most common malignancy occurring after organ transplantation. Although previous research has reported an increased risk of skin cancer in solid organ transplant recipients (OTRs), no study has estimated the posttransplant population-based incidence in the United States. Objective: To determine the incidence and evaluate the risk factors for posttransplant skin cancer, including squamous cell carcinoma (SCC), melanoma (MM), and Merkel cell carcinoma (MCC) in a cohort of US OTRs receiving a primary organ transplant in 2003 or 2008. Design, Setting, and Participants: This multicenter retrospective cohort study examined 10 649 adult recipients of a primary transplant performed at 26 centers across the United States in the Transplant Skin Cancer Network during 1 of 2 calendar years (either 2003 or 2008) identified through the Organ Procurement and Transplantation Network (OPTN) database. Recipients of all organs except intestine were included, and the follow-up periods were 5 and 10 years. Main Outcomes and Measures: Incident skin cancer was determined through detailed medical record review. Data on predictors were obtained from the OPTN database. The incidence rates for posttransplant skin cancer overall and for SCC, MM, and MCC were calculated per 100 000 person-years. Potential risk factors for posttransplant skin cancer were tested using multivariate Cox regression analysis to yield adjusted hazard ratios (HR). Results: Overall, 10 649 organ transplant recipients (mean [SD] age, 51 [12] years; 3873 women [36%] and 6776 men [64%]) contributed 59 923 years of follow-up. The incidence rates for posttransplant skin cancer was 1437 per 100 000 person-years. Specific subtype rates for SCC, MM, and MCC were 812, 75, and 2 per 100 000 person-years, respectively. Statistically significant risk factors for posttransplant skin cancer included pretransplant skin cancer (HR, 4.69; 95% CI, 3.26-6.73), male sex (HR, 1.56; 95% CI, 1.34-1.81), white race (HR, 9.04; 95% CI, 6.20-13.18), age at transplant 50 years or older (HR, 2.77; 95% CI, 2.20-3.48), and being transplanted in 2008 vs 2003 (HR, 1.53; 95% CI, 1.22-1.94). Conclusions and Relevance: Posttransplant skin cancer is common, with elevated risk imparted by increased age, white race, male sex, and thoracic organ transplantation. A temporal cohort effect was present. Understanding the risk factors and trends in posttransplant skin cancer is fundamental to targeted screening and prevention in this population.

Samples of lumbosacral trunk, posterior tibial nerve, and sural nerve obtained at autopsy from diabetic and nondiabetic patients without mononeuropathy multiplex were evaluated using 1-mu-thick epoxy sections and teased nerve fiber preparations. Focal fascicular lesions characterized by reduced density of myelinated axons within fascicles were found predominantly in the specimens from diabetics, mainly in the posterior tibial nerve and lumbosacral trunk. In severe examples, the perineurium and even surrounding epineurium were damaged, stamping the lesions as ischemic. In addition, identical lesions were found in biopsies of nerves of nondiabetics with vasculitis. Density of myelinated fibers at the three sites demonstrated a proximal-distal graded loss that was significantly greater in the diabetic samples. The loss from the lumbosacral trunk to the posterior tibial nerve was correlated with the density of focal lesions in the lumbosacral trunk in the diabetic (p = 0.025), indicating that distal fiber loss was partly due to the focal lesions. Teased nerve fiber abnormalities were common only in sural nerves of diabetics, suggesting that they are secondary. We conclude that beyond the possible metabolic abnormalities involved in the genesis of diabetic polyneuropathy, focal fascicular lesions, likely due to diabetic microangiopathy, are also important in the development of diabetic neuropathy.