Providence VA Medical Center

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

IMPORTANCE: Understanding skin cancer incidence is critical for planning prevention and treatment strategies and allocating medical resources. However, owing to lack of national reporting and previously nonspecific diagnosis classification, accurate measurement of the US incidence of nonmelanoma skin cancer (NMSC) has been difficult. OBJECTIVE: To estimate the incidence of NMSC (keratinocyte carcinomas) in the US population in 2012 and the incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in the 2012 Medicare fee-for-service population. DESIGN, SETTING, AND PARTICIPANTS: This study analyzes US government administrative data including the Centers for Medicare & Medicaid Services Physicians Claims databases to calculate totals of skin cancer procedures performed for Medicare beneficiaries from 2006 through 2012 and related parameters. The population-based National Ambulatory Medical Care Survey database was used to estimate NMSC-related office visits for 2012. We combined these analyses to estimate totals of new skin cancer diagnoses and affected individuals in the overall US population. MAIN OUTCOMES AND MEASURES: Incidence of NMSC in the US population in 2012 and BCC and SCC in the 2012 Medicare fee-for-service population. RESULTS: The total number of procedures for skin cancer in the Medicare fee-for-service population increased by 13% from 2,048,517 in 2006 to 2,321,058 in 2012. The age-adjusted skin cancer procedure rate per 100,000 beneficiaries increased from 6075 in 2006 to 7320 in 2012. The number of procedures in Medicare beneficiaries specific for NMSC increased by 14% from 1,918,340 in 2006 to 2,191,100 in 2012. The number of persons with at least 1 procedure for NMSC increased by 14% (from 1,177,618 to 1,336,800) from 2006 through 2012. In the 2012 Medicare fee-for-service population, the age-adjusted procedure rate for BCC and SCC were 3280 and 3278 per 100,000 beneficiaries, respectively. The ratio of BCC to SCC treated in Medicare beneficiaries was 1.0. We estimate the total number of NMSCs in the US population in 2012 at 5,434,193 and the total number of persons in the United States treated for NMSC at 3,315,554. CONCLUSIONS AND RELEVANCE: This study is a thorough nationwide estimate of the incidence of NMSC and provides evidence of continued increases in numbers of skin cancer diagnoses and affected patients in the United States. This study also demonstrates equal incidence rates for BCC and SCC in the Medicare population.

BACKGROUND: Effective rehabilitative therapies are needed for patients with long-term deficits after stroke. METHODS: In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks. RESULTS: At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], -0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, -0.14 points; 95% CI, -2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, -8.10 seconds; 95% CI, -13.61 to -2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported. CONCLUSIONS: In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.)

UNLABELLED: Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease that is strongly associated with obesity. Currently, there is no approved therapy for NASH. Weight reduction is typically recommended, but efficacy data are lacking. We performed a randomized controlled trial to examine the effects of lifestyle intervention using a combination of diet, exercise, and behavior modification, with a goal of 7% to 10% weight reduction, on clinical parameters of NASH. The primary outcome measure was the change in NASH histological activity score (NAS) after 48 weeks of intervention. Thirty-one overweight or obese individuals (body mass index [BMI], 25-40 kg/m(2)) with biopsy-proven NASH were randomized in a 2:1 ratio to receive intensive lifestyle intervention (LS) or structured education (control). After 48 weeks of intervention, participants assigned to LS lost an average of 9.3% of their weight versus 0.2% in the control group (P = 0.003). A higher proportion of participants in the LS group had a reduction of NAS of at least 3 points or had posttreatment NAS of 2 or less as compared with the control group (72% versus 30%, P = 0.03). NAS improved significantly in the LS group (from 4.4 to 2.0) in comparison with the control group (from 4.9 to 3.5) (P = 0.05). Percent weight reduction correlated significantly with improvement in NAS (r = 0.497, P = 0.007). Participants who achieved the study weight loss goal (>or=7%), compared with those who lost less than 7%, had significant improvements in steatosis (-1.36 versus -0.41, P < 0.001), lobular inflammation (-0.82 versus -0.24, P = 0.03), ballooning injury (-1.27 versus -0.53, P = 0.03) and NAS (-3.45 versus -1.18, P < 0.001). CONCLUSION: Weight reduction achieved through lifestyle intervention leads to improvements in liver histology in NASH.

CONTEXT: The prevalence of posttraumatic stress disorder (PTSD) is elevated among women who have served in the military, but no prior study has evaluated treatment for PTSD in this population. Prior research suggests that cognitive behavioral therapy is a particularly effective treatment for PTSD. OBJECTIVE: To compare prolonged exposure, a type of cognitive behavioral therapy, with present-centered therapy, a supportive intervention, for the treatment of PTSD. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial of female veterans (n=277) and active-duty personnel (n=7) with PTSD recruited from 9 VA medical centers, 2 VA readjustment counseling centers, and 1 military hospital from August 2002 through October 2005. INTERVENTION: Participants were randomly assigned to receive prolonged exposure (n = 141) or present-centered therapy (n = 143), delivered according to standard protocols in 10 weekly 90-minute sessions. MAIN OUTCOME MEASURES: Posttraumatic stress disorder symptom severity was the primary outcome. Comorbid symptoms, functioning, and quality of life were secondary outcomes. Blinded assessors collected data before and after treatment and at 3- and 6-month follow-up. RESULTS: Women who received prolonged exposure experienced greater reduction of PTSD symptoms relative to women who received present-centered therapy (effect size, 0.27; P = .03). The prolonged exposure group was more likely than the present-centered therapy group to no longer meet PTSD diagnostic criteria (41.0% vs 27.8%; odds ratio, 1.80; 95% confidence interval, 1.10-2.96; P = .01) and achieve total remission (15.2% vs 6.9%; odds ratio, 2.43; 95% confidence interval, 1.10-5.37; P = .01). Effects were consistent over time in longitudinal analyses, although in cross-sectional analyses most differences occurred immediately after treatment. CONCLUSIONS: Prolonged exposure is an effective treatment for PTSD in female veterans and active-duty military personnel. It is feasible to implement prolonged exposure across a range of clinical settings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00032617.

These clinical practice guidelines are an update of the guidelines published by the Infectious Diseases Society of America (IDSA) in 2009, prior to the 2009 H1N1 influenza pandemic. This document addresses new information regarding diagnostic testing, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal influenza. It is intended for use by primary care clinicians, obstetricians, emergency medicine providers, hospitalists, laboratorians, and infectious disease specialists, as well as other clinicians managing patients with suspected or laboratory-confirmed influenza. The guidelines consider the care of children and adults, including special populations such as pregnant and postpartum women and immunocompromised patients.

BACKGROUND: The optimal pharmacologic means to restore and maintain sinus rhythm in patients with atrial fibrillation remains controversial. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 665 patients who were receiving anticoagulants and had persistent atrial fibrillation to receive amiodarone (267 patients), sotalol (261 patients), or placebo (137 patients) and monitored them for 1 to 4.5 years. The primary end point was the time to recurrence of atrial fibrillation beginning on day 28, determined by means of weekly transtelephonic monitoring. RESULTS: Spontaneous conversion occurred in 27.1 percent of the amiodarone group, 24.2 percent of the sotalol group, and 0.8 percent of the placebo group, and direct-current cardioversion failed in 27.7 percent, 26.5 percent, and 32.1 percent, respectively. The median times to a recurrence of atrial fibrillation were 487 days in the amiodarone group, 74 days in the sotalol group, and 6 days in the placebo group according to intention to treat and 809, 209, and 13 days, respectively, according to treatment received. Amiodarone was superior to sotalol (P<0.001) and to placebo (P<0.001), and sotalol was superior to placebo (P<0.001). In patients with ischemic heart disease, the median time to a recurrence of atrial fibrillation was 569 days with amiodarone therapy and 428 days with sotalol therapy (P=0.53). Restoration and maintenance of sinus rhythm significantly improved the quality of life and exercise capacity. There were no significant differences in major adverse events among the three groups. CONCLUSIONS: Amiodarone and sotalol are equally efficacious in converting atrial fibrillation to sinus rhythm. Amiodarone is superior for maintaining sinus rhythm, but both drugs have similar efficacy in patients with ischemic heart disease. Sustained sinus rhythm is associated with an improved quality of life and improved exercise performance.

Importance: Frailty is a common geriatric syndrome of significant public health importance, yet there is limited understanding of the risk of frailty development at a population level. Objective: To estimate the global incidence of frailty and prefrailty among community-dwelling adults 60 years or older. Data Sources: MEDLINE, Embase, PsycINFO, Web of Science, CINAHL Plus, and AMED (Allied and Complementary Medicine Database) were searched from inception to January 2019 without language restrictions using combinations of the keywords frailty, older adults, and incidence. The reference lists of eligible studies were hand searched. Study Selection: In the systematic review, 2 authors undertook the search, article screening, and study selection. Cohort studies that reported or had sufficient data to compute incidence of frailty or prefrailty among community-dwelling adults 60 years or older at baseline were eligible. Data Extraction and Synthesis: The methodological quality of included studies was assessed using The Joanna Briggs Institute's Critical Appraisal Checklist for Prevalence and Incidence Studies. Meta-analysis was conducted using a random-effects (DerSimonian and Laird) model. Main Outcomes and Measures: Incidence of frailty (defined as new cases of frailty among robust or prefrail individuals) and incidence of prefrailty (defined as new cases of prefrailty among robust individuals), both over a specified duration. Results: Of 15 176 retrieved references, 46 observational studies involving 120 805 nonfrail (robust or prefrail) participants from 28 countries were included in this systematic review. Among the nonfrail individuals who survived a median follow-up of 3.0 (range, 1.0-11.7) years, 13.6% (13 678 of 100 313) became frail, with the pooled incidence rate being 43.4 (95% CI, 37.3-50.4; I2 = 98.5%) cases per 1000 person-years. The incidence of frailty was significantly higher in prefrail individuals than robust individuals (pooled incidence rates, 62.7 [95% CI, 49.2-79.8; I2 = 97.8%] vs 12.0 [95% CI, 8.2-17.5; I2 = 94.9%] cases per 1000 person-years, respectively; P for difference < .001). Among robust individuals in 21 studies who survived a median follow-up of 2.5 (range, 1.0-10.0) years, 30.9% (9974 of 32 268) became prefrail, with the pooled incidence rate being 150.6 (95% CI, 123.3-184.1; I2 = 98.9%) cases per 1000 person-years. The frailty and prefrailty incidence rates were significantly higher in women than men (frailty: 44.8 [95% CI, 36.7-61.3; I2 = 97.9%] vs 24.3 [95% CI, 19.6-30.1; I2 = 8.94%] cases per 1000 person-years; prefrailty: 173.2 [95% CI, 87.9-341.2; I2 = 99.1%] vs 129.0 [95% CI, 73.8-225.0; I2 = 98.5%] cases per 1000 person-years). The incidence rates varied by diagnostic criteria and country income level. The frailty and prefrailty incidence rates were significantly reduced when accounting for the risk of death. Conclusions and Relevance: Results of this study suggest that community-dwelling older adults are prone to developing frailty. Increased awareness of the factors that confer high risk of frailty in this population subgroup is vital to inform the design of interventions to prevent frailty and to minimize its consequences.

BACKGROUND: Approximately 10 percent of infants with intrauterine growth retardation remain small, and the causes of their growth deficits are often unclear. We postulated that mutations in the gene for the insulin-like growth factor I receptor (IGF-IR) might underlie some cases of prenatal and postnatal growth failure. METHODS: We screened two groups of children for abnormalities in the IGF-IR gene. In one group of 42 patients with unexplained intrauterine growth retardation and subsequent short stature, we used single-strand conformation polymorphism analysis, followed by direct DNA sequencing of any abnormalities found. A second cohort consisted of 50 children with short stature who had elevated circulating IGF-I concentrations. Complete sequencing of the IGF-IR gene was performed with DNA from nine children. We also studied a control group of 43 children with normal birth weights. RESULTS: In the first cohort, we identified one girl who was a compound heterozygote for point mutations in exon 2 of the IGF-IR gene that altered the amino acid sequence to Arg108Gln in one allele and Lys115Asn in the other. Fibroblasts cultured from the patient had decreased IGF-I-receptor function, as compared with that in control fibroblasts. No such mutations were found in the 43 controls. In the second group, we identified one boy with a nonsense mutation (Arg59stop) that reduced the number of IGF-I receptors on fibroblasts. Both children had intrauterine growth retardation and poor postnatal growth. CONCLUSIONS: Mutations in the IGF-IR gene that lead to abnormalities in the function or number of IGF-I receptors may also retard intrauterine and subsequent growth in humans.

CONTEXT: Elderly patients are at high risk of both abnormal hematocrit values and cardiovascular complications of noncardiac surgery. Despite nearly universal screening of patients for abnormal preoperative hematocrit levels, limited evidence demonstrates the adverse effects of preoperative anemia or polycythemia. OBJECTIVE: To evaluate the prevalence of preoperative anemia and polycythemia and their effects on 30-day postoperative outcomes in elderly veterans undergoing major noncardiac surgery. DESIGN: Retrospective cohort study using the VA National Surgical Quality Improvement Program database. Based on preoperative hematocrit levels, we stratified patients into standard categories of anemia (hematocrit <39.0%), normal hematocrit (39.0%-53.9%), and polycythemia (hematocrit > or =54%). We then estimated increases in 30-day postoperative cardiac event and mortality risks in relation to each hematocrit point deviation from the normal category. SETTING AND PATIENTS: A total of 310,311 veterans aged 65 years or older who underwent major noncardiac surgery between 1997 and 2004 in 132 Veterans' Affairs medical centers across the United States. MAIN OUTCOME MEASURES: The primary outcome measure was 30-day postoperative mortality; a secondary outcome measure was composite 30-day postoperative mortality or cardiac events (cardiac arrest or Q-wave myocardial infarction). RESULTS: Thirty-day mortality and cardiac event rates increased monotonically, with either positive or negative deviations from normal hematocrit levels. We found a 1.6% (95% confidence interval, 1.1%-2.2%) increase in 30-day postoperative mortality associated with every percentage-point increase or decrease in the hematocrit value from the normal range. Additional analyses suggest that the adjusted risk of 30-day postoperative mortality and cardiac morbidity begins to rise when hematocrit levels decrease to less than 39% or exceed 51%. CONCLUSIONS: Even mild degrees of preoperative anemia or polycythemia were associated with an increased risk of 30-day postoperative mortality and cardiac events in older, mostly male veterans undergoing major noncardiac surgery. Future studies should determine whether these findings are reproducible in other populations and if preoperative management of anemia or polycythemia decreases the risk of postoperative mortality.

Abstract Speech brain–computer interfaces (BCIs) have the potential to restore rapid communication to people with paralysis by decoding neural activity evoked by attempted speech into text 1,2 or sound 3,4 . Early demonstrations, although promising, have not yet achieved accuracies sufficiently high for communication of unconstrained sentences from a large vocabulary 1–7 . Here we demonstrate a speech-to-text BCI that records spiking activity from intracortical microelectrode arrays. Enabled by these high-resolution recordings, our study participant—who can no longer speak intelligibly owing to amyotrophic lateral sclerosis—achieved a 9.1% word error rate on a 50-word vocabulary (2.7 times fewer errors than the previous state-of-the-art speech BCI 2 ) and a 23.8% word error rate on a 125,000-word vocabulary (the first successful demonstration, to our knowledge, of large-vocabulary decoding). Our participant’s attempted speech was decoded at 62 words per minute, which is 3.4 times as fast as the previous record 8 and begins to approach the speed of natural conversation (160 words per minute 9 ). Finally, we highlight two aspects of the neural code for speech that are encouraging for speech BCIs: spatially intermixed tuning to speech articulators that makes accurate decoding possible from only a small region of cortex, and a detailed articulatory representation of phonemes that persists years after paralysis. These results show a feasible path forward for restoring rapid communication to people with paralysis who can no longer speak.

BACKGROUND: Previous reports on molecular rapid diagnostic testing (mRDT) do not consistently demonstrate improved clinical outcomes in bloodstream infections (BSIs). This meta-analysis seeks to evaluate the impact of mRDT in improving clinical outcomes in BSIs. METHODS: We searched PubMed, CINAHL, Web of Science, and EMBASE through May 2016 for BSI studies comparing clinical outcomes between mRDT and conventional microbiology methods. RESULTS: Thirty-one studies were included with 5920 patients. The mortality risk was significantly lower with mRDT than with conventional microbiology methods (odds ratio [OR], 0.66; 95% confidence interval [CI], .54-.80), yielding a number needed to treat of 20. The mortality risk was slightly lower with mRDT in studies with antimicrobial stewardship programs (ASPs) (OR, 0.64; 95% CI, .51-.79), and non-ASP studies failed to demonstrate a significant decrease in mortality risk (0.72; .46-1.12). Significant decreases in mortality risk were observed with both gram-positive (OR, 0.73; 95% CI, .55-.97) and gram-negative organisms (0.51; .33-.78) but not yeast (0.90; .49-1.67). Time to effective therapy decreased by a weighted mean difference of -5.03 hours (95% CI, -8.60 to -1.45 hours), and length of stay decreased by -2.48 days (-3.90 to -1.06 days). CONCLUSIONS: For BSIs, mRDT was associated with significant decreases in mortality risk in the presence of a ASP, but not in its absence. mRDT also decreased the time to effective therapy and the length of stay. mRDT should be considered as part of the standard of care in patients with BSIs.

BACKGROUND: Major adverse cardiovascular events (MACE) are increasingly used as composite outcomes in randomized controlled trials (RCTs) and observational studies. However, it is unclear how observational studies most commonly define MACE in the literature when using administrative data. METHODS: We identified peer-reviewed articles published in MEDLINE and EMBASE between January 1, 2010 to October 9, 2020. Studies utilizing administrative data to assess the MACE composite outcome using International Classification of Diseases 9th or 10th Revision diagnosis codes were included. Reviews, abstracts, and studies not providing outcome code definitions were excluded. Data extracted included data source, timeframe, MACE components, code definitions, code positions, and outcome validation. RESULTS: A total of 920 articles were screened, 412 were retained for full-text review, and 58 were included. Only 8.6% (n = 5/58) matched the traditional three-point MACE RCT definition of acute myocardial infarction (AMI), stroke, or cardiovascular death. None matched four-point (+unstable angina) or five-point MACE (+unstable angina and heart failure). The most common MACE components were: AMI and stroke, 15.5% (n = 9/58); AMI, stroke, and all-cause death, 13.8% (n = 8/58); and AMI, stroke and cardiovascular death 8.6% (n = 5/58). Further, 67% (n = 39/58) did not validate outcomes or cite validation studies. Additionally, 70.7% (n = 41/58) did not report code positions of endpoints, 20.7% (n = 12/58) used the primary position, and 8.6% (n = 5/58) used any position. CONCLUSIONS: Components of MACE endpoints and diagnostic codes used varied widely across observational studies. Variability in the MACE definitions used and information reported across observational studies prohibit the comparison, replication, and aggregation of findings. Studies should transparently report the administrative codes used and code positions, as well as utilize validated outcome definitions when possible.

OBJECTIVE: To describe incidence trends for cutaneous T-cell lymphoma (CTCL) in the United States. DESIGN: Population-based study. SETTING: Data were obtained from 13 population-based cancer registries of the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute from 1973 through 2002. PARTICIPANTS: A total of 4783 cases of CTCL were identified for the period 1973 through 2002. MAIN OUTCOME MEASURE: Diagnosis of CTCL. RESULTS: The overall annual age-adjusted incidence of CTCL was 6.4 per million persons. Annual incidence increased by 2.9 x 10(-6) per decade over the study period. Incidence was higher among blacks (9.0 x 10(-6)) than among whites (6.1 x 10(-6)) and was higher among men (8.7 x 10(-6)) than among women (4.6 x 10(-6)). The racial differences in incidence decreased with age, while the sex differences increased with age and decreased over time. Substantial geographic variation in incidence was found. Incidence was correlated with high physician density, high family income, high percentage of population with a bachelor's degree or higher, and high home values. Changes in International Classification of Diseases for Oncology (ICD-O) morphologic definitions have resulted in the redistribution of the cases of CTCL among specific subclassifications. CONCLUSIONS: The continued rise in incidence of CTCL is substantial, and the cause of this increase is unknown. The racial, ethnic, sex, and geographic differences in incidence may be of etiologic importance. Changes in ICD-O definitions have made it difficult to evaluate incidence trends for subclassifications of CTCL such as mycosis fungoides. In addition, these changes resulted in the creation of ambiguous histologic codes, which may have caused coding errors. These errors along with the lack of independent verification are limitations of our study. An epidemiological investigation using population-based data is important to better understand this disorder.

The ongoing pilot clinical trial of the BrainGate neural interface system aims in part to assess the feasibility of using neural activity obtained from a small-scale, chronically implanted, intracortical microelectrode array to provide control signals for a neural prosthesis system. Critical questions include how long implanted microelectrodes will record useful neural signals, how reliably those signals can be acquired and decoded, and how effectively they can be used to control various assistive technologies such as computers and robotic assistive devices, or to enable functional electrical stimulation of paralyzed muscles. Here we examined these questions by assessing neural cursor control and BrainGate system characteristics on five consecutive days 1000 days after implant of a 4 × 4 mm array of 100 microelectrodes in the motor cortex of a human with longstanding tetraplegia subsequent to a brainstem stroke. On each of five prospectively-selected days we performed time-amplitude sorting of neuronal spiking activity, trained a population-based Kalman velocity decoding filter combined with a linear discriminant click state classifier, and then assessed closed-loop point-and-click cursor control. The participant performed both an eight-target center-out task and a random target Fitts metric task which was adapted from a human-computer interaction ISO standard used to quantify performance of computer input devices. The neural interface system was further characterized by daily measurement of electrode impedances, unit waveforms and local field potentials. Across the five days, spiking signals were obtained from 41 of 96 electrodes and were successfully decoded to provide neural cursor point-and-click control with a mean task performance of 91.3% ± 0.1% (mean ± s.d.) correct target acquisition. Results across five consecutive days demonstrate that a neural interface system based on an intracortical microelectrode array can provide repeatable, accurate point-and-click control of a computer interface to an individual with tetraplegia 1000 days after implantation of this sensor.

Objective To quantify the accuracy and reproducibility of pathologists’ diagnoses of melanocytic skin lesions. Design Observer accuracy and reproducibility study. Setting 10 US states. Participants Skin biopsy cases (n=240), grouped into sets of 36 or 48. Pathologists from 10 US states were randomized to independently interpret the same set on two occasions (phases 1 and 2), at least eight months apart. Main outcome measures Pathologists’ interpretations were condensed into five classes: I (eg, nevus or mild atypia); II (eg, moderate atypia); III (eg, severe atypia or melanoma in situ); IV (eg, pathologic stage T1a (pT1a) early invasive melanoma); and V (eg, ≥pT1b invasive melanoma). Reproducibility was assessed by intraobserver and interobserver concordance rates, and accuracy by concordance with three reference diagnoses. Results In phase 1, 187 pathologists completed 8976 independent case interpretations resulting in an average of 10 (SD 4) different diagnostic terms applied to each case. Among pathologists interpreting the same cases in both phases, when pathologists diagnosed a case as class I or class V during phase 1, they gave the same diagnosis in phase 2 for the majority of cases (class I 76.7%; class V 82.6%). However, the intraobserver reproducibility was lower for cases interpreted as class II (35.2%), class III (59.5%), and class IV (63.2%). Average interobserver concordance rates were lower, but with similar trends. Accuracy using a consensus diagnosis of experienced pathologists as reference varied by class: I, 92% (95% confidence interval 90% to 94%); II, 25% (22% to 28%); III, 40% (37% to 44%); IV, 43% (39% to 46%); and V, 72% (69% to 75%). It is estimated that at a population level, 82.8% (81.0% to 84.5%) of melanocytic skin biopsy diagnoses would have their diagnosis verified if reviewed by a consensus reference panel of experienced pathologists, with 8.0% (6.2% to 9.9%) of cases overinterpreted by the initial pathologist and 9.2% (8.8% to 9.6%) underinterpreted. Conclusion Diagnoses spanning moderately dysplastic nevi to early stage invasive melanoma were neither reproducible nor accurate in this large study of pathologists in the USA. Efforts to improve clinical practice should include using a standardized classification system, acknowledging uncertainty in pathology reports, and developing tools such as molecular markers to support pathologists’ visual assessments.

BACKGROUND: Actinic keratoses (AKs) are established as direct precursors of squamous cell carcinoma (SCC), but there is significant controversy regarding the rate at which AKs progress to SCC. The authors of this report studied a high-risk population to estimate the risk of progression of AK to SCC and to basal cell carcinoma (BCC) and the risk of spontaneous regression of untreated AKs. METHODS: Data were obtained from participants in the Department of Veterans Affairs Topical Tretinoin Chemoprevention Trial. Participants were examined every 6 months for up to 6 years. At each examination, the locations on the face and ears of clinically diagnosed AKs and lesions scheduled for biopsy were marked, and high-resolution digital photographs were taken. These photographs were used later to map and track the presence, absence, or biopsy of each AK across visits. RESULTS: In total, 7784 AKs were identified on the face and ears of 169 participants. The risk of progression of AK to primary SCC (invasive or in situ) was 0.60% at 1 year and 2.57% at 4 years. Approximately 65% of all primary SCCs and 36% of all primary BCCs diagnosed in the study cohort arose in lesions that previously were diagnosed clinically as AKs. The majority of AKs (55%) that were followed clinically were not present at the 1-year follow-up, and the majority (70%) were not present at the 5-year follow-up. CONCLUSIONS: In the current study, the authors quantified the malignant potential of clinically diagnosed AKs for both SCC and BCC, although many did not persist, and the results suggested that AKs may play a greater role in the overall burden of keratinocyte carcinomas than previously documented.

There is an urgent need to identify lifestyle activities that reduce functional decline and dementia associated with population aging. The goals of this article are to review critically the evidence on the benefits associated with formal volunteering among older adults, propose a theoretical model of how volunteering may reduce functional limitations and dementia risk, and offer recommendations for future research. Database searches identified 113 papers on volunteering benefits in older adults, of which 73 were included. Data from descriptive, cross-sectional, and prospective cohort studies, along with 1 randomized controlled trial, most consistently reveal that volunteering is associated with reduced symptoms of depression, better self-reported health, fewer functional limitations, and lower mortality. The extant evidence provides the basis for a model proposing that volunteering increases social, physical, and cognitive activity (to varying degrees depending on characteristics of the volunteer placement) which, through biological and psychological mechanisms, leads to improved functioning; we further propose that these volunteering-related functional improvements should be associated with reduced dementia risk. Recommendations for future research are that studies (a) include more objective measures of psychosocial, physical, and cognitive functioning; (b) integrate qualitative and quantitative methods in prospective study designs; (c) explore further individual differences in the benefits associated with volunteering; (d) include occupational analyses of volunteers' specific jobs in order to identify their social, physical, and cognitive complexity; (e) investigate the independent versus interactive health benefits associated with volunteering relative to engagement in other forms of activity; and (f) examine the relationship between volunteering and dementia risk.

Seasonal influenza A and B virus epidemics are associated with significant morbidity and mortality each year in the United States and worldwide. One study estimated that during 2010–2016, the seasonal incidence of symptomatic influenza among all ages in the United States was approximately 8% and varied from 3% to 11% [1]. Most people recover from uncomplicated influenza, but influenza can cause complications that result in severe illness and death, particularly among very young children, older adults, pregnant and postpartum women within 2 weeks of delivery, people with neurologic disorders, and people with certain chronic medical conditions including chronic pulmonary, cardiac, and metabolic disease, and those who are immunocompromised [2–8]. During 2010–2018, seasonal influenza epidemics were associated with an estimated 4.3–23 million medical visits, 140 000–960 000 hospitalizations, and 12 000–79 000 respiratory and circulatory deaths each year in the United States [9]. A recent modeling study estimated that 291 243–645 832 seasonal influenza–associated respiratory deaths occur annually worldwide [10]. Use of available diagnostic modalities and proper interpretation of results can accurately identify patients presenting with influenza. Timely diagnosis may decrease unnecessary laboratory testing for other etiologies and use of antibiotics, improve the effectiveness of infection prevention and control measures, and increase appropriate use of antiviral medications [11, 12]. Early treatment with antivirals reduces the duration of symptoms and risk of some complications (bronchitis, otitis media, and pneumonia) and hospitalization, and may decrease mortality among high-risk populations [13–16]. Annual vaccination is the best method for preventing or mitigating the impact of influenza, but in certain situations, chemoprophylaxis with antiviral medications can be used for preexposure or postexposure prevention and can help control outbreaks in certain populations. These clinical practice guidelines are an update of the guidelines published by the Infectious Diseases Society of America (IDSA) in 2009 [17]. The guidelines consider the care of children, pregnant and postpartum women, and nonpregnant adults and include special considerations for patients who are severely immunocompromised such as hematopoietic stem cell and solid organ transplant recipients. The target audience includes primary care clinicians, obstetricians, emergency medicine providers, hospitalists, and infectious disease specialists. The guidelines may be also useful for occupational health physicians and clinicians working in long-term care facilities. It adds new information on diagnostic testing, use of antivirals, and considerations of when to use antibiotics and when to test for antiviral resistance, and presents evidence on harm associated with routine use of corticosteroids. The panel followed a process used in the development of previous IDSA guidelines that included a systematic weighting of the strength of recommendations and quality of evidence based upon the US Public Health Service Grading System for ranking recommendations in clinical guidelines as utilized in the previous 2009 guidelines (Table 1) [17]. Summarized below are the recommendations. A detailed description of background, methods, evidence summary, and rationale that support each recommendation, and research needs are included in the full document. Infectious Diseases Society of America–US Public Health Service Grading System for Ranking Recommendations in Clinical Guidelines Adapted from the Canadian Task Force on the Periodic Health Examination [6]. Infectious Diseases Society of America–US Public Health Service Grading System for Ranking Recommendations in Clinical Guidelines Adapted from the Canadian Task Force on the Periodic Health Examination [6]. Because prevention and control of influenza is a dynamic field, clinicians should consult the website of the Centers for Disease Control and Prevention (CDC) for the latest information about influenza vaccines, influenza tests, and approved antiviral medications. 1. During influenza activity (defined as the circulation of seasonal influenza A and B viruses among persons in the local community): Clinicians should test for influenza in high-risk patients, including immunocompromised persons who present with influenza-like illness, pneumonia, or nonspecific respiratory illness (eg, cough without fever) if the testing result will influence clinical management (A-III). Clinicians should test for influenza in patients who present with acute onset of respiratory symptoms with or without fever, and either exacerbation of chronic medical conditions (eg, asthma, chronic obstructive pulmonary disease [COPD], heart failure) or known complications of influenza (eg, pneumonia) if the testing result will influence clinical management (A-III) (see Table 3). Clinicians can consider influenza testing for patients not at high risk for influenza complications who present with influenza-like illness, pneumonia, or nonspecific respiratory illness (eg, cough without fever) and who are likely to be discharged home if the results might influence antiviral treatment decisions or reduce use of unnecessary antibiotics, further diagnostic testing, and time in the emergency department, or if the results might influence antiviral treatment or chemoprophylaxis decisions for high-risk household contacts (see recommendations 40–42) (C-III). 2. During low influenza activity without any link to an influenza outbreak: Clinicians can consider influenza testing in patients with acute onset of respiratory symptoms with or without fever, especially for immunocompromised and high-risk patients (B-III). Clinical Manifestations and Complications Associated With Influenza Adapted from Jani AA, Uyeki TM. Chapter 46. Influenza. In: Emergency management of infectious diseases. 2nd ed. Chin RL, ed. Cambridge, UK: Cambridge University Press, 2018. Clinical Manifestations and Complications Associated With Influenza Adapted from Jani AA, Uyeki TM. Chapter 46. Influenza. In: Emergency management of infectious diseases. 2nd ed. Chin RL, ed. Cambridge, UK: Cambridge University Press, 2018. 3. During influenza activity: Clinicians should test influenza on admission in all patients requiring hospitalization with acute respiratory illness, including pneumonia, with or without fever (A-II). Clinicians should test for influenza on admission in all patients with acute worsening of chronic cardiopulmonary disease (eg, COPD, asthma, coronary artery disease, or heart failure), as influenza can be associated with exacerbation of underlying conditions (A-III). Clinicians should test for influenza on admission in all patients who are immunocompromised or at high risk of complications and present with acute onset of respiratory symptoms with or without fever, as the manifestations of influenza in such patients are frequently less characteristic than in immunocompetent individuals (A-III). Clinicians should test for influenza in all patients who, while hospitalized, develop acute onset of respiratory symptoms, with or without fever, or respiratory distress, without a clear alternative diagnosis (A-III). 4. During periods of low influenza activity: Clinicians should test for influenza on admission in all patients requiring hospitalization with acute respiratory illness, with or without fever, who have an epidemiological link to a person diagnosed with influenza, an influenza outbreak or outbreak of acute febrile respiratory illness of uncertain cause, or who recently traveled from an area with known influenza activity (A-II). Clinicians can consider testing for influenza in patients with acute, febrile respiratory tract illness, especially children and adults who are immunocompromised or at high risk of complications, or if the results might influence antiviral treatment or chemoprophylaxis decisions for high-risk household contacts (see recommendations 41–43) (B-III). 5. Clinicians should collect upper respiratory tract specimens from outpatients for influenza testing as soon after illness onset as possible, preferably within 4 days of symptom onset (A-II). Nasopharyngeal specimens should be collected over other upper respiratory tract specimens to increase detection of influenza viruses (A-II). If nasopharyngeal specimens are not available, nasal and throat swab specimens should be collected and combined together for influenza testing over single specimens from either site (particularly over throat swabs) to increase detection of influenza viruses (A-II). Mid-turbinate nasal swab specimens should be collected over throat swab specimens to increase detection of influenza viruses (A-II). Flocked swab specimens should be collected over nonflocked swab specimens to improve detection of influenza viruses (A-II). 6. Clinicians should collect nasopharyngeal (optimally, as for outpatients), mid-turbinate nasal, or combined nasal–throat specimens from hospitalized patients without severe lower respiratory tract disease for influenza testing as soon as possible (A-II). 7. Clinicians should collect endotracheal aspirate or bronchoalveolar lavage fluid specimens from hospitalized patients with respiratory failure receiving mechanical ventilation, including patients with negative influenza testing results on upper respiratory tract specimens, for influenza testing as soon as possible (A-II). 8. Clinicians should not collect or routinely test specimens for influenza from nonrespiratory sites such as blood, plasma, serum, cerebrospinal fluid, urine, and stool (A-III). 9. Clinicians should not collect serum specimens, including single or paired sera, for serological diagnosis of seasonal influenza virus infection for clinical management purposes (A-III). 10. Clinicians should use rapid molecular assays (ie, nucleic acid amplification tests) over rapid influenza diagnostic tests (RIDTs) in outpatients to improve detection of influenza virus infection (A-II) (see Table 6). 11. Clinicians should use reverse-transcription polymerase chain reaction (RT-PCR) or other molecular assays over other influenza tests in hospitalized patients to improve detection of influenza virus infection (A-II) (see Table 6). 12. Clinicians should use multiplex RT-PCR assays targeting a panel of respiratory pathogens, including influenza viruses, in hospitalized immunocompromised patients (A-III). 13. Clinicians can consider using multiplex RT-PCR assays targeting a panel of respiratory pathogens, including influenza viruses, in hospitalized patients who are not immunocompromised if it might influence care (eg, aid in cohorting decisions, reduce testing, or decrease antibiotic use) (B-III). 14. Clinicians should not use immunofluorescence assays for influenza virus antigen detection in hospitalized patients except when more sensitive molecular assays are not available (A-II), and follow-up testing with RT-PCR or other molecular assays should be performed to confirm negative immunofluorescence test results (A-III). 15. Clinicians should not use RIDTs in hospitalized patients except when more sensitive molecular assays are not available (A-II), and follow-up testing with RT-PCR or other molecular assays should be performed to confirm negative RIDT results (A-II). 16. Clinicians should not use viral culture for initial or primary diagnosis of influenza because results will not be available in a timely manner to inform clinical management (A-III), but viral culture can be considered to confirm negative test results from RIDTs and immunofluorescence assays, such as during an institutional outbreak, and to provide isolates for further characterization (C-II). 17. Clinicians should not use serologic testing for diagnosis of influenza because results from a single serum specimen cannot be reliably interpreted, and collection of paired (acute/convalescent) sera 2–3 weeks apart are needed for serological testing (A-III). Influenza Diagnostic Tests for Respiratory Specimens Negative results may not rule out influenza. Respiratory tract specimens should be collected as close to illness onset as possible for testing. Clinicians should consult the manufacturer’s package insert for the specific test for the approved respiratory specimen(s). Most US Food and Drug Administration (FDA)–cleared influenza diagnostic tests are approved for upper respiratory tract specimens but not for sputum or lower respiratory tract specimens. Specificities are generally high (>90%) for all tests compared to RT-PCR. FDA-cleared rapid influenza diagnostic tests are Clinical Laboratory Improvement Amendments (CLIA)–waived; most FDA-cleared rapid influenza molecular assays are CLIA-waived, depending on the specimen. Abbreviation: RT-PCR, reverse-transcription polymerase chain reaction. Influenza Diagnostic Tests for Respiratory Specimens Negative results may not rule out influenza. Respiratory tract specimens should be collected as close to illness onset as possible for testing. Clinicians should consult the manufacturer’s package insert for the specific test for the approved respiratory specimen(s). Most US Food and Drug Administration (FDA)–cleared influenza diagnostic tests are approved for upper respiratory tract specimens but not for sputum or lower respiratory tract specimens. Specificities are generally high (>90%) for all tests compared to RT-PCR. FDA-cleared rapid influenza diagnostic tests are Clinical Laboratory Improvement Amendments (CLIA)–waived; most FDA-cleared rapid influenza molecular assays are CLIA-waived, depending on the specimen. Abbreviation: RT-PCR, reverse-transcription polymerase chain reaction. 18. Clinicians should start antiviral treatment as soon as possible for adults and children with documented or suspected influenza, irrespective of influenza vaccination history, who meet the following criteria: Persons of any age who are hospitalized with influenza, regardless of illness duration prior to hospitalization (A-II). Outpatients of any age with severe or progressive illness, regardless of illness duration (A-III). Outpatients who are at high risk of complications from influenza, including those with chronic medical conditions and immunocompromised patients (A-II). Children younger than 2 years and adults ≥65 years (A-III). Pregnant women and those within 2 weeks postpartum (A-III). 19. Clinicians can consider antiviral treatment for adults and children who are not at high risk of influenza complications, with documented or suspected influenza, irrespective of influenza vaccination history, who are either: Outpatients with illness onset ≤2 days before presentation (C-I). Symptomatic outpatients who are household contacts of persons who are at high risk of developing complications from influenza, particularly those who are severely immunocompromised (C-III). Symptomatic healthcare providers who care for patients who are at high risk of developing complications from influenza, particularly those who are severely immunocompromised (C-III). 20. Clinicians should start antiviral treatment as soon as possible with a single neuraminidase inhibitor (NAI) (either oral oseltamivir, inhaled zanamivir, or intravenous peramivir) and not use a combination of NAIs (A-1). 21. Clinicians should not routinely use higher doses of US Food and Drug Administration–approved NAI drugs for the treatment of seasonal influenza (A-II). 22. Clinicians should treat uncomplicated influenza in otherwise healthy ambulatory patients for 5 days with oral oseltamivir or inhaled zanamivir, or a single dose of intravenous peramivir (A-1). 23. Clinicians can consider longer duration of antiviral treatment for patients with a documented or suspected immunocompromising condition or patients requiring hospitalization for severe lower respiratory tract disease (especially pneumonia or acute respiratory distress syndrome [ARDS]), as influenza viral replication is often protracted (C-III). 24. Clinicians should investigate and empirically treat bacterial coinfection in patients with suspected or laboratory-confirmed influenza who present initially with severe disease (extensive pneumonia, respiratory failure, hypotension, and fever), in addition to antiviral treatment for influenza (A-II). 25. Clinicians should investigate and empirically treat bacterial coinfection in patients who deteriorate after initial improvement, particularly in those treated with antivirals (A-III). 26. Clinicians can consider investigating bacterial coinfection in patients who fail to improve after 3–5 days of antiviral treatment (C-III). 27. Clinicians should investigate other causes besides influenza virus infection in influenza patients who fail to improve or deteriorate despite antiviral treatment (A-III). 28. Influenza NAI resistance testing can be considered for: Patients who develop laboratory-confirmed influenza while on or immediately after NAI chemoprophylaxis (C-III). Patients with an immunocompromising condition and evidence of persistent influenza viral replication (eg, after 7–10 days, demonstrated by persistently positive RT-PCR or viral culture results) and remain ill during or after NAI treatment (B-III). Patients with laboratory-confirmed influenza who inadvertently received subtherapeutic NAI dosing (C-III). Patients with severe influenza who do not improve with NAI treatment and have evidence of persistent influenza viral replication (eg, after 7–10 days) (C-II). 29. Clinicians should remain informed on current CDC and World Health Organization surveillance data on the frequency and geographic distribution of NAI-resistant influenza viruses during influenza season, and with the latest CDC antiviral treatment recommendations (A-III). 30. Clinicians should not administer corticosteroid adjunctive therapy for the treatment of adults or children with suspected or confirmed seasonal influenza, influenza-associated pneumonia, respiratory failure, or ARDS, unless clinically indicated for other reasons (A-III). 31. Clinicians should not routinely administer immunomodulation using immunoglobulin preparations such as intravenous immunoglobulin for treatment of adults or children with suspected or confirmed seasonal influenza (A-III). Antiviral drugs should not be used for routine or widespread chemoprophylaxis outside of institutional outbreaks; antiviral chemoprophylaxis can be considered in certain situations: 32. Clinicians can consider antiviral chemoprophylaxis for the duration of the influenza season for adults and children aged ≥3 months who are at very high risk of developing complications from influenza and for whom influenza vaccination is contraindicated, unavailable, or expected to have low effectiveness (eg, persons who are severely immunocompromised) (C-II). 33. Clinicians can consider antiviral chemoprophylaxis for the duration of the influenza season for adults and children aged ≥3 months who have the highest risk of influenza-associated complications, such as recipients of hematopoietic stem cell transplant in the first 6–12 months posttransplant and lung transplant recipients (B-II). 34. Clinicians can consider short-term antiviral chemoprophylaxis in conjunction with prompt administration of inactivated influenza vaccine for unvaccinated adults and children aged ≥3 months who are at high risk of developing complications from influenza in whom influenza vaccination is expected to be effective (but not yet administered) when influenza activity has been detected in the community (C-II). 35. Clinicians can consider short-term antiviral chemoprophylaxis for unvaccinated adults, including healthcare personnel, and for children aged ≥3 months who are in close contact with persons at high risk of developing influenza complications during periods of influenza activity when influenza vaccination is contraindicated or unavailable and these high-risk persons are to antiviral chemoprophylaxis (C-III). Clinicians can consider patients and of patients to for of antiviral treatment as an alternative to antiviral chemoprophylaxis (C-III). Clinicians should use an NAI oseltamivir or inhaled if preexposure chemoprophylaxis for influenza is than an antiviral (A-II). Clinicians should administer preexposure antiviral chemoprophylaxis for adults and children aged ≥3 months who are at very high risk of developing complications from influenza (eg, severely immunocompromised persons such as hematopoietic stem cell transplant for whom influenza vaccination is contraindicated, unavailable, or expected to have low as soon as influenza activity is detected in the community and for the duration of community influenza activity (A-II). Clinicians should test for influenza and to antiviral treatment dosing in persons receiving preexposure antiviral chemoprophylaxis who preferably with an antiviral with a resistance if not contraindicated (A-II). Clinicians can consider postexposure antiviral chemoprophylaxis for adults and children aged ≥3 months who are at very high risk of developing complications from influenza (eg, severely immunocompromised and for whom influenza vaccination is contraindicated, unavailable, or expected to have low after household to influenza (C-II). Clinicians can consider postexposure antiviral chemoprophylaxis conjunction with influenza for adults and children aged ≥3 months who are unvaccinated and are household contacts of a person at very high risk of complications from influenza (eg, severely immunocompromised after to influenza (C-II). Clinicians can consider patients and for of antiviral treatment as an alternative to postexposure antiviral chemoprophylaxis (C-III). If chemoprophylaxis is clinicians should administer postexposure antiviral chemoprophylaxis as soon as possible after than after (A-III). Clinicians should not administer postexposure antiviral chemoprophylaxis if has antiviral treatment should be as soon as symptoms if treatment is indicated (A-III). Antiviral Clinicians should administer postexposure antiviral chemoprophylaxis in a for days after the most recent to a close contact with influenza (A-III). 46. Clinicians should test for influenza and to antiviral treatment dosing in persons receiving postexposure antiviral chemoprophylaxis who preferably with an antiviral with a resistance if not contraindicated (A-III). Antiviral for Clinicians should administer an NAI or oral if postexposure chemoprophylaxis for influenza is than an antiviral (A-II). surveillance for should be as soon as possible when laboratory-confirmed influenza is in a or of laboratory-confirmed influenza is in a long-term care (A-III). control should be as soon as possible, including antiviral chemoprophylaxis of and surveillance for new when 2 of laboratory-confirmed influenza are within of each other in or patients of the or (A-III). of outbreak control can be considered as soon as possible if or more or patients has suspected influenza and results of influenza molecular testing are not available on the of specimen collection (B-III). an influenza outbreak has been in a long-term care or influenza testing should be for any with or more acute respiratory symptoms, with or without fever, or any of the following without respiratory or or (A-III). antiviral treatment should be as soon as possible to any or with suspected influenza during an influenza outbreak without for the results of influenza diagnostic testing (A-III). Antiviral chemoprophylaxis should be as soon as possible to all or patients who do not have suspected or laboratory-confirmed influenza regardless of influenza vaccination history, in addition to of all other influenza outbreak control measures, when an influenza outbreak has been in a long-term care or (A-III). Antiviral chemoprophylaxis should be to on in addition to surveillance for new influenza the (A-II). Clinicians can consider antiviral chemoprophylaxis for unvaccinated including those for whom chemoprophylaxis may be indicated based upon underlying conditions of the or household (see recommendations 41–43) for the duration of the outbreak (C-III). Clinicians can consider antiviral chemoprophylaxis for who inactivated influenza vaccine during an institutional influenza outbreak for days (C-III). Clinicians can consider antiviral chemoprophylaxis for regardless of influenza vaccination to reduce the risk of in and clinical is and to reduce to care for patients with suspected influenza (C-III). Clinicians should administer antiviral chemoprophylaxis for days and for at days after the onset of symptoms in the during an institutional influenza outbreak (A-III). The panel for of an by and The panel and for and in of the for with systematic and for in and recommendations. IDSA to present and the information in these guidelines is without any of or either or IDSA or will be for any or with to any including or in with these guidelines or on the information The and in are those of the and do not the of the for these guidelines was by the Infectious Diseases Society of of The following is a of has been to the provide the IDSA full of all regardless of to the of such as of is by a process that includes by the and Guidelines the to the development panel and the of to the and if the Task Force of the of for possible will be based on the of the (ie, and the of the (ie, the to an might be by an as to the or of The of these guidelines should be of when the of is from the of Health and from in the of Public and the of is a of the on at is an of the on Infectious Diseases at and is an of the at from and the and from the and outside the from and during the of the and support from and from and the Society of and from the of Health and from the World Health Organization and the University of Antiviral Drug and other from and support and to a and for and for in developing influenza or and from support from and from the the Health and the Centers for and and the of Emergency System outside the from and from and during the of the and for on a data from from and the Canadian of Health and for infection surveillance from the Public Health of outside the and other from and and from and the outside the as a to the and in as a for the of and as a for as a to from the and for and for and and for from the of and Infectious Diseases and the other from and from and outside the other of have the for of of that the consider to the of the have been

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third ( n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.