Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

Camouflage using three-dimensional surface disruption.

Disruptive markings are common in animal patterns and can provide camouflage benefits by concealing the body's true edges and/or by breaking the surface of the body into multiple depth planes. Disruptive patterns that are accentuated by high contrast borders are most likely to provide false depth cues to enhance camouflage, but studies to date have used visual detection models or humans as predators. We presented three-dimensional-printed moth-like targets to wild bird predators to determine whether: (1) three-dimensional prey with disrupted body surfaces have higher survival than three-dimensional prey with continuous surfaces, (2) two-dimensional prey with disruptive patterns or enhanced edge markings have higher survival than non-patterned two-dimensional prey. We found a survival benefit for three-dimensional prey with disrupted surfaces, and a significant effect of mean wing luminance. There was no evidence that false depth cues provided the same protective benefits as physical surface disruption in three-dimensional prey, perhaps because our treatments did not mimic the complexity of patterns found in natural animal markings. Our findings indicate that disruption of surface continuity is an important strategy for concealing a three-dimensional body shape.

Intraoperative diagnosis of type 1 diabetes and diabetic ketoacidosis during scoliosis surgery.

Diabetic ketoacidosis is the leading cause of morbidity and mortality in children with type 1 diabetes. Management of diabetic ketoacidosis requires meticulous monitoring and treatment of severe dehydration and metabolic derangement. We present an adolescent patient who was diagnosed with diabetic ketoacidosis during spinal fusion for idiopathic scoliosis and discuss the management of this unexpected intraoperative emergency.

Fascia Iliaca Pain Block Results in Lower Overall Opioid Usage and Shorter Hospital Stays than Epidural Anesthesia After Hip Reconstruction in Children With Cerebral Palsy.

INTRODUCTION AND OBJECTIVE: Epidural anesthesia (EA) is often used for pain control in children with cerebral palsy (CP) who undergo hip reconstructions. The purpose of this study is to determine if preoperative fascia iliaca (FI) pain blocks would improve pain scores, decrease opioid use, and result in shorter hospital stays in comparison to the use of EA. METHODS: This is a nonrandomized retrospective cohort study examining 60 consecutive patients with CP who underwent hip reconstruction utilizing either a fascia iliac compartment nerve block (FICNB) (N=37) or continuous lumbar epidural (N=22) from January 2017 to March 2019. Age at surgery was 8.5±4.6 years. We recorded age, weight, operating room (OR) time, FLACC (Face, Legs, Activity, Cry, Consolability scale) scores on postoperative days (PODs) 0, 1, 2, and 3, opioid doses, overall opioid (mg) used, and length of stay. We compared pain scores, opioid usage, OR time, and lengths of stay between our 2 patient groups. RESULTS: Pain scores were similar between groups on POD #0, 2, and 3 but were statistically improved on POD #1 (1.8±1.3 vs. 3.1±1.4, P<0.001). Total number of opiod doses (7.9±4.4 vs. 10.7±2.3, P=0.004), total milligram given (18.3±11.8 vs. 24.7±12.3, P<0.05), and milligram per kilogram given (0.77±0.42 vs. 1.11 mg/kg±0.36 mg/kg, P=0.001) were less for the FI group versus the epidural group. The OR time (which includes time for blocks/epidurals) was lower in the FI group (4.6±1.2 vs. 5.7±1.1 h, P=0.0002). Overall hospital stays were lower in the FI group (3.4±1.5 vs. 4.1±1.0 d, P<0.05). CONCLUSIONS: This study demonstrates that in the setting of hip reconstruction, patients that received preoperative FI blocks used a lower amount of opioids, required fewer rescue doses and ultimately had a shorter hospital length of stay than those undergoing EA.

Cigarette Smoking and Risk Perceptions During the COVID-19 Pandemic Reported by Recently Hospitalized Participants in a Smoking Cessation Trial.

BACKGROUND: Cigarette smoking is a risk factor for severe COVID-19 disease. Understanding smokers' responses to the pandemic will help assess its public health impact and inform future public health and provider messages to smokers. OBJECTIVE: To assess risk perceptions and change in tobacco use among current and former smokers during the COVID-19 pandemic. DESIGN: Cross-sectional survey conducted in May-July 2020 (55% response rate) PARTICIPANTS: 694 current and former daily smokers (mean age 53, 40% male, 78% white) who had been hospitalized pre-COVID-19 and enrolled into a smoking cessation clinical trial at hospitals in Massachusetts, Pennsylvania, and Tennessee. MAIN MEASURES: Perceived risk of COVID-19 due to tobacco use; changes in tobacco consumption and interest in quitting tobacco use; self-reported quitting and relapse since January 2020. KEY RESULTS: 68% (95% CI, 65-72%) of respondents believed that smoking increases the risk of contracting COVID-19 or having a more severe case. In adjusted analyses, perceived risk was higher in Massachusetts where COVID-19 had already surged than in Pennsylvania and Tennessee which were pre-surge during survey administration (AOR 1.56, 95% CI, 1.07-2.28). Higher perceived COVID-19 risk was associated with increased interest in quitting smoking (AOR 1.72, 95% CI 1.01-2.92). During the pandemic, 32% (95% CI, 27-37%) of smokers increased, 37% (95% CI, 33-42%) decreased, and 31% (95% CI, 26-35%) did not change their cigarette consumption. Increased smoking was associated with higher perceived stress (AOR 1.49, 95% CI 1.16-1.91). Overall, 11% (95% CI, 8-14%) of respondents who smoked in January 2020 (pre-COVID-19) had quit smoking at survey (mean, 6 months later) while 28% (95% CI, 22-34%) of former smokers relapsed. Higher perceived COVID-19 risk was associated with higher odds of quitting and lower odds of relapse. CONCLUSIONS: Most smokers believed that smoking increased COVID-19 risk. Smokers' responses to the pandemic varied, with increased smoking related to stress and increased quitting associated with perceived COVID-19 vulnerability.

Countershading enhances camouflage by reducing prey contrast.

A three-dimensional body shape is problematic for camouflage because overhead lighting produces a luminance gradient across the body's surface. Countershading, a form of patterning where animals are darkest on their uppermost surface, is thought to counteract this luminance gradient and enhance concealment, but the mechanisms of protection remain unclear. Surprisingly, no study has examined how countershading alters prey contrast, or investigated how the presence of a dorsoventral luminance gradient affects detection under controlled viewing conditions. It has also been suggested that the direction of the dorsoventral luminance gradient (darkest or lightest on top) may interfere with predators' abilities to resolve prey's three-dimensional shape, yet this intriguing idea has never been tested. We used live fish predators (western rainbowfish, Melanotaenia australis) and computer-generated prey images to compare the detectability of uniformly pigmented (i.e. non-countershaded) prey with that of optimally countershaded prey of varying contrasts against the background. Optimally countershaded prey were difficult for predators to detect, and the probability and speed of detection depended on prey luminance contrast with the background. In comparison, non-countershaded prey were always highly detectable, even though their average luminance closely matched the luminance of the background. Our findings suggest that uniformly pigmented three-dimensional prey are highly conspicuous to predators because overhead lighting increases luminance contrast between different body parts or between the body and the background. We found no evidence for the notion that countershading interferes with predator perception of three-dimensional form.

The effect of ecological factors on eye morphology in the western rainbowfish, Melanotaenia australis.

Ecological factors such as spatial habitat complexity and diet can explain variation in visual morphology, but few studies have sought to determine whether visual specialisation can occur among populations of the same species. We used a small Australian freshwater fish (the western rainbowfish, Melanotaenia australis) to determine whether populations showed variation in eye size and eye position, and whether this variation could be explained by environmental (light availability, turbidity) and ecological (predation risk, habitat complexity, invertebrate abundance) variables. We investigated three aspects of eye morphology - (1) eye size relative to body size, (2) pupil size relative to eye size and (3) eye position in the head - for fish collected from 14 sites in a major river catchment in northwest Western Australia. We found significant variation among populations in all three measures of eye morphology, but no effect of sex on eye size or eye position. Variation in eye diameter and eye position was best explained by the level of habitat complexity. Specifically, fish occurring in habitats with low complexity (i.e. open water) tended to have smaller, more dorsally located eyes than those occurring in more complex habitats (i.e. vegetation present). The size of the pupil relative to the size of the eye was most influenced by the presence of surrounding rock formations; fish living in gorge habitats had significantly smaller pupils (relative to eye size) than those occupying semi-gorge sites or open habitats. Our findings reveal that different ecological and environmental factors contribute to habitat-specific visual specialisations within a species.

Enhancing employer coverage of smoking cessation treatment: A randomized trial of the Partners in Helping You Quit (PiHQ) program.

The workplace is a key channel for delivering tobacco cessation treatment to a population. Employers can provide workplace-based programs and/or financial incentives such as health insurance benefits that cover the cost of treatment accessed outside the workplace. Little is known about the effect of combining these strategies. We tested the benefit of adding a workplace cessation program, Partners in Helping You Quit (PiHQ), to comprehensive health insurance coverage of smoking cessation medications by Partners HealthCare, a large Boston-based healthcare delivery system. PiHQ offers biweekly telephone-based behavioral support, additional automated calls, and medication care coordination for 3 months then monthly telephone monitoring for 9 months. In a pragmatic randomized trial, employees who smoked were informed about the insurance benefit, then randomly assigned (2:1) to PiHQ or to active referral to a free 3-month phone-based community program, Massachusetts Quitline (QL). Outcomes were assessed at 3, 6, and 12 months. During 2015-2018, 106 smokers (n = 73 PiHQ, n = 33 QL) enrolled (64% female; 75% white, 21% black; mean age 46 years, mean cigarettes/day = 13). More PiHQ than QL participants made a quit attempt by 3 months (82 vs. 61%, p < .02) and achieved the primary outcome, verified past 7-day cigarette abstinence at 6 months (31 vs. 12%, odds ratio 3.34, 95% CI, 1.05-10.60). Among participants using behavioral support, PiHQ participants completed more scheduled calls and rated counseling helpfulness higher than did QL participants. These results suggest that employers can enhance the impact of providing comprehensive health insurance coverage of smoking cessation medication by adding a phone-based worksite cessation program.

Proactive Population Health Strategy to Offer Tobacco Dependence Treatment to Smokers in a Primary Care Practice Network.

BACKGROUND: Population-based strategies can expand the reach of tobacco cessation treatment beyond clinical encounters. OBJECTIVE: To determine the effect of two population-based tobacco cessation strategies, compared with usual care, on providing tobacco treatment outside of clinical encounters. DESIGN: 3-arm pragmatic randomized controlled trial. PARTICIPANTS: Current smokers ≥ 18 years old with a primary care provider at one of five community health centers in Massachusetts were identified via the electronic health record (n = 5225) and recruited using automated phone calls. INTERVENTIONS: One intervention group involved engagement with a health system-based tobacco coach (internal care coordination), and the other connected patients to a national quitline (external community referral). MEASUREMENTS: Proportion of smokers with documentation of any evidence-based cessation treatment in the 6 months after enrollment. KEY RESULTS: Of 639 individuals who responded to the proactive treatment offer, 233 consented and were randomized 1:1:1 to study arm. At 6-month follow-up, the pooled intervention group, compared with usual care, had higher documentation of any smoking cessation treatment (63% vs. 34%, p < 0.001), cessation medication prescription (52% vs. 30%, p = 0.002), and counseling (47% vs. 9%, p < 0.001). Internal care coordination was more effective than external community referral at connecting smokers to any cessation treatment (76% vs. 50%, p = 0.001) and at providing cessation medication (66% vs. 39%, p < 0.001), but comparable at linking smokers to cessation counseling resources. CONCLUSIONS: Smokers responding to a population-based, proactive outreach strategy had better provision of tobacco cessation treatment when referred to either a health system-based or community-based program compared with usual care. The health system-based strategy outperformed the quitline-based one in several measures. Future work should aim to improve population reach and test the effect on smoking cessation rates. TRIAL REGISTRATION: ClinicalTrials.gov NCT03612895.

Association of E-Cigarette Use With Smoking Cessation Among Smokers Who Plan to Quit After a Hospitalization: A Prospective Study.

Background: Many smokers report using e-cigarettes to help them quit smoking, but whether e-cigarettes aid cessation efforts is uncertain. Objective: To determine whether e-cigarette use after hospital discharge is associated with subsequent tobacco abstinence among smokers who plan to quit and are advised to use evidence-based treatment. Design: Secondary data analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01714323 [parent trial]). Setting: 3 hospitals. Participants: 1357 hospitalized adult cigarette smokers who planned to stop smoking, received tobacco cessation counseling in the hospital, and were randomly assigned at discharge to a tobacco treatment recommendation (control) or free tobacco treatment (intervention). Measurements: Self-reported e-cigarette use (exposure) was assessed 1 and 3 months after discharge; biochemically validated tobacco abstinence (outcome) was assessed 6 months after discharge. Results: Twenty-eight percent of participants used an e-cigarette within 3 months after discharge. In an analysis of 237 propensity score-matched pairs, e-cigarette users were less likely than nonusers to abstain from tobacco use at 6 months (10.1% vs. 26.6%; risk difference, -16.5% [95% CI, -23.3% to -9.6%]). The association between e-cigarette use and quitting varied between intervention patients, who were given easy access to conventional treatment (7.7% vs. 29.8%; risk difference, -22.1% [CI, -32.3% to -11.9%]), and control patients, who received only treatment recommendations (12.0% vs. 24.1%; risk difference, -12.0% [CI, -21.2% to 2.9%]) (P for interaction = 0.143). Limitations: Patients self-selected e-cigarette use. Unmeasured confounding is possible in an observational study. Conclusion: During 3 months after hospital discharge, more than a quarter of smokers attempting to quit used e-cigarettes, mostly to aid cessation, but few used them regularly. This pattern of use was associated with less tobacco abstinence at 6 months than among smokers who did not use e-cigarettes. Additional study is needed to determine whether regular use of e-cigarettes aids or hinders smoking cessation. Primary Funding Source: National Heart, Lung, and Blood Institute.

Scary clowns: adaptive function of anemonefish coloration.

Clownfishes, with their showy coloration, are well known for their symbiosis with sea anemones and for their hierarchical reproductive system, but the function of their coloration is unclear. We used a phylogeny of 27 clownfish species to test whether fish coloration (i) serves a protective function that involves their anemone hosts, or (ii) signals species identity in species with overlapping host ranges that can potentially share the same host. We tested for an association between fish colour pattern traits, host morphology and host toxicity and examined coloration in relation to host sharing and geographic proximity. Fish with fewer stripes occupied fewer anemone species, and hosts with shorter tentacles, than fish with multiple stripes. There was a negative relationship between anemone toxicity and tentacle length and these protective traits together were correlated with the evolution of stripes. Host sharing or range overlap was not associated with coloration divergence. We propose that ancestral anemonefishes had multiple stripes that served for hiding/camouflage among the hosts' long tentacles, whereas increased specialization towards fewer and more toxic hosts (with shorter tentacles) led to the use of coloration as an aposematic signal. The intriguing notion that an aposematic signal could advertise the defence of another species may reflect the unique symbiotic relationship between anemonefishes and their hosts.

Phenotypic assortment by body shape in wild-caught fish shoals.

Phenotypic variation plays a critical role in determining the structural organisation and ecological function of wild populations. Animal groups are often structured according to factors such as species, sex, body size and parasite load, but it is unclear whether body shape also influences patterns of social organisation, and thus contributes to population phenotypic structure. Here, we use geometric morphometric analyses to determine whether wild-caught shoals of a freshwater fish, the western rainbowfish (Melanotaenia australis), are structured according to body size and shape. Using randomisation analyses, we show that the level of variation in size and shape observed in natural group assemblages is lower than that expected under a null model of random shoal composition. In addition, we found evidence of further phenotypic structuring along an upstream-downstream environmental gradient. The putative benefits of morphological assortment include a reduction in predation risk (due to prey oddity and predator confusion effects) and increased hydrodynamic or foraging efficiency. We suggest that morphological variation is a neglected component of population social organisation that can affect population processes, such as patterns of gene flow, and ecological interactions, such as predator-prey dynamics.

Interactive Voice Response Calls to Promote Smoking Cessation after Hospital Discharge: Pooled Analysis of Two Randomized Clinical Trials.

BACKGROUND: Hospitalization offers smokers an opportunity to quit smoking. Starting cessation treatment in hospital is effective, but sustaining treatment after discharge is a challenge. Automated telephone calls with interactive voice response (IVR) technology could support treatment continuance after discharge. OBJECTIVE: To assess smokers' use of and satisfaction with an IVR-facilitated intervention and to test the relationship between intervention dose and smoking cessation. DESIGN: Analysis of pooled quantitative and qualitative data from the intervention groups of two similar randomized controlled trials with 6-month follow-up. PARTICIPANTS: A total of 878 smokers admitted to three hospitals. All received cessation counseling in hospital and planned to stop smoking after discharge. INTERVENTION: After discharge, participants received free cessation medication and five automated IVR calls over 3 months. Calls delivered messages promoting smoking cessation and medication adherence, offered medication refills, and triaged smokers to additional telephone counseling. MAIN MEASURES: Number of IVR calls answered, patient satisfaction, biochemically validated tobacco abstinence 6 months after discharge. KEY RESULTS: Participants answered a median of three of five IVR calls; 70% rated the calls as helpful, citing the social support, access to counseling and medication, and reminders to quit as positive factors. Older smokers (OR 1.36, 95% CI 1.20-1.54 per decade) and smokers hospitalized for a smoking-related disease (OR 1.65, 95% CI 1.21-2.23) completed more calls. Smokers who completed more calls had higher quit rates at 6-month follow-up (OR 1.49, 95% CI 1.30-1.70, for each additional call) after multivariable adjustment for age, sex, education, discharge diagnosis, nicotine dependence, duration of medication use, and perceived importance of and confidence in quitting. CONCLUSIONS: Automated IVR calls to support smoking cessation after hospital discharge were viewed favorably by patients. Higher IVR utilization was associated with higher odds of tobacco abstinence at 6-month follow-up. IVR technology offers health care systems a potentially scalable means of sustaining tobacco cessation interventions after hospital discharge. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT01177176, NCT01714323.

Bone Density in the Obese Child: Clinical Considerations and Diagnostic Challenges.

The prevalence of obesity in children has reached epidemic proportions. Concern about bone health in obese children, in part, derives from the potentially increased fracture risk associated with obesity. Additional risk factors that affect bone mineral accretion, may also contribute to obesity, such as low physical activity and nutritional factors. Consequences of obesity, such as inflammation, insulin resistance, and non-alcoholic fatty liver disease, may also affect bone mineral acquisition, especially during the adolescent years when rapid increases in bone contribute to attaining peak bone mass. Further, numerous pediatric health conditions are associated with excess adiposity, altered body composition, or endocrine disturbances that can affect bone accretion. Thus, there is a multitude of reasons for considering clinical assessment of bone health in an obese child. Multiple diagnostic challenges affect the measurement of bone density and its interpretation. These include greater precision error, difficulty in positioning, and the effects of increased lean and fat tissue on bone health outcomes. Future research is required to address these issues to improve bone health assessment in obese children.

Functional diversity of the lateral line system among populations of a native Australian freshwater fish.

Fishes use their mechanoreceptive lateral line system to sense nearby objects by detecting slight fluctuations in hydrodynamic motion within their immediate environment. Species of fish from different habitats often display specialisations of the lateral line system, in particular the distribution and abundance of neuromasts, but the lateral line can also exhibit considerable diversity within a species. Here, we provide the first investigation of the lateral line system of the Australian western rainbowfish (Melanotaenia australis), a species that occupies a diversity of freshwater habitats across semi-arid northwest Australia. We collected 155 individuals from eight populations and surveyed each habitat for environmental factors that may contribute to lateral line specialisation, including water flow, predation risk, habitat structure and prey availability. Scanning electron microscopy and fluorescent dye labelling were used to describe the lateral line system in M. australis, and to examine whether the abundance and arrangement of superficial neuromasts (SNs) varied within and among populations. We found that the SNs of M. australis were present in distinct body regions rather than lines. The abundance of SNs within each body region was highly variable, and also differed among populations and individuals. Variation in SN abundance among populations was best explained by habitat structure and the availability of invertebrate prey. Our finding that specific environmental factors explain among-population variation in a key sensory system suggests that the ability to acquire sensory information is specialised for the particular behavioural needs of the animal.

Smoking Status Confirmation by Proxy: Validation in a Smoking Cessation Trial.

INTRODUCTION: Biochemical confirmation (BC) of self-report is the gold standard of evidence for abstinence in smoking cessation research, but difficulty in obtaining samples may bias estimates of quit rates. Proxy confirmation (PC) has not been validated in cessation trials. We assessed the feasibility and validity of PC in a cessation trial for hospitalized smokers. METHODS: We enrolled 402 daily cigarette smokers during a hospital admission. At enrollment, participants provided demographics, smoking history, and named proxies to confirm their smoking status at follow-up. Participants provided self-reported (SR) 7-day tobacco abstinence by telephone at 6 months post-discharge. SR quitters were asked to mail a saliva sample for BC. Incentives were offered for survey completion ($20) and returned samples ($50). We called proxies for all those with SR to obtain PC. Quit rates were calculated with missing data indicating smoking. We assessed associations of nonresponse with baseline characteristics using chi-squared tests and logistic regression. We calculated the sensitivity and specificity of PC in detecting smokers as determined by BC. RESULTS: All patients named at least one proxy. Response rates were 82% for SR, 84% for PC, and 69% for BC. Observed participant characteristics were unrelated to provision of sample for BC. Estimated quit rates were 35% for SR, 27% for SR + PC, 21% for SR + BC and 27% for SR + BC or PC. Sensitivity of PC was not higher than SR (73% vs. 77%); specificity was lower (84% vs. 100%). CONCLUSION: PC was feasible but not superior to self-report in a cessation trial.

Comparative Effectiveness of Post-Discharge Strategies for Hospitalized Smokers: study protocol for the Helping HAND 2 randomized controlled trial.

BACKGROUND: Smoking cessation interventions for hospitalized smokers are effective in promoting smoking cessation, but only if the tobacco dependence treatment continues after the patient leaves the hospital. Sustaining tobacco dependence treatment after hospital discharge is a challenge for health care systems. Our previous single-site randomized controlled trial demonstrated the effectiveness of an intervention that facilitated the delivery of comprehensive tobacco cessation treatment, including both medication and counseling, after hospital discharge. We subsequently streamlined the intervention model to increase its potential for dissemination. This new model is being tested in a larger multi-site trial with broader eligibility criteria in order to enroll a more representative sample of hospitalized smokers. This paper describes the trial design and contrasts it with the earlier study. METHODS/DESIGN: A 2-arm, 3-site randomized controlled trial is testing the hypothesis that a multi-component Sustained Care intervention is more effective than Standard Care in helping hospitalized cigarette smokers stop smoking after hospital discharge. The trial enrolls adult daily cigarette smokers who are admitted to 1 of 3 participating hospitals in Massachusetts or Pennsylvania. Participants receive the same smoking cessation intervention in the hospital. They are randomly assigned to receive either Standard Care or Sustained Care after hospital discharge. Participants in the Sustained Care arm receive a free 3-month supply of FDA-approved smoking cessation medication and 5 interactive voice response calls that provide tailored motivational messages, medication refills, and access to a live tobacco treatment counselor. Participants in the Standard Care arm receive a smoking cessation medication recommendation and information about community resources. Outcomes are assessed at 1, 3, and 6 months after discharge. The primary outcome is biochemically-validated tobacco abstinence for the past 7 days at 6-month follow-up. Other outcome measures include self-reported tobacco abstinence measures, use of medication and counseling after discharge, hospital readmissions, and program cost-effectiveness. DISCUSSION: We adapted a proven intervention for hospitalized smokers to enhance its potential for dissemination and are testing it in a multi-site trial. Study enrollment data suggests that the trial achieved the goal of recruiting a broader sample of hospitalized smokers. TRIAL REGISTRATION: Comparative Effectiveness of Post-Discharge Strategies for Hospitalized Smokers (Helping HAND2) NCT01714323. Registered October 22, 2012.

Atomic-level insights into metabolite recognition and specificity of the SAM-II riboswitch.

Although S-adenosylhomocysteine (SAH), a metabolic by-product of S-adenosylmethionine (SAM), differs from SAM only by a single methyl group and an overall positive charge, SAH binds the SAM-II riboswitch with more than 1000-fold less affinity than SAM. Using atomistic molecular dynamics simulations, we investigated the molecular basis of such high selectivity in ligand recognition by SAM-II riboswitch. The biosynthesis of SAM exclusively generates the (S,S) stereoisomer, and (S,S)-SAM can spontaneously convert to the (R,S) form. We, therefore, also examined the effects of (R,S)-SAM binding to SAM-II and its potential biological function. We find that the unfavorable loss in entropy in SAM-II binding is greater for (S,S)- and (R,S)-SAM than SAH, which is compensated by stabilizing electrostatic interactions with the riboswitch. The positively charged sulfonium moiety on SAM acts as the crucial anchor point responsible for the formation of key ionic interactions as it fits favorably in the negatively charged binding pocket. In contrast, SAH, with its lone pair of electrons on the sulfur, experiences repulsion in the binding pocket of SAM-II and is enthalpically destabilized. In the presence of SAH, similar to the unbound riboswitch, the pseudoknot structure of SAM-II is not completely formed, thus exposing the Shine-Dalgarno sequence. Unlike SAM, this may further facilitate ribosomal assembly and translation initiation. Our analysis of the conformational ensemble sampled by SAM-II in the absence of ligands and when bound to SAM or SAH reveals that ligand binding follows a combination of conformational selection and induced-fit mechanisms.

Male sperm storage compromises sperm motility in guppies.

Sperm senescence can have important evolutionary implications due to its deleterious effects on sperm quality and offspring performance. Consequently, it has been argued that polyandry (female multiple mating) may facilitate the selection of younger, and therefore competitively superior, sperm when ejaculates from multiple males compete for fertilization. Surprisingly, however, unequivocal evidence that sperm ageing influences traits that underlie sperm competitiveness is lacking. Here, we used a paired experimental design that compares sperm quality between 'old' and 'young' ejaculates from individual male guppies (Poecilia reticulata). We show that older sperm exhibit significant reductions in sperm velocity compared with younger sperm from the same males. We found no evidence that the brightness of the male's orange (carotenoid) spots, which are thought to signal resistance to oxidative stress (and thus age-related declines in sperm fitness), signals a male's ability to withstand the deleterious effects of sperm ageing. Instead, polyandry may be a more effective strategy for females to minimize the likelihood of being fertilized by aged sperm.

Sustained care intervention and postdischarge smoking cessation among hospitalized adults: a randomized clinical trial.

IMPORTANCE: Health care systems need effective models to manage chronic diseases like tobacco dependence across transitions in care. Hospitalizations provide opportunities for smokers to quit, but research suggests that hospital-delivered interventions are effective only if treatment continues after discharge. OBJECTIVE: To determine whether an intervention to sustain tobacco treatment after hospital discharge increases smoking cessation rates compared with standard care. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial compared sustained care (a postdischarge tobacco cessation intervention) with standard care among 397 hospitalized daily smokers (mean age, 53 years; 48% were males; 81% were non-Hispanic whites) who wanted to quit smoking after discharge and received a tobacco dependence intervention in the hospital; 92% of eligible patients and 44% of screened patients enrolled. The study was conducted from August 2010 through November 2012 at Massachusetts General Hospital. INTERVENTIONS: Sustained care participants received automated interactive voice response telephone calls and their choice of free smoking cessation medication (any type approved by the US Food and Drug Administration) for up to 90 days. The automated telephone calls promoted cessation, provided medication management, and triaged smokers for additional counseling. Standard care participants received recommendations for postdischarge pharmacotherapy and counseling. MAIN OUTCOMES AND MEASURES: The primary outcome was biochemically confirmed past 7-day tobacco abstinence at 6-month follow-up after discharge from the hospital; secondary outcomes included self-reported tobacco abstinence. RESULTS: Smokers randomly assigned to sustained care (n = 198) used more counseling and more pharmacotherapy at each follow-up assessment than those assigned to standard care (n = 199). Biochemically validated 7-day tobacco abstinence at 6 months was higher with sustained care (26%) than with standard care (15%) (relative risk [RR], 1.71 [95% CI, 1.14-2.56], P = .009; number needed to treat, 9.4 [95% CI, 5.4-35.5]). Using multiple imputation for missing outcomes, the RR for 7-day tobacco abstinence was 1.55 (95% CI, 1.03-2.21; P = .04). Sustained care also resulted in higher self-reported continuous abstinence rates for 6 months after discharge (27% vs 16% for standard care; RR, 1.70 [95% CI, 1.15-2.51]; P = .007). CONCLUSIONS AND RELEVANCE: Among hospitalized adult smokers who wanted to quit smoking, a postdischarge intervention providing automated telephone calls and free medication resulted in higher rates of smoking cessation at 6 months compared with a standard recommendation to use counseling and medication after discharge. These findings, if replicated, suggest an approach to help achieve sustained smoking cessation after a hospital stay. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01177176.