Effectiveness of full Pulpotomy compared with Root canal treatment in managing teeth with signs and symptOms indicative of irreversible pulpitis: a protocol for prospectiVE meta-analysis of individual participant data of linked randomised clinical trials (PROVE).

BACKGROUND: Full pulpotomy has been proposed as an alternative to root canal treatment in teeth with signs and symptoms indicative of irreversible pulpitis (IRP), but the evidence is limited, relying on underpowered studies with a high risk of bias. The aim of this study is to conduct a prospective meta-analysis (PMA) of individual participant data of a series of individual randomised trials to provide robust evidence on the clinical and cost-effectiveness of pulpotomy compared with root canal treatment. METHODS: Individual participant data will be obtained from a series of randomised trials designed and conducted by a consortium of multi-national investigators with an interest in vital pulp treatment. These individualised trials will be conducted using a specified protocol, defined outcomes, and outcome measures. Ten parallel-group randomised trials currently being conducted in 10 countries will provide data from more than 500 participants. The primary outcome is a composite measure defined as (1) the absence of pain indicative of IRP, (2) the absence of signs and symptoms indicative of acute or chronic apical periodontitis, and (3) the absence of radiographic evidence of failure including radiolucency or resorption. Individual participant data will be obtained, assessed, and checked for quality by two independent reviewers prior to the PMA. Pooled estimates on treatment effects will be generated using a 2-stage meta-analysis approach. The first stage involves a standard regression analysis in each trial to produce aggregate data on treatment effect estimates followed by an inverse variance weighted meta-analysis to combine these aggregate data and produce summary statistics and forest plots. Cost-effectiveness analysis based on the composite outcome will be undertaken as a process evaluation to evaluate treatment fidelity and acceptability by patients and dentists. RESULTS: The research question and trial protocol were developed and approved by investigators in all 10 sites. All sites use shared resources including study protocols, data collection forms, participant information leaflets, and consent forms in order to improve flow, consistency, and reproducibility. Each site obtained its own Institutional Review Board approval, and trials were registered in appropriate open access platforms. Patient recruitment has started in most sites, as of July 2023. DISCUSSION: PMA offers a rigorous, flexible, and efficient methodology to answer this important research question and provide results with improved generalisability and external validity compared with traditional trials and retrospective meta-analyses. The results of this study will have implications for both the delivery of clinical practice and structured clinical guidelines' development. TRIAL REGISTRATION: PROSPERO CRD42023446809. Registered on 08 February 2023.

Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle.

Robot-actuated mechanical loading (ML)-based therapies ("mechanotherapies") can promote regeneration after severe skeletal muscle injury, but the effectiveness of such approaches during aging is unknown and may be influenced by age-associated decline in the healing capacity of skeletal muscle. To address this knowledge gap, this work used a noninvasive, load-controlled robotic device to impose highly defined tissue stresses to evaluate the age dependence of ML on muscle repair after injury. The response of injured muscle to robot-actuated cyclic compressive loading was found to be age sensitive, revealing not only a lack of reparative benefit of ML on injured aged muscles but also exacerbation of tissue inflammation. ML alone also disrupted the normal regenerative processes of aged muscle stem cells. However, these negative effects could be reversed by introducing anti-inflammatory therapy alongside ML application, leading to enhanced skeletal muscle regeneration even in aged mice.

Prospective 12-month outcomes of combined iStent inject implantation and phacoemulsification in Asian eyes with normal tension glaucoma.

BACKGROUND: Glaucoma is the leading cause of irreversible blindness. Normal tension glaucoma (NTG) is a subset of open-angle glaucoma, demonstrating glaucomatous optic nerve damage in the absence of raised intraocular pressure (IOP). NTG is more prevalent in Asian populations. While generally slow-progressing, NTG may be associated with significant central visual field loss. In recent years, minimally invasive glaucoma surgery has been added to the armamentarium of glaucoma surgery. This prospective study aims to evaluate 12-month surgical outcomes of combined iStent inject (Glaukos Corporation, Laguna Hills, CA) implantation and phacoemulsification in Asian eyes with NTG. METHODS: This is a prospective, single-centre case series of 30 eyes followed up until 12 months after surgery. Outcome measures included IOP, number of glaucoma medications, best-corrected visual acuity (BCVA) and intra and postoperative complications. RESULTS: Mean age of subjects was 73.1 ± 6.3 years. Majority were ethnic Chinese (n = 27, 90%). Baseline medicated mean IOP was 13.8 ± 2.4 mmHg and mean number of glaucoma medications was 1.3 ± 0.7. Mean Humphrey visual field mean deviation was - 13.7 ± 7.6. The mean IOP reduction at all timepoints from postoperative month (POM) 3 onwards was statistically significant (all P < 0.05), with mean reduction of 1.2 mmHg (95% CI: 0.1-2.2, P = 0.037) by POM12. There was statistically significant reduction in mean number of medications from postoperative day (POD) 1 onwards (all P < 0.05), with mean decrease of 1.0 medication (95% CI: 0.9-1.1, P < 0.001) by POM12. By POM12, 25 (83.3%) eyes were medication-free. Three (10%) eyes had stent occlusion by iris requiring laser iridoplasty. One eye had gross hyphema which resolved on conservative management before POM1. Mean BCVA improved from the baseline 0.3 ± 0.3 logMAR to 0.1 ± 0.1 logMAR postoperatively (P < 0.001). There were no major adverse or sight-threatening events. No eyes required further glaucoma surgery during the 12-month follow-up period. CONCLUSION: Asian eyes with NTG which underwent combined iStent inject implantation and phacoemulsification demonstrated a significant and sustained reduction in IOP and glaucoma medications, up to 12 months postoperatively.

Salivary concentrations of IL-8 and IL-1ra after HIIT and MICT in young, healthy adults: A randomized exercise study.

The purpose of this study was to determine whether six weeks of high intensity interval training (HIIT) would lead to greater changes in resting concentrations of salivary IL-8 and IL-1ra than moderate intensity continuous training (MICT) in young, healthy adults, and to determine whether changes in IL-8 and IL-1ra after six weeks of either HIIT or MICT were associated with changes in maximal exercise capacity (VO2max). Participants were randomly assigned to 6 weeks of HIIT (n = 12) or MICT (n = 11), matched for workload. Saliva samples were collected at the beginning (T1) and end (T2) of the intervention, and analyzed for IL-8 and IL-1ra. Participants in both groups had significant improvements in VO2max; there were no group differences in improvements. A greater reduction in IL-8 was observed in the MICT group when compared to the HIIT group (HIIT median: -9.5; MICT median: -82.3 pg/µg of protein; U = 11.5, p < 0.001). When combining the HIIT and MICT group, there were significant reductions in IL-8 from T1 to T2. There was no correlation between changes in IL-8 (r < 0.00) or IL-1ra (r = -0.013) with changes in VO2max. In conclusion, 6 weeks of exercise training leads to a reduction in IL-8; MICT may lead to greater reductions when compared to HIIT. Future research examining longer intervention periods is needed to further elucidate the effects of HIIT and MICT on different pro and anti-inflammatory cytokines.

Earth's anomalous middle-age magmatism driven by plate slowdown.

The mid-Proterozoic or "boring billion" exhibited extremely stable environmental conditions, with little change in atmospheric oxygen levels, and mildly oxygenated shallow oceans. A limited number of passive margins with extremely long lifespans are observed from this time, suggesting that subdued tectonic activity-a plate slowdown-was the underlying reason for the environmental stability. However, the Proterozoic also has a unique magmatic and metamorphic record; massif-type anorthosites and anorogenic Rapakivi granites are largely confined to this period and the temperature/pressure (thermobaric ratio) of granulite facies metamorphism peaked at over 1500 °C/GPa during the Mesoproterozoic. Here, we develop a method of calculating plate velocities from the passive margin record, benchmarked against Phanerozoic tectonic velocities. We then extend this approach to geological observations from the Proterozoic, and provide the first quantitative constraints on Proterozoic plate velocities that substantiate the postulated slowdown. Using mantle evolution models, we calculate the consequences of this slowdown for mantle temperatures, magmatic regimes and metamorphic conditions in the crust. We show that higher mantle temperatures in the Proterozoic would have resulted in a larger proportion of intrusive magmatism, with mantle-derived melts emplaced at the Moho or into the lower crust, enabling the production of anorthosites and Rapakivi granites, and giving rise to extreme thermobaric ratios of crustal metamorphism when plate velocities were slowest.

Combined phacoemulsification and iStent inject implantation in Asian eyes.

PURPOSE: To evaluate the safety and efficacy of the iStent inject device combined with phacoemulsification in Asian eyes with primary open angle glaucoma. METHODS: A retrospective study of combined phacoemulsification and iStent inject surgeries performed in a single institution from July 2017 to August 2019 on patients with co-existing cataracts and primary open angle glaucoma (POAG). Outcome measures included best-corrected visual acuity, intraocular pressure (IOP), number of glaucoma eyedrop medications, and surgical complications. RESULTS: A total of 95 eyes were included. Majority of subjects were male (59, 62.1%) and Chinese (83, 87.4%). Mean age was 74.7 ± 8.7 years. Pre-operatively, mean IOP was 16.2 ± 4.3 mmHg and number of medications was 1.9 ± 0.9. Significant post-operative reduction in mean IOP was observed at all timepoints - post-operative month (POM)1: 3.0 ± 5.6 mmHg reduction (n = 95, p < 0.05); POM3: 1.6 ± 3.8 mmHg (n = 66, p < 0.05); POM6: 1.8 ± 4.7 mmHg (n = 55, p < 0.05); POM12: 1.3 ± 4.2 mmHg (n = 48) (p < 0.05). The number of glaucoma medications was also reduced from a mean of 1.9 ± 0.8 to 0.6 ± 1.0 at POM12 (p < 0.05). Intraoperatively, one case of malignant glaucoma occurred. Post operatively, implant obstruction by iris was observed in two eyes post-operatively requiring iridoplasty. One case of cystoid macular edema and one case of drop in visual acuity due to glaucoma progression was/were also observed. CONCLUSION: Asian eyes undergoing combined phacoemulsification and iStent inject surgery demonstrate a significant and sustained reduction in both IOP and number of glaucoma medications. Overall, there is a good safety profile for iStent inject.

Stress-related health depreciation: Using allostatic load to predict self-rated health.

Approximately one quarter of UK adults are currently diagnosed with two or more chronic conditions, often referred to as multimorbidity. Chronic stress has been implicated in the development of many diseases common to multimorbidity. Policymakers and clinicians have acknowledged the need for more preventative approaches to deal with the rise of multimorbidity and "early ageing". However divergence may occur between an individual's self-rated health and objectively measured health that may preclude preventative action. The use of biomarkers which look 'under the skin' provide crucial information on an individual's underlying health to facilitate lifestyle change or healthcare utilisation. The UK's Understanding Society dataset, was used to examine whether baseline variation in biomarkers measuring stress-related "wear and tear" - Allostatic Load (AL) - predict changes in future self-rated health (SRH) while adjusting for baseline SRH, socioeconomic and lifestyle factors, and healthcare inputs. An interaction between baseline AL and baseline SRH was included to test for differential rates of SRH change. We examined SRH using the SF6D instrument, measuring health-related-quality of life (HRQoL), as well as its physical and mental health components separately. We found that HRQoL and physical health decline faster for those with higher baseline AL (indicating greater "wear and tear") however the same pattern was not observed for mental health. These findings provide novel insights for clinicians and policymakers on the usefulness of AL in capturing health trajectories of which individual's may not be aware and its importance in targeting resilience enhancing measures earlier in the lifecourse to delay physical health decline.

Spatiotemporal patterns in the natural and anthropogenic additions to the soundscape in parts of the Salish Sea, British Columbia, 2018-2020.

Passive acoustic recorders were deployed over two years (February 2018-March 2020) in the Salish Sea to monitor the underwater soundscape. Seasonal cycles and differences between the open Strait of Juan de Fuca and protected inner waterways were pervasive during this period. A comparison between natural and human-derived noise demonstrated the impact of anthropogenic activities on the sound field. Elevated ambient noise levels during winter resulted predominantly from greater sea states and storm events. Abiotic additions were defined through correlations to wind speed, wave and precipitation measures. Vessel noise was a pervasive anthropogenic addition; commercial vessel noise was consistently present, whereas smaller vessels showed weekly and diurnal patterns, especially during the summer when their presence increased. A better understanding of the different soundscape constituents, and when each dominates, is crucial to understanding the human impact on underwater ecosystems and the organisms within them, leading to more effective mitigation measures.

COVID-19 pandemic - Inequities and inequalities to exercise and their consequences on the physical and mental health of women with cardiovascular disease: recommendations on how to address the needs of women.

The coronavirus disease (COVID-19) pandemic disproportionately affects those with pre-existing conditions and has exacerbated gender inequalities. Cardiovascular disease (CVD) is the leading cause of death among Canadian women. Exercise improves physical and mental health and CVD management. Amid the pandemic, women are experiencing an increase in caregiving responsibilities, job insecurities, and domestic violence creating competing demands for prioritizing their health. Recommendations on how to meet the unique needs of Canadian women with CVD through exercise are provided. Novelty: Exercise recommendations amid the pandemic for women with CVD need to be flexible, feasible, and fun.

A 25-year dynamic ecological analysis of psychiatric hospital admissions and prison committals: Penrose's hypothesis updated.

AIMS: There is renewed interest in the inverse association between psychiatric hospital and prison places, with reciprocal time trends shown in more than one country. We hypothesised that the numbers of admissions to psychiatric hospitals and committals to prisons in Ireland would also correlate inversely over time (i.e. dynamic measures of admission and committal rather than static, cross-sectional numbers of places). METHOD: Publicly available activity statistics for psychiatric hospitals and prisons in Ireland were collated from 1986 to 2010. RESULTS: There was a reciprocal association between psychiatric admissions and prison committals (Pearson r=-0.788, p<0.001), an increase of 91 prison committals for every 100 psychiatric hospital admissions foregone. CONCLUSION: Penrose's hypothesis applies to admissions to psychiatric hospitals and prisons in Ireland over time (dynamic measures), just as it does to the numbers of places in psychiatric hospitals and prisons in Ireland and elsewhere (static, cross-sectional measures). Although no causal connection can be definitively established yet, mentally disordered prisoners are usually known to community mental health services. Psychiatric services for prisons and the community should be linked to ensure that the needs of those currently accessing care through prisons can also be met in the community.

Organic osmolytes increase expression of specific tight junction proteins in skin and alter barrier function in keratinocytes.

BACKGROUND: The epidermal barrier is important for water conservation, failure of which is evident in dry-skin conditions. Barrier function is fulfilled by the stratum corneum, tight junctions (TJs, which control extracellular water) and keratinocyte mechanisms, such as organic osmolyte transport, which regulate intracellular water homeostasis. Organic osmolyte transport by keratinocytes is largely unexplored and nothing is known regarding how cellular and extracellular mechanisms of water conservation may interact. OBJECTIVES: We aimed to characterize osmolyte transporters in skin and keratinocytes, and, using transporter inhibitors, to investigate whether osmolytes can modify TJs. Such modification would suggest a possible link between intracellular and extracellular mechanisms of water regulation in skin. METHODS: Immunostaining and quantitative polymerase chain reaction of organic osmolyte-treated organ-cultured skin were used to identify changes to organic osmolyte transporters, and TJ protein and gene expression. TJ functional assays were performed on organic osmolyte-treated primary human keratinocytes in culture. RESULTS: Immunostaining demonstrated the expression of transporters for betaine, taurine and myo-inositol in transporter-specific patterns. Treatment of human skin with either betaine or taurine increased the expression of claudin-1, claudin-4 and occludin. Osmolyte transporter inhibition abolished this response. Betaine and taurine increased TJ function in primary human keratinocytes in vitro. CONCLUSIONS: Treatment of skin with organic osmolytes modulates TJ structure and function, which could contribute to the epidermal barrier. This emphasizes a role for organic osmolytes beyond the maintenance of intracellular osmolarity. This could be harnessed to enhance topical therapies for diseases characterized by skin barrier dysfunction.

Lacticaseibacillus rhamnosus GG inhibits infection of human keratinocytes by Staphylococcus aureus through mechanisms involving cell surface molecules and pH reduction.

Beneficial bacteria represent an emerging tool against topical diseases, including infection caused by Staphylococcus aureus. Here, we investigated several anti-pathogenic mechanisms of the model probiotic Lacticaseibacillus rhamnosus GG against a clinical S. aureus isolate by implementing various mutants lacking important cell surface molecules. We analysed adhesion of L. rhamnosus and competitive adhesion with S. aureus to primary human keratinocytes, L. rhamnosus and S. aureus auto- and co-aggregation, S. aureus growth inhibition, keratinocyte viability increase, and monocyte Toll-like receptor (TLR) activation by L. rhamnosus as such, or with S. aureus. L. rhamnosus mutated in SpaCBA pili exhibited reduced adhesion to keratinocytes, reduced ability to prevent S. aureus adhesion to keratinocytes and reduced co-aggregation with S. aureus. Mutants in cell wall exopolysaccharides showed enhanced adhesion to keratinocytes and TLR activation in monocytes, suggesting involvement of additional cell surface molecules masked by exopolysaccharides. All L. rhamnosus strains inhibited S. aureus growth, likely due to acidification of the medium. Live (but not UV-inactivated) L. rhamnosus significantly reduced inflammatory TLR activation in monocytes by S. aureus. These data suggest the key role of SpaCBA pili and additional contribution of other cell surface molecules as well as secreted components of L. rhamnosus GG in the multifactorial inhibition of S. aureus adhesion and toxicity in the skin niche.

Remote CB1 receptor antagonist administration reveals multiple sites of tonic and phasic endocannabinoid neuroendocrine regulation.

Endogenous cannabinoids (endocannabinoids, eCB) are expressed throughout the body and contribute to regulation of the hypothalamo-pituitary-adrenal (HPA) axis and general stress reactivity. This study assessed the contributions of CB1 receptors (CB1R) in the modulation of basal and stress-induced neural and HPA axis activities. Catheterized adult male rats were placed in chambers to acclimate overnight, with their catheters connected and exteriorized from the chambers for relatively stress-free remote injections. The next morning, the CB1R antagonist AM251 (1 or 2 mg/kg) or vehicle was administered, and 30 min later, rats were exposed to loud noise stress (30 min) or no noise (basal condition). Blood, brains, pituitary and adrenal glands were collected immediately after the procedures for analysis of c-fos and CB1R mRNAs, corticosterone (CORT) and adrenocorticotropin hormone (ACTH) plasma levels. Basally, CB1R antagonism induced c-fos mRNA in the basolateral amygdala (BLA) and auditory cortex (AUD) and elevated plasma CORT, indicating disruption of eCB-mediated constitutive inhibition of activity. CB1R blockade also potentiated stress-induced hormone levels and c-fos mRNA in several regions such as the bed nucleus of the stria terminalis (BST), lateral septum (LS), and basolateral amygdala (BLA) and the paraventricular nucleus of the hypothalamus (PVN). CB1R mRNA was detected in all central tissues investigated, and the adrenal cortex, but at very low levels in the anterior pituitary gland. Interestingly, CB1R mRNA was rapidly and bidirectionally regulated in response to stress and/or antagonist treatment in some regions. eCBs therefore modulate the HPA axis by regulating both constitutive and activity-dependent inhibition at multiple levels.

CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease).

The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating monogenetic lysosomal disorders that affect children and young adults with no cure or effective treatment currently available. One of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutations in the palmitoyl-protein thioesterase 1 (PPT1) gene and severely reduces the child's lifespan to approximately 9 years of age. In order to better translate the human condition than is possible in mice, we sought to produce a large animal model employing CRISPR/Cas9 gene editing technology. Three PPT1 homozygote sheep were generated by insertion of a disease-causing PPT1 (R151X) human mutation into the orthologous sheep locus. This resulted in a morphological, anatomical and biochemical disease phenotype that closely resembles the human condition. The homozygous sheep were found to have significantly reduced PPT1 enzyme activity and accumulate autofluorescent storage material, as is observed in CLN1 patients. Clinical signs included pronounced behavioral deficits as well as motor deficits and complete loss of vision, with a reduced lifespan of 17 ± 1 months at a humanely defined terminal endpoint. Magnetic resonance imaging (MRI) confirmed a significant decrease in motor cortical volume as well as increased ventricular volume corresponding with observed brain atrophy and a profound reduction in brain mass of 30% at necropsy, similar to alterations observed in human patients. In summary, we have generated the first CRISPR/Cas9 gene edited NCL model. This novel sheep model of CLN1 disease develops biochemical, gross morphological and in vivo brain alterations confirming the efficacy of the targeted modification and potential relevance to the human condition.

Straight-to-test for the two-week-wait colorectal cancer pathway under the updated NICE guidelines reduces time to cancer diagnosis and treatment.

INTRODUCTION: The 2015 National Institute for Health and Care Excellence guidelines widened the referral criteria for the two-week-wait pathway for suspected lower gastrointestinal cancer. We implemented a straight-to-test protocol to accommodate the anticipated increase in referrals. We evaluated the impact of these changes for relevant pathway metrics and clinical outcomes using a retrospective cohort study with historic controls. MATERIALS AND METHODS: We analysed data from all patients referred to a teaching hospital via the two-week-wait pathway for suspected lower gastrointestinal cancer under the previous guidelines between 1 March and 31 August 2015 compared with the same period in 2016, when the updated guidelines and straight-to-test protocol had been implemented. RESULTS: In the 2015 cohort, there were 64 cancer diagnoses from 664 referrals (9.6% pick-up) compared with 58 cancer diagnoses from 954 referrals in the 2016 cohort (6.1% pick-up). Our straight-to-test protocol reduced the median time to cancer diagnosis by 12.5 days (P < 0.001) and reduced the median time to cancer treatment by 7.5 days (P < 0.05) An increased proportion of non-colorectal cancers were diagnosed in 2016 compared with 2015, (37.9% vs 17.2%, P < 0.05) and more adenomas were removed in 2016 compared with 2015 (377 vs 193). DISCUSSION AND CONCLUSION: Our straight-to-test protocol has resulted in a reduction in times to cancer diagnosis and cancer treatment, despite an increase in the number of referrals. The new referral criteria have considerable resource implications, but their implementation did not result in an increase in the total number of cancers diagnosed.

Effects of chronic caffeine exposure during adolescence and subsequent acute caffeine challenge during adulthood on rat brain serotonergic systems.

Caffeine is the most commonly used drug in the world. However, animal studies suggest that chronic consumption of caffeine during adolescence can result in enhanced anxiety-like behavioral responses during adulthood. One mechanism through which chronic caffeine administration may influence subsequent anxiety-like responses is through actions on brainstem serotonergic systems. In order to explore potential effects of chronic caffeine consumption on brainstem serotonergic systems, we evaluated the effects of a 28-day exposure to chronic caffeine (0.3 g/L; postnatal day 28-56) or vehicle administration in the drinking water, followed by 24 h caffeine withdrawal, and subsequent challenge with caffeine (30 mg/kg; s.c.) or vehicle in adolescent male rats. In Experiment 1, acute caffeine challenge induced a widespread activation of serotonergic neurons throughout the dorsal raphe nucleus (DR); this effect was attenuated in rats that had been exposed to chronic caffeine consumption. In Experiment 2, acute caffeine administration profoundly decreased tph2 and slc22a3 mRNA expression throughout the DR, with no effects on htr1a or slc6a4 mRNA expression. Chronic caffeine exposure for four weeks during adolescence was sufficient to decrease tph2 mRNA expression in the DR measured 28 h after caffeine withdrawal. Chronic caffeine administration during adolescence did not impact the ability of acute caffeine to decrease tph2 or slc22a3 mRNA expression. Together, these data suggest that both chronic caffeine administration during adolescence and acute caffeine challenge during adulthood are important determinants of serotonergic function and serotonergic gene expression, effects that may contribute to chronic effects of caffeine on anxiety-like responses.

Asthma prevalence and control levels among Special Olympics athletes, and asthma-related knowledge of their coaches.

BACKGROUND: The prevalence of asthma among athletes with intellectual disabilities, and the asthma knowledge levels of their coaches, is unknown. METHODS: Special Olympics Canada athletes completed a demographic questionnaire (n = 208). Athletes who identified as having ever or current asthma completed the Asthma Control Questionnaire and the Mini Asthma Quality of Life Questionnaire and were measured for height, weight and lung function (n = 73). National level coaches (n = 27) completed a questionnaire pertaining to asthma knowledge. RESULTS: The prevalence of ever and current asthma were 35.5% (n = 73) and 21.1% (n = 44), respectively. Athletes with asthma reported that they had inadequately controlled asthma, but good quality of life. Coaches correctly answered 43% true/false questions on the survey, indicating suboptimal asthma knowledge. CONCLUSIONS: Athletes with intellectual disabilities appear to have a greater prevalence of asthma than the general population; however, coaches of these athletes appear to have limited knowledge pertaining to asthma and exercise-induced asthma.

A treatment algorithm for couples with unexplained infertility based on sperm chromatin assessment.

OBJECTIVE: To design a reproductive treatment algorithm based on the sperm DNA fragmentation (SDF) for couples with unexplained infertility following a poor intrauterine insemination (IUI) outcome. DESIGN: Couples that failed IUI with no apparent reproductive issue in both partners were allocated to diverse reproductive treatments on the basis of SDF. SETTING: Reproductive medical center in an academic setting. PATIENT(S): Over 4 years, couples with an unexpected poor IUI outcome and no apparent female or male partner reproductive issues were recruited. INTERVENTION(S): IUI, IVF, and ICSI were performed in the standard fashion following sperm SDF assays. MAIN OUTCOMES MEASURE(S): Fertilization rate, implantation rate, pregnancy characteristics, and delivery rates. RESULT(S): A total of 354 couples with unexplained infertility and normal semen parameters underwent 1133 IUI cycles. Clinical pregnancy rate (CPR) with IUI at our center in an age-matched cohort is 23.9% while the study cohort had 1.8%. Following SDF assessment, couples with failed IUI attempts but normal SDF (SCSA 9.8 ± 4.6%; TUNEL 11.8 ± 6.2%) underwent IVF with a CPR of 12.7%; those with abnormal SDF underwent ICSI with ejaculated spermatozoa, resulting in a CPR of 18.7%. This group included couples with normal SDF that had failed IVF. Couples with abnormal SDF that failed ICSI with ejaculated spermatozoa achieved a CPR of 31.0% with surgically retrieved spermatozoa. CONCLUSION(S): Couples with unexplained infertility that present with unexpectedly poor IUI outcomes can be funneled into a treatment algorithm guided by the integrity of the sperm genome for higher chances of pregnancy using an alternate method of insemination.

Cost-effectiveness of secukinumab as first biologic treatment, compared with other biologics, for moderate to severe psoriasis in Germany.

BACKGROUND: Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin 17A, has demonstrated strong and sustained efficacy in adults with moderate to severe psoriasis in clinical trials. OBJECTIVE: This analysis compared the cost per responder of secukinumab as first biologic treatment of moderate to severe psoriasis, with adalimumab, infliximab, etanercept and ustekinumab in Germany. METHODS: A 52-week decision-tree model was developed. Response to treatment was assessed based on the likelihood of achieving a predefined Psoriasis Area and Severity Index (PASI) response to separate the cohort into responders (PASI ≥75), partial responders (PASI 50 to 74) and non-responders (PASI <50). Responders at week 16 continued initial treatment, whereas partial responders and non-responders were switched to standard of care, which included methotrexate, cyclosporine, phototherapy and topical corticosteroids. Sustained response was defined as 16-week response maintained at week 52. A German healthcare system perspective was adopted. Clinical efficacy data were obtained from a mixed-treatment comparison; 2016 resource unit costs from national sources; and adverse events and discontinuation rates from the literature. We calculated cost per PASI 90 responder over week 16 and week 52, as well as cost per sustained responder between weeks 16 and 52. RESULTS: Secukinumab had the lowest cost per PASI 90 responder over 16 weeks (€18 026) compared with ustekinumab (€18 080), adalimumab (€23 499), infliximab (€29 599) and etanercept (€34 037). Over 52 weeks, costs per PASI 90 responder ranged from €42 409 (secukinumab) to €70 363 (etanercept). Likewise, secukinumab had the lowest cost per sustained 52-week PASI 90 responder (€22 690) compared with other biologic treatments. Sensitivity analyses, excluding patient copayments, showed similar results. CONCLUSIONS: First biologic treatment with secukinumab for moderate to severe psoriasis is cost-effective, with lowest cost per responder compared with other biologic treatments in Germany.