Immuno-informatics analysis predicts B and T cell consensus epitopes for designing peptide vaccine against SARS-CoV-2 with 99.82% global population coverage.

The current global pandemic due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has taken a substantial number of lives across the world. Although few vaccines have been rolled-out, a number of vaccine candidates are still under clinical trials at various pharmaceutical companies and laboratories around the world. Considering the intrinsic nature of viruses in mutating and evolving over time, persistent efforts are needed to develop better vaccine candidates. In this study, various immuno-informatics tools and bioinformatics databases were deployed to derive consensus B-cell and T-cell epitope sequences of SARS-CoV-2 spike glycoprotein. This approach has identified four potential epitopes which have the capability to initiate both antibody and cell-mediated immune responses, are non-allergenic and do not trigger autoimmunity. These peptide sequences were also evaluated to show 99.82% of global population coverage based on the genotypic frequencies of HLA binding alleles for both MHC class-I and class-II and are unique for SARS-CoV-2 isolated from human as a host species. Epitope number 2 alone had a global population coverage of 98.2%. Therefore, we further validated binding and interaction of its constituent T-cell epitopes with their corresponding HLA proteins using molecular docking and molecular dynamics simulation experiments, followed by binding free energy calculations with molecular mechanics Poisson-Boltzmann surface area, essential dynamics analysis and free energy landscape analysis. The immuno-informatics pipeline described and the candidate epitopes discovered herein could have significant impact upon efforts to develop globally effective SARS-CoV-2 vaccines.

A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.

LESSONS LEARNED: Despite strong preclinical rationale, combined cobimetinib-mediated MEK inhibition and GDC-0994-mediated ERK inhibition was not tolerable on two 28-day dosing schedules in which GDC-0994 was given for 21 days continuously and cobimetinib administered over 21 days either continuously or intermittently. Adverse events were as expected for mitogen-activated protein kinase pathway inhibition, but overlapping and cumulative toxicities could not be managed on either dosing schedule. Pharmacokinetic parameters of cobimetinib and GDC-0994 given in combination were similar to those previously observed in monotherapy studies, so that there was no evidence of drug-drug interaction. Cycle 1 metabolic responses were observed by 18F-fluorodeoxyglucose-positron emission tomography but were not predictive of outcome measured by RECIST 1.1. BACKGROUND: Simultaneous targeting of multiple nodes in the mitogen-activated protein kinase (MAPK) pathway offers the prospect of enhanced activity in RAS-RAF-mutant tumors. This phase Ib trial evaluated the combination of cobimetinib (MEK inhibitor) and GDC-0994 (ERK inhibitor) in patients with locally advanced or metastatic solid tumors. METHODS: Cobimetinib and GDC-0994 were administered orally on two separate dosing schedules. Arm A consisted of concurrent cobimetinib and GDC-0994 once daily for 21 days of a 28-day cycle; Arm B consisted of intermittent dosing of cobimetinib on a 28-day cycle concurrent with GDC-0994 daily for 21 days of a 28-day cycle. RESULTS: In total, 24 patients were enrolled. For Arm A, owing to cumulative grade 1-2 toxicity, the dose of cobimetinib was decreased. For Arm B, dose increases of GDC-0994 and cobimetinib were intolerable with grade 3 dose-limiting toxicities of myocardial infarction and rash. Pharmacokinetic data did not show evidence of a drug-drug interaction. Overall, seven patients had a best overall response of stable disease (SD) and one patient with pancreatic adenocarcinoma had an unconfirmed partial response. CONCLUSION: The safety profile of MEK and ERK inhibition demonstrated classic MAPK inhibitor-related adverse events (AEs). However, overlapping AEs and cumulative toxicity could not be adequately managed on either dosing schedule, restricting the ability to further develop this combination.

Absence of Pharmacokinetic Interactions between the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate.

Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of Bruton's tyrosine kinase being investigated for treatment of rheumatoid arthritis in patients with inadequate responses to methotrexate (MTX). This study interrogated the potential for pharmacokinetic drug interactions between fenebrutinib and MTX. Eighteen healthy male subjects were enrolled in the study. They received a single oral dose of MTX (7.5 mg) on day 1 followed by a 13-day washout period. Subsequently, on days 15-20 the participants received 200 mg of fenebrutinib twice daily. On day 21, they received a 7.5 mg dose of MTX and a 200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios of MTX area under the plasma concentration-time curve (AUC) and C max on day 21 relative to day 1 (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 1.05 (0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and C max for day 21 relative to day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02 (0.90-1.15), respectively. The combination treatment was well tolerated, with an adverse event profile similar to that reported in other MTX trials. These results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX.

Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies.

INTRODUCTION: In a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity. METHODS: LUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies. RESULTS: The median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose-response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed. CONCLUSIONS: These data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment. TRIAL REGISTRATION NUMBERS: The LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov.

Genomic, Proteomic, and Phenotypic Biomarkers of COVID-19 Severity: Protocol for a Retrospective Observational Study.

BACKGROUND: Health organizations and countries around the world have found it difficult to control the spread of COVID-19. To minimize the future impact on the UK National Health Service and improve patient care, there is a pressing need to identify individuals who are at a higher risk of being hospitalized because of severe COVID-19. Early targeted work was successful in identifying angiotensin-converting enzyme-2 receptors and type II transmembrane serine protease dependency as drivers of severe infection. Although a targeted approach highlights key pathways, a multiomics approach will provide a clearer and more comprehensive picture of severe COVID-19 etiology and progression. OBJECTIVE: The COVID-19 Response Study aims to carry out an integrated multiomics analysis to identify biomarkers in blood and saliva that could contribute to host susceptibility to SARS-CoV-2 and the development of severe COVID-19. METHODS: The COVID-19 Response Study aims to recruit 1000 people who recovered from SARS-CoV-2 infection in both community and hospital settings on the island of Ireland. This protocol describes the retrospective observational study component carried out in Northern Ireland (NI; Cohort A); the Republic of Ireland cohort will be described separately. For all NI participants (n=519), SARS-CoV-2 infection has been confirmed by reverse transcription-quantitative polymerase chain reaction. A prospective Cohort B of 40 patients is also being followed up at 1, 3, 6, and 12 months postinfection to assess longitudinal symptom frequency and immune response. Data will be sourced from whole blood, saliva samples, and clinical data from the electronic care records, the general health questionnaire, and a 12-item general health questionnaire mental health survey. Saliva and blood samples were processed to extract DNA and RNA before whole-genome sequencing, RNA sequencing, DNA methylation analysis, microbiome analysis, 16S ribosomal RNA gene sequencing, and proteomic analysis were performed on the plasma. Multiomics data will be combined with clinical data to produce sensitive and specific prognostic models for severity risk. RESULTS: An initial demographic and clinical profile of the NI Cohort A has been completed. A total of 249 hospitalized patients and 270 nonhospitalized patients were recruited, of whom 184 (64.3%) were female, and the mean age was 45.4 (SD 13) years. High levels of comorbidity were evident in the hospitalized cohort, with cardiovascular disease and metabolic and respiratory disorders being the most significant (P<.001), grouped according to the International Classification of Diseases 10 codes. CONCLUSIONS: This study will provide a comprehensive opportunity to study the mechanisms of COVID-19 severity in recontactable participants. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50733.

Pregnancy outcomes after maternal exposure to rituximab.

Rituximab is a chimeric anti-CD20 monoclonal B cell-depleting antibody indicated for certain hematologic malignancies and active rheumatoid arthritis with inadequate response to tumor necrosis factor antagonists. Despite counseling to avoid pregnancy, women may inadvertently become pregnant during or after rituximab treatment. Using the rituximab global drug safety database, we identified 231 pregnancies associated with maternal rituximab exposure. Maternal indications included lymphoma, autoimmune cytopenias, and other autoimmune diseases. Most cases were confounded by concomitant use of potentially teratogenic medications and severe underlying disease. Of 153 pregnancies with known outcomes, 90 resulted in live births. Twenty-two infants were born prematurely; with one neonatal death at 6 weeks. Eleven neonates had hematologic abnormalities; none had corresponding infections. Four neonatal infections were reported (fever, bronchiolitis, cytomegalovirus hepatitis, and chorioamnionitis). Two congenital malformations were identified: clubfoot in one twin, and cardiac malformation in a singleton birth. One maternal death from pre-existing autoimmune thrombocytopenia occurred. Although few congenital malformations or neonatal infections were seen among exposed neonates, women should continue to be counseled to avoid pregnancy for ≤ 12 months after rituximab exposure; however, inadvertent pregnancy does occasionally occur. Practitioners are encouraged to report complete information to regulatory authorities for all pregnancies with suspected or known exposure to rituximab.

The Mediating Roles of Mental Health and Substance Use on Suicidal Behavior Among Undergraduate Students With ADHD.

OBJECTIVE: To evaluate the prevalence of suicidal ideation (SI), plans and attempts, and non-suicidal self-injury (NSSI) among students with attention deficit hyperactivity disorder (ADHD). Furthermore, we explored the mediating effects of depression, anxiety, alcohol and substance use on the association between ADHD and suicidal behaviors and NSSI. METHOD: Participants were first-year undergraduate students (n = 1,829) recruited as part of the World Mental Health International College Student Initiative. Participants completed validated clinical measures online. RESULTS: The prevalence of suicide behaviors and NSSI were significantly higher among students with ADHD than those without. Mediation analyses indicated that ADHD directly and indirectly increased suicidal behaviors and NSSI. While ADHD increased suicidal behaviors and NSSI through depression, ADHD and the co-variates age and gender also had indirect effects on suicidal behaviors via substance use. CONCLUSIONS: Specific predictors of risk were identified for students with ADHD which may inform the development of more targeted mental health and suicide prevention strategies across campuses.

Suicidal behaviours and mental health disorders among students commencing college.

The increase in psychological disorders and suicidal behaviour in students is a reason for growing concern. Some may start university with pre-existing problems, while others develop problems during this time. It is important to evaluate mental health and wellbeing early, identifying those at risk. The aim of this study was to compare mental health problems and help-seeking behaviour between students in Northern Ireland (NI) and the Republic of Ireland (ROI). Whilst geographically proximate, the institutions span a cross-border region with distinct education and healthcare systems. First-year undergraduate students (n = 1828) were recruited in September 2019 as part of the World Mental Health International College Student Initiative. Suicidal behaviour, mental health and substance disorders were investigated using the World Mental Health- Composite International Diagnostic Interview. Prevalence of disorders was high, with more ROI students experiencing problems than NI students. Students were significantly more likely to experience mental health problems if they were female (p<0.001), non-heterosexual (p<0.0001), and over the age of 21 (p<0.0001). These findings show that many students are starting university with high levels of psychopathology and suicidal behaviour, highlighting the importance of early intervention which may need to be tailored to different student populations.

Variations in psychological disorders, suicidality, and help-seeking behaviour among college students from different academic disciplines.

BACKGROUND: Elevated levels of suicidality, ADHD, mental ill-health and substance disorders are reported among college students globally, yet few receive treatment. Some faculties and courses appear to have more at-risk students than others. The current study aimed to determine if students commencing college in different academic disciplines were at a heightened risk for psychopathology, substance use disorders and suicidal behaviour, and examined variations in help-seeking behaviour. MATERIALS AND METHODS: The study utilised data collected from 1,829 first-year undergraduate students as part of the Student Psychological Intervention Trial (SPIT) which commenced in September 2019 across four Ulster University campuses in Northern Ireland and an Institute of Technology, in the North-West of Ireland. The SPIT study is part of the World Mental Health International College Student Initiative (WMH-ICS) which uses the WMH-CIDI to identify 12-month and lifetime disorders. RESULTS: Students from Life and Health Sciences reported the lowest rates of a range of psychological problems in the year prior to commencing college, while participants studying Arts and Humanities displayed the highest levels (e.g. depression 20.6%; social anxiety 38.8%). However, within faculty variations were found. For example, psychology students reported high rates, while nursing students reported low rates. Variations in help seeking behaviour were also revealed, with male students less likely to seek help. CONCLUSIONS: Detecting specific cohorts at risk of psychological disorders and suicidality is challenging. This study revealed that some academic disciplines have more vulnerable students than others, with many reluctant to seek help for their problems. It is important for educators to be aware of such issues and for colleges to provide information and support to students at risk. Tailored interventions and prevention strategies may be beneficial to address the needs of students from different disciplines.

Variations in the oral microbiome are associated with depression in young adults.

A growing body of evidence supports an important role for alterations in the brain-gut-microbiome axis in the aetiology of depression and other psychiatric disorders. The potential role of the oral microbiome in mental health has received little attention, even though it is one of the most diverse microbiomes in the body and oral dysbiosis has been linked to systemic diseases with an underlying inflammatory aetiology. This study examines the structure and composition of the salivary microbiome for the first time in young adults who met the DSM-IV criteria for depression (n = 40) and matched controls (n = 43) using 16S rRNA gene-based next generation sequencing. Subtle but significant differences in alpha and beta diversity of the salivary microbiome were observed, with clear separation of depressed and healthy control cohorts into distinct clusters. A total of 21 bacterial taxa were found to be differentially abundant in the depressed cohort, including increased Neisseria spp. and Prevotella nigrescens, while 19 taxa had a decreased abundance. In this preliminary study we have shown that the composition of the oral microbiome is associated with depression in young adults. Further studies are now warranted, particuarly investigations into whether such shifts play any role in the underling aetiology of depression.

Depression, anxiety and suicidal behaviour among college students: Comparisons pre-COVID-19 and during the pandemic.

BACKGROUND: Many students struggle with psychological problems during their college years. These problems may be even more apparent during the COVID-19 pandemic with the accompanying restrictions and transition to an online learning environment, but few longitudinal studies have been conducted to date. The aim of this study was to compare symptoms of depression, anxiety and suicidality prior to and during the pandemic, and identify stressors. METHODS: This study was conducted among students attending Ulster University, Northern Ireland (NI) and LYIT, Republic of Ireland (ROI), as part of the World Mental Health International College Student Initiative (WMH-ICS). Data was collected from first year students in September 2019. The completed response rate was 25.22% (NI) and 41.9% (ROI) in relation to the number of first-year students registered. A follow up study was conducted in Autumn 2020, with 884 students fully completing the online survey in both years, equating to just under half of those who completed initially. RESULTS: High levels of mental health problems were found in year 1, especially in the ROI. Levels of depression increased significantly in year 2, particularly among students in NI, however, levels of anxiety decreased. No significant variations were found for suicidal behaviour. Several stressors were revealed, including increased social isolation, and worrying about loved ones. LIMITATIONS: The findings may not be generalised to other student populations. CONCLUSIONS: This study reveals variation in symptoms of depression and anxiety since the onset of the pandemic. In particular, the large increase in students with depression is of concern.

Phase I/II Trial of Vemurafenib in Dogs with Naturally Occurring, BRAF-mutated Urothelial Carcinoma.

BRAF-targeted therapies including vemurafenib (Zelboraf) induce dramatic cancer remission; however, drug resistance commonly emerges. The purpose was to characterize a naturally occurring canine cancer model harboring complex features of human cancer, to complement experimental models to improve BRAF-targeted therapy. A phase I/II clinical trial of vemurafenib was performed in pet dogs with naturally occurring invasive urothelial carcinoma (InvUC) harboring the canine homologue of human BRAF V600E The safety, MTD, pharmacokinetics, and antitumor activity were determined. Changes in signaling and immune gene expression were assessed by RNA sequencing and phosphoproteomic analyses of cystoscopic biopsies obtained before and during treatment, and at progression. The vemurafenib MTD was 37.5 mg/kg twice daily. Anorexia was the most common adverse event. At the MTD, partial remission occurred in 9 of 24 dogs (38%), with a median progression-free interval of 181 days (range, 53-608 days). In 18% of the dogs, new cutaneous squamous cell carcinoma and papillomas occurred, a known pharmacodynamic effect of vemurafenib in humans. Upregulation of genes in the classical and alternative MAPK-related pathways occurred in subsets of dogs at cancer progression. The most consistent transcriptomic changes were the increase in patterns of T lymphocyte infiltration during the first month of vemurafenib, and of immune failure accompanying cancer progression. In conclusion, the safety, antitumor activity, and cutaneous pharmacodynamic effects of vemurafenib, and the development of drug resistance in dogs closely mimic those reported in humans. This suggests BRAF-mutated canine InvUC offers an important complementary animal model to improve BRAF-targeted therapies in humans.

The epigenetics of sex differences in the brain.

Epigenetic changes in the nervous system are emerging as a critical component of enduring effects induced by early life experience, hormonal exposure, trauma and injury, or learning and memory. Sex differences in the brain are largely determined by steroid hormone exposure during a perinatal sensitive period that alters subsequent hormonal and nonhormonal responses throughout the lifespan. Steroid receptors are members of a nuclear receptor transcription factor superfamily and recruit multiple proteins that possess enzymatic activity relevant to epigenetic changes such as acetylation and methylation. Thus steroid hormones are uniquely poised to exert epigenetic effects on the developing nervous system to dictate adult sex differences in brain and behavior. Sex differences in the methylation pattern in the promoter of estrogen and progesterone receptor genes are evident in newborns and persist in adults but with a different pattern. Changes in response to injury and in methyl-binding proteins and steroid receptor coregulatory proteins are also reported. Many steroid-induced epigenetic changes are opportunistic and restricted to a single lifespan, but new evidence suggests endocrine-disrupting compounds can exert multigenerational effects. Similarly, maternal diet also induces transgenerational effects, but the impact is sex specific. The study of epigenetics of sex differences is in its earliest stages, with needed advances in understanding of the hormonal regulation of enzymes controlling acetylation and methylation, coregulatory proteins, transient versus stable DNA methylation patterns, and sex differences across the epigenome to fully understand sex differences in brain and behavior.

Methylome profiling of young adults with depression supports a link with immune response and psoriasis.

BACKGROUND: Currently the leading cause of global disability, clinical depression is a heterogeneous condition characterised by low mood, anhedonia and cognitive impairments. Its growing incidence among young people, often co-occurring with self-harm, is of particular concern. We recently reported very high rates of depression among first year university students in Northern Ireland, with over 25% meeting the clinical criteria, based on DSM IV. However, the causes of depression in such groups remain unclear, and diagnosis is hampered by a lack of biological markers. The aim of this exploratory study was to examine DNA methylation patterns in saliva samples from individuals with a history of depression and matched healthy controls. RESULTS: From our student subjects who showed evidence of a total lifetime major depressive event (MDE, n = 186) we identified a small but distinct subgroup (n = 30) with higher risk scores on the basis of co-occurrence of self-harm and attempted suicide. Factors conferring elevated risk included being female or non-heterosexual, and intrinsic factors such as emotional suppression and impulsiveness. Saliva samples were collected and a closely matched set of high-risk cases (n = 16) and healthy controls (n = 16) similar in age, gender and smoking status were compared. These showed substantial differences in DNA methylation marks across the genome, specifically in the late cornified envelope (LCE) gene cluster. Gene ontology analysis showed highly significant enrichment for immune response, and in particular genes associated with the inflammatory skin condition psoriasis, which we confirmed using a second bioinformatics approach. We then verified methylation gains at the LCE gene cluster at the epidermal differentiation complex and at MIR4520A/B in our cases in the laboratory, using pyrosequencing. Additionally, we found loss of methylation at the PSORSC13 locus on chromosome 6 by array and pyrosequencing, validating recent findings in brain tissue from people who had died by suicide. Finally, we could show that similar changes in immune gene methylation preceded the onset of depression in an independent cohort of adolescent females. CONCLUSIONS: Our data suggests an immune component to the aetiology of depression in at least a small subgroup of cases, consistent with the accumulating evidence supporting a relationship between inflammation and depression. Additionally, DNA methylation changes at key loci, detected in saliva, may represent a valuable tool for identifying at-risk subjects.

A First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors.

PURPOSE: ERK1/2 signaling can be dysregulated in cancer. GDC-0994 is an oral inhibitor of ERK1/2. A first-in-human, phase I dose escalation study of GDC-0994 was conducted in patients with locally advanced or metastatic solid tumors. PATIENTS AND METHODS: GDC-0994 was administered once daily on a 21-day on/7-day off schedule to evaluate safety, pharmacokinetics, and preliminary signs of efficacy. Patients with pancreatic adenocarcinoma and BRAF-mutant colorectal cancer were enrolled in the expansion stage. RESULTS: Forty-seven patients were enrolled in six successive cohorts (50-800 mg). A single DLT of grade 3 rash occurred at 600 mg. The most common drug-related adverse events (AE) were diarrhea, rash, nausea, fatigue, and vomiting. Pharmacokinetic data showed dose-proportional increases in exposure, with a mean half-life of 23 hours, supportive of once daily dosing. In evaluable paired biopsies, MAPK pathway inhibition ranged from 19% to 51%. Partial metabolic responses by FDG-PET were observed in 11 of 20 patients across dose levels in multiple tumor types. Overall, 15 of 45 (33%) patients had a best overall response of stable disease and 2 patients with BRAF-mutant colorectal cancer had a confirmed partial response. CONCLUSIONS: GDC-0994 had an acceptable safety profile and pharmacodynamic effects were observed by FDG-PET and in serial tumor biopsies. Single-agent activity was observed in 2 patients with BRAF-mutant colorectal cancer.

The effect of warm-up, static stretching and dynamic stretching on hamstring flexibility in previously injured subjects.

BACKGROUND: Warm-up and stretching are suggested to increase hamstring flexibility and reduce the risk of injury. This study examined the short-term effects of warm-up, static stretching and dynamic stretching on hamstring flexibility in individuals with previous hamstring injury and uninjured controls. METHODS: A randomised crossover study design, over 2 separate days. Hamstring flexibility was assessed using passive knee extension range of motion (PKE ROM). 18 previously injured individuals and 18 uninjured controls participated. On both days, four measurements of PKE ROM were recorded: (1) at baseline; (2) after warm-up; (3) after stretch (static or dynamic) and (4) after a 15-minute rest. Participants carried out both static and dynamic stretches, but on different days. Data were analysed using Anova. RESULTS: Across both groups, there was a significant main effect for time (p < 0.001). PKE ROM significantly increased with warm-up (p < 0.001). From warm-up, PKE ROM further increased with static stretching (p = 0.04) but significantly decreased after dynamic stretching (p = 0.013). The increased flexibility after warm-up and static stretching reduced significantly (p < 0.001) after 15 minutes of rest, but remained significantly greater than at baseline (p < 0.001). Between groups, there was no main effect for group (p = 0.462), with no difference in mean PKE ROM values at any individual stage of the protocol (p > 0.05). Using ANCOVA to adjust for the non-significant (p = 0.141) baseline difference between groups, the previously injured group demonstrated a greater response to warm-up and static stretching, however this was not statistically significant (p = 0.05). CONCLUSION: Warm-up significantly increased hamstring flexibility. Static stretching also increased hamstring flexibility, whereas dynamic did not, in agreement with previous findings on uninjured controls. The effect of warm-up and static stretching on flexibility was greater in those with reduced flexibility post-injury, but this did not reach statistical significance. Further prospective research is required to validate the hypothesis that increased flexibility improves outcomes. TRIAL REGISTRATION: ACTRN12608000638336.

A systematic review investigating if genetic or epigenetic markers are associated with postnatal depression.

BACKGROUND: Postnatal depression (PND) is common, affects the health of the mother, the development of the infant and places a large financial burden on services. Genetic and epigenetic biomarkers for PND could potentially improve the accuracy of current antenatal screening approaches. The aim of this systematic review is to report on the evidence for an association between genetic or epigenetic factors and postnatal depression. METHOD: A systematic search of five databases (Medline, EMBASE, PILOT, PsychINFO and SCOPUS) was carried out using the following (MeSh) terms and keywords: postpartum, depression, postnatal depression, genetics, genetic polymorphisms and epigenetics. Inclusion criteria were applied and quality of studies was assessed using guidelines from the HuGE Review Handbook (Little and Higgins, 2006). RESULTS: Following removal of duplicate articles, 543 remained; of these 37 met the inclusion criteria. Positive associations have been reported between PND and polymorphisms in the HMNC1, COMT, MAOT, PRKCB, ESR1, SLC6A4 genes in the presence of stressful life events, the BDNF gene when the postnatal period occurs during autumn and winter months and the OXT and OXTR genes in the presence of childhood adversity experienced by the mother. Epigenetic interactions with genotype, estrogen, and childhood adversity were identified that are predictive of PND. LIMITATIONS: The number of studies investigating some of the markers was small and grey literature was not included. CONCLUSION: This review highlights the importance of examining the interaction between epigenetic, genetic, hormonal and environmental factors in order to fully understand the risk factors for PND and to improve the accuracy of current antenatal and early postnatal screening procedures. Women susceptible to PND appear to have heightened epigenetic sensitivity to the physiological changes of childbirth or to environmental factors conferred by genotype.

Readiness to change and barriers to treatment seeking in college students with a mental disorder.

BACKGROUND: College students have high prevalence of mental disorders and suicidal thoughts and behaviours, and low rates of treatment uptake. This study assesses treatment access, intentions to seek help, and perceived barriers to help-seeking, considering gender and suicidal thoughts or behaviours (STBs) as predictors. METHODS: Data is from the Ulster University Student Wellbeing study (2015) conducted in Northern Ireland (NI), as part of the WHO World Mental Health Surveys International College Student Project. Participants are 392 new college entrants (162 males (41.3%)/230 females (58.7%)), who all reported some lifetime mental disorder or STBs. RESULTS: Receipt of treatment was low (37.8%), particularly among males and those with no STBs. Males were less likely to intend to access external professional services and were less likely than females to rate embarrassment (OR = 0.60) or worry about being treated differently (OR = 0.63) as important reasons for not seeking treatment. Those with STBs rated wanting to handle things on their own as a more important barrier those with no STBs (OR = 0.55 for non STBs group) and rated being unsure where to go as a less important barrier than those with no STBs (OR = 1.80 for non STBs group). LIMITATIONS: Data is correlational and concerns lifetime criteria for mental disorder, with no consideration of current mental status nor disorder type. CONCLUSIONS: These findings have implications for the active screening and intervention for vulnerable college students, particularly males and those with mental disorders but no STBs.

Coping, stress, and negative childhood experiences: The link to psychopathology, self-harm, and suicidal behavior.

Early life experiences, such as childhood adversities or poor parenting practices, can impact on the ability to cope with stressors across the lifespan. Furthermore, poor coping skills can lead to the development of mental illnesses, self-harm, and suicidal behavior. This study aimed to examine demographic differences in stress levels and to determine if those who had endured negative childhood experiences would be more likely to develop psychological problems and display suicidal behavior when current stress levels were accounted for. The study also explored the link between coping and mental health problems. Finally, it aimed to predict risk and protective factors related to good coping skills. The study utilized data obtained from the Ulster University Student Wellbeing Study, conducted across four university campuses in Northern Ireland in 2015 (n = 716) as part of the World Health Organization World Mental Health (WMH) International College Student Initiative. Mental health problems and early childhood experiences were examined using questions adapted from the WMH Composite International Diagnostic Interview, with self-harm and suicidal behavior measured using the Self-Injurious Thoughts and Behaviors Interview (SITBI). Females, non-heterosexuals, and older students experienced more current stress. When current stress levels were high, childhood adversities and parental overcontrol and overindulgence were related to higher rates of mental health problems, self-harm, and suicidal behavior. Poor coping skills were associated with negative mental health outcomes. Social support and good emotion-regulation strategies were related to effective coping, while parental overcontrol and overindulgence, female gender, and younger age were related to poorer coping. The study highlights the importance of developing good coping skills to deal with life stressors, thereby minimizing the risk of psychological problems and suicidal behavior. The findings provide support for initiatives to help parents improve their parenting skills and other programs to help young people cope with stress, and to develop social networks and adaptive emotion-regulation strategies.

Correction: First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL.

[This corrects the article DOI: 10.18632/oncotarget.24310.].