Economic burden of Huntington disease in Europe and the USA: Results from the Huntington's Disease Burden of Illness study.

BACKGROUND AND PURPOSE: The prevalence of Huntington disease (HD) has increased over time; however, there is a lack of up-to-date evidence documenting the economic burden of HD by disease stage. This study provides an estimate of the annual direct medical, nonmedical, and indirect costs associated with HD from participants in the Huntington's Disease Burden of Illness (HDBOI) study in five European countries and the USA. METHODS: The HDBOI is a retrospective, cross-sectional study. Data collection was conducted between September 2020 and May 2021. Participants were recruited by their HD-treating physicians and categorized as early stage (ES), mid stage (MS), or advanced stage (AS) HD. Data were collected via three questionnaires: a case report form, completed by physicians who collected health care resource use associated with HD to compute direct medical cost, and optional patient and caregiver questionnaires, which included information used to compute nondirect medical and indirect costs. Country-specific unit cost sources were used. RESULTS: HDBOI cost estimates were €12,663 (n = 2094) for direct medical costs, €2984 (n = 359) for nondirect medical costs, and €47,576 (n = 436) for indirect costs. Costs are higher in patients who are at later stages of disease; for example, direct medical costs estimates were €9220 (n = 846), €11,885 (n = 701), and €18,985 (n = 547) for ES, MS, and AS, respectively. Similar trends were observed for nondirect and indirect costs. Costs show large variations between patients and countries. CONCLUSIONS: Cost estimates from the HDBOI study show that people with HD and their caregivers bear a large economic burden that increases as disease progresses.

Multifilament Collagen Fiber Bundles with Tendon-like Structure and Mechanical Performance.

Collagen multifilament bundles comprised of thousands of monofilaments are prepared by multipin contact drawing of an entangled polymer solution consisting of collagen and poly(ethylene oxide) (PEO). The multifilament bundles are hydrated in graded concentrations of PEO and phosphate buffered saline (PBS) to promote assembly of collagen fibrils within each monofilament while preserving the structure of the multifilament bundle. Multiscale structural characterization reveals that the hydrated multifilament bundle contains properly folded collagen molecules packed in collagen fibrils containing microfibrils, staggered by exactly one-sixth of the microfibril D-band spacing to produce a periodicity of 11 nm. Sequence analysis predicts that in this structure, phenylalanine residues are close enough within and between microfibrils to become ultraviolet C (UVC) crosslinked. In agreement with this analysis, the ultimate tensile strength (UTS) and Young's modulus of the hydrated collagen multifilament bundles crosslinked by UVC radiation increase nonlinearly with total UVC energy to reach values in the range of native tendons without damage to the collagen molecules. This fabrication method recapitulates the structure of a tendon across multiple length scales and offers tunability in tensile properties using only collagen molecules and no other chemical additives in addition to PEO, which is almost entirely removed during the hydration process.

Personalising care for patients: implementing a treatment summary folder following cytoreductive surgery.

BACKGROUND: A patient survey highlighted that patients treated with cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) at one NHS trust lacked confidence with the transition of care between teams. A personalised folder of treatment information was designed and given to patients prior to discharge. AIMS: To obtain patient feedback on the implementation and content of the folder. METHODS: 30 consecutive patients were given the folder at discharge. Participants completed an online questionnaire to determine whether the information in the folder was appropriate, given at the right time in the pathway and enhanced confidence on discharge. FINDINGS: 90% response rate was achieved. Of the respondents, 96% strongly agreed/agreed that the folder was helpful, 4% disagreed; 92% strongly agreed/agreed that the amount of information was right, 8% preferred more information, none less; 74% agreed/strongly agreed that the folder was provided at the right time; 96% said that the content met their expectations. CONCLUSION: Patients treated with CRS and HIPEC have specific needs related to their treatment. Implementation of the patient information folder at discharge increases patient confidence.

Mentoring Medical Students Towards Oncology: Results from a Pilot Multi-institutional Mentorship Programme.

The mounting global cancer burden has generated an increasing demand for oncologists to join the workforce. Yet, students report limited oncology exposure in undergraduate medical curricula, while undergraduate oncology mentorships remain underutilised. We established an undergraduate oncology society-led mentorship programme aimed at medical students across several UK universities to increase medical student oncology exposure. We electronically recruited and paired oncologist mentors and medical student mentees and distributed a dedicated questionnaire (pre- and post-mentorship) to compare mentees' self-reported cancer specialty knowledge and oncology career motivation after undertaking a 6-week mentorship. We also determined students' interest across specialties and subspecialties and measured mentor availability via percentage programme uptake. Statistical analysis included univariate inferential tests on SPSS software. Twentynine (23.4%) of 124 oncology specialists agreed to become mentors. The mentorship was completed by 30 students across three medical schools: 16 (53.3%) Barts, 10 (33.3%) Birmingham, and 4 (13.3%) King's; 11 (36.7%) mentored by medical oncologists, 10 (33.3%) by clinical/radiation oncologists, and 9 (30%) by surgical oncologists. The mentorship generated a statically significant increase in students' knowledge of the multidisciplinary team and all oncology-related specialties including academia/research but not interest towards a career in oncology. Undergraduate oncology mentoring is an effective educational, networking and motivational tool for medical students. Student societies are a valuable asset in cultivating medical student oncology interest by connecting students to faculty and increasing mentor accessibility. Further research should focus on developing an optimal mentorship structure and evaluating long-term outcomes of such educational initiatives.

Impact of Treatment Delay on Outcome in the International Subarachnoid Aneurysm Trial.

Background and Purpose- ISAT (International Subarachnoid Aneurysm Trial) demonstrated that 1 year after aneurysmal subarachnoid hemorrhage, coiling resulted in a significantly better clinical outcome than clipping. After 5 years, this difference did not reach statistical significance, but mortality was still higher in the clipping group. Here, we present additional analyses, reporting outcome after excluding pretreatment deaths. Methods- Outcome measures were death with or without dependency at 1 and 5 years after treatment, after exclusion of all pretreatment deaths. Treatment differences were assessed using relative risks (RRs). With sensitivity and exploratory analyses, the relation between treatment delay and outcome was analyzed. Results- After exclusion of pretreatment deaths, at 1-year follow-up coiling was favorable over clipping for death or dependency (RR, 0.77 [95% CI, 0.67-0.89]) but not for death alone (RR, 0.88 [95% CI, 0.66-1.19]). After 5 years, no significant differences were observed, neither for death or dependency (RR, 0.88 [95% CI, 0.77-1.02]) nor for death alone (RR, 0.82 [95% CI, 0.64-1.05]). Sensitivity analyses showed a similar picture. In good-grade patients, coiling remained favorable over clipping in the long-term. Time between randomization and treatment was significantly longer in the clipping arm (mean 1.7 versus 1.1 days; P<0.0001), during which 17 patients died because of rebleeding versus 6 pretreatment deaths in the endovascular arm (RR, 2.81 [95% CI, 1.11-7.11]). Conclusions- These additional analyses support the conclusion of ISAT that at 1-year follow-up after aneurysmal subarachnoid hemorrhage coiling has a better outcome than clipping. After 5 years, with pretreatment mortality excluded, the difference between coiling and clipping is not significant. The high number of pretreatment deaths in the clipping group highlights the importance of urgent aneurysm treatment to prevent early rebleeding.

Association of suicidal behavior with exposure to suicide and suicide attempt: A systematic review and multilevel meta-analysis.

BACKGROUND: Exposure to suicidal behavior may be associated with increased risk of suicide, suicide attempt, and suicidal ideation and is a significant public health problem. However, evidence to date has not reliably distinguished between exposure to suicide versus suicide attempt, nor whether the risk differs across suicide-related outcomes, which have markedly different public health implications. Our aim therefore was to quantitatively assess the independent risk associated with exposure to suicide and suicide attempt on suicide, suicide attempt, and suicidal ideation outcomes and to identify moderators of this risk using multilevel meta-analysis. METHODS AND FINDINGS: We systematically searched MEDLINE, Embase, PsycINFO, CINAHL, ASSIA, Sociological Abstracts, IBSS, and Social Services Abstracts from inception to 19 November 2019. Eligible studies included comparative data on prior exposure to suicide, suicide attempt, or suicidal behavior (composite measure-suicide or suicide attempt) and the outcomes of suicide, suicide attempt, and suicidal ideation in relatives, friends, and acquaintances. Dichotomous events or odds ratios (ORs) of suicide, suicide attempt, and suicidal ideation were analyzed using multilevel meta-analyses to accommodate the non-independence of effect sizes. We assessed study quality using the National Heart, Lung, and Blood Institute quality assessment tool for observational studies. Thirty-four independent studies that presented 71 effect sizes (exposure to suicide: k = 42, from 22 independent studies; exposure to suicide attempt: k = 19, from 13 independent studies; exposure to suicidal behavior (composite): k = 10, from 5 independent studies) encompassing 13,923,029 individuals were eligible. Exposure to suicide was associated with increased odds of suicide (11 studies, N = 13,464,582; OR = 3.23, 95% CI = 2.32 to 4.51, P < 0.001) and suicide attempt (10 studies, N = 121,836; OR = 2.91, 95% CI = 2.01 to 4.23, P < 0.001). However, no evidence of an association was observed for suicidal ideation outcomes (2 studies, N = 43,354; OR = 1.85, 95% CI = 0.97 to 3.51, P = 0.06). Exposure to suicide attempt was associated with increased odds of suicide attempt (10 studies, N = 341,793; OR = 3.53, 95% CI = 2.63 to 4.73, P < 0.001), but not suicide death (3 studies, N = 723; OR = 1.64, 95% CI = 0.90 to 2.98, P = 0.11). By contrast, exposure to suicidal behavior (composite) was associated with increased odds of suicide (4 studies, N = 1,479; OR = 3.83, 95% CI = 2.38 to 6.17, P < 0.001) but not suicide attempt (1 study, N = 666; OR = 1.10, 95% CI = 0.69 to 1.76, P = 0.90), a finding that was inconsistent with the separate analyses of exposure to suicide and suicide attempt. Key limitations of this study include fair study quality and the possibility of unmeasured confounders influencing the findings. The review has been prospectively registered with PROSPERO (CRD42018104629). CONCLUSIONS: The findings of this systematic review and meta-analysis indicate that prior exposure to suicide and prior exposure to suicide attempt in the general population are associated with increased odds of subsequent suicidal behavior, but these exposures do not incur uniform risk across the full range of suicide-related outcomes. Therefore, future studies should refrain from combining these exposures into single composite measures of exposure to suicidal behavior. Finally, future studies should consider designing interventions that target suicide-related outcomes in those exposed to suicide and that include efforts to mitigate the adverse effects of exposure to suicide attempt on subsequent suicide attempt outcomes.

Commentary: Adolescent self-harm prevention and intervention in secondary schools: a survey of staff in England and Wales - a reflection on Evans et al. (2019).

Self-harm (SH) continues to be a worldwide concern among adolescents and there is a great need for programming aimed at reducing SH in adolescents. Evans and colleagues discuss the opinions of school staff from a representative sample of secondary schools across England and Wales regarding their school's current prevention and intervention practices in responding to self-harm and how this should be addressed in future practice. The most salient points include the high prevalence of SH internationally, the existing barriers to SH prevention and intervention and possible solutions to these barriers. There is clearly an urgent need for high quality, evidence-based interventions that can be embedded in school settings, and have the capacity to overcome both the individual and structural barriers to supporting these vulnerable young people.

Distinct gene expression program dynamics during erythropoiesis from human induced pluripotent stem cells compared with adult and cord blood progenitors.

BACKGROUND: Human-induced pluripotent stem cells (hiPSCs) are a potentially invaluable resource for regenerative medicine, including the in vitro manufacture of blood products. HiPSC-derived red blood cells are an attractive therapeutic option in hematology, yet exhibit unexplained proliferation and enucleation defects that presently preclude such applications. We hypothesised that substantial differential regulation of gene expression during erythroid development accounts for these important differences between hiPSC-derived cells and those from adult or cord-blood progenitors. We thus cultured erythroblasts from each source for transcriptomic analysis to investigate differential gene expression underlying these functional defects. RESULTS: Our high resolution transcriptional view of definitive erythropoiesis captures the regulation of genes relevant to cell-cycle control and confers statistical power to deploy novel bioinformatics methods. Whilst the dynamics of erythroid program elaboration from adult and cord blood progenitors were very similar, the emerging erythroid transcriptome in hiPSCs revealed radically different program elaboration compared to adult and cord blood cells. We explored the function of differentially expressed genes in hiPSC-specific clusters defined by our novel tunable clustering algorithms (SMART and Bi-CoPaM). HiPSCs show reduced expression of c-KIT and key erythroid transcription factors SOX6, MYB and BCL11A, strong HBZ-induction, and aberrant expression of genes involved in protein degradation, lysosomal clearance and cell-cycle regulation. CONCLUSIONS: Together, these data suggest that hiPSC-derived cells may be specified to a primitive erythroid fate, and implies that definitive specification may more accurately reflect adult development. We have therefore identified, for the first time, distinct gene expression dynamics during erythroblast differentiation from hiPSCs which may cause reduced proliferation and enucleation of hiPSC-derived erythroid cells. The data suggest several mechanistic defects which may partially explain the observed aberrant erythroid differentiation from hiPSCs.

The durability of endovascular coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the International Subarachnoid Aneurysm Trial (ISAT).

BACKGROUND: Previous analyses of the International Subarachnoid Aneurysm Trial (ISAT) cohort have reported on the risks of recurrent subarachnoid haemorrhage and death or dependency for a minimum of 5 years and up to a maximum of 14 years after treatment of a ruptured intracranial aneurysm with either neurosurgical clipping or endovascular coiling. At 1 year there was a 7% absolute and a 24% relative risk reduction of death and dependency in the coiling group compared with the clipping group, but the medium-term results showed the increased need for re-treatment of the target aneurysm in the patients given coiling. We report the long-term follow-up of patients in this UK cohort. METHODS: In ISAT, patients were randomly allocated to either neurosurgical clipping or endovascular coiling after a subarachnoid haemorrhage, assuming treatment equipoise, between Sept 12, 1994, and May 1, 2002. We followed up 1644 patients in 22 UK neurosurgical centres for death and clinical outcomes for 10·0-18·5 years. We assessed dependency as self-reported modified Rankin scale score obtained through yearly questionnaires. Data for recurrent aneurysms and rebleeding events were collected from questionnaires and from hospital and general practitioner records. The Office for National Statistics supplied data on deaths. This study is registered, number ISRCTN49866681. FINDINGS: At 10 years, 674 (83%) of 809 patients allocated endovascular coiling and 657 (79%) of 835 patients allocated neurosurgical clipping were alive (odds ratio [OR] 1·35, 95% CI 1·06-1·73). Of 1003 individuals who returned a questionnaire at 10 years, 435 (82%) patients treated with endovascular coiling and 370 (78%) patients treated with neurosurgical clipping were independent (modified Rankin scale score 0-2; OR 1·25; 95% CI 0·92-1·71). Patients in the endovascular treatment group were more likely to be alive and independent at 10 years than were patients in the neurosurgery group (OR 1·34, 95% CI 1·07-1·67). 33 patients had a recurrent subarachnoid haemorrhage more than 1 year after their initial haemorrhage (17 from the target aneurysm). INTERPRETATION: Although rates of increased dependency alone did not differ between groups, the probability of death or dependency was significantly greater in the neurosurgical group than in the endovascular group. Rebleeding was more likely after endovascular coiling than after neurosurgical clipping, but the risk was small and the probability of disability-free survival was significantly greater in the endovascular group than in the neurosurgical group at 10 years. FUNDING: UK Medical Research Council.

Correction: McKay et al. Parent Education for Responding to and Supporting Youth with Suicidal Thoughts (PERSYST): An Evaluation of an Online Gatekeeper Training Program with Australian Parents. Int. J. Environ. Res. Public Health 2022, 19, 5025.

There was an error in the original publication [...].

Global gene expression analysis of human erythroid progenitors.

Understanding the pattern of gene expression during erythropoiesis is crucial for a synthesis of erythroid developmental biology. Here, we isolated 4 distinct populations at successive erythropoietin-dependent stages of erythropoiesis, including the terminal, pyknotic stage. The transcriptome was determined using Affymetrix arrays. First, we demonstrated the importance of using defined cell populations to identify lineage and temporally specific patterns of gene expression. Cells sorted by surface expression profile not only express significantly fewer genes than unsorted cells but also demonstrate significantly greater differences in the expression levels of particular genes between stages than unsorted cells. Second, using standard software, we identified more than 1000 transcripts not previously observed to be differentially expressed during erythroid maturation, 13 of which are highly significantly terminally regulated, including RFXAP and SMARCA4. Third, using matched filtering, we identified 12 transcripts not previously reported to be continuously up-regulated in maturing human primary erythroblasts. Finally, using transcription factor binding site analysis, we identified potential transcription factors that may regulate gene expression during terminal erythropoiesis. Our stringent lists of differentially regulated and continuously expressed transcripts containing many genes with undiscovered functions in erythroblasts are a resource for future functional studies of erythropoiesis. Our Human Erythroid Maturation database is available at https://cellline.molbiol.ox.ac.uk/eryth/index.html. [corrected].

Fabrication and Performance of Continuous 316 Stainless Steel Fibre-Reinforced 3D-Printed PLA Composites.

This study investigates the feasibility of 3D printing continuous stainless steel fibre-reinforced polymer composites. The printing study was carried out using 316L stainless steel fibre (SSF) bundles with an approximate diameter of 0.15 mm. This bundle was composed of 90 fibres with a 14 µm diameter. This fibre bundle was first coated with polylactic acid (PLA) in order to produce a polymer-coated continuous stainless steel filament, with diameters tailored in the range from 0.5 to 0.9 mm. These filaments were then used to print composite parts using the material extrusion (MEX) technique. The SSF's volume fraction (Vf) was controlled in the printed composite structures in the range from 4 to 30 Vf%. This was facilitated by incorporating a novel polymer pressure vent into the printer nozzle, which allowed the removal of excess polymer. This thus enabled the control of the metal fibre content within the printed composites as the print layer height was varied in the range from 0.22 to 0.48 mm. It was demonstrated that a lower layer height yielded a more homogeneous distribution of steel fibres within the PLA polymer matrix. The PLA-SSF composites were assessed to evaluate their mechanical performance, volume fraction, morphology and porosity. Composite porosities in the range of 2-21% were obtained. Mechanical testing demonstrated that the stainless steel composites exhibited a twofold increase in interlaminar shear strength (ILSS) and a fourfold increase in its tensile strength compared with the PLA-only polymer prints. When comparing the 4 and 30 Vf% composites, the latter exhibited a significant increase in both the tensile strength and modulus. The ILSS values obtained for the steel composites were up to 28.5 MPa, which is significantly higher than the approximately 13.8 MPa reported for glass fibre-reinforced PLA composites.

Cerecyte coil trial: angiographic outcomes of a prospective randomized trial comparing endovascular coiling of cerebral aneurysms with either cerecyte or bare platinum coils.

BACKGROUND AND PURPOSE: We report the primary outcome of the Cerecyte Coil Trial, a randomized trial to determine whether polymer-loaded Cerecyte coils compared with Micrus bare platinum coils improved the proportion of patients with angiographic occlusion of the aneurysm at 6 months when assessed by a core laboratory. The secondary objectives were to compare the clinical outcomes and retreatment rates in the 2 groups. METHODS: Five hundred patients between 18 and 70 years of age with a ruptured or unruptured target aneurysm were randomized to be treated with either Cerecyte or bare platinum coils in 23 centers worldwide. Two hundred forty-nine patients were assigned to Cerecyte coils and 251 to bare platinum coils. Analysis was by intention to treat. RESULTS: Four hundred ninety-four patients were eligible for analysis. Four hundred eighty-one patients underwent coil treatment of their aneurysm, 227 patients with recently ruptured aneurysms and 254 with unruptured aneurysms. Four hundred thirty-three follow-up angiograms were assessed by the core laboratory; 127 of 215 (59%) and 118 of 218 (54%) in the Cerecyte and bare platinum groups, respectively, fulfilled the trial prespecified definition of success, namely that the treated aneurysm showed complete angiographic occlusion, had stable neck remnant, or improved in angiographic appearance compared with the end-of-treatment angiogram (P=0.17). Late retreatment was performed in 25 of 452 (5.5%) patients, 17 (7.7%) Cerecyte versus 8 (3.5%) bare platinum (P=0.064; range, 4-34 months). The clinical outcomes did not differ between the groups. CONCLUSIONS: There was no significant difference at 6 months in the angiographic outcomes between Cerecyte coils and bare platinum coils when assessed by the core laboratory. Clinical Trial Registration Information- URL: www.controlled-trials.com. Unique Identifier: ISRCTN82461286.

Parent Education for Responding to and Supporting Youth with Suicidal Thoughts (PERSYST): An Evaluation of an Online Gatekeeper Training Program with Australian Parents.

The gatekeeper training of parents is a promising approach for suicide prevention in young people, but little research has addressed the effectiveness of such training, especially using online delivery. This study aimed to evaluate the efficacy and acceptability of the delivery of an online suicide prevention training program, LivingWorks Start, to improve the capacity of parents to support young people at risk of suicide. The participants were 127 parents of young people aged 12-25 who completed the LivingWorks Start training and consented to participate in the evaluation. The participants completed online surveys before, after, and 3 months after training. The participants showed increases in perceived self-efficacy and formal help-seeking intentions, and reductions in suicide stigma, although stigma returned to the baseline three months post-training. Suicide literacy also increased, but only at the three-month follow-up. Most parents found the training acceptable, and did not find it upsetting. Prior mental health, suicide-related experiences, and pre-participation vulnerability were not predictive of finding the training distressing. Overall, the findings show that online gatekeeper training for parents can be beneficial, and is rarely associated with distress.

Morbidity and mortality associated with gastrointestinal dysfunction in neuromuscular disease: a single-centre case series.

Gastrointestinal dysfunction in neuromuscular disease is associated with significant morbidity and mortality. It is often underreported despite its prevalence in this cohort. There are a number of issues reported, with gastrointestinal dysmotility and intestinal pseudo-obstruction carrying a poor outcome. We present a case-series of six patients attending a single-centre specialist muscle clinic with a confirmed diagnosis of a neuromuscular disorder (Duchenne muscular dystrophy, mitochondrial disorders, and desmin-related myopathy) and problematic gastrointestinal dysfunction. We advocate prompt recognition and early management, as part of the multi-disciplinary team, to prevent clinical deterioration.

Exploring provider attitudes and perspectives related to men's health in cystic fibrosis.

BACKGROUND: New modulator therapies have markedly improved the health of people with cystic fibrosis (CF), allowing an increased focus on quality-of-life improvements for men with CF, including those related to sexual and reproductive health (SRH). This study explored CF providers' attitudes and experiences with addressing men's health in CF. METHODS: We interviewed geographically diverse adult and pediatric United States (U.S.) CF program directors via semi-structured telephone interviews exploring their perspectives and practices related to men's SRH in CF. Two coders analyzed transcribed interviews and created a codebook to identify key themes. RESULTS: We interviewed 20 providers and identified the following themes: 1) Men's SRH is important to address within CF care, but there is no standardization around this aspect of care; 2) There is no consensus about the recommendation or utilization of semen analysis to assess men's infertility; 3) There are many barriers to men's SRH care provision in CF centers, including the low priority of SRH concerns and provider discomfort and lack of expertise in SRH; 4) Providers desire clear evidence-based guidelines and patient resources related to men's SRH in CF; and 5) Providers believe future research should focus on testosterone and the impact of modulators on men's SRH. CONCLUSIONS: CF center directors acknowledge the importance of addressing SRH with men with CF, but there is a lack of standardization and research in this aspect of care. Existing barriers to optimal SRH care and identified facilitators in this study can serve as targets for interventions in the CF care model.

Men's sexual and reproductive health in cystic fibrosis in the era of highly effective modulator therapies-A qualitative study.

BACKGROUND: As people with cystic fibrosis (CF) are living longer, men with CF increasingly face both general and disease-specific sexual and reproductive health (SRH) concerns. This study explored the SRH experiences and preferences of men with CF in health care in the era of widespread use of highly effective CF modulator therapies. METHODS: We recruited men with CF aged 18 years and older to participate in a qualitative descriptive study using semi-structured telephone interviews to explore experiences and preferences related to CF SRH care. Two independent researchers coded interview transcripts and conducted content and thematic analysis using an inductive approach. FINDINGS: We interviewed 24 participants (mean age 33.7 ± 11.8 years, range 19-60) and identified five major themes: 1) CF SRH concerns, specifically infertility, can have negative impacts on men's perceptions of masculinity, relationships, and mental health; 2) As life expectancy increases, addressing male SRH is increasingly important in CF care; 3) Men with CF experience lack of SRH counseling and care; 4) Conversations about SRH should begin in early adolescence and be addressed regularly by CF providers in a stepwise fashion; 5) Men with CF value peer support and SRH information featuring the experiences of other men with CF. CONCLUSIONS: Men with CF acknowledge the need for comprehensive CF care that includes SRH and value early, stepwise, provider-initiated SRH conversations. Future work should seek a broader understanding of the impact of SRH on the mental health of men with CF as these concerns can have significant effects on the lives and self-identities of men with CF.

Metalation calculators for E. coli strain JM109 (DE3): aerobic, anaerobic, and hydrogen peroxide exposed cells cultured in LB media.

Three Web-based calculators, and three analogous spreadsheets, have been generated that predict in vivo metal occupancies of proteins based on known metal affinities. The calculations exploit estimates of the availabilities of the labile buffered pools of different metals inside a cell. Here, metal availabilities have been estimated for a strain of Escherichia coli that is commonly used in molecular biology and biochemistry research, e.g. in the production of recombinant proteins. Metal availabilities have been examined for cells grown in Luria-Bertani (LB) medium aerobically, anaerobically, and in response to H2O2 by monitoring the abundance of a selected set of metal-responsive transcripts by quantitative polymerase chain reaction (qPCR). The selected genes are regulated by DNA-binding metal sensors that have been thermodynamically characterized in related bacterial cells enabling gene expression to be read out as a function of intracellular metal availabilities expressed as free energies for forming metal complexes. The calculators compare these values with the free energies for forming complexes with the protein of interest, derived from metal affinities, to estimate how effectively the protein can compete with exchangeable binding sites in the intracellular milieu. The calculators then inter-compete the different metals, limiting total occupancy of the site to a maximum stoichiometry of 1, to output percentage occupancies with each metal. In addition to making these new and conditional calculators available, an original purpose of this article was to provide a tutorial that discusses constraints of this approach and presents ways in which such calculators might be exploited in basic and applied research, and in next-generation manufacturing.

Augmented currents of an HCN2 variant in patients with febrile seizure syndromes.

The genetic architecture of common epilepsies is largely unknown. HCNs are excellent epilepsy candidate genes because of their fundamental neurophysiological roles. Screening in subjects with febrile seizures and genetic epilepsy with febrile seizures plus revealed that 2.4% carried a common triple proline deletion (delPPP) in HCN2 that was seen in only 0.2% of blood bank controls. Currents generated by mutant HCN2 channels were approximately 35% larger than those of controls; an effect revealed using automated electrophysiology and an appropriately powered sample size. This is the first association of HCN2 and familial epilepsy, demonstrating gain of function of HCN2 current as a potential contributor to polygenic epilepsy.

Iron overload in the Asian community.

Hereditary hemochromatosis is an iron overload disorder that can lead to the impairment of multiple organs and is caused by mutations in one or more different genes. Type 1 hemochromatosis is the most common form of the disease and results from mutations in the HFE gene. Juvenile hemochromatosis (JH) is the most severe form, usually caused by mutations in hemojuvelin (HJV) or hepcidin (HAMP). The autosomal dominant form of the disease, type 4, is due to mutations in the SLC40A1 gene, which encodes for ferroportin (FPN). Hereditary hemochromatosis is commonly found in populations of European origin. By contrast, hemochromatosis in Asia is rare and less well understood and can be masked by the presence of iron deficiency and secondary iron overload from thalassemia. Here, we provide a comprehensive report of hemochromatosis in a group of patients of Asian origin. We have identified novel mutations in HJV, HAMP, and SLC40A1 in countries not normally associated with hereditary hemochromatosis (Pakistan, Bangladesh, Sri Lanka, and Thailand). Our family studies show a high degree of consanguinity, highlighting the increased risk of iron overload in many countries of the developing world and in countries in which there are large immigrant populations from these regions.