High-resolution HLA genotyping in inclusion body myositis refines 8.1 ancestral haplotype association to DRB1*03:01:01 and highlights pathogenic role of arginine-74 of DRß1 chain.

OBJECTIVES: Inclusion body myositis (IBM) is a progressive inflammatory-degenerative muscle disease of older individuals, with some patients producing anti-cytosolic 5'-nucleotidase 1A (NT5C1A, aka cN1A) antibodies. Human Leukocyte Antigens (HLA) is the highest genetic risk factor for developing IBM. In this study, we aimed to further define the contribution of HLA alleles to IBM and the production of anti-cN1A antibodies. METHODS: We HLA haplotyped a Western Australian cohort of 113 Caucasian IBM patients and 112 ethnically matched controls using Illumina next-generation sequencing. Allele frequency analysis and amino acid alignments were performed using the Genentech/MiDAS bioinformatics package. Allele frequencies were compared using Fisher's exact test. Age at onset analysis was performed using the ggstatsplot package. All analysis was carried out in RStudio version 1.4.1717. RESULTS: Our findings validated the independent association of HLA-DRB1*03:01:01 with IBM and attributed the risk to an arginine residue in position 74 within the DRß1 protein. Conversely, DRB4*01:01:01 and DQA1*01:02:01 were found to have protective effects; the carriers of DRB1*03:01:01 that did not possess these alleles had a fourteenfold increased risk of developing IBM over the general Caucasian population. Furthermore, patients with the abovementioned genotype developed symptoms on average five years earlier than patients without. We did not find any HLA associations with anti-cN1A antibody production. CONCLUSIONS: High-resolution HLA sequencing more precisely characterised the alleles associated with IBM and defined a haplotype linked to earlier disease onset. Identification of the critical amino acid residue by advanced biostatistical analysis of immunogenetics data offers mechanistic insights and future directions into uncovering IBM aetiopathogenesis.

Sodalis praecaptivus subsp. spalangiae subsp. nov., a nascent bacterial endosymbiont isolated from the parasitoid wasp, Spalangia cameroni.

An endosymbiotic bacterium of the genus Sodalis, designated as strain HZT, was cultured from the parasitoid wasp Spalangia cameroni, which develops on the pupae of various host flies. The bacterium was detected in S. cameroni developed on houseflies, Musca domestica, in a poultry facility in Hazon, northern Israel. After culturing, this bacterium displayed no surface motility on Luria-Bertani agar and was rod-shaped and irregular in size, ~10-30 nm in diameter and 5-20 µm in length. Phylogenetic analyses revealed that strain HZT is closely related to Sodalis praecaptivus strain HST, a free-living species of the genus Sodalis that includes many insect endosymbionts. Although these bacteria maintain >98% sequence identity in shared genes, genomic characterization revealed that strain HZT has undergone substantial reductive evolution, such that it lacks many gene functions that are maintained in S. praecaptivus strain HST. Based on the results of phylogenetic, genomic and chemotaxonomic analyses, we propose that this endosymbiont should be classified in a new subspecies as S. praecaptivus subsp. spalangiae subsp. nov. The type strain for this new subspecies is HZT (=ATCC TSD-398T=NCIMB 15482T). The subspecies Sodalis praecaptivus subsp. praecaptivus strain HST is created automatically with the type strain ATCC BAA-2554T (=DSMZ 27494T).

Professional perspectives on applying the NICE and British Psychological Society Guidelines for the management of Behaviours that Challenge in dementia care: an e-survey.

OBJECTIVES: Behaviours that challenge (BtC) reflect the most costly and burdensome aspects of dementia where non-pharmacological interventions rather than antipsychotic medication have been recommended as first-line approaches for over a decade (NICE 2006). This paper outlines professionals' views about their application of the Dementia NICE Guideline 97 (2018) and a British Psychological Society, Division of Clinical Psychology (BPS-DCP) Briefing paper (2013) on alternatives to antipsychotics. METHODS: A mixed-methods 34-item e-survey, with five items about the use of the NICE Guideline 97 (2018) and the BPS-DCP Briefing paper (2013) for the management of BtC, was conducted. Participants were recruited through multidisciplinary professional dementia networks across the United Kingdom. Quantitative data were descriptively summarized and thematic analysis of open-ended questions undertaken. RESULTS: Two hundred and forty-seven participants completed the questions relating to guidelines. Mean ratings of 'moderately useful' for both the NICE and BPS-DCP guidance were obtained across professions and geographical locations, with the exception of psychiatrists who rated the NICE guidance as 'slightly useful'. The qualitative themes identified were a mix of positive and cautionary perspectives, relating to 'evidence base', the 'accessibility of the guides', 'problems with implementation', and 'lack of detail and clarity'. CONCLUSION: Professionals were cautiously positive regarding the guidance for BtC management, but highlighted a need for improved clarity about the use of non-pharmacological approaches, and more specificity about how these can be implemented in clinical settings. Tailored 'setting-specific' toolkits are required to update and refine the BPS-DCP (2013) if the aspirations of the NICE Dementia Guideline 97 (2018) are to inform professional practice. PRACTITIONER POINTS: Owing to major concerns about the problematic side effects of using psychotropics in the treatment of behaviours that challenge (BtC), there is a need for national guidance on the use on non-drug alternatives. The NICE (2018) guidance was seen by participants as accessible and clear but lacking in detail in the use of non-pharmacological interventions, which are the first-line treatments for BtC. The BPS Guidelines on 'Alternatives to antipsychotics' (2013) were seen as having good structured advice for allocating non-pharmacological resources but were lacking in flexibility for meeting individual needs or what might be an acceptable fit for clinical services. The findings suggest that we need to develop UK-wide bespoke specific advice for practitioners and services for both the use and the delivery of non-pharmacological evidence-based interventions for BtC.

The experiences of care home staff during the COVID-19 pandemic: A systematic review.

Objectives: To examine experiences of care home staff to better understand how to support them during the ongoing pandemic and in the future.Method: A systematic review examining experiences of care staff over the last year (March 2020-2021).Results: Fourteen papers related to experiences of staff and one was an intervention study. Quantitatively there was evidence of anxiety, PTSD and depression amongst the staff. Qualitatively, seven themes were identified: Poor working conditions; Lack of skills and knowledge; Psychological/Mental health concerns; Feeling undervalued and abandoned; Fears of contagion; Support and the positive impacts of COVID. The intervention study recommended employing needs-based approaches, including educational and wellbeing components.Conclusion: Recommendations are made in terms of how to work with staff, both practically and clinically. There are also suggestions about how to deal with similar situations if they were to reoccur. It is evident that lessons need to be learned because errors were made. Indeed, from a UK perspective, discharging thousands back to care homes, without testing, cost lives. This may have been done to protect the NHS, but it unwittingly 'lockdown' the virus within the care sector.

Reflections on a personalized cognitive rehabilitation intervention: Experiences of people living with dementia and their carers participating in the GREAT trial.

Cognitive rehabilitation for people living with early-stage dementia improves functional ability in areas targeted in the therapy, but little is known about how participants experience this intervention. This qualitative paper investigates participants' views about a cognitive rehabilitation intervention in a randomized controlled trial (the GREAT trial) and aims to help explain and interpret the findings and to inform further intervention development. Using in-depth thematic analysis, 43 semi-structured interviews (35 individual and 8 dyadic) were conducted with 25 people living with dementia and 26 family carers from three sites. The person-centred, individualized approach was valued. Some participants' views about dementia were questioned as a consequence of taking part in the therapy; they considered the effectiveness of the intervention in the context of the progressive nature of the condition. Certain participants continued to be doubtful, focussing on the inevitability of decline, rather than the possibility of reablement. Such views may have influenced engagement. The therapeutic relationship played a vital role as it was how personalized care was provided and participants' views had changed positively. Therapists engendered greater confidence and reduced anxiety and social isolation. Positive responses support personalized rehabilitative care to address the specific needs of people living with dementia.

Critical evaluation of stents in coronary angioplasty: a systematic review.

BACKGROUND: Coronary stents are routinely placed in the treatment and prophylaxis of coronary artery disease (CAD). Current coronary stent designs are prone to developing blockages: in-stent thrombosis (IST) and in-stent re-stenosis (ISR). This is a systematic review of the design of current coronary stent models, their structural properties and their modes of application, with a focus on their associated risks of IST and ISR. The primary aim of this review is to identify the best stent design features for reducing the risk of IST and ISR. To review the three major types of stents used in clinical settings today, determining best and relevant clinical practice by exploring which types and features of offer improved patient outcomes regarding coronary angioplasty. This information can potentially be used to increase the success rate of coronary angioplasty and stent technology in the future taking into account costs and benefits. METHODS: Scientific databases were searched to find studies concerning stents. After the exclusion criteria were applied, 19 of the 3192 searched literature were included in this review. Studies investigating three major types of stent design were found: bare-metal stents (BMS), drug-eluting stents (DES) and bioresorbable stents (BRS). The number of participants varied between 14 and 1264. On average 77.4% were male, with a mean age of 64 years. RESULTS: From the findings of these studies, it is clear that DES are superior in reducing the risk of ISR when compared to BMS. Conflicting results do not clarify whether BRS are superior to DES at reducing IST occurrence, although studies into newer BRS technologies show reducing events of IST to 0, creating a promising future for BRS showing them to be non-inferior. Thinner stents were shown to reduce IST rates, due to better re-endothelialisation. Scaffold material has also been shown to play a role with cobalt alloy stents reducing the risk of IST. This study found that thinner stents that release drugs were better at preventing re-blockages. Some dissolvable stents might be better at stopping blood clots blocking the arteries when compared to metal stents. The method and procedure of implanting the stent during coronary angioplasty influences success rate of these stents, meaning stent design is not the only significant factor to consider. CONCLUSIONS: Positive developments in coronary angioplasty could be made by designing new stents that encompass all the most desirable properties of existing stent technology. Further work is needed to investigate the benefits of BRS in reducing the risk of IST compared to DES, as well as to investigate the effects of different scaffold materials on IST and ISR outcomes.

Novel Vascular Anastomoses and Moyamoya Disease in a Woman with Down Syndrome.

A 56-year-old woman with Down syndrome presented with right-sided weakness and dysarthria, and was found on CT/CTA to have a left middle cerebral artery infarct secondary to moyamoya disease. Her left posterior inferior cerebellar artery (PICA) was fed both by the left vertebral artery, and the left ascending pharyngeal artery (APA), with a variant origin from the internal carotid artery (ICA), then passing through the jugular foramen (Figure 1). Her right PICA originated exclusively from her right occipital artery, also via the jugular foramen (Figure 2). The left vertebral artery originated directly from the aortic arch, whereas the right vertebral artery originated from the brachiocephalic trunk. In addition, she had a trifurcated anterior cerebral artery (ACA), and just prior to this trifurcation, her left ACA was partially supplied by the left ICA, via a superior hypophyseal artery. This case is noteworthy for several reasons. First, though it is exceedingly rare to have the PICA supplied by the jugular branch of the APA, this is the first reported case with an ICA origin of that APA.1,2 The fact that both PICAs in this patient originate from the anterior circulation should remind clinicians that in unexplained posterior circulation infarctions, vascular anatomy should be explored, as carotid-vertebrobasilar anastomoses such as these are rare, but possible. Lastly, the conjunction of moyamoya disease and anomalies of the vertebrobasilar system in a patient with Down syndrome raises interesting questions about the influence of trisomy 21 on the developing vasculature. Connections from the APA to the vertebrobasilar system are hypothesized to result from a lack of regression of an embryological anastomosis, in line with the more common persistent trigeminal and persistent hypoglossal arteries.1 Patients with moyamoya disease have a significantly higher rate of persistent carotid-vertebrobasilar anastomoses than the general population,3 and are also 26 times more likely to have Down syndrome.4 Correspondingly, patients with Down syndrome have significantly higher levels of moyamoya disease, and are more than 10 times as likely as the general population to have abnormalities of the Circle of Willis5 and vertebral arteries.6 Several genes on chromosome 21 are known to affect angiogenesis, namely collagen XIII/endostatin (COL18A1), DYRK1A, and Down syndrome candidate region 1 (DSCR1), possibly through inhibition of VEGF activity.7 Whether additional copies of these genes are responsible for the anomalous vascular development seen in Down syndrome, in turn predisposing to the development of moyamoya disease, could benefit from further exploration.

UK clinicians' views on the use of formulations for the management of BPSD: a multidisciplinary survey.

BACKGROUND AND OBJECTIVES: The process of formulating in the area of dementia care is at an early stage of development. A review published in 2016, identified 14 different types of formulation-based approaches for the management of Behavioural and Psychological Symptoms of Dementia (BPSD). The present study examines professionals' views about the use of systematic formulations for choosing first-line non-pharmacological interventions for BPSD. METHODS: A 34-item online survey, with six items about formulation-based interventions for the management of BPSD, was circulated to multi-disciplinary UK dementia networks. Quantitative data were examined for the use of formulation-based frameworks in practice. Thematic analyses provided insight into the practicalities of using formulations. RESULTS: The majority of the 355 participants responding to the questions stated they used formulation-led models to inform interventions, but 24% stated they did not. Thirty-two types of formulation frameworks were named, and there was a diverse spread across the UK. The Newcastle model was the most frequently used framework, with fifty percent of the participants who formulated reporting using this framework. Four themes regarding the use of formulation emerged, relating to function, process, reported outcomes and obstacles. CONCLUSION: Formulation-based approaches to targeting intervention are becoming popular in dementia care in the UK. More types of formulation frameworks are used in practice compared with the 2016 review. The use of formulations are seen as key to offering an alternative to pharmacological treatments. Understanding both the value of formulation-led approaches and the obstacles to their use are important to implementing NICE 2018 recommendations.

The use of therapeutic untruths by staff supporting people with an intellectual disability who display behaviours that challenge.

BACKGROUND: Therapeutic untruths (TU) are used in dementia services to de-escalate distressing situations. The present authors explored the use of TU by care staff supporting people with an intellectual disability who displayed behaviours that challenged. METHOD: Data were collected from 126 staff (female = 72.2%; mean age = 41.9 years, SD = 10.7) via an online survey in relation to three areas: responses to three scenarios, reported use of different forms of TU and ratings of perceived effectiveness of, and level of comfort using, each type. RESULTS: 96% of participants reported using TU themselves and observing their colleagues doing likewise. Models that included perceived effectiveness of, and level of staff comfort with using, different TU were significant, although only perceived effectiveness significantly independently contributed to the model. CONCLUSION: The use of TU was common, with levels consistent with those found in dementia services. The limitations and implications of the findings are discussed.

HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms.

BACKGROUND: Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell-mediated adverse drug reactions, which has led to preventive screening strategies for some drugs. OBJECTIVE: We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS. METHODS: Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele. RESULTS: Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10-8) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10-16). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01-positive group indicated that 19.2% had DRESS and did so within 4 weeks. CONCLUSIONS: HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.

The use of therapeutic untruths by learning disability nursing students.

BACKGROUND: The use of therapeutic untruths raises a number of ethical issues, which have begun to be explored to some extent, particularly in dementia care services, where their use has been found to be high. Little is known, however, about their use by health professionals working in learning disability services. RESEARCH QUESTION: The study aimed to explore the frequency of use of therapeutic untruths by student learning disability nurses, and by their colleagues; how effective the students perceived them to be as a means of responding to behaviours that challenge; and their level of comfort with using them. RESEARCH DESIGN: A correlational design was used to gather data from an online version of the Best Interest Scale, adapted for a learning disability context. Participants were 30 learning disability student nurses (female = 28, ages 18-48 years, M = 26.8, standard deviation = 7.3) studying at a university in the North-East of England. ETHICAL CONSIDERATIONS: The study was reviewed and received ethical approval from the first author's university ethics committee. FINDINGS: Overall, 96% of participants reported using therapeutic untruths. 'Omission' was the most frequently used type of therapeutic untruths, the most effective and the type that the students felt most comfortable using. Frequency of use of therapeutic untruths correlated significantly and positively with perceived effectiveness and the level of comfort that the students felt when using them, for all types of therapeutic untruths. CONCLUSION: The use of therapeutic untruths by the student nurses was consistent with that found in research in dementia care services in the United Kingdom and abroad. Further research to explore the generalisability of the results to the wider context of learning disability services is needed. The study highlights that there may be a need for more formal guidance and educational input to student nurses in the use of therapeutic untruths with people with a learning disability.

Individual goal-oriented cognitive rehabilitation to improve everyday functioning for people with early-stage dementia: A multicentre randomised controlled trial (the GREAT trial).

OBJECTIVES: To determine whether individual goal-oriented cognitive rehabilitation (CR) improves everyday functioning for people with mild-to-moderate dementia. DESIGN AND METHODS: Parallel group multicentre single-blind randomised controlled trial (RCT) comparing CR added to usual treatment (CR) with usual treatment alone (TAU) for people with an ICD-10 diagnosis of Alzheimer, vascular or mixed dementia, and mild-to-moderate cognitive impairment (Mini-Mental State Examination [MMSE] score ≥ 18), and with a family member willing to contribute. Participants allocated to CR received 10 weekly sessions over 3 months and four maintenance sessions over 6 months. Participants were followed up 3 and 9 months post randomisation by blinded researchers. The primary outcome was self-reported goal attainment at 3 months. Secondary outcomes at 3 and 9 months included informant-reported goal attainment, quality of life, mood, self-efficacy, and cognition and study partner stress and quality of life. RESULTS: We randomised (1:1) 475 people with dementia; 445 (CR = 281) were included in the intention to treat analysis at 3 months and 426 (CR = 208) at 9 months. At 3 months, there were statistically significant large positive effects for participant-rated goal attainment (d = 0.97; 95% CI, 0.75-1.19), corroborated by informant ratings (d = 1.11; 95% CI, 0.89-1.34). These effects were maintained at 9 months for both participant (d = 0.94; 95% CI, 0.71-1.17) and informant (d = 0.96; 95% CI, 0.73-1.2) ratings. The observed gains related to goals directly targeted in the therapy. There were no significant differences in secondary outcomes. CONCLUSIONS: CR enables people with early-stage dementia to improve their everyday functioning in relation to individual goals targeted in the therapy.

Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer.

Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. TRIAL REGISTRATION: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

Therapeutic Lies in Dementia Care: Should Psychologists Teach Others to be Person-Centred Liars?

BACKGROUND: Therapeutic lies are frequently used communication strategies, often employed when the person with dementia does not share the same reality as the carer (James and Jackman, 2017; Tuckett 2004; Blum, 1994). Their use is complex and controversial, and a number of protocols have been produced to guide their usage (Mental Health Foundation, 2016). AIMS: The study examined clinicians' perspective on using therapeutic lies in their daily practice and their roles in encouraging the proper use of such a communication strategy. METHOD: This project sampled the views of clinicians, mainly psychologists, before and after attending a workshop on communication in dementia care; they were asked whether psychologists should have a role in teaching others to lie more effectively. RESULTS: It was found that following a comprehensive discussion on the use of lies, the clinicians recognized they lied more than they had originally thought, and were also significantly more supportive of having a role in teaching others to lie effectively. CONCLUSIONS: Clinicians, mainly psychologists, increased their support in the use of therapeutic lying. They considered others would benefit from the psychologists giving supervision in how to lie effectively.

A process evaluation of a Psychomotor Dance Therapy Intervention (DANCIN) for behavior change in dementia: attitudes and beliefs of participating residents and staff.

BACKGROUND: In a previous paper, we presented results from a 12-week study of a Psychomotor DANCe Therapy INtervention (DANCIN) based on Danzón Latin Ballroom that involves motor, emotional-affective, and cognitive domains, using a multiple-baseline single-case design in three care homes. This paper reports the results of a complementary process evaluation to elicit the attitudes and beliefs of home care staff, participating residents, and family members with the aim of refining the content of DANCIN in dementia care. METHODS: An external researcher collected bespoke questionnaires from ten participating residents, 32 care home staff, and three participants' family members who provided impromptu feedback in one of the care homes. The Behavior Change Technique Taxonomy v1 (BCTTv1) provided a methodological tool for identifying active components of the DANCIN approach warranting further exploration, development, and implementation. RESULTS: Ten residents found DANCIN beneficial in terms of mood and socialization in the care home. Overall, 78% of the staff thought DANCIN led to improvements in residents' mood; 75% agreed that there were improvements in behavior; 56% reported increased job satisfaction; 78% of staff were enthusiastic about receiving further training. Based on participants' responses, four BCTTv1 labels-Social support (emotional), Focus on past success and verbal persuasion to boost self-efficacy, Restructuring the social environment and Habit formation-were identified to describe the intervention. Residents and staff recommended including additional musical genres and extending the session length. Discussions of implementing a supervision system to sustain DANCIN regularly regardless of management or staff turnover were suggested. CONCLUSIONS: Care home residents with mild to moderate dementia wanted to continue DANCIN as part of their routine care and staff and family members were largely supportive of this approach. This study argues in favor of further dissemination of DANCIN in care homes. We provide recommendations for the future development of DANCIN based on the views of key stakeholder groups.

HLA Class I and II alleles, heterozygosity and HLA-KIR interactions are associated with rates of genital HSV shedding and lesions.

Variation at HLA and KIR loci is associated with the severity of viral infections. To assess associations of genital HSV-2 infection with human HLA and KIR genetic loci, we measured the frequencies of genital herpes simplex virus (HSV) DNA detection and of genital lesions in HSV-2 seropositive persons. We followed 267 HSV-2 seropositive persons who collected daily genital swabs and recorded lesions for ⩾30 days. All persons were laboratory-documented as HIV-seronegative, and all were Caucasian by self-report. HSV detection rate and lesion frequency were compared by genotype using Poisson regression. Overall, HSV was detected on 19.1% of days and lesions on 11.6% of days. The presence of HLA-A*01 was directly associated with HSV detection frequency, whereas the presence of HLA-C*12 was inversely associated with HSV detection frequency. The presence of HLA-A*01 was directly associated with lesion rate, while HLA-A*26, -C*01 and -DQB1*0106 were associated with decreased lesions. We observed an interaction between the absence of both 2DS4del and HLA-Bw4 and higher lesion rate. Heterozygosity of HLA was also associated with reduced lesion frequency. Immune control of genital HSV infection relies on multiple interacting immunogenetic elements, including epistatic interactions between HLA and KIR.

HLA targeting efficiency correlates with human T-cell response magnitude and with mortality from influenza A infection.

Experimental and computational evidence suggests that HLAs preferentially bind conserved regions of viral proteins, a concept we term "targeting efficiency," and that this preference may provide improved clearance of infection in several viral systems. To test this hypothesis, T-cell responses to A/H1N1 (2009) were measured from peripheral blood mononuclear cells obtained from a household cohort study performed during the 2009-2010 influenza season. We found that HLA targeting efficiency scores significantly correlated with IFN-γ enzyme-linked immunosorbent spot responses (P = 0.042, multiple regression). A further population-based analysis found that the carriage frequencies of the alleles with the lowest targeting efficiencies, A*24, were associated with pH1N1 mortality (r = 0.37, P = 0.031) and are common in certain indigenous populations in which increased pH1N1 morbidity has been reported. HLA efficiency scores and HLA use are associated with CD8 T-cell magnitude in humans after influenza infection. The computational tools used in this study may be useful predictors of potential morbidity and identify immunologic differences of new variant influenza strains more accurately than evolutionary sequence comparisons. Population-based studies of the relative frequency of these alleles in severe vs. mild influenza cases might advance clinical practices for severe H1N1 infections among genetically susceptible populations.

First trimester screening cut-offs for noninvasive prenatal testing as a contingent screen: Balancing detection and screen-positive rates for trisomy 21.

OBJECTIVE: To provide data on how screen-positive and detection rates of first trimester prenatal screening for fetal Down syndrome vary with changes in the risk cut-off and maternal age to inform contingency criteria for publicly funded noninvasive prenatal testing. MATERIALS AND METHODS: First trimester screening and diagnostic data were collected for all women attending for first trimester fetal aneuploidy screening in Western Australia between 2005 and 2009. Prenatal screening and diagnostic data were linked to pregnancy outcomes, including data from the Midwives' Notification System and the Western Australian Registry of Developmental Anomalies. The prevalence of Down syndrome and performance of screening by risk cut-off and/or for women >35 years were analysed. RESULTS: The current screening risk cut-off of 1:300 has screen-positive and detection rates of 3.5% and 82%. The screen-positive rate increases by 0.7-0.8% for each 100 point change in risk, up to 19.2% at 1:2500 (96% detection rate). Including all women >35 years as screen positive would increase the screen-positive rate and detection rates to 30.2% and 97.2%. CONCLUSION: Variation in screening risk cut-off and the use of maternal age to assess eligibility for noninvasive testing could significantly impact the demand for, and cost of, the test. A contingent first trimester screening approach for risk assessment is superior to the use of a combination of screening and maternal age alone. These data will inform decisions regarding the criteria used to determine eligibility for publicly funded noninvasive prenatal testing.

Helicobacter pylori infection as a protective factor against multiple sclerosis risk in females.

BACKGROUND: In recent years, a relationship between Helicobacter pylori and many disease conditions has been reported, however, studies in its relationship with multiple sclerosis (MS) have had contradictory results. OBJECTIVE: To determine the association between the H. pylori infection and MS. METHODS: 550 patients with MS were included in the study and were matched by gender and year of birth to 299 controls. Patients were assessed for clinical and demographic parameters. An enzyme immunoassay was used to detect the presence of specific IgG antibodies against H. pylori in the serum sample of both groups. RESULTS: H. pylori seropositivity was found to be lower in the patients with MS than in controls (16% vs 21%) with the decrease pertaining to females (14% vs 22%, p=0.027) but not males (19% vs 20%, p=1.0). When adjusted for age at onset, year of birth and disease duration, H. pylori seropositive females presented with a lower disability score than seronegative females (p=0.049), while among males the reverse was true (p=0.025). There was no significant association between H. pylori seropositivity and relapse rate. CONCLUSIONS: Our results could reflect a protective role of H. pylori in the disease development. However, it may be that H. pylori infection is a surrogate marker for the 'hygiene hypothesis', a theory which postulates that early life infections are essential to prime the immune system and thus prevent allergic and autoimmune conditions later in life. The fact that the association between H. pylori seropositivity and MS risk was seen almost exclusively in females requires further investigation.