Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone.

OBJECTIVE: Most families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence-based recommendations for their integration into practice. METHODS: In total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research-led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required. RESULTS: Integration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for <4% (6 out of 152) of diagnoses while 36.2% of solved families (55 out of 152) harbored at least one splice-altering or structural variant in a known neuromuscular disorder gene. We posit that contemporary neuromuscular disorder gene-panel sequencing could likely provide 66% (100 out of 152) of our diagnoses today. INTERPRETATION: Our results emphasize thorough clinical phenotyping to enable deep scrutiny of all rare genetic variation in phenotypically consistent genes. Post-exome auxiliary investigations extended our diagnostic yield by 81% overall (34-62%). We present a diagnostic algorithm that details deployment of genomic and auxiliary investigations to obtain these diagnoses today most effectively. We hope this provides a practical guide for clinicians as they gain greater access to clinical genome and transcriptome sequencing.

Social care planning and provision for people with young onset dementia and their families: Protocol for the DYNAMIC study.

BACKGROUND: Social care is vital to quality of life for people with young onset dementia and their families. Yet care is hugely variable, frequently lacking and poorly coordinated. We aim to establish current practice in English social care for people with young onset dementia and co-produce evidence-based recommendations and resources for improvement. METHODS AND ANALYSIS: In Work-Package 1, we will gather qualitative data from 25 people with young onset dementia and/or main supporters residing in England. We will ask them about their experiences of social care (broadly defined, including independent and voluntary sector provision) and suggestions for improvement. In Work-Package 2, we will conduct a short on-line survey with a wide range of staff with a role in adult social care in England. We will find out about current awareness, knowledge and practice and suggestions for improvements. Quantitative and qualitative analysis will provide a picture of current practice. In Work-Package 3, we will use convergence analysis to synthesise the findings from Work-Packages 1 and 2 and present the findings to a stakeholder workshop, to identify feasible priorities for improvement. We will establish what is already known about good practice relating to these key priorities using a scoping review and interviews with professionals. This knowledge will then feed into the co-production of resources and recommendations with key stakeholders to improve social care for people with young onset dementia and their families. DISCUSSION: This study seeks to address a gap in our understanding of social care provision for people with young onset dementia and develop recommendations and practical resources for improvements. The findings will help people with young onset dementia and supporters to receive higher quality social care. TRIAL REGISTRATION: Study registration number: ISRCTN10653250.

A qualitative analysis of free-text patient satisfaction responses in Care Response, a database of patient-reported outcome and experience measures.

BACKGROUND: Databases have become important tools in improving health care. Care Response is a database containing information on tens of thousands of chiropractic patients internationally. It has been collecting patient-reported outcomes and patient satisfaction information for more than 10 years. The purpose of this study was to contribute to the understanding of patient perceptions and priorities for chiropractic care by analysing free text entered into the patient reported experience measure (PREM) questionnaires within the Care Response system. METHODS: There were two questions of interest on the PREM for this study. One requested information about "good points" patients perceived about patients' care experience, and the other requested information on "improvements" that could make the experience better. We conducted a word frequency analysis using a word counting macro in Microsoft Word, then used those results as a starting point for a qualitative analysis. Data were collected on 30 May 2022. RESULTS: The people who participated in the Care Response system often reported positive experiences with their chiropractors, including that they had reduced pain, improved function, and felt validated in their clinical condition. In addition, they appreciated having diagnostic and treatment procedures explained to them. They valued friendly, professional, and on-time service. The negative experiences were the opposite: being rushed through treatment, that the treatment was not worth the cost, or that they weren't treated professionally, empathetically, or with respect for them as individuals. The most important themes that emerged under "good points" were satisfaction (with care), value (as a person), safety, comfort, and professionalism. Their opposites, dissatisfaction, lack of value, lack of safety, lack of comfort, and lack of professionalism emerged as the most important themes under "improvements". We report some nuances of patient experience that have not previously been explored in the literature. CONCLUSIONS: Respondents seemed to value effective care provided in a safe, professional, friendly, and aesthetically pleasing environment. Chiropractors should note these priorities and engage with patients according to them. Education institutions should consider how good practice in these areas might be incorporated into curricula.

A Relational Approach to the Drivers of Child Acute Malnutrition.

BACKGROUND: This article presents a new analytical approach to acute malnutrition causal analysis that is different from the orthodox approach in 2 respects. First, it engages with basic causes, that is, beyond the usual focus on individuals and households. Second, it uses a relational view in the causal analysis. The orthodox approach identifies the malnourished and their individual and household characteristics. In contrast, a relational approach explores the ways in which the relationships between people, their livelihoods, and the environment, mediated by systems and institutions, create the underlying drivers associated with acute malnutrition for some, while simultaneously creating better conditions for others. METHODS: The article draws on 2 case study communities in West Darfur, Sudan, first considering the Darfur context and the inequitable policies and weakened institutions that have led to ethnic polarization, multilayered conflict, and humanitarian crises. The article explores how this context has played out differently in each community, contrasting their livelihood specializations, conflict-related losses, and livelihood diversification over time. FINDINGS: This analysis shows how the relative vulnerability of some people versus others is strongly influenced by their social, economic, and political relationships, as reflected in their shifting power relations and uneven control over livelihood resources. CONCLUSIONS: Shifting the focus to the basic drivers, especially the institutional structures, processes, and relationships, will deepen the causal analysis of child acute malnutrition, make it more meaningful, and provide a new direction for engagement, learning, and action to address the deepening problem of child acute malnutrition.

Plain language titleA Relational Approach to the Drivers of Acute MalnutritionPlain language summaryThis article introduces a new approach to understanding the causes of child acute malnutrition that differs from the traditional methods in 2 key ways. First, it goes beyond focusing solely on individuals and households by examining the underlying and basic causes. Secondly, it adopts a relational perspective in analyzing the causes. The traditional approach to studying the causes of acute malnutrition identifies malnourished individuals and examines their personal and household characteristics. In contrast, the relational approach looks at how the connections between people, their livelihoods, and the environment, influenced by systems and institutions, contribute to the development of acute malnutrition while also creating better conditions for some others. To illustrate this approach, the article presents findings from 2 communities in West Darfur, Sudan. It examines the Darfur context, including the policy and institutional context that has contributed to ethnic polarization and multiple conflicts and led to humanitarian crises. The article compares these 2 communities, focusing on their livelihood specializations, losses related to conflict, and changes in livelihood strategies over time. The article argues that by concentrating on the basic drivers of acute malnutrition, particularly the institutional structures, processes, and relationships, we can gain a deeper understanding of the issue. This approach can make the analysis of child acute malnutrition more meaningful and provide new insights for addressing this pressing problem.

Seasonality of Acute Malnutrition in African Drylands: Evidence From 15 Years of SMART Surveys.

Reduction of wasting, or low weight-for-height, is a critical target for the Zero Hunger Sustainable Development Goal, yet robust evidence establishing continuous seasonal patterns of wasting is presently lacking. The current consensus of greatest hunger during the preharvest period is based on survey designs and analytical methods, which discretize time frame into preharvest/postharvest, dry/wet, or lean/plenty seasons. We present a spatiotemporally nuanced study of acute malnutrition seasonality in African drylands using a 15-year data set of Standardized Monitoring and Assessment of Relief and Transition surveys (n = 412,370). Climatological similarity was ensured by selecting subnational survey regions with 1 rainy season and by spatially matching each survey to aridity and livelihood zones. Harmonic logit regression models indicate 2 peaks of wasting during the calendar year. Greatest wasting prevalence is estimated in April to May, coincident with the primary peak of temperature. A secondary peak of wasting is observed in August to October, coinciding with the primary peak of rainfall and secondary peak of temperature. This pattern is retained across aridity and livelihood zones and is sensitive to temperature, precipitation, and vegetation. Improved subnational estimation of acute malnutrition seasonality can thus assist decision makers and practitioners in data-sparse settings and facilitate global progress toward Zero Hunger.

Plain language titleFifteen Years of Rapid Assessment Surveys Indicate Seasonal Variability in Prevalence of Acute Malnutrition Among Children Younger Than 5 Years in African DrylandsPlain language summaryWasting or low weight-for-height is a key indicator of short-term or acute malnutrition. The timing of highest wasting prevalence, particularly among children younger than 5 years, is of interest for humanitarian efforts to reduce hunger. Current knowledge about this timing derives from survey designs, which discretize continuous time into preharvest/postharvest, dry/wet, or lean/plenty seasons. Instead of this categorical approach, we utilize harmonic regressions that allow for modeling of continuous time in our analysis of 15 years of Standardized Monitoring and Assessment of Relief and Transition surveys. Surveys conducted in parts of North Africa with 1 rainy season (unimodal regions) were selected for similar climate, and survey locations were further subdivided by aridity and livelihood zones. The seasonal pattern of extreme wasting prevalence in each group was modeled using survey data for a total of 412,370 children. We identified 2 periods of highest wasting prevalence in April to May and August to October. The April to May peak occurs during highest temperatures, and the August to October peak occurs during periods of highest rainfall and warmer temperatures in the study area. These findings can inform the timing of nutrition programs in unimodal dryland regions and guide future quantitative models of acute malnutrition seasonality.

The Complexity of the Seasonality of Nutritional Status: Two Annul Peaks in Child Wasting in Eastern Chad.

BACKGROUND: Understanding seasonal patterns in nutritional status is critical for achieving and tracking global nutrition goals. However, the majority of nutrition seasonality research design draws on 2 or 3 within-year time points based on existing assumptions of seasonality, missing a more nuanced pattern. OBJECTIVE: We aimed to identify the intra-year variability of childhood wasting, severe wasting, and weight-for-height z-scores (WHZ) in a dryland single wet-season context and illustrate an analytical approach for improving analysis of the seasonality of nutritional status. METHODS: To quantify the intra-year variability in nutritional status, we use data from a 23-month panel study (May 2018 to March 2020) following 231 children (6-59 months of age) in eastern Chad. We apply a mixed-effects harmonic regression with child- and village-level fixed effects on the odds of being wasted, severely wasted, and on WHZ, testing for multiple and nonsymmetrical seasonal peaks, adjusted for child sex and age. We triangulate our findings using climate data on temperature, vegetation, and precipitation. RESULTS: We identify 2 annual peaks of wasting and severe wasting. Wasting peaks at 14.7% (confidence interval [CI], 11.8-18.2) at the end of the dry season, while the smaller peak corresponds to the start of the harvest period at 13.4% (CI, 10.7-16.6). The odds of being wasted decline during the rainy season to 11.8% (CI, 9.4-14.7), with the lowest prevalence of 8.8% (CI, 6.9-11.1) occurring during the start of the dry season. In addition, a 1°C monthly increase in temperature is significantly associated with a 5% (CI, 1.4-8.7) and 12% (CI, 3.0-20.3) increase in the odds that a child is wasted and severely wasted, respectively. CONCLUSIONS: Intra-year variability of child wasting is far more complex and nuanced than identified by the literature, with 2 peaks, as opposed to 1, likely corresponding to different seasonal drivers, such as food insecurity, disease, water contamination, and care practices at different times of year. Better seasonality analysis can go a long way in improving the timing and content of programming with the goal of reducing child wasting.

Plain language titleTwo Seasonal Peaks of Acute Malnutrition in ChadPlain language summaryUnderstanding seasonal patterns in nutrition is crucial for achieving and monitoring global nutrition goals. However, most research on nutrition seasonality relies on only a few time points within a year, which oversimplifies the true pattern. In our study conducted in Chad, a dryland environment with a single rainy season, we examined various indicators of acute malnutrition, including severe acute malnutrition. We analyzed 23 months of data from 231 children aged 6 to 59 months, considering factors such as sex, age, monthly rainfall, temperature, and vegetation. Our findings revealed 2 peaks of acute malnutrition, challenging the prevailing notion of a single peak identified in existing literature. The first, larger peak occurred at the onset of the rainy season, followed by a decline and then a second peak just before the harvest period. This pattern aligned with temperature variations rather than rainfall. The complex and nuanced seasonal patterns we observed suggest that different factors such as food insecurity, disease, water contamination, and care practices may contribute to acute malnutrition at different times of the year. Improved analysis of seasonality can significantly enhance the timing and effectiveness of interventions aimed at reducing child wasting.

Inhibition of vascular endothelial growth factor-A downregulates angiogenesis in psoriasis: A pilot study.

Background: Vascular Endothelial Growth Factor (VEGF)-A-mediated angiogenesis participates in the pathogenesis of psoriasis, thus inviting the hypothesis that anti-VEGF-A therapy could be beneficial in psoriasis. While anti-angiogenic agents are used in oncology and ophthalmology, these therapeutic strategies remain unexplored for the management of psoriasis. Objective: Our objective was to investigate ex vivo how VEGF-A blockade impacts blood vessels, epidermis and immune cells in organ-cultured plaque and non-lesional skin from patients with psoriasis. Methods: Skin biopsies from patients with psoriasis (n = 6; plaque and non-lesional skin) and healthy controls (n = 6) were incubated with anti-VEGF-A monoclonal antibody (bevacizumab, Avastin®) or a human IgG1 isotype control for 72-h in serum-free organ culture. CD31/LYVE-1, Ki-67, and mast cell tryptase expression were assessed by quantitative immunohistomorphometry. VEGF-A levels in plasma, PBMCs and skin culture supernatants were measured. Results: Inhibition of VEGF-A blocked all free VEGF-A ex vivo, reduced blood vessel area and the number of blood vessel endothelial cells in plaques of psoriasis (*p < 0.05). The treatment effect correlated significantly with levels of VEGF-A in organ culture supernatants (r = 0.94; *p < 0.05) from plaque skin and with plasma levels of VEGF-A from patients with psoriasis (r = 0.943; *p = 0.017). Conclusions: These ex vivo data are the first studies to objectively investigate the potential of VEGF-A inhibition as a novel adjuvant treatment strategy for psoriasis. Taken together, our data encourage further investigation by clinical trial to explore whether downregulating pathological angiogenesis has clinical utility, especially in patients with severe psoriasis or those with elevated levels of VEGF-A in plasma and/or skin.

The use of liquid formulation pentoxifylline and vitamin E in both established and as a prophylaxis for dental extractions "at risk" of osteoradionecrosis.

BACKGROUND: Osteoradionecrosis (ORN) of the jaws remains one of the most debilitating complications of radiotherapy (RT) in patients with head and neck cancer (HNC). Liquid pentoxifylline and vitamin E (PVe) presents an alternative formulation to tablets for patients with dysphagia or enteric feeding. OBJECTIVE: This study aimed to assess the clinical outcomes of using a liquid formulation of PVe for both established ORN and as a prophylaxis to avoid its occurrence after dental extractions. A secondary objective was to determine patient-reported side effects in relation to the liquid formulation of PVe. STUDY DESIGN: The clinical records of 111 patients with HNC who were prescribed liquid PVe were reviewed retrospectively (66 with established ORN and 45 as prophylaxis before an invasive dental procedure). RESULTS: In established ORN, 44% healed, and 41% were stable. In the prophylaxis group, 96% of surgical sites healed completely, with 4% (n = 2) developing ORN. Most patients (89%) were able to tolerate liquid PVe. Of the 11% (n = 12) who could not tolerate this regime, the most commonly reported side effect was gastric irritation (n = 5/12), whereas no more than 1 patient reported dizziness, malaise, and bleeding. CONCLUSIONS: This retrospective review suggests that liquid PVe is efficacious for both established ORN and as a prophylaxis. Side effects reported were similar to those recognized for the tablet formulation.

Connective tissue presentation in two families expands the phenotypic spectrum of PYROXD1 disorders.

Recessive variants in the oxidoreductase PYROXD1 are reported to cause a myopathy in 22 affected individuals from 15 families. Here, we describe two female probands from unrelated families presenting with features of a congenital connective tissue disorder including osteopenia, blue sclera, soft skin, joint hypermobility and neuromuscular junction dysfunction in addition to known features of PYROXD1 myopathy including respiratory difficulties, weakness, hypotonia and oromotor dysfunction. Proband AII:1 is compound heterozygous for the recurrent PYROXD1 variant Chr12(GRCh38):g.21452130A>G;NM_024854.5:c.464A>G;p.(N155S) and Chr12(GRCh38):g.21462019_21462022del;NM_024854.5:c.892_895del;p.(V298Mfs*4) and proband BII:1 is compound heterozygous for Chr12(GRCh38):g.21468739-21468741del;NM_024854.5:c.1488_1490del;p.(E496del) and Chr12(GRCh38):g.21467619del;NM_024854.5:c.1254+1del. RNA studies demonstrate c.892_895del;p.(V298Mfs*4) is targeted by nonsense mediated decay and c.1254+1delG elicits in-frame skipping of exon-11. Western blot from cultured fibroblasts shows reduced PYROXD1 protein levels in both probands. Testing urine from BII:1 and six individuals with PYROXD1 myopathy showed elevated levels of deoxypyridinoline, a mature collagen crosslink, correlating with PYROXD1-disorder severity. Urine and serum amino acid testing of the same individuals revealed no reportable changes. In contrast to PYROXD1 knock-out, we find no evidence for disrupted tRNA ligase activity, as measured via XBP1 splicing, in fibroblasts expressing PYROXD1 variants. In summary, we expand the clinical spectrum of PYROXD1-related disorders to include an overlapping connective tissue and myopathy presentation, identify three novel, pathogenic PYROXD1 variants, and provide preliminary evidence that elevated urine DPD crosslinks may provide a clinical biomarker for PYROXD1 disorders. Our results advocate consideration of PYROXD1 variants in the differential diagnosis for undiagnosed individuals presenting with a connective tissue disorder and myopathy.

Cutaneous vascular structure and perfusion in patients with chronic plaque psoriasis.

BACKGROUND: Vascular dysfunction is a significant contributor to the pathophysiology of psoriasis. Some individuals have variation within the gene for vascular endothelial growth factor-A (VEGF-A), which confers an increased risk of developing psoriasis and having a severe disease phenotype, and may determine responsiveness to treatment. AIM: To determine whether patients with psoriasis have alterations in cutaneous microvascular anatomy and physiology due to expression of VEGF and whether laser Doppler imaging has utility in the assessment of this. METHODS: Twelve adult volunteers with Type 1 chronic plaque psoriasis underwent laser Doppler imaging of plaque and uninvolved skin. Skin biopsies were taken from the areas imaged for immunohistochemistry, including blood and lymphatic vessel markers, and VEGF-A isotype analysis (VEGF-A121, VEGF-A165 and VEGF-D). Venous blood was collected for DNA extraction, VEGF-A genotyping and peripheral blood mononuclear cell culture. RESULTS: Mean blood vessel area (P < 0·01), number of blood vessels (P < 0·001), number of lymphatic vessels (P < 0·001) and blood flow (P < 0·001) was significantly increased in psoriasis plaques, as was expression of VEGF-A121 (P < 0·01), VEGF-A165 (P < 0·04) and VEGF-D (P < 0·01). Blood flow within psoriasis plaques was independent of their increased vascularity (P < 0·01) and may be associated with baseline productivity of VEGF. The number of blood vessels within uninvolved skin in patients with psoriasis was associated with the VEGF-A (rs833061) genotype (P = 0·01), in a relationship suggesting an allele dosing effect. CONCLUSION: Noninvasive imaging of blood flow may help determine the cutaneous vascular signature for individual patients. This may be a useful prognostic indicator of psoriasis susceptibility and severity, and thus support selection of treatments.

Developing an aerobic exercise intervention for patients with psoriasis to support lifestyle behaviour change and improve health outcomes.

BACKGROUND: Patients with psoriasis do not exercise to the extent recommended for cardiovascular health, which may contribute to the increased risk of cardiovascular disease (CVD) and metabolic syndrome observed in this patient group. We previously identified that patients with psoriasis have significant disease-specific barriers to exercise. Others have reported that individuals with psoriasis develop higher heart rates and systolic blood pressure during bouts of exercise, followed by a slower recovery than healthy control subjects. AIMS: We hypothesized that a bespoke, evidenced-based, exercise programme could be developed for patients with psoriasis. METHODS: We convened a multidisciplinary Working Group comprising key stakeholders, including patients with psoriasis, along with sports scientists and clinicians, to develop the programme. RESULTS: To allow for different levels of fitness, lifestyle and motivation a 10-week intervention comprising two group walking sessions per week each of 1 h duration [led by a sports scientist (RS)] was designed using the Mapometer website. Walking distance was validated by a Walkmeter application, which uses global positioning system technology. The volume of exercise per session was calculated so that participants could incrementally progress to heart-healthy levels of exercise over the course of the programme. Maps of 20 unique walking routes were developed. A GENEactiv Original accelerometer and Newfeel Onwalk 900 pedometer were selected as wearable devices. CONCLUSION: We developed an exercise programme which specifically removed barriers to exercise for those with psoriasis, in partnership with patients. Regular exercise may offer significant health benefits for patients with psoriasis, including reduced CVD risk and increased psychosocial functioning, and this programme merits further investigation.

Offshore detention: cross-sectional analysis of the health of children and young people seeking asylum in Australia.

OBJECTIVE: To describe the health and well-being of children and young people (CYP) seeking asylum subjected to Australia's immigration policy of indefinite mandatory detention on Nauru. DESIGN: Cross-sectional analysis of a cohort of CYP seeking asylum. SETTING: Australian paediatric clinicians from 10 health services completed detailed health assessments around the time of transfer from Nauru, mostly to Australia. PARTICIPANTS: Sixty-two CYP who were ≤18 years on entry into offshore immigration detention on Nauru between 2013 and 2019. Mean age at health assessment was 9 years. MAIN MEASURES: Health outcomes were categorised as physical, mental or neurodevelopmental concerns/conditions. Risk and protective factor data were collected using the adverse childhood experiences and refugee-specific adverse childhood experiences tools. RESULTS: Over half of the CYP (n=32, 52%) were held on Nauru for ≥4 years. The vast majority of CYP had physical health (n=55, 89%) and mental health (n=49, 79%) concerns including self-harm or suicidal ideation/attempt (n=28, 45%). Mental health concerns were more likely in CYP who were school-aged (p=0.001), had been held on Nauru for ≥1 year (p=0.01); originated from the Eastern Mediterranean region (p<0.05); witnessed trauma (p<0.05) or had exposure to ≥4 refugee-specific adverse childhood experiences (p<0.05). Neurodevelopmental concerns were seen in eight children (13%). CONCLUSIONS: This study highlights the almost universal physical and mental health difficulties in a sample of CYP who experienced forced migration and were subjected to Australia's offshore immigration detention policy. Immigration detention in recipient countries, a known adverse childhood experience, may contribute to or exacerbate harmful outcomes in CYP seeking asylum.

Evaluation of ferritin and the ferritin index as prognostic biomarkers in septic shock.

BACKGROUND: Ferritin, an acute phase reactant, and the ferritin index (FI = observed ferritin level/upper limit of normal level for age and sex) may be prognostic biomarkers in septic shock and cardiac surgery patients. OBJECTIVE: The purpose of this exploratory study is to assess the outcome associations of ferritin and FI levels in septic shock compared to post-cardiac surgery patients. DESIGN: This was a prospective, double-centre, observational study. SETTING: The study setting involved two adult intensive care units (ICUs) in Victoria, Australia. PARTICIPANTS: Sixty-one septic shock and 30 post-cardiac surgery patients participated in this study. MAIN OUTCOME MEASURES: We measured ferritin and FI on ICU admission (T1) and 24 h later (T2) to assess its correlation with mortality, illness severity, and hospital length of stay (LOS). RESULTS: The baseline characteristics of patients in the septic shock group and cardiac surgery group were similar apart from illness severity scores (APACHE III and modified SOFA score). Septic shock patients had more physiological derangements as well as greater use and higher doses of norepinephrine at both T1 and T2. Septic shock patients had significantly higher median ferritin levels (372 µg/L versus 198 µg/L; p < 0.001 at T1, 457 µg/L versus 264 µg/L; p = 0.001 at T2) than post-cardiac surgery patients. Ferritin levels, however, did not have a linear correlation with illness severity or hospital mortality. Instead, there was an association between high ferritin levels at T2 and longer ICU (p = 0.017) and hospital LOS (p = 0.013). Females with septic shock had significantly higher FI (p < 0.001 at T1, p = 0.004 at T2) than males. CONCLUSION: In septic shock patients, ferritin levels and FI were twice the level compared to post-cardiac surgery patients. Both had no association with mortality, but levels above the median at 24 h were associated with longer ICU and hospital LOS.

The top 10 research priorities in psoriatic arthritis: a James Lind Alliance Priority Setting Partnership.

OBJECTIVES: To identify and prioritize the top 10 research questions for PsA. METHODS: The British Psoriatic Arthritis Consortium (BritPACT) formed a Priority Setting Partnership (PSP) comprising of people living with PsA, carers and clinicians, supported by the James Lind Alliance (JLA). This PSP followed the established three-stage JLA process: first, an online survey of people living with PsA, carers and clinicians to identify PsA questions, asking, 'What do you think are the most important unanswered questions in psoriatic arthritis research?' The questions were checked against existing evidence to establish 'true uncertainties' and grouped as 'indicative questions' reflecting the overarching themes. Then a second online survey ranked the 'true uncertainties' by importance. Finally, a workshop including people living with PsA and clinician stakeholders finalized the top 10 research priorities. RESULTS: The initial survey attracted 317 respondents (69% people living with PsA, 15% carers), with 988 questions. This generated 46 indicative questions. In the second survey, 422 respondents (78% people living with PsA, 4% carers) prioritized these. Eighteen questions were taken forward to the final online workshop. The top unanswered PsA research question was 'What is the best strategy for managing patients with psoriatic arthritis including non-drug and drug treatments?' Other top 10 priorities covered diagnosis, prognosis, outcome assessment, flares, comorbidities and other aspects of treatment (https://www.jla.nihr.ac.uk). CONCLUSION: The top 10 priorities will guide PsA research and enable PsA researchers and those who fund research to know the most important questions for people living with PsA.

Circadian rhythms in psoriasis and the potential of chronotherapy in psoriasis management.

The physiology and pathology of the skin are influenced by daily oscillations driven by a master clock located in the brain, and peripheral clocks in individual cells. The pathogenesis of psoriasis is circadian-rhythmic, with flares of disease and symptoms such as itch typically being worse in the evening/night-time. Patients with psoriasis have changes in circadian oscillations of blood pressure and heart rate, supporting wider circadian disruption. In addition, shift work, a circadian misalignment challenge, is associated with psoriasis. These features may be due to underlying circadian control of key effector elements known to be relevant in psoriasis such as cell cycle, proliferation, apoptosis and inflammation. Indeed, peripheral clock pathology may lead to hyperproliferation of keratinocytes in the basal layers, insufficient apoptosis of differentiating keratinocytes in psoriatic epidermis, dysregulation of skin-resident and migratory immune cells and modulation of angiogenesis through circadian oscillation of vascular endothelial growth factor A (VEGF-A) in epidermal keratinocytes. Chronotherapeutic effects of topical steroids and topical vitamin D analogues have been reported, suggesting that knowledge of circadian phase may improve the efficacy, and therapeutic index of treatments for psoriasis. In this viewpoint essay, we review the current literature on circadian disruption in psoriasis. We explore the hypothesis that psoriasis is circadian-driven. We also suggest that investigation of the circadian components specific to psoriasis and that the in vitro investigation of circadian regulation of psoriasis will contribute to the development of a novel chronotherapeutic treatment strategy for personalised psoriasis management. We also propose that circadian oscillations of VEGF-A offer an opportunity to enhance the efficacy and tolerability of a novel anti-VEGF-A therapeutic approach, through the timed delivery of anti-VEGF-A drugs.

Antivascular endothelial growth factor-A therapy: a novel personalized treatment approach for psoriasis.

Chronic plaque psoriasis is an inflammatory skin disease in which genetic predisposition along with environmental factors lead to the development of the disease, which affects 2% of the UK's population and is associated with extracutaneous morbidities and a reduced quality of life. A complex crosstalk between innate and adaptive immunity, the epithelia and the vasculature maintain the inflammatory milieu in psoriasis. Despite the development of promising treatment strategies, mostly targeting the immune system, treatments fail to fulfil every patient's goals. Vascular endothelial growth factor-A (VEGF-A) mediates angiogenesis and is upregulated in the plaques and plasma of patients with psoriasis. Transgenic expression of VEGF-A in experimental models led to the development of skin lesions that share many psoriasis features. Targeting VEGF-A in in vivo models of psoriasis-like inflammation resulted in disease clearance. Anti-angiogenesis treatments are widely used for cancer and eye disease and there are clinical reports of patients treated with VEGF-A inhibitors who have experienced Psoriasis Area and Severity Index improvement. Existing psoriasis treatments downregulate VEGF-A and angiogenesis as part of their therapeutic effect. Pharmacogenetics studies suggest the existence of different genetic signatures within patients with psoriasis that correspond with different treatment responsiveness and disease severity. There is a subset of patients with psoriasis with an increased predisposition to produce high levels of VEGF-A, who may be most likely to benefit from anti-VEGF-A therapy, offering an opportunity to personalize treatment in psoriasis. Anti-VEGF-A therapies may offer an alternative to existing anticytokine strategies or be complementary to standard treatments for the management of psoriasis.

How Seasonality of Malnutrition Is Measured and Analyzed.

Seasonality is a critical source of vulnerability across most human activities and natural processes, including the underlying and immediate drivers of acute malnutrition. However, while there is general agreement that acute malnutrition is highly variable within and across years, the evidence base is limited, resulting in an overreliance on assumptions of seasonal peaks. We review the design and analysis of 24 studies exploring the seasonality of nutrition outcomes in Africa's drylands, providing a summary of approaches and their advantages and disadvantages. Over half of the studies rely on two to four time points within the year and/or the inclusion of time as a categorical variable in the analysis. While such approaches simplify interpretation, they do not correspond to the climatic variability characteristic of drylands or the relationship between climatic variability and human activities. To better ground our understanding of the seasonality of acute malnutrition in a robust evidence base, we offer recommendations for study design and analysis, including drawing on participatory methods to identify community perceptions of seasonality, use of longitudinal data and panel analysis with approaches borrowed from the field of infectious diseases, and linking oscillations in nutrition data with climatic data.