Challenges and opportunities for medical referrals at a mobile community health clinic serving sexual and gender minorities in rural South Carolina: a qualitative approach.

BACKGROUND: Sexual and gender minorities (SGM) in the Southern United States face challenges in accessing sexual and gender affirming health care. Alternative care models, like inclusive mobile clinics, help mitigate barriers to care for SGM. There is limited data in the literature on the experience of medical referral processes for SGM individuals accessing services from mobile health clinics. AIMS AND OBJECTIVES: The purpose of this study is to describe the medical referral experiences of SGM clients and their providers at a mobile health clinic in the Southern United States. METHODS: We recruited English-speaking individuals who provided care or received care from the mobile health clinic in South Carolina between June 2019 and August 2020. Participants completed a brief demographic survey and a virtual in-depth, semi-structured individual interview. Data analysis was conducted using an iterative process to generate codes, categories, and themes. Data collection and analysis were terminated once thematic saturation was achieved. RESULTS: The findings from this study indicated that the mobile health clinic had an inconsistent referral process that was largely dependent on providers' knowledge. Furthermore, clients and providers expressed individual barriers to the referral process, such as financial barriers, and opportunities to improve the referral process, such as an opt-in follow-up from the mobile clinic and increased mobile clinic resources. CONCLUSION: The findings in this study underscore the importance of having mobile clinics create a structured referral process that all medical providers are familiar with, and the value of hiring patient navigators that can support and refer clients to care that goes beyond the mobile health clinic setting.

Interventions to prevent or manage obesity in Maori and Pacific adults: a systematic review and narrative synthesis.

OBJECTIVES: Obesity and its sequelae are an increasing problem, disproportionally affecting Maori and Pacific peoples, secondary to multifactorial systemic causes, including the effects of colonisation and the impact of globalisation. There is limited synthesised evidence on interventions to address obesity in these populations. The objective of this review is to identify evaluated interventions for prevention and management of obesity amongst Maori and Pacific adults, assess the effectiveness of these interventions, and identify enablers and barriers to their uptake. DESIGN: Systematic review of databases (Medline, PubMed, EMBASE, CINAHL, Scopus, CENTRAL), key non-indexed journals, and reference lists of included articles were searched from inception to June 2021. Eligibility criteria defined using a Population, Intervention, Control, Outcome format and study/publication characteristics. Quantitative and qualitative data were extracted and analysed using narrative syntheses. Study quality was assessed using modified GRADE approach. RESULTS: From the 8190 articles identified, 21 were included, with 18 eligible for quantitative and five for qualitative analysis. The studies were heterogenous, with most graded as low quality. Some studies reported small but statistically significant improvements in weight and body mass index. Key enablers identified were social connection, making achievable sustainable lifestyle changes, culturally-centred interventions and incentives including money and enjoyment. Barriers to intervention uptake included difficulty in maintaining adherence to a programme due to intrinsic programme factors such as lack of social support and malfunctioning or lost equipment. CONCLUSIONS: Normal weight trajectory is progressive increase over time. Modest weight loss or no weight gain after several years may have a positive outcome in lowering progression to diabetes, or improvement of glycaemic control in people with diabetes. We recommend urgent implementation of Maori and Pacific-led, culturally-tailored weight loss programmes that promote holistic, small and sustainable lifestyle changes delivered in socially appropriate contexts.

Outpatient Opioid Dispensing Patterns for SC Medicaid Children 1-36 Months Old.

OBJECTIVES: We sought to identify the most common diagnostic categories linked to dispensed opioid prescriptions among children 1-36 months old and changes in patterns over the years 2000 to 2017. METHODS: This study used South Carolina's Medicaid claims data of pediatric dispensed outpatient opioid prescriptions between 2000 and 2017. The major opioid-related diagnostic category (indication) for each prescription was identified using visit primary diagnoses and the Clinical Classification System (AHRQ-CCS) software. The variables of interest were the rate of opioid prescriptions per 1,000 visits for each diagnostic category and the relative percentage of opioid prescriptions assigned to each category compared to all categories. RESULTS: Six major diagnostic categories were identified; Diseases of the respiratory system (RESP), Congenital anomalies (CONG), Injury (INJURY), Diseases of the nervous system and sense organs (NEURO), Diseases of the digestive system (GI), and Diseases of the genitourinary system (GU). The overall rate of dispensed opioid prescriptions per category declined significantly for four diagnostic categories throughout the study period, RESP by 15.13, INJURY by 8.49, NEURO by 7.33, and GI by 5.93. Two categories increased during the same time, CONG (by 9.47) and GU (by 6.98). RESP was the most prevalent category linked to a dispensed opioid prescription within 2010-2012 (almost 25%) but CONG was the most prevalent by 2014 (17.77%). CONCLUSIONS FOR PRACTICE: Among Medicaid children 1-36 months old, annual dispensed opioid prescription rates declined for most major diagnostic categories (RESP, INJURY, NEURO, and GI). Future studies should explore alternatives to current opioid dispensing practices for GU and CONG cases.

HIV Preexposure Prophylaxis Care Continuum Among Individuals Receiving Medication for Opioid Use Disorder, South Carolina, 2020-2021.

We implemented the HIV preexposure prophylaxis (PrEP) care continuum among individuals receiving medication for opioid use disorder (MOUD). We screened HIV-negative MOUD participants for PrEP eligibility by assessing injection drug use risk factors and sexual behaviors. Implementation of the PrEP care continuum was challenging; less than a third of MOUD participants were aware of PrEP, and very few initiated PrEP. Findings should promote the development of effective interventions to increase engagement in PrEP during MOUD treatment. (Am J Public Health. 2022;112(1):34-37. https://doi.org/10.2105/AJPH.2021.306566).

A-kinase-anchoring protein 1 (dAKAP1)-based signaling complexes coordinate local protein synthesis at the mitochondrial surface.

Compartmentalization of macromolecules is a ubiquitous molecular mechanism that drives numerous cellular functions. The appropriate organization of enzymes in space and time enables the precise transmission and integration of intracellular signals. Molecular scaffolds constrain signaling enzymes to influence the regional modulation of these physiological processes. Mitochondrial targeting of protein kinases and protein phosphatases provides a means to locally control the phosphorylation status and action of proteins on the surface of this organelle. Dual-specificity protein kinase A anchoring protein 1 (dAKAP1) is a multivalent binding protein that targets protein kinase A (PKA), RNAs, and other signaling enzymes to the outer mitochondrial membrane. Many AKAPs recruit a diverse set of binding partners that coordinate a broad range of cellular processes. Here, results of MS and biochemical analyses reveal that dAKAP1 anchors additional components, including the ribonucleoprotein granule components La-related protein 4 (LARP4) and polyadenylate-binding protein 1 (PABPC1). Local translation of mRNAs at organelles is a means to spatially control the synthesis of proteins. RNA-Seq data demonstrate that dAKAP1 binds mRNAs encoding proteins required for mitochondrial metabolism, including succinate dehydrogenase. Functional studies suggest that the loss of dAKAP1-RNA interactions reduces mitochondrial electron transport chain activity. Hence, dAKAP1 plays a previously unappreciated role as a molecular interface between second messenger signaling and local protein synthesis machinery.

Identification of clinically useful predictive genetic variants in pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16,KRT6A,KRT17,KRT6B or KRT6C). Current disease classification is based on the gene harbouring disease-causing variants. AIMS: We harnessed the International Pachyonychia Congenita Research Registry (IPCRR) containing both clinical and molecular data on patients with PC worldwide, to identify genetic variants predicting disease severity. METHODS: We ascertained 815 individuals harbouring keratin mutations registered in the IPCRR. We looked for statistically significant associations between genetic variants and clinical manifestations in a subgroup of patients carrying mutations found in at least 10% of the cohort. Data were analysed using χ2 and Kruskal-Wallis tests. RESULTS: We identified five mutations occurring in at least 10% of the patients registered in the IPCRR. The KRT16 p.L132P mutation was significantly associated with younger age of onset, presence of palmar keratoderma oral leucokeratosis and a higher number of involved nails. By contrast, the KRT16 p.N125S and p.R127C mutations resulted in a milder phenotype featuring a decreased number of involved nails and older age of onset. Patients carrying the p.N125S mutation were less likely to develop palmar keratoderma while p.R127C was associated with an older age of palmoplantar keratoderma onset. Moreover, the KRT17 p.L99P mutation resulted in an increased number of involved fingernails and patients demonstrating 20-nail dystrophy, while the opposite findings were observed with KRT17 p.N92S mutation. CONCLUSIONS: We have identified novel and clinically useful genetic predictive variants in the largest cohort of patients with PC described to date.

Single nucleotide polymorphisms alter kinase anchoring and the subcellular targeting of A-kinase anchoring proteins.

A-kinase anchoring proteins (AKAPs) shape second-messenger signaling responses by constraining protein kinase A (PKA) at precise intracellular locations. A defining feature of AKAPs is a helical region that binds to regulatory subunits (RII) of PKA. Mining patient-derived databases has identified 42 nonsynonymous SNPs in the PKA-anchoring helices of five AKAPs. Solid-phase RII binding assays confirmed that 21 of these amino acid substitutions disrupt PKA anchoring. The most deleterious side-chain modifications are situated toward C-termini of AKAP helices. More extensive analysis was conducted on a valine-to-methionine variant in the PKA-anchoring helix of AKAP18. Molecular modeling indicates that additional density provided by methionine at position 282 in the AKAP18γ isoform deflects the pitch of the helical anchoring surface outward by 6.6°. Fluorescence polarization measurements show that this subtle topological change reduces RII-binding affinity 8.8-fold and impairs cAMP responsive potentiation of L-type Ca2+ currents in situ. Live-cell imaging of AKAP18γ V282M-GFP adducts led to the unexpected discovery that loss of PKA anchoring promotes nuclear accumulation of this polymorphic variant. Targeting proceeds via a mechanism whereby association with the PKA holoenzyme masks a polybasic nuclear localization signal on the anchoring protein. This led to the discovery of AKAP18ε: an exclusively nuclear isoform that lacks a PKA-anchoring helix. Enzyme-mediated proximity-proteomics reveal that compartment-selective variants of AKAP18 associate with distinct binding partners. Thus, naturally occurring PKA-anchoring-defective AKAP variants not only perturb dissemination of local second-messenger responses, but also may influence the intracellular distribution of certain AKAP18 isoforms.

Estimates of intra- and interclass correlation coefficients for rump touches and the number of steps during estrus in postpartum cows.

Estrus traits have economic value in dairy production systems and could be incorporated into genetic selection indices. In an effort to further understand selection responses, 2 studies were performed to estimate the intra- and interclass correlation coefficients for estrus traits. Holstein-Friesian cows (n = 1,197; study 1) across 5 pasture-based grazing dairy herds were fitted with a capacitive touch sensing (CTS) device on the rump (FlashMate, Farmshed Labs Limited, Hamilton, New Zealand). The daily number of rump touches were subjected to a peak detection program to objectively identify periods of increased rump touches above baseline (indicative of estrus). The number of times touched and the sum of the touch duration were used to compare farms and estimate the intraclass correlation (repeatability). For study 2, postpartum Holstein (n = 85) and Guernsey (n = 5) cows in a confinement-style dairy were used. Cows were fitted with an IceQube accelerometer (IceRobotics Ltd., Edinburgh, United Kingdom) to measure steps taken per hour and a CTS device was applied to both rumps. The interclass correlation for the number of rump touches and number of steps taken during estrus was calculated. Data collected from 5 herds (study 1) demonstrated a 2- to 3-fold difference between herds in the number of rump touches and total touch time during estrus. The intraclass correlation (repeatability; estimates of maximum heritability) for rump touches during estrus was 0.22. For study 2, the number of steps and the number of rump touches during estrus increased in a synchronous manner. The intraclass correlation (repeatability) for number of steps during estrus was 0.26. The interclass correlation (r) for the number of rump touches and the number of steps was 0.46 (R2 = 0.21). Based on the R2, at least 20% of the variation in the number of steps during estrus was explained by the number of touches to the rump of the cow. Selecting cows for the number of steps taken during estrus could increase the number of rump touches (mounts, chin rests, and so on, received from other cows) if a genetic correlation exists for the phenotypic correlation that we observed.

Short communication: Simultaneous measurements of estrus behavior and plasma concentrations of estradiol during estrus in lactating and nonlactating dairy cows.

Estrus is an important behavior that can potentially be subjected to genomic selection. Circulating estradiol concentrations at estrus may be a useful phenotype if the absolute concentrations of estradiol are associated with overt phenotypes for estrus (activity, rump touches, or both; e.g., mounts, chinrests) that can be easily observed. The objective was to measure plasma estradiol concentrations at estrus and associate these measurements with the increase in activity (steps per hour) and rump touches received at estrus. We also tested the effect of lactation on the estrus traits that we measured. Cows (n = 11 lactating and n = 9 nonlactating) were treated with PGF2α to synchronize estrus. A jugular vein was cannulated to collect blood every 2 h for plasma estradiol measurement. Plasma LH was measured during the periestrual period to determine the time of the LH surge. Cows were fitted with an accelerometer to measure activity (steps per hour) and a capacitive touch sensing device to measure the number of rump touches and total touch time. Plasma estradiol concentrations were poorly correlated with overt signs of estrus during the period leading up to maximum estrus activity. After peak estrus activity (when cows were going out of estrus and plasma estradiol concentrations were decreasing), a stronger correlation was detected between overt signs of estrus and plasma estradiol concentrations. Effective selection for improved estrus expression based on plasma estradiol concentrations will depend on whether the cow is coming into or going out of estrus at the time of blood sampling. An association existed between lactation and fewer number of hours in estrus when estrus was defined by an increase in activity (steps per hour). Lactating cows had a shorter interval from the onset of estrus to the LH surge, and the shorter interval to the LH surge may have reduced the period of elevated estradiol during estrus in the lactating cows. Understanding mechanisms that control the sensitivity of the cow to estradiol and making appropriate selection decisions based on these mechanisms will likely increase overt signs of estrus in dairy cows.

Emotional adjustment post-stroke: A qualitative study of an online stroke community.

Understanding of emotional adjustment after stroke is limited. Under one-third of stroke survivors reporting emotional problems receive support. The aim of this study was to explore the process of emotional adjustment post-stroke and investigate the role played by participation in an online stroke community. We applied thematic analysis to 124 relevant posts within 114 discussion threads, written by 39 survivors and 29 carers. The contribution of online community engagement to emotional adjustment was explored using the Social Support Behaviour Code. Stroke survivors share common experiences of emotional adjustment and may not necessarily reach complete acceptance. Positive and negative trajectories of emotional adjustment were identified. Survivors progressed along, or moved between, positive and negative pathways not in a time-dependent manner but in response to "trigger events," such as physical setbacks or anti-depressant treatment, which may occur at any chronological time. An adapted version of Suhr's 1990 Social Support Behaviour Code showed that support provided through the online community took many forms, including advice, teaching, empathy and normalization of concerns. Participation in the stroke community was itself deemed to be a positive "trigger event." There is need to improve awareness of emotional adjustment and their "triggers" amongst stroke survivors, carers and clinicians.

Depletion of dAKAP1-protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility.

Breast cancer screening and new precision therapies have led to improved patient outcomes. Yet, a positive prognosis is less certain when primary tumors metastasize. Metastasis requires a coordinated program of cellular changes that promote increased survival, migration, and energy consumption. These pathways converge on mitochondrial function, where distinct signaling networks of kinases, phosphatases, and metabolic enzymes regulate these processes. The protein kinase A-anchoring protein dAKAP1 compartmentalizes protein kinase A (PKA) and other signaling enzymes at the outer mitochondrial membrane and thereby controls mitochondrial function and dynamics. Modulation of these processes occurs in part through regulation of dynamin-related protein 1 (Drp1). Here, we report an inverse relationship between the expression of dAKAP1 and mesenchymal markers in breast cancer. Molecular, cellular, and in silico analyses of breast cancer cell lines confirmed that dAKAP1 depletion is associated with impaired mitochondrial function and dynamics, as well as with increased glycolytic potential and invasiveness. Furthermore, disruption of dAKAP1-PKA complexes affected cell motility and mitochondrial movement toward the leading edge in invasive breast cancer cells. We therefore propose that depletion of dAKAP1-PKA "signaling islands" from the outer mitochondrial membrane augments progression toward metastatic breast cancer.

Revisiting pachyonychia congenita: a case-cohort study of 815 patients.

BACKGROUND: Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The establishment of an international registry containing clinical and molecular data led to the development of a disease classification based on the mutant gene and associated features. OBJECTIVES: To harness the same resource to clarify the prevalence of PC-associated clinical features, delineate phenotype-genotype correlations and identify prognostic features for disease severity. METHODS: In total, 815 individuals with confirmed keratin mutations registered in the International Pachyonychia Congenita Research Registry were surveyed for clinical findings associated with PC. Data were analysed using various statistical methods, including the Student's t-test, χ2 -test and anova tests for differences in means/proportions. Spearman correlation and logistic regression were used for phenotype-genotype correlations. RESULTS: KRT6A mutations were associated with oral leucokeratosis, hoarseness, youngest age or highest number of fingernails/toenails involved, and use of walking aids. KRT17 mutations were most commonly associated with cysts and natal teeth. Using logistic regression, we found that oral leucokeratosis was correlated with earlier toenail involvement, walking aids, nursing difficulties and hoarseness. Cysts were correlated with oral leucokeratosis, natal teeth and ear wax. Natal teeth predicted earlier toenail involvement, walking difficulties and cyst formation. Hoarseness was correlated with an increased number of involved fingernails. CONCLUSIONS: Here, we establish phenotype-genotype correlations in the largest cohort of patients with PC described to date and reveal novel and clinically useful predictors of disease course and manifestations. What's already known about this topic? Pachyonychia congenita (PC) is a group of autosomal dominant disorders caused by mutations in one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17). The main clinical features are nail dystrophy, palmoplantar keratoderma, oral leucokeratosis and cysts. The establishment of an international registry containing the clinical and molecular data of patients with PC led to the development of a disease classification based on the mutant gene and associated features. What does this study add? Data were collected via an international registry to clarify the prevalence of PC-associated clinical features, delineate phenotype-genotype correlations and identify prognostic features for disease severity. This is the largest cohort of patients with PC described to date. The earliest clinical manifestations of PC are nail dystrophy and palmoplantar keratoderma. Diagnosis can be suspected and confirmed in preschool years. Painful plantar keratoderma has the most profound and debilitating effect on quality of life and daily function. Linked Editorial: Steele and O'Toole. Br J Dermatol 2020; 182:521-522. Linked Comment: Mordaunt. Br J Dermatol 2020; 182:537.

Symptomatic mucosal involvement in pachyonychia congenita: challenges in infants and young children.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17). Characteristic features of PC are painful palmoplantar keratoderma, variable nail dystrophy, cysts, follicular hyperkeratosis and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life-threatening obstruction. OBJECTIVES: To characterize patients with PC with symptomatic mucosal involvement. METHODS: We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction. CONCLUSIONS: It is important for dermatologists and otolaryngologists to be aware that symptomatic mucosal involvement, and very rarely laryngeal obstruction, can occur in patients with PC. Usually simple feeding solutions may prevent complications and failure to thrive. What's already known about this topic? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers. Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease. Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life-threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention. Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS). Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment: Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536-537.

Reaching out to reduce health inequities for Maori youth.

AIM: This paper describes an initiative facilitating comprehensive assessment and delivery of brief interventions for Maori youth in Northland, New Zealand. BACKGROUND: The population in Northland is predominantly Maori and is one of New Zealand's most deprived populations. Maori youth have the highest youth suicide rate in the developed world and elevated numbers of youth displaying mental health issues and/or risk behaviours are of grave national concern. Like Indigenous peoples worldwide, inequities persist for Maori youth accessing and engaging with healthcare services. DESCRIPTION: Taking services out to Maori youth in remote and isolated areas, Northland's youth specialist nurses are reducing some barriers to accessing health care. The youth version of the Case-finding and Help Assessment Tool is a New Zealand-developed, e-screening tool for youth psychosocial issues, facilitating comprehensive assessment and brief intervention delivery. DISCUSSION: Early detection of, and timely intervention for, mental health and risk behaviours can significantly improve health outcomes in youth. However, for this to happen barriers preventing youth from accessing appropriate care need to be overcome. CONCLUSION: Youth specialist nurses could improve access to care for youth from ethnic minorities, rural and isolated regions, and areas of high deprivation without overwhelming the medical profession. IMPLICATIONS FOR NURSING POLICY: Specialist nurses are trained and empowered to practice at the top of their scope. With general practitioner oversight and standing order sign off specialist nurses can work autonomously to improve access to health services, without increasing the workload of doctors. IMPLICATIONS FOR NURSING PRACTICE: Encouraging continuous self-reflection of the nurse's effectiveness in meeting patient needs, holistically and culturally, facilitates the provision of accessible care that is patient-centred and culturally safe.

Resource allocation to growth or luxury consumption drives mycorrhizal responses.

Highly variable phenotypic responses in mycorrhizal plants challenge our functional understanding of plant-fungal mutualisms. Using non-invasive high-throughput phenotyping, we observed that arbuscular mycorrhizal (AM) fungi relieved phosphorus (P) limitation and enhanced growth of Brachypodium distachyon under P-limited conditions, while photosynthetic limitation under low nitrogen (N) was exacerbated by the fungus. However, these responses were strongly dependent on host genotype: only the faster growing genotype (Bd3-1) utilised P transferred from the fungus to achieve improved growth under P-limited conditions. Under low N, the slower growing genotype (Bd21) had a carbon and N surplus that was linked to a less negative growth response compared with the faster growing genotype. These responses were linked to the regulation of N : P stoichiometry, couples resource allocation to growth or luxury consumption in diverse plant lineages. Our results attest strongly to a mechanism in plants by which plant genotype-specific resource economics drive phenotypic outcomes during AM symbioses.

A cohort study of local excision followed by adjuvant therapy incorporating a contact X-ray brachytherapy boost instead of radical resection in 180 patients with rectal cancer.

AIM: Recent data have suggested near-equivalent oncological results when treating early rectal cancer by local excision followed by radio- ± chemotherapy rather than salvage radical surgery. The aim of this retrospective study was to assess the use of contact X-ray brachytherapy within this paradigm. METHOD: All patients had undergone local excision and were referred to our radiotherapy centre for treatment with contact X-ray brachytherapy. Postoperative (chemo)radiotherapy was also given in their local hospital in most cases. Variables assessed were local excision method, postoperative therapy received, follow-up duration, disease-free survival, salvage surgery and stoma-free survival. RESULTS: In total, 180 patients with a median age of 70 (range 36-99) years were assessed. Following local excision, pT stages were pT1 = 131 (72%), pT2 = 44 (26%), pT3 = 5 (2%). All patients received contact X-ray brachytherapy boosting at our centre and, in addition, 110 received chemoradiotherapy and 60 received radiotherapy alone. After a median follow-up of 36 months (range 6-48), 169 patients (94%) remained free of local recurrence. Of the 11 patients with local recurrence (three isolated nodal), five underwent salvage abdominoperineal excision. Eight patients developed distant disease, of whom five underwent metastasis surgery. At last included follow-up 173 (96%) patients were free of all disease and 170 (94%) were stoma free. CONCLUSIONS: Contact therapy can be offered in addition to external beam radio (±chemo) therapy instead of radical surgery as follow-on treatment after local excision of early rectal cancer. This combination can provide equivalent outcomes to radical surgery. The added value of contact therapy should be formally assessed in a clinical trial.

Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma.

Mutations in keratin genes underlie a variety of epidermal and nonepidermal cell-fragility disorders, and are the genetic basis of many inherited palmoplantar keratodermas (PPKs). Epidermolytic PPK (EPPK) is an autosomal dominant disorder that can be due to mutations in the keratin 1 gene, KRT1. Epidermolytic ichthyosis (EI), the major keratinopathic ichthyosis, is characterized by congenital erythroderma, blistering and erosions of the skin. Causative mutations in KRT1 and KRT10 have been described, with PPK being present primarily in association with the former. We report four unrelated cases (one with sporadic EI and three with autosomal dominant PPK), due to two novel and two recurrent KRT1 mutations. Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern.

The weekend effect in status epilepticus: a national cohort study.

Higher mortality following admission to hospital at the weekend has been reported for several conditions. It is unclear whether this variation is due to differences in patients or their care. Status epilepticus mandates hospital admission and usually critical care: its study might provide new insights into the nature of any weekend effect. We studied 20,922 adults admitted to UK critical care with status epilepticus from 2010 to 2015. We used multiple logistic regression to evaluate the association between weekend admission and in-hospital mortality, comparing university hospitals with other hospitals. There were 2462 in-hospital deaths (12%). There was no difference in mortality after weekend admission to university hospitals, adjusted odds ratio (95%CI) 0.99 (0.84-1.16), p = 0.89. Mortality was less after weekend admission than after admissions Monday to Friday in hospitals not associated with a university, adjusted odds ratio (95%CI) 0.74 (0.64-0.87), p = 0.0001. There is no evidence that adults admitted to UK critical care at the weekend in status epilepticus are more likely to die than similar patients admitted during the week.

E2~Ub conjugates regulate the kinase activity of Shigella effector OspG during pathogenesis.

Pathogenic bacteria introduce effector proteins directly into the cytosol of eukaryotic cells to promote invasion and colonization. OspG, a Shigella spp. effector kinase, plays a role in this process by helping to suppress the host inflammatory response. OspG has been reported to bind host E2 ubiquitin-conjugating enzymes activated with ubiquitin (E2~Ub), a key enzyme complex in ubiquitin transfer pathways. A co-crystal structure of the OspG/UbcH5c~Ub complex reveals that complex formation has important ramifications for the activity of both OspG and the UbcH5c~Ub conjugate. OspG is a minimal kinase domain containing only essential elements required for catalysis. UbcH5c~Ub binding stabilizes an active conformation of the kinase, greatly enhancing OspG kinase activity. In contrast, interaction with OspG stabilizes an extended, less reactive form of UbcH5c~Ub. Recognizing conserved E2 features, OspG can interact with at least ten distinct human E2s~Ub. Mouse oral infection studies indicate that E2~Ub conjugates act as novel regulators of OspG effector kinase function in eukaryotic host cells.

High fat diet consumption differentially affects adipose tissue inflammation and adipocyte size in obesity-prone and obesity-resistant rats.

BACKGROUND/OBJECTIVES: Expanding visceral adiposity is associated with increased inflammation and increased risk for developing obesity-related comorbidities. The goal of this study was to examine high fat diet (HFD)-induced differences in adipocyte size and cytokine/chemokine expression in visceral and subcutaneous adipose depots in obesity-prone (OP) and obesity-resistant (OR) rats. METHODS: OP and OR rats were fed either a low fat diet (LFD, 10% kilocalories from fat) or HFD (60% kilocalories from fat) for 7 weeks. Adipocyte size and the presence of crown-like structures in epididymal and inguinal adipose tissue were determined. A multiplex cytokine/chemokine panel was used to assess the expression of inflammatory markers in epididymal and inguinal adipose tissues. RESULTS: A higher percentage of large adipocytes (>5000 µm2) was detected in the epididymal and inguinal adipose tissues of OP rats and a higher percentage of small adipocytes (<4000 µm2) was detected in the epididymal and inguinal adipose tissues of OR rats. More crown-like structures were identified in epididymal adipose tissue of OP rats fed a LFD, compared to OR rats. Consumption of a HFD increased the number of crown-like structures in OR, but not OP rats. Epididymal expression of pro-inflammatory cytokines (IL-1ß and TNF-α) was higher in OP rats, compared to OR rats fed LFD. HFD consumption increased epididymal expression of GM-CSF, IL-1α, IL-1ß, IL-6, MIP-2 and TNF-α in OP and OR rats. Inguinal expression of pro-inflammatory cytokines (IL-1α, IL-1ß and TNF-α) was higher in OP rats, compared to OR rats. CONCLUSIONS: Overall, these data suggest that a higher susceptibility to developing obesity is characterized by large adipocytes and increased visceral adipose inflammation. Interestingly, in OR rats, the detrimental effects of HFD consumption on visceral adipose inflammation are evident with only small increases in weight and adiposity, suggesting that HFD also increases the risk for obesity-related comorbidities in OR rats.