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Basal cell carcinoma (BCC) is the most common skin cancer, and solar ultraviolet ray exposure is the most significant risk factor for its development. The plantar foot is infrequently exposed to the sun, thus the presence of BCC on the sole is rare. We report a case of BCC on the sole of the foot and its treatment in the hope to facilitate its detection.

The late Palaeocene to the middle Eocene (57.5 to 46.5 Ma) recorded a total of 39 hyperthermals – periods of rapid global warming documented by prominent negative carbon isotope excursions (CIEs) as well as peaks in iron content – have been recognized in marine cores. Documenting how the Earth system responded to rapid climatic shifts during hyperthermals provides fundamental information to constrain climatic models. However, while hyperthermals have been well documented in the marine sedimentary record, only a few have been recognized and described in continental deposits, thereby limiting our ability to understand the effect and record of global warming on terrestrial systems. Hyperthermals in the continental record could be a powerful correlation tool to help connect marine and continental deposits, addressing issues of environmental signal propagation from land to sea. In this study, we generate new stable carbon isotope data (δ13C values) across the well-exposed and time-constrained fluvial sedimentary succession of the early Eocene Castissent Formation in the south central Pyrenees (Spain). The δ13C values of pedogenic carbonate reveal – similarly to the global records – stepped CIEs, culminating in a minimum δ13C value that we correlate with the hyperthermal event “U” at ca. 50 Ma. This general trend towards more negative values is most probably linked to higher primary productivity leading to an overall higher respiration of soil organic matter during these climatic events. The relative enrichment in immobile elements (Zr, Ti, Al) and higher estimates of mean annual precipitation together with the occurrence of small iron oxide and iron hydroxide nodules during the CIEs suggest intensification of chemical weathering and/or longer exposure of soils in a highly seasonal climate. The results show that even relatively small-scale hyperthermals compared with their prominent counterparts, such as PETM, ETM2, and ETM3, can leave a recognizable signature in the terrestrial stratigraphic record, providing insights into the dynamics of the carbon cycle in continental environments during these events.

Background: Multiple sclerosis (MS) is a heterogeneous disorder with a progressive course that is difficult to predict on a case-by-case basis. Natural history studies of MS have demonstrated that age influences clinical progression independent of disease duration. Objective: To determine whether age would be associated with greater CNS injury as detected by magnetization transfer MRI. Materials and methods: Forty MS patients were recruited from out-patient clinics into two groups stratified by age but with similar clinical disease duration as well as thirteen controls age-matched to the older MS group. Images were segmented by automated programs and blinded readers into normal appearing white matter (NAWM), normal appearing gray matter (NAGM), and white matter lesions (WMLs) and gray matter lesions (GMLs) in the MS groups. WML and GML were delineated on T2-weighted 3D fluid-attenuated inversion recovery (FLAIR) and T1 weighted MRI volumes. Mean magnetization transfer ratio (MTR), region volume, as well as MTR histogram skew and kurtosis were calculated for each region. Results: All MTR measures in NAGM and MTR histogram metrics in NAWM differed between MS subjects and controls, as expected and previously reported by several studies, but not between MS groups. However, MTR measures in the WML did significantly differ between the MS groups, in spite of no significant differences in lesion counts and volumes. Conclusions: Despite matching for clinical disease duration and recording no significant WML volume difference, we demonstrated strong MTR differences in WMLs between younger and older MS patients. These data suggest that aging-related processes modify the tissue response to inflammatory injury and its clinical outcome correlates in MS.

Background: Aquaporin-4 (AQP4) antibody associated neuromyelitis optica (NMOSD) requires long-term immunosuppression. Rituximab is increasingly used worldwide, however the optimal regime is not established., Methods: We retrospectively examined different rituximab regimens in AQP4-NMOSD. Standard monotherapy (SM; 6 monthly infusions), SM plus oral steroids (SM+S), extended interval dosing (EID; guided by CD19 repopulation) and EID with oral steroids (EID+S) were compared. The primary outcome was time to first clinical relapse. Potential confounders including age, gender, number of previous relapses, and onset phenotype were included., Results: 77 patients were included: 67 females, median onset age 35.6, median DSS at rituximab initiation 5.0. 39 were on SM+S, 20 SM, 6 EID, and 12 EID+S. 25/77 patients relapsed during a median follow-up of 44.0 months. No significant difference in time to first relapse was observed between any rituximab regimen. Pooled analyses to compare regimens that use standard monotherapy (SM and SM+S) against those that use extended interval dosing (EID and EID+S) showed no significant difference. Pooled analysis of regimens using steroids with those not using steroids also showed no significant difference. Adjusted Cox proportional hazard model revealed no significant difference between rituximab regimens or influence of demographic factors. 9 significant adverse events were recorded, 5 in the SM group and 4 in SM+S., Conclusions: This study provides some basis for further exploring EID as a viable option for long term treatment of AQP4-NMOSD. This may improve patient experience and consolidate use of hospital resources., Competing Interests: Declaration of competing interest N/A., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Higher body mass index (BMI) during early life is thought to be a causal risk factor for multiple sclerosis (MS). We used longitudinal Mendelian randomisation (MR) to determine whether there is a critical window during which BMI influences MS risk., Methods: Summary statistics for childhood BMI (n ~ 28,000 children) and for MS susceptibility were obtained from recent large genome-wide association studies (GWAS) (n = 14,802 MS, 26,703 controls). We generated exposure instruments for BMI during four non-overlapping age epochs (< 3 months, 3 months-1.5 years, 2-5 years, and 7-8 years) and performed MR using the inverse variance weighted method with standard sensitivity analyses. Multivariable MR was used to account for effects mediated via later-life BMI., Results: For all age epochs other than birth, genetically determined higher BMI was associated with an increased liability to MS: Birth [Odds Ratio (OR) 0.81, 95% Confidence Interval (CI) 0.50-1.31, Number of Single-Nucleotide Polymorphisms (N SNPs ) = 7, p = 0.39], Infancy (OR 1.18, 95% CI 1.04-1.33, N SNPs  = 18, p = 0.01), Early childhood (OR 1.31, 95% CI 1.03-1.66, N SNPs  = 4, p = 0.03), Later childhood (OR 1.34, 95% CI 1.08-1.66, N SNPs  = 4, p = 0.01). Multivariable MR suggested that these effects may be mediated by effects on adult BMI., Conclusion: We provide evidence using MR that genetically determined higher BMI during early life is associated with increased MS risk. This effect may be driven by shared genetic architecture with later-life BMI., (© 2022. The Author(s).)

Determining effective means of preventing Multiple Sclerosis (MS) relies on testing preventive strategies in trial populations. However, because of the low incidence of MS, demonstrating that a preventive measure has benefit requires either very large trial populations or an enriched population with a higher disease incidence. Risk scores which incorporate genetic and environmental data could be used, in principle, to identify high-risk individuals for enrolment in preventive trials. Here we discuss the concepts of developing predictive scores for identifying individuals at high risk of MS. We discuss the empirical efforts to do so using real cohorts, and some of the challenges-both theoretical and practical-limiting this work. We argue that such scores could offer a means of risk stratification for preventive trial design, but are unlikely to ever constitute a clinically-helpful approach to predicting MS for an individual., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hone, Giovannoni, Dobson and Jacobs.)

Background: Early coronavirus disease 2019 (COVID-19) diagnosis prior to laboratory testing results is crucial for infection control in hospitals. Models exist predicting COVID-19 diagnosis, but significant concerns exist regarding methodology and generalizability., Aim: To generate the first COVID-19 diagnosis risk score for use at the time of hospital admission using the TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) checklist., Design: A multivariable diagnostic prediction model for COVID-19 using the TRIPOD checklist applied to a large single-centre retrospective observational study of patients with suspected COVID-19., Methods: 581 individuals were admitted with suspected COVID-19; the majority had laboratory-confirmed COVID-19 (420/581, 72.2%). Retrospective collection was performed of electronic clinical records and pathology data., Results: The final multivariable model demonstrated AUC 0.8535 (95% confidence interval 0.8121-0.8950). The final model used six clinical variables that are routinely available in most low and high-resource settings. Using a cut-off of 2, the derived risk score has a sensitivity of 78.1% and specificity of 86.8%. At COVID-19 prevalence of 10% the model has a negative predictive value (NPV) of 96.5%., Conclusions: Our risk score is intended for diagnosis of COVID-19 in individuals admitted to hospital with suspected COVID-19. The score is the first developed for COVID-19 diagnosis using the TRIPOD checklist. It may be effective as a tool to rule out COVID-19 and function at different pandemic phases of variable COVID-19 prevalence. The simple score could be used by any healthcare worker to support hospital infection control prior to laboratory testing results., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: Excessive gestational weight gain increases risk of gestational diabetes mellitus (GDM) but it remains unclear whether weight control after GDM diagnosis improves outcomes. We assessed whether: (1) total gestational weight gain during pregnancy (0-36 weeks); (2) early gestational weight gain (0-28 weeks, before GDM diagnosis); or (3) late gestational weight gain (28-36 weeks, after diagnosis) are associated with maternal-fetal outcomes., Methods: Some 546 women with GDM who delivered viable singleton infants at a single UK obstetric centre (October 2014 to March 2017) were included in this retrospective observational study., Results: Higher total gestational weight gain was associated with Caesarean section [n = 376; odds ratio (OR) 1.05; confidence intervals (CI) 1.02-1.08, P < 0.001] and large for gestational age (OR 1.08; CI 1.03-1.12, P < 0.001). Higher late gestational weight gain (28-36 weeks; n = 144) was associated with large for gestational age (OR 1.17; CI 1.01-1.37, P < 0.05), instrumental deliveries (OR 1.26; CI 1.03-1.55, P < 0.01), higher total daily insulin doses (36 weeks; beta coefficient 4.37; CI 1.92-6.82, P < 0.001), and higher post-partum 2-h oral glucose tolerance test concentrations (beta coefficient 0.12; CI 0.01-0.22, P < 0.05). Women who avoided substantial weight gain after GDM diagnosis had 0.7 mmol/l lower postnatal 2-h glucose and needed half the amount of insulin/day at 36 weeks compared with women with substantial weight gain after diagnosis. There were no significant associations between early gestational weight gain (0-28 weeks) and pregnancy outcomes., Conclusions: These findings suggest that controlling gestational weight gain should be a priority following GDM diagnosis to optimize pregnancy outcomes and improve maternal postnatal glucose homeostasis. The period after diagnosis of GDM (often 28 weeks gestation) is not too late to offer lifestyle advice or intervention to improve weight management and pregnancy outcomes., (© 2018 Diabetes UK.)