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Background: CYLD cutaneous syndrome (CCS) is caused by germline heterozygous pathogenic variants in CYLD and results in progressive formation of cylindromas, spiradenomas, or trichoepitheliomas. Malignant cylindroma is a rare skin adnexal tumour occurring in CCS that can metastasize with lethal outcomes and has limited genomic characterization. BRCA2 loss in CCS is not described and may modulate the cutaneous cancer risk of CCS., Objectives: To establish if BRCA deficiency drives metastatic malignant cylindroma and report the phenotype of three siblings with digenic inheritance of CYLD and BRCA2 pathogenic variants, one of whom developed metastatic cylindroma aged 28., Methods: A kindred study reporting seven members of a CCS family was conducted in a tertiary hospital setting within the United Kingdom from April 2021 - February 2023. Clinical phenotype, pathological, radiological and genetic findings, and treatment data were collected. Whole genome sequencing of the primary malignant cylindroma occurring in one patient was performed to identify targetable driver mutations and signatures., Results: Malignant cylindroma arose in one (proband) of the two male siblings with digenic inheritance of BRCA2 (c.5158insT) and CYLD (c.2689-2A>G) pathogenic variants. A further female sibling with digenic inheritance of the same BRCA2 and CYLD PVs developed early breast cancer. Whole genome sequencing of the primary malignant cylindroma in the affected patient showed loss of heterozygosity of both BRCA2 and CYLD. Bioinformatic analysis revealed confirmed homologous repair deficiency (HRD). These data supported the use of the poly ADP ribose (PARP) inhibitor, Rucaparib, to target HRD in a non-canonical BRCA deficient skin cancer., Conclusions: Digenic inheritance of pathogenic variants in cancer predisposing genes should prompt clinicians to be vigilant for atypical malignant presentations. We demonstrate that rapid whole genome sequencing can inform the treatment of metastatic malignant cylindroma and identify novel systemic therapies., (© The Author(s) 2025. Published by Oxford University Press on behalf of British Association of Dermatologists.)

In the age of telehealth medicine, an individual's facial features may provide the only physical clues signaling the presence of a heritable cancer predisposition syndrome. These syndromes include APC -associated polyposis, Birt-Hogg-Dubé syndrome, CYLD cutaneous syndrome, hereditary leiomyomatosis and renal cell cancer, multiple endocrine neoplasia, neurofibromatosis type 1, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome, and tuberous sclerosis complex 1 and 2, among others. Correctly identifying characteristic features is important for genetic and nongenetic specialists as early detection can enable prompt intervention, improving patient outcomes. Advancements in the availability of genetic testing allow patients and their relatives to have more information about their genetic risk profile than before. These changes in clinical pathways, combined with improvements in screening and risk-reducing treatment, highlight the need to outline the cutaneous and morphologic features of high-risk cancer syndromes for clinicians. In this review, we describe the important facial features of hereditary cancer predisposition, with emphasis on diagnosis, cutaneous and extracutaneous manifestations, and screening.

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

Background & Aims: Few studies have explored the prolonged effects of dietary nitrate on vascular health. This pilot study tested the effects of prolonged consumption (13 weeks) of a range of doses of dietary nitrate (NO 3 - ), provided as beetroot juice (BJ), on blood pressure (BP) and endothelial function in overweight and obese older participants., Methods and Results: Sixty-two overweight or obese older participants (60-75 years) were randomized to the following interventions: (1) high NO 3 - (2) medium NO 3 - , (3) low NO 3 - , or (4) placebo. Resting clinic and home BP were measured pre- and post-intervention. Laser Doppler iontophoresis was used to quantify changes in endothelial-dependent and independent microvascular blood flow., Results: This pilot study showed that medium and low doses of NO 3 - were more effective in lowering resting-clinic SBP (P = 0.04 and, P = 0.03, respectively) than was PL. The lower doses of NO 3 - also resulted in significant increases in microvascular perfusion (medium, P = 0.02; low, P = 0.002) relative to baseline values., Conclusion: These findings indicate that supplementation with medium and low, but not high, doses of NO 3 - for 13 weeks had positive effects on BP and endothelial function in older overweight and obese adults. These findings require confirmation in larger studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Conflicts of interest the authors declare they have no conflicts of interest.

Competing Interests: None disclosed.

Nitrate-rich food increases nitric oxide (NO) production and may have beneficial effects on vascular, metabolic, and brain function. This pilot study tested the effects of prolonged consumption of a range of doses of dietary nitrate (NO 3 - ), provided as beetroot juice, on cognitive function and cerebral blood flow (CBF) in overweight and obese older participants. The study had a 13-week single-blind, randomised, parallel design, and 62 overweight and obese older participants (aged 60 to 75 years) received the following interventions: (1) high NO 3 - (2 × 70 mL beetroot juice/day) (2) medium NO 3 - (70 mL beetroot juice/day), (3) low NO 3 - (70 mL beetroot juice on alternate days), or (4) placebo (70 mL of NO 3 - -depleted beetroot juice on alternate days). Cognitive functions were assessed using the Computerised Mental Performance Assessment System (COMPASS) assessment battery. CBF, monitored by concentration changes in oxygenated and deoxygenated haemoglobin, was assessed in the frontal cortex using near-infrared spectroscopy. The findings of this pilot study showed that cognitive function and CBF were not affected by supplementation with NO 3 - -rich beetroot juice for 13 weeks, irrespective of the NO 3 - dose administered. These findings require confirmation in larger studies using more sophisticated imaging methods (i.e., MRI) to determine whether prolonged dietary NO 3 - supplementation influences brain function in older overweight people.

Sub-Saharan African countries are experiencing an alarming increase in hypertension prevalence. This study evaluated the feasibility and acceptability of nitrate-rich beetroot and folate supplementation, alone or combined, for the reduction of blood pressure (BP) in Tanzanian adults with elevated BP. This was a three-arm double-blind, placebo-controlled, parallel randomised clinical trial. Forty-eight participants were randomised to one of three groups to follow a specific 60-day intervention which included a: (1) combined intervention (beetroot juice + folate), (2) single intervention (beetroot juice + placebo), and (3) control group (nitrate-depleted beetroot juice + placebo). Forty-seven participants (age: 50-70 years) completed the study. The acceptability of the interventions was high. Self-reported compliance to the interventions was more than 90% which was confirmed by the significant increase in nitrate and folate concentrations in plasma and saliva samples in the treatment arms. This study provides important information for the design of high-nitrate interventions to reduce BP in Sub-Saharan African countries.

Nitrate-rich food can increase nitric oxide production and improve vascular and brain functions. This study examines the feasibility of a randomised controlled trial (RCT) testing the effects of prolonged consumption of different doses of dietary nitrate (NO 3 - ) in the form of beetroot juice (BJ) in overweight and obese older participants. A single-blind, four-arm parallel pilot RCT was conducted in 62 overweight and obese (30.4 ± 4 kg/m 2 ) older participants (mean ± standard deviation (SD), 66 ± 4 years). Participants were randomized to: (1) high-NO 3 - (HN: 2 × 70 mL BJ/day) (2) medium-NO 3 - (MN: 70 mL BJ/day), (3) low-NO 3 - (LN: 70 mL BJ on alternate days) or (4) Placebo (PL: 70 mL of NO 3 - -depleted BJ on alternate days), for 13 weeks. Compliance was checked by a daily log of consumed BJ, NO 3 - intake, and by measuring NO 3 - and NO 2 - concentrations in plasma, saliva, and urine samples. Fifty participants completed the study. Self-reported compliance to the interventions was >90%. There were significant positive linear relationships between NO 3 - dose and the increase in plasma and urinary NO 3 - concentration (R 2 = 0.71, P < 0.001 and R 2 = 0.46 P < 0.001, respectively), but relationships between NO 3 - dose and changes in salivary NO 3 - and NO 2 - were non-linear (R 2 = 0.35, P = 0.002 and R 2 = 0.23, P = 0.007, respectively). The results confirm the feasibility of prolonged BJ supplementation in older overweight and obese adults., Competing Interests: The authors declare no conflict of interest.

Purpose: Muller cells seem to be important in maintaining foveal morphology through connections between their foot processes and the internal limiting membrane (ILM). Internal limiting membrane peeling causes Muller cell trauma. We hypothesized that leaving a rim of unpeeled ILM around idiopathic macular holes undergoing vitrectomy surgery would improve postoperative foveal morphology and vision., Methods: Prospective pilot study of fovea-sparing ILM peeling in a consecutive cohort of patients with macular holes over a 12-month period. Spectral-domain optical coherence tomography and Early Treatment Diabetic Retinopathy Study letters best-corrected visual acuity were assessed preoperatively and postoperatively, and foveal morphology and metamorphopsia postoperatively. The foveal sparing group was compared with a second consecutive cohort who received standard ILM peeling (control group)., Results: Thirty-four eyes of 34 patients were included in each group. Groups showed no significant preoperative differences. 34/34 holes were successfully closed with surgery in the foveal sparing group and 32/34 in the control group. The foveal sparing group showed better postoperative best-corrected visual acuity (67.7 vs. 63.8, P = 0.003) and best-corrected visual acuity improvement (25.1 vs. 20.2, P = 0.03). The foveal sparing group demonstrated thicker minimum foveal thickness (211 vs. 173 μm, P = 0.002) and less steep foveal depression (158 vs. 149, P = 0.002)., Conclusion: Preserving nonpeeled ILM around macular holes resulted in a high closure rate, improved foveal morphology, and better postoperative best-corrected visual acuity. An appropriately powered randomized controlled study is warranted.

Background: In Sub-Saharan Africa, current strategies are struggling to control the burgeoning hypertension epidemic. Dietary interventions such as inorganic nitrate or folic acid supplementation could represent promising strategies for reducing blood pressure (BP) in this setting., Objectives: This feasibility study explores the effects of dietary inorganic nitrate supplementation, alone or in combination with folic acid, on BP in Tanzanian adults with elevated BP in Tanzania., Methods: A placebo-controlled, double-blind, randomized controlled feasibility trial was conducted. Forty-seven middle-aged and older participants (age: 50-70 y, BMI: 26.3-29.1 kg/m2) were randomly assigned to 3 conditions for a period of 60 d: 1) high-nitrate beetroot juice (∼400 mg nitrate) and folic acid (∼5 mg folic acid) (N + F), 2) high-nitrate beetroot juice and placebo (N + P), or 3) nitrate-depleted beetroot juice and placebo (P + P). Clinic and 24-h ambulatory BP and measurements of compliance in plasma (nitrate and folate concentrations) and saliva (nitrate and nitrite) were obtained at baseline, 30 d, and 60 d., Results: Baseline resting systolic and diastolic BP (mean ± SD) was 151.0 ± 19.4 mm Hg and 91.8 ± 11.7 mm Hg, respectively. Compliance to the interventions was high (>90%) in all groups which was confirmed by the significant increase in nitrate and folic acid concentrations in plasma and saliva samples in the treatment arms. After 60 d, 24-h systolic BP dropped by -10.8 ± 9.8 mm Hg (P < 0.001), -6.1 ± 13.2 mm Hg (P = 0.03), and -0.3 ± 9.7 mm Hg (P = 0.83) in the N + P, N + F, and P + P groups, respectively. There was a significant decrease in 24-h diastolic BP in the N + P group (-5.4 ± 5.0 mm Hg, P = 0.004), whereas changes were not significant in the N + F (-1.8 ± 8.1 mm Hg, P = 0.32) and P + P (1.6 ± 8.3 mm Hg, P = 0.43) groups., Conclusions: Dietary inorganic nitrate represents a potential nutritional strategy to lessen the hypertension epidemic in Sub-Saharan Africa. These findings support the rationale for future long-term investigations exploring the efficacy of dietary nitrate for lowering BP and attenuating cardiovascular disease risk in this setting.This trial was registered at isrctn.com as ISRCTN67978523., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)