A Review of Atomic-Force Microscopy in Skin Barrier Function Assessment.

Skin barrier function (SBF) disorders are a class of pathologies that affect a significant portion of the world population. These disorders cause skin lesions with intense itch, impacting patients' physical and psychological well-being as well as their social functioning. It is in the interest of patients that their disorder be monitored closely while under treatment to evaluate the effectiveness of the ongoing therapy and any potential adverse reactions. Symptom-based assessment techniques are widely used by clinicians; however, they carry some limitations. Techniques to assess skin barrier impairment are critical for understanding the nature of the disease and for helping personalize treatment. This review recalls the anatomy of the skin barrier and describes an atomic-force microscopy approach to quantitatively monitor its disorders and their response to treatment. We review a panel of studies that show that this technique is highly relevant for SBF disorder research, and we aim to motivate its adoption into clinical settings.

RNA-sequencing of paired tape-strips and skin biopsies in atopic dermatitis reveals key differences.

BACKGROUND: Skin tape-strips and biopsies are widely used methods for investigating the skin in atopic dermatitis (AD). Biopsies are more commonly used but can cause scarring and pain, whereas tape-strips are noninvasive but sample less tissue. The study evaluated the performance of skin tape-strips and biopsies for studying AD. METHODS: Whole-transcriptome RNA-sequencing was performed on paired tape-strips and biopsies collected from lesional and non-lesional skin from AD patients (n = 7) and non-AD controls (n = 5). RNA yield, mapping efficiency, and differentially expressed genes (DEGs) for the two methods (tape-strip/biopsy) and presence of AD (AD/non-AD) were compared. RESULTS: Tape-strips demonstrated a lower RNA yield (22 vs. 4596 ng) and mapping efficiency to known genes (28% vs. 93%) than biopsies. Gene-expression profiles of paired tape-strips and biopsies demonstrated a medium correlation (R2 = 0.431). Tape-strips and biopsies demonstrated systematic differences in measured expression levels of 6483 genes across both AD and non-AD samples. Tape-strips preferentially detected many itch (CCL3/CCL4/OSM) and immune-response (CXCL8/IL4/IL5/IL22) genes as well as markers of epidermal dendritic cells (CD1a/CD207), while certain cytokines (IL18/IL37), skin-barrier genes (KRT2/FLG2), and dermal fibroblasts markers (COL1A/COL3A) were preferentially detected by biopsies. Tape-strips identified more DEGs between AD and non-AD (3157 DEGs) then biopsies (44 DEGs). Tape-strips also detected higher levels of bacterial mRNA than biopsies. CONCLUSIONS: This study concludes that tape-strips and biopsies each demonstrate respective advantages for measuring gene-expression changes in AD. Thus, the specific skin layers and genes of interest should be considered before selecting either method.

Prevalence and incidence of hand eczema in healthcare workers: A systematic review and meta-analysis.

Healthcare workers (HCWs) are considered a high-risk group for developing hand eczema (HE), mainly owing to wet work and contact with allergens at work. To meta-analyse the prevalence and incidence of HE in HCWs, as well as mapping the prevalence of atopic dermatitis (AD) and HE severity in HCWs. A systematic review and meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 guidelines. Published literature from 2000 to 2022 was eligible based on predefined inclusion and exclusion criteria. A total of 18 studies were included. Pooled life-time, 1-year and point prevalence of self-reported HE in HCWs was 33.4% (95% confidence interval [CI]: 28.3-38.6), 27.4% (95% CI: 19.3-36.5) and 13.5% (95% CI: 9.3-18.4), respectively. AD prevalence was 15.4% (95% CI: 11.3-19.9). Overall, the majority of HCWs reported mild HE. One included study assessed HE incidence reporting 34 cases/1000 person years. Most studies scored low-moderate using the New Ottawa Scale and the pooled point prevalence data showed broad CIs. In conclusion, the high prevalence of HE in HCWs underlines the increased risk and need for preventive measures for this professional group. There is, however, a need of further standardized high-quality studies.

Demographics, characteristics and medical treatment among adults with hand eczema in Denmark. A cross-sectional validation and registry-based study.

BACKGROUND: The international classification of diseases, 10th revision (ICD-10) includes several unvalidated diagnostic codes for hand eczema (HE). Knowledge is sparse on HE patient characteristics. OBJECTIVES: To validate selected HE ICD-10 codes in the Danish National Patient Registry (DNPR) and describe disease characteristics, lifestyle factors and medication use in adult HE patients. METHODS: Nineteen HE ICD-10 codes were selected and validated based on patient charts. Five cohorts were constructed based on the diagnostic code, DL30.8H (HE unspecified), in the DNPR: (i) patients with DL30.8H code (n = 8386), (ii) patients with DL30.8H code, but without atopic dermatitis (AD) (n = 7406), (iii) sex- and age-matched general population (n = 8386) without HE. Two additional cohorts nested in the DNPR included participants from the Danish Skin Cohort, (iv) patients with DL30.8H code but without AD (n = 1340) and (v) general population cohort (n = 9876). RESULTS: ICD-10 codes revealed positive predictive values ≥90% except irritant contact dermatitis (unspecified) (79.7%) and hyperkeratotic hand and foot eczema (84.1%). HE patients were most often women, middle-aged or older, of Danish ethnicity, had an atopic medical history and were smokers. Topical corticosteroid prescriptions were almost doubled in HE cohorts compared to general populations. CONCLUSION: We validated several HE ICD-10 codes and identified important HE patient characteristics.

Kidney Disease in Women With Previous Gestational Diabetes Mellitus: A Nationwide Register-Based Cohort Study.

OBJECTIVE: The association between gestational diabetes mellitus (GDM) and incident kidney disease, the mediating effects of diabetes and hypertension, and the impact of severity of metabolic dysfunction during pregnancy on the risk of incident kidney disease were investigated in this study. RESEARCH DESIGN AND METHODS: This Danish, nationwide, register-based cohort study included all women giving birth between 1997 and 2018. Outcomes included chronic kidney disease (CKD) and acute kidney disease, based on diagnosis codes. Cox regression analyses explored the association between GDM and kidney disease. A proxy for severity of metabolic dysfunction during pregnancy was based on GDM diagnosis and insulin treatment during GDM in pregnancy and was included in the models as an interaction term. The mediating effects of subsequent diabetes and hypertension prior to kidney disease were quantified using mediation analyses. RESULTS: Data from 697,622 women were used. Median follow-up was 11.9 years. GDM was associated with higher risk of CKD (adjusted hazard ratio [aHR] 1.92; 95% CI 1.67-2.21), whereas acute kidney disease was unrelated to GDM. The proportions of indirect effects of diabetes and hypertension on the association between GDM and CKD were 75.7% (95% CI 61.8-89.6) and 30.3% (95% CI 25.2-35.4), respectively, as assessed by mediation analyses. The CKD risk was significantly increased in women with insulin-treated GDM and no subsequent diabetes compared with women without GDM (aHR 2.35; 95% CI 1.39-3.97). CONCLUSIONS: The risk of CKD was significantly elevated after GDM irrespective of subsequent development of diabetes and hypertension. Furthermore, women with severe metabolic dysfunction during pregnancy had the highest CKD risk.

Quantitative proteomics defines mechanisms of antiviral defence and cell death during modified vaccinia Ankara infection.

Modified vaccinia Ankara (MVA) virus does not replicate in human cells and is the vaccine deployed to curb the current outbreak of mpox. Here, we conduct a multiplexed proteomic analysis to quantify >9000 cellular and ~80% of viral proteins throughout MVA infection of human fibroblasts and macrophages. >690 human proteins are down-regulated >2-fold by MVA, revealing a substantial remodelling of the host proteome. >25% of these MVA targets are not shared with replication-competent vaccinia. Viral intermediate/late gene expression is necessary for MVA antagonism of innate immunity, and suppression of interferon effectors such as ISG20 potentiates virus gene expression. Proteomic changes specific to infection of macrophages indicate modulation of the inflammatory response, including inflammasome activation. Our approach thus provides a global view of the impact of MVA on the human proteome and identifies mechanisms that may underpin its abortive infection. These discoveries will prove vital to design future generations of vaccines.

Psychiatric Morbidity in Women With Previous Gestational Diabetes Mellitus: A Nationwide Register-Based Cohort Study.

OBJECTIVE: To investigate associations between previous gestational diabetes mellitus (GDM) and incident psychiatric morbidity, and to explore the role of subsequent diabetes development in psychiatric morbidity risk. RESEARCH DESIGN AND METHODS: A nationwide register-based cohort study including all women delivering in Denmark from 1997 to 2018 was conducted. GDM exposure was based on diagnosis code, whereas psychiatric morbidity outcome was based on diagnosis code and psychopharmacological medication use. Multiple Cox regression and mediation analyses were performed. RESULTS: In a study population of 660,017 women, previous GDM was associated with increased risk of depression based on diagnosis code and/or medication use (adjusted hazard ratio [aHR] 1.22 [95% CI 1.18-1.27]), any psychiatric diagnosis (aHR 1.20 [95% CI 1.13-1.27]), and any psychopharmacological medication use (aHR 1.21 [95% CI 1.17-1.25]). Moreover, risk of depressive and anxiety disorders, as well as antidepressant and antipsychotic medication use, was increased, with aHRs ranging from 1.14 (95% CI 1.05-1.25) to 1.32 (95% CI 1.22-1.42). No associations were found regarding substance use disorders, psychotic disorders, bipolar disorders, postpartum psychiatric disease, or anxiolytic medication use. Psychiatric morbidity risk was higher in women with versus without subsequent diabetes development. However, GDM history affected risk estimates only in women without subsequent diabetes. Subsequent diabetes mediated 35-42% of the associations between GDM and psychiatric morbidity. CONCLUSIONS: GDM was associated with increased psychiatric morbidity risk. Subsequent diabetes development played a significant role in future psychiatric morbidity risk after GDM, although it only partly explained the association.

Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication.

Orthomyxo- and bunyaviruses steal the 5' cap portion of host RNAs to prime their own transcription in a process called "cap snatching." We report that RNA modification of the cap portion by host 2'-O-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from Streptomyces, called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its S-adenosyl-l-methionine binding pocket to restrict influenza virus replication. Mechanistically, TFMT impairs the association of host cap RNAs with the viral polymerase basic protein 2 subunit in human lung explants and in vivo in mice. TFMT acts synergistically with approved anti-influenza drugs.

The association between mental disorders and subsequent years of working life: a Danish population-based cohort study.

BACKGROUND: Mental disorders can affect workforce participation via a range of mechanisms. In this study, we aimed to estimate the association between different types of mental disorders and working years lost, defined as the number of years not actively working or enrolled in an educational programme. METHODS: In this population-based cohort study, we included all people aged 18-65 years (mean 38·0 [SD 13·9]) in the Danish Civil Registration System from Jan 1, 1995 to Dec 31, 2016. Information on mental disorders was obtained from the Danish Psychiatric Central Research Register and information on labour market characteristics was obtained from administrative registers. Follow-up started at age 18 years, immigration to Denmark, or on Jan 1, 1995, whichever came later; and it ended at age 65 years, death, emigration from Denmark, disability pension, voluntary early retirement, or Dec 31, 2016 (whichever came earlier). As the main outcome, we estimated working years lost for those diagnosed with any mental disorder and 24 types of mental disorders, as well as for the general population of same age and sex. We decomposed total working years lost into periods of unemployment or sick leave, disability pension, voluntary early retirement, or death. Data on ethnicity were not available through administrative registers. FINDINGS: A total of 5 163 321 individuals, 2 642 383 men and 2 520 938 women, were followed up for 65·4 million person-years. Overall, 488 775 (9·47%) individuals were diagnosed with a mental disorder. On average, individuals with mental disorders lost an additional 10·52 (95% CI 10·48-10·57) years of working life compared with the general Danish population. Receiving a disability pension (7·54 [7·49-7·59] years) and longer periods of unemployment (2·24 [2·21-2·27] years) accounted for most of this difference. INTERPRETATION: Our findings foreground the substantial impact of mental disorders on workforce participation. There is a need to invest in programmes that reduce the burden of working years lost and assist people with mental disorders in returning to the workforce. FUNDING: Lundbeck Foundation and Danish National Research Foundation.

The health care cost of comorbidity in individuals with mental disorders: A Danish register-based study.

AIM: The aim of the study was to estimate the annual health care cost by number of comorbid mental and somatic disorders in persons with a mental disorder. METHODS: All persons living in Denmark between 2004 and 2017 with a hospital diagnosis of a mental disorder were identified. We investigated the cost of different health care services: psychiatric hospitals, somatic hospitals, primary health care (e.g. general practitioners, psychologists and so on) and subsidised prescriptions. Within those with at least one mental disorder, we examined the costs for people with (a) counts of different types of mental disorders (e.g. exactly 1, exactly 2 and so on up to 8 or more) and (b) counts of different types of somatic disorders (e.g. no somatic disorders, exactly 1, exactly 2 and so on up to 15 or more). The estimates are reported in average cost per case and nationwide annual cost in Euro 2017. RESULTS: In total, 447,209 persons (238,659 females and 208,550 males) were diagnosed with at least one mental disorder in the study period. The average annual health care cost per case and nationwide cost was 4471 Euros and 786 million Euro, respectively, for persons with exactly one mental disorder, and 33,273 Euro and 3.6 million Euro for persons with eight or more mental disorders. The annual health care cost was 4613 Euro per case and 386 million Euro for persons without any somatic disorders, while the cost per case was 16,344 Euro and 0.7 million Euro in nationwide cost for persons with 15 or more disorders. The amount and proportion of the different health care costs varied by type of comorbidity and count of disorders. CONCLUSIONS: The annual health care cost per case was higher with increasing number of comorbid mental and somatic disorders, while the nationwide annual health care cost was lower with increasing number of comorbid disorders for persons with a mental disorder in Denmark.

Prevalence and incidence of hand eczema in healthcare workers: protocol for a systematic review and meta-analysis.

INTRODUCTION: Healthcare workers (HCWs) constitute a high-risk group for developing occupational hand eczema (HE). The present systematic review and meta-analysis will compile and appraise evidence regarding prevalence and incidence of HE in HCWs. METHODS AND ANALYSIS: Systematic searches will be performed in three electronic literature databases (PubMed/Medline, Web of Science-Core Collection and Embase). Further references will be retrieved by a manual search of included studies' reference lists using snowballing techniques. We will include experimental studies, observational studies, survey-based studies and clinical studies (publications in English, French and German from 2000 onwards) reporting on certified and apprentice HCWs, who actively work in the job. We will look at the following outcomes: Prevalence and incidence of clinically assessed as well as self-reported HE in the style of the Nordic Occupational Skin Questionnaire-2002; HE severity (measured by eg, Hand Eczema Severity Index, Osnabrück Hand Eczema Severity Index, Physician Global Assessment or other validated instruments as well as self-reported or by using undefined categories such as 'mild', 'moderate' or 'severe'); clinically assessed (eg, clinical diagnosis, UK Working Party's diagnostic criteria, Hanifin and Rajka diagnostic criteria for atopic dermatitis (AD)) and self-reported AD. We will assess the risk of bias within studies using detailed criteria according to the Newcastle-Ottawa Scale. As we expect heterogeneity in methods and outcomes, we will conduct sensitivity analyses. A narrative synthesis of results instead of a meta-analysis will be done in case that quantitative pooling is not feasible. ETHICS AND DISSEMINATION: Ethical approval and patient consent are not required as this work is based on published studies. The results will be published in an international, peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022303044.

The contribution of general medical conditions to the non-fatal burden of mental disorders: register-based cohort study in Denmark.

BACKGROUND: General medical conditions (GMCs) often co-occur with mental and substance use disorders (MSDs). AIMS: To explore the contribution of GMCs to the burden of disease in people with MSDs, and investigate how this varied by age. METHOD: A population-based cohort of 6 988 507 persons living in Denmark during 2000-2015 followed for up to 16 years. Danish health registers were used to identify people with MSDs and GMCs. For each MSD, years lived with disability and health loss proportion (HeLP) were estimated for comorbid MSDs and GMCs, using a multiplicative model for disability weights. RESULTS: Those with any MSD lost the equivalent of 43% of healthy life (HeLP = 0.43, 95% CI 0.40-0.44) after including information on GMCs, which was an increase from 25% before including GMCs (HeLP = 0.25, 95% CI 0.23-0.27). Schizophrenia was associated with the highest burden of disease (HeLP = 0.77, 95% CI 0.68-0.85). However, within each disorder, the relative contribution of MSDs and GMCs varied. For example, in those diagnosed with schizophrenia, MSDs and GMCs accounted for 86% and 14% of the total health loss; in contrast, in those with anxiety disorders, the same proportions were 59% and 41%. In general, HeLP increased with age, and was mainly associated with increasing rates of pulmonary, musculoskeletal and circulatory diseases. CONCLUSIONS: In those with mental disorders, the relative contribution of comorbid GMCs to the non-fatal burden of disease increases with age. GMCs contribute substantially to the non-fatal burden of disease in those with MSDs.

Cardiovascular and metabolic morbidity in women with previous gestational diabetes mellitus: a nationwide register-based cohort study.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes and has maternal health implications reaching beyond the perinatal period. We aimed to investigate the incidence and severity of cardiovascular and metabolic morbidity in women with previous GDM in a Danish population and to study whether proxies of impaired beta cell function-insulin treatment during GDM pregnancy and development of subsequent manifest diabetes mellitus-influence incident risk of cardiovascular and metabolic morbidity. METHODS: A nationwide register-based cohort study was conducted on the complete cohort of 700,648 women delivering in Denmark during 1997-2018. The exposure variable was GDM and primary outcome was overall cardiovascular and metabolic morbidity. Secondary outcomes were major cardiovascular disease (ischemic heart disease, heart failure, and/or stroke/transient cerebral ischemia), hypertension, dyslipidemia, and venous thrombosis. Severity of morbidity was assessed using number of hospital contacts with diagnosis codes related to cardiovascular and metabolic morbidity and number of redemptions of prescribed medication related to cardiovascular and metabolic morbidity in women who developed cardiovascular and metabolic morbidity after pregnancy. RESULTS: The median follow-up period was 10.2-11.9 years with a total range of 0-21.9 years. GDM was associated with increased risk of any cardiovascular and metabolic morbidity (adjusted HR 2.13 [95% CI 2.07-2.20]), major cardiovascular disease (adjusted HR 1.69 [95% CI 1.55-1.84]), hypertension (adjusted HR 1.89 [95% CI 1.82-1.96], dyslipidemia (adjusted HR 4.48 [95% CI 4.28-4.69]), and venous thrombosis (adjusted HR 1.32 [95% CI 1.16-1.50]). Insulin treatment during pregnancy and subsequent development of manifest diabetes exacerbated the risk estimates. Previous GDM was associated with more hospital contacts and more redeemed prescriptions in women developing cardiovascular and metabolic morbidity (p < 0.001). CONCLUSIONS: Previous GDM was associated with significantly higher risk of cardiovascular and metabolic morbidity, especially incident dyslipidemia. Risks were exacerbated by proxies of beta cell impairment. Severity of morbidity was significantly worse if GDM preceded cardiovascular and metabolic morbidity.

Long-Term Metabolic Outcomes after Gestational Diabetes Mellitus (GDM): Results from the Odense GDM Follow-Up Study (OGFUS).

Aims: To compare metabolic profiles and the long-term risk of metabolic dysfunction between women with previous gestational diabetes mellitus (pGDM) and women without pGDM (non-GDM) matched on age, prepregnancy body mass index (BMI), and parity. Methods: In total, 128 women with pGDM (median follow-up: 7.8 years) and 70 non-GDM controls (median follow-up: 10.0 years) completed a 2 h oral glucose tolerance test (OGTT) with assessment of glucose, C-peptide, insulin, and other metabolic measures. Additionally, anthropometrics, fat mass, and blood pressure were assessed and indices of insulin sensitivity and beta cell function were calculated. Results: The prevalence of type 2 diabetes mellitus (T2DM) was significantly higher in the pGDM group compared to the non-GDM group (26% vs. 0%). For women with pGDM, the prevalence of prediabetes (38%) and the metabolic syndrome (MetS) (59%) were approximately 3-fold higher than in non-GDM women (p's < 0.001). Both insulin sensitivity and beta cell function were significantly reduced in pGDM women compared to non-GDM women. Conclusion: Despite similar BMI, women with pGDM had a substantially higher risk of developing T2DM, prediabetes, and the MetS compared to controls. Both beta cell dysfunction and reduced insulin sensitivity seem to contribute to this increased risk.

Analysis of mortality metrics associated with a comprehensive range of disorders in Denmark, 2000 to 2018: A population-based cohort study.

BACKGROUND: The provision of different types of mortality metrics (e.g., mortality rate ratios [MRRs] and life expectancy) allows the research community to access a more informative set of health metrics. The aim of this study was to provide a panel of mortality metrics associated with a comprehensive range of disorders and to design a web page to visualize all results. METHODS AND FINDINGS: In a population-based cohort of all 7,378,598 persons living in Denmark at some point between 2000 and 2018, we identified individuals diagnosed at hospitals with 1,803 specific categories of disorders through the International Classification of Diseases-10th Revision (ICD-10) in the National Patient Register. Information on date and cause of death was obtained from the Registry of Causes of Death. For each of the disorders, a panel of epidemiological and mortality metrics was estimated, including incidence rates, age-of-onset distributions, MRRs, and differences in life expectancy (estimated as life years lost [LYLs]). Additionally, we examined models that adjusted for measures of air pollution to explore potential associations with MRRs. We focus on 39 general medical conditions to simplify the presentation of results, which cover 10 broad categories: circulatory, endocrine, pulmonary, gastrointestinal, urogenital, musculoskeletal, hematologic, mental, and neurologic conditions and cancer. A total of 3,676,694 males and 3,701,904 females were followed up for 101.7 million person-years. During the 19-year follow-up period, 1,034,273 persons (14.0%) died. For 37 of the 39 selected medical conditions, mortality rates were larger and life expectancy shorter compared to the Danish general population. For these 37 disorders, MRRs ranged from 1.09 (95% confidence interval [CI]: 1.09 to 1.10) for vision problems to 7.85 (7.77 to 7.93) for chronic liver disease, while LYLs ranged from 0.31 (0.14 to 0.47) years (approximately 16 weeks) for allergy to 17.05 (16.95 to 17.15) years for chronic liver disease. Adjustment for air pollution had very little impact on the estimates; however, a limitation of the study is the possibility that the association between the different disorders and mortality could be explained by other underlying factors associated with both the disorder and mortality. CONCLUSIONS: In this study, we show estimates of incidence, age of onset, age of death, and mortality metrics (both MRRs and LYLs) for a comprehensive range of disorders. The interactive data visualization site (https://nbepi.com/atlas) allows more fine-grained analysis of the link between a range of disorders and key mortality estimates.

Carriers of COL3A1 pathogenic variants in Denmark: Interfamilial variability in severity and outcome of elective surgical procedures.

The study describes all patients in Denmark with vascular Ehlers-Danlos syndrome (vEDS). Carriers of pathogenic or likely pathogenic COL3A1 variants were retrospectively identified through registries and specialized clinics. Medical records were reviewed for vascular- or organ ruptures and invasive procedures performed. Identified families were divided by variant type (null, splice, and missense) and familial phenotypes (severe or attenuated). Families in which at least one carrier has suffered a major event before the age of 30 were classified as severe, whereas families in which at least three carriers had reached the age of 40 without a major event were classified as attenuated. Eighty-seven persons (59 still alive) from 25 families were included with a mean observation time of 44 years. Sixty-seven percent of patients could be subclassified in a familial phenotype. Thirty-one major events were observed. Eleven complications in 172 invasive procedures were recorded. No fatal complications to elective surgery were observed. The type of COL3A1 variant did not reliably predict phenotype, but a pattern of intrafamilial consistency emerged with some families showing an attenuated form of vEDS. Elective medical procedures appear to be safer than previously thought, although data only allow for conclusions regarding individuals from families with the attenuated form of vEDS.

Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome.

Importance: People with Down syndrome have a high risk of developing Alzheimer disease dementia. However, penetrance and age at onset are considered variable, and the association of this disease with life expectancy remains unclear because of underreporting in death certificates. Objective: To assess whether the variability in symptom onset of Alzheimer disease in Down syndrome is similar to autosomal dominant Alzheimer disease and to assess its association with mortality. Design, Setting, and Participants: This study combines a meta-analysis with the assessment of mortality data from US death certificates (n = 77 347 case records with a International Classification of Diseases code for Down syndrome between 1968 to 2019; 37 900 [49%] female) and from a longitudinal cohort study (n = 889 individuals; 46% female; 3.2 [2.1] years of follow-up) from the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI). Main Outcomes and Measures: A meta-analysis was conducted to investigate the age at onset, age at death, and duration of Alzheimer disease dementia in Down syndrome. PubMed/Medline, Embase, Web of Science, and CINAHL were searched for research reports, and OpenGray was used for gray literature. Studies with data about the age at onset or diagnosis, age at death, and disease duration were included. Pooled estimates with corresponding 95% CIs were calculated using random-effects meta-analysis. The variability in disease onset was compared with that of autosomal dominant Alzheimer disease. Based on these estimates, a hypothetical distribution of age at death was constructed, assuming fully penetrant Alzheimer disease. These results were compared with real-world mortality data. Results: In this meta-analysis, the estimate of age at onset was 53.8 years (95% CI, 53.1-54.5 years; n = 2695); the estimate of age at death, 58.4 years (95% CI, 57.2-59.7 years; n = 324); and the estimate of disease duration, 4.6 years (95% CI, 3.7-5.5 years; n = 226). Coefficients of variation and 95% prediction intervals of age at onset were comparable with those reported in autosomal dominant Alzheimer disease. US mortality data revealed an increase in life expectancy in Down syndrome (median [IQR], 1 [0.3-16] years in 1968 to 57 [49-61] years in 2019), but with clear ceiling effects in the highest percentiles of age at death in the last decades (90th percentile: 1990, age 63 years; 2019, age 65 years). The mortality data matched the limits projected by a distribution assuming fully penetrant Alzheimer disease in up to 80% of deaths (corresponding to the highest percentiles). This contrasts with dementia mentioned in 30% of death certificates but is in agreement with the mortality data in DABNI (78.9%). Important racial disparities persisted in 2019, being more pronounced in the lower percentiles (10th percentile: Black individuals, 1 year; White individuals, 30 years) than in the higher percentiles (90th percentile: Black individuals, 64 years; White individuals, 66 years). Conclusions and Relevance: These findings suggest that the mortality data and the consistent age at onset were compatible with fully penetrant Alzheimer disease. Lifespan in persons with Down syndrome will not increase until disease-modifying treatments for Alzheimer disease are available.

Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.

Assessment of Frequency of Rosacea Subtypes in Patients With Rosacea: A Systematic Review and Meta-analysis.

Importance: Four distinct rosacea subtypes have traditionally been recognized, but the frequency of these subtypes among patients with rosacea remains unknown. Objective: To assess the frequency of 4 rosacea subtypes. Data Sources: This systemic review and meta-analysis included a search of 2 databases, PubMed and Embase, from inception of the databases to November 2, 2021. The search was filtered to include only studies of human participants published in English, French, and German. Study Selection: Studies were screened independently by 2 of the authors and were included if they were original with a sample size of 25 or more patients and reported absolute numbers or frequency of patients affected by rosacea subtypes. Studies that did not report sufficient data to calculate the proportions of subtypes were excluded. Data Extraction and Synthesis: Data extraction was performed independently and in duplicate by 2 of the authors, using the search term rosacea, according to the Preferred Reporting items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The search term, objectives, and study protocol methods were defined before the study was initiated. A total of 292 studies were included for full-text assessment. Owing to the heterogeneity of the included studies, a random-effects model was used. Main Outcome and Measures: The main outcome was the proportion of patients with rosacea in each of the 4 major subtype groups defined by the 2002 National Rosacea Society classification system. Measures were absolute numbers or frequency of patients affected by each of the 4 rosacea subtypes. Results: A total of 39 studies examining 9190 patients with rosacea were included. The pooled proportion of erythematotelangiectatic rosacea was 56.7% (95% CI, 51.4%-62.0%), of papulopustular rosacea was 43.2% (95% CI, 38.8%-47.6%), of phymatous rosacea was 7.4% (95% CI, 6.1%-8.9%), and of ocular rosacea was 11.1% (95% CI, 6.7%-16.3%). Subtype distribution occurred equally among men and women except for phymatous rosacea, which was more prevalent in men. Studies from Africa showed the lowest proportion of erythematotelangiectatic rosacea. Differences in frequency of subtypes were observed when stratification by publication year was performed. Conclusion and Relevance: In this systematic review and meta-analysis, differences were found in rosacea subtypes by patient sex and by continent of origin and publication year of included studies. Erythematotelangiectatic and papulopustular rosacea were the most prevalent subtypes, but data should be interpreted with caution. Future studies should use the phenotype-based rosacea approach.

Mortality Associated With Mental Disorders and Comorbid General Medical Conditions.

Importance: Premature mortality has been observed among people with mental disorders. Comorbid general medical conditions contribute substantially to this reduction in life expectancy. Objective: To provide an analysis of mortality associated with comorbidity between a broad range of mental disorders and general medical conditions. Design, Setting, and Participants: Population-based cohort study of 5 946 800 individuals born in Denmark from 1900 to 2015 and residing in the country at the start of follow-up (January 1, 2000, or their date of birth, whichever occurred later). Exposures: Danish health registers were used to identify people with mental disorders and general medical conditions. Main Outcomes and Measures: Considering pairs of mental disorders and general medical conditions, we calculated mortality rate ratios (MRRs) and differences in life expectancy (ie, life-years lost) to assess the association of mortality with both disorders of interest compared with the mental disorder of interest, the general medical condition of interest, and neither disorder of interest. Results: The study population comprised 2 961 397 males and 2 985 403 females, with a median (IQR) age of 32.0 years (7.3-52.9) at start of follow-up and 48.9 years (42.5-68.8) at the end. Based on all pairs of comorbid mental disorders and general medical conditions, the mean MRR compared with people without these conditions was 5.90 (median, 4.94; IQR, 3.80-7.30), and the mean reduction of life expectancy compared with the general population was 11.35 years (median, 11.08; range, 5.27-23.53; IQR, 8.22-13.72). The association with general medical condition comorbidity in those with mental disorders varied by general medical condition; for example, the addition of a neurological condition for each of the mental disorders was associated with a mean MRR of 1.22, whereas for cancer, the mean MRR for all mental disorders was 4.07. Conclusions and Relevance: In this study, shorter life expectancy was associated with comorbid mental disorders and general medical conditions compared with the entire population and also when compared with patients who had either mental disorders only or general medical conditions only. Prevention and early detection of comorbidities could reduce premature mortality in patients with mental disorders.