Comprehensive genomic filtering algorithm to expose the cause of skewed X chromosome inactivation. The proof of concept in female haemophilia expression.

BACKGROUND: Exploring the expression of X linked disorders like haemophilia A (HA) in females involves understanding the balance achieved through X chromosome inactivation (XCI). Skewed XCI (SXCI) may be involved in symptomatic HA carriers. We aimed to develop an approach for dissecting the specific cause of SXCI and verify its value in HA. METHODS: A family involving three females (two symptomatic with severe/moderate HA: I.2, the mother, and II.1, the daughter; one asymptomatic: II.2) and two related affected males (I.1, the father and I.3, the maternal uncle) was studied. The genetic analysis included F8 mutational screening, multiplex ligation-dependent probe amplification, SNP microarray, whole exome sequencing (WES) and Sanger sequencing. XCI patterns were assessed in ectoderm/endoderm and mesoderm-derived tissues using AR-based and RP2-based systems. RESULTS: The comprehensive family analysis identifies I.2 female patient as a heterozygous carrier of F8:p.(Ser1414Ter) excluding copy number variations. A consistent XCI pattern of 99.5% across various tissues was observed. A comprehensive filtering algorithm for WES data was designed, developed and applied to I.2. A Gly58Arg missense variant in VMA21 was revealed as the cause for SXCI.Each step of the variant filtering system takes advantage of publicly available genomic databases, non-SXCI controls and case-specific molecular data, and aligns with established concepts in the theoretical background of SXCI. CONCLUSION: This study acts as a proof of concept for our genomic filtering algorithm's clinical utility in analysing X linked disorders. Our findings clarify the molecular aspects of SXCI and improve genetic diagnostics and counselling for families with X linked diseases like HA.

Safety of biologic therapy in combination with methotrexate in moderate to severe psoriasis: a cohort study from the BIOBADADERM registry.

BACKGROUND: Safety is an important consideration in decisions on treatment for patients with moderate-to-severe psoriasis and the study of drug safety is the main purpose of the BIOBADADERM registry. The combination of a biologic agent and a conventional systemic drug [generally methotrexate (MTX)] is a common treatment in clinical practice. However, there is a paucity of evidence from real-world practice on the safety of such combination regimens in the treatment of psoriasis. OBJECTIVES: The primary objective of this study was to ascertain whether the use of regimens combining biologic drugs with MTX in the management of moderate-to-severe psoriasis increases the risk of adverse events (AEs) or serious AEs (SAEs). We compared monotherapy using tumour necrosis factor (TNF), interleukin (IL)-17 and IL-23 inhibitors with the use of the same drugs in combination with MTX. METHODS: Using data from the BIOBADADERM registry, we compared biologic monotherapies with therapies that were combined with MTX. We estimated adjusted incidence rate ratios (aIRR) using a random effects Poisson regression with 95% confidence intervals for all AEs, SAEs, infections and serious infections and other AEs by system organ class. RESULTS: We analysed data from 2829 patients and 5441 treatment cycles, a total of 12 853 patient-years. The combination of a biologic with MTX was not associated with statistically significant increases in overall risk of AEs or SAEs in any treatment group. No increase in the total number of infections or serious infections in patients receiving combined therapy was observed for any group. However, treatment with a TNF inhibitor combined with MTX was associated with an increase in the incidence of gastrointestinal AEs (aIRR 2.50, 95% CI 1.57-3.98; P < 0.002). CONCLUSIONS: The risk of AEs and SAEs was not significantly increased in patients with moderate-to-severe psoriasis receiving different classes of biologic drugs combined with MTX compared with those on biologic monotherapy.

Continued decline in the incidence of myocardial infarction beyond the COVID-19 pandemic: a nationwide study of the Swedish population aged 60 and older during 2015-2022.

The number of myocardial infarctions declined during the early COVID-19 pandemic but mechanisms behind these declines are poorly understood. COVID-19 infection is also associated with an increased risk of myocardial infarction which could lead to higher incidence rates in the population. This study aims to shed light on the seemingly paradoxical relationship between COVID-19 and myocardial infarction occurrence on the population level by exploring long-term trends in incidence rates, case fatality, and proportion of patients dying before reaching a hospital. Our work is based on a linkage of administrative registers covering the entire population aged 60 + in Sweden. Considering both long-term trends since 2015 and seasonal variability, we compared observed incidence, case fatality, and proportions of patients hospitalized to expected values during 2020-2022. Despite more than 200 laboratory-confirmed COVID-19 cases per 1000 inhabitants by the end of 2022, incidence rates of myocardial infarction continued to decline, thus following the long-term trend observed already before 2020. During the first pandemic wave there was an additional incidence decline corresponding to 13% fewer myocardial infarctions than expected. This decline was neither accompanied by increasing case fatality nor by lower shares of patients being hospitalized. We found no increase in the population-level incidence of myocardial infarction despite large-scale exposure to COVID-19, which suggests that the effect of COVID-19 on myocardial infarction risk is not substantial. Increased pressure on the Swedish health care system has not led to increased risks or poorer outcomes for patients presenting with acute myocardial infarction.

US Racial-Ethnic Mortality Gap Adjusted for Population Structure.

BACKGROUND: US racial-ethnic mortality disparities are well documented and central to debates on social inequalities in health. Standard measures, such as life expectancy or years of life lost, are based on synthetic populations and do not account for the real underlying populations experiencing the inequalities. METHODS: We analyze US mortality disparities comparing Asian Americans, Blacks, Hispanics, and Native Americans/Alaska Natives to Whites using 2019 CDC and NCHS data, using a novel approach that estimates the mortality gap, adjusted for population structure by accounting for real-population exposures. This measure is tailored for analyses where age structures are fundamental, not merely a confounder. We highlight the magnitude of inequalities by comparing the population structure-adjusted mortality gap against standard metrics' estimates of loss of life due to leading causes. RESULTS: Based on the population structure-adjusted mortality gap, Black and Native American mortality disadvantage exceedsmortality from circulatory diseases. The disadvantage is 72% among Blacks (men: 47%, women: 98%) and 65% among Native Americans (men: 45%, women: 92%), larger than life expectancy measured disadvantage. In contrast, estimated advantages for Asian Americans are over three times (men: 176%, women: 283%) and, for Hispanics, two times (men: 123%; women: 190%) larger than those based on life expectancy. CONCLUSIONS: Mortality inequalities based on standard metrics' synthetic populations can differ markedly from estimates of the population structure-adjusted mortality gap. We demonstrate that standard metrics underestimate racial-ethnic disparities through disregarding actual population age structures. Exposure-corrected measures of inequality may better inform health policies around allocation of scarce resources.

Years of life lost during the Covid-19 pandemic in Sweden considering variation in life expectancy by level of geriatric care.

The Covid-19 pandemic has not affected the population evenly. This must be acknowledged when it comes to understanding the Covid-19 death toll and answering the question of how many life years have been lost. We use level of geriatric care to account for variation in remaining life expectancy among individuals that died during 2020. Based on a linkage of administrative registers, we estimate remaining life expectancy stratified by age, sex, and care status using an incidence-based multistate model and analyze the number of years of life lost (YLL) during 2020 in Sweden. Our results show that remaining life expectancy between individuals with and without care differs substantially. More than half of all Covid-19 deaths had a remaining life expectancy lower than 4 years. Yet, in a 1-year perspective, Covid-19 did not seem to replace other causes of death. Not considering the differences in remaining life expectancy in the affected populations overestimated YLL by 40% for women and 30% for men, or around 2 years per death. While the unadjusted YLL from Covid-19 amounted to an average of 7.5 years for women and 8.6 years for men, the corresponding YLL adjusted for care status were 5.4 and 6.6, respectively. The total number of YLL to Covid-19 in 2020 is comparable to YLL from ischemic heart disease in 2019 and 2020. Our results urge the use of subgroup specific mortality when counting the burden of Covid-19. YLL are considerably reduced when the varying susceptibility for death is considered, but even if most lifespans were cut in the last years of life, the YLL are still substantial.

Secukinumab is effective and safe in the long-term treatment of plaque psoriasis in a daily practice setting: Multicenter study in 384 Spanish patients.

The aim of the study was to assess the long-term effectiveness and safety of secukinumab in Spanish patients with moderate-to-severe psoriasis in a daily practice setting. Nationwide multicenter, observational, retrospective, non-interventional, single-cohort study including patients who initiated treatment with secukinumab in daily clinical practice conditions. Subjects were followed for a minimum of 3 months and a maximum of 24 months. Psoriasis Area Severity Index (PASI), Body Surface Area and Physician's Global Assessments were collected at baseline and months 3, 6, 12, 18 and 24 during treatment. Adverse events and reasons for secukinumab withdrawal were collected and classified for analyses. A total of 384 patients were enrolled in the study. Median PASI declined rapidly from 14.3 at baseline to 2.7 at month 3, 2.1 at month 12, and remained low (2.8) at month 24. Within the group of patients with PASI ≥10 at baseline (n = 278), 58.3%, 60.4% and 56.5% achieved a PASI90 response at months 3, 12 and 24, respectively. As for absolute PASI, 86.5%, 69.5%, 42.7% and 37% achieved PASI <5, < 3, < 1 and 0, respectively, at month 3. Secukinumab was more effective in biologic-naïve patients and in those with lower Body Mass Index. Secukinumab presented a good long-term safety profile. Secukinumab was effective and safe in a routine clinical setting, in a large cohort of patients with moderate-to-severe plaque psoriasis, in the short-, medium- and long-term (up to 24 months).

Fast and sustained improvement of patient-reported outcomes in psoriatic patients treated with secukinumab in a daily practice setting.

Psoriasis is a chronic dermatological disease with great impact on patients' quality of life (QoL). The main objective of this study was to assess the impact of secukinumab treatment on different patient-reported outcomes (PROs) during a long-term follow-up in Spanish patients with moderate-to-severe psoriasis under real-world conditions. Retrospective, observational, open-label, nationwide multicenter cohort study that included patients who initiated treatment with secukinumab in daily clinical practice conditions. PROs assessing disease impact and QoL included Dermatology Life Quality Index (DLQI), Patient's Global Psoriasis Assessment, Itch Numerical Rating Scale and EuroQoL Thermometer Visual Analogue Scale. Outcomes, including PROs and Psoriasis Area and Severity Index (PASI), were assessed at months 3, 6, 12, 18, and 24 during treatment. A total of 238 patients were enrolled in the study. Patients had a mean DLQI score of 14.9 at baseline; 78.3%, 73.7%, and 71.7% of them achieved a DLQI 0/1 response at months 6, 12, and 24, respectively. DLQI score was lower in the long term for naïve patients. A sharp decrease in mean DLQI was observed during the first 3 months, reaching a plateau that was maintained until the end of follow-up. Similar findings were observed for the rest of QoL assessments. There was a close association between improvement in QoL and skin clearance (PASI), which progressively increased during follow-up. In this study, secukinumab sustainably improved patient's QoL during a 24-month follow-up, with strongest effects in patients naïve to biological therapies and with a direct correlation with PASI improvement.

Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort.

The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness.

Age-Specific Incidence of Influenza A Responds to Change in Virus Subtype Dominance.

When H3N2 replaced H1N1 as the dominant influenza A subtype during the 2018-2019 season, the pattern of age-specific incidence shifted due to the lingering effects of antigenic imprinting. The characteristic shape that imprinting leaves on influenza susceptibility could foster important advances in understanding and predicting the epidemiology of influenza.

Long-term safety of nine systemic medications for psoriasis: A cohort study using the Spanish Registry of Adverse Events for Biological Therapy in Dermatological Diseases (BIOBADADERM) Registry.

BACKGROUND: Registry studies broadly describing the safety of systemic drugs in psoriasis are needed. OBJECTIVE: To describe the safety findings of the systemic drugs acitretin, adalimumab, apremilast, cyclosporine, etanercept, infliximab, methotrexate, secukinumab, and ustekinumab used for the treatment of moderate to severe psoriasis in patients included in the Spanish Registry of Adverse Events for Biological Therapy in Dermatological Diseases (BIOBADADERM) Registry. METHODS: The incidence rate ratio (IRR) and adjusted IRR (including propensity scores) of identified adverse events for each drug, using methotrexate as reference, were determined by means of a prospective cohort. RESULTS: Our study included 2845 patients (8954 treatment cycles; 9642 patient-years). Ustekinumab and secukinumab had the lowest rate of adverse events for several of the system organ classes, with a statistically significant decreased rate ratio (IRR of <1), whereas cyclosporine and infliximab had the highest, with an increased rate ratio (IRR of ≥5). LIMITATIONS: Observational study, drug allocation not randomized, depletion of susceptibles, and prescribed doses not registered. CONCLUSION: Our data provide comparative safety information in the real-life setting that could help clinicians selecting between available products.

Ixekizumab vs ustekinumab for skin clearance in patients with moderate to severe psoriasis after a year of treatment: Real-world practice.

There is a lack of real practice studies comparing ustekinumab and ixekizumab effectiveness and safety. The main aim of this study was to compare the effectiveness and safety of both drugs used to treat moderate-to-severe psoriasis patients over 52 weeks. The secondary objective was to identify which clinical variables could have an impact on its effectiveness. A retrospective observational study was carried out, comparing the first 28 patients treated with ustekinumab after its commercialization was compared to the first 35 patients treated with ixekizumab. Although a higher level of skin clearance was achieved with ixekizumab with a PASI 90 and 100 response of 54.3% and 40% compared to 42.9% and 25% for ustekinumab, these differences were not statistically significant. Ixekizumab achieved a higher PASI 90 response in those patients with BMI > 27 (slightly overweight), which was statistically significant (P = .024). Ustekinumab had a greater survival at 52 weeks than ixekizumab, with a trend towards statistical significance (P = .052). Ixekizumab achieved higher skin clearance rates (PASI 90 and 100 response) than ustekinumab, with no statistically significant differences. However, ixekizumab should be specially considered in overweight patients.

Comparative study of the efficacy and safety of secukinumab vs ixekizumab in moderate-to-severe psoriasis after 1 year of treatment: Real-world practice.

There are no studies which directly compare efficacy in Psoriasis Area and Severity Index (PASI) response of secukinumab and ixekizumab. The main aim of this study was to compare the efficacy and safety of both drugs used to treat moderate-to-severe psoriasis patients over 52 weeks. Secondary objectives were to identify which factors related to prior biologic treatment influenced their efficacy and analyze data obtained at 12 weeks. A retrospective observational study was carried out, in which a group of the first 59 patients treated with secukinumab after its commercialization, was compared with another group of the first 29 patients treated with ixekizumab. The PASI 75, 90, and 100 response obtained at 52 weeks was 64.4%, 49.2%, and 41.4% for secukinumab and 75.9%, 62.1%, and 41.4% for ixekizumab, respectively, with no statistically significant differences. Regarding previous biological treatment, both treatments showed a decrease in efficacy as the number of prior biologics increases. No differences were found between secukinumab and ixekizumab in bio-naïve or bio-experienced patients, with the exception of a higher PASI 75 response at week 52 for ixekizumab in those patients with two or more previous biologics (P = .039) Secukinumab and ixekizumab have demonstrated high efficacy and safety, with no statistically significant differences.

Quality of Life of Cohabitants of People Living with Acne.

The aim of this study was to analyse the levels of anxiety, depression, and quality of life of individuals living with acne patients (cohabitants). The study included patients, cohabitants, and controls; a total of 204 participants. Patients' health-related quality of life was measured with the Dermatology Life Quality Index (DLQI), while cohabitants' quality of life was measured with the Family Dermatology Life Quality Index (FDLQI). The psychological state of all participants was measured with the Hospital Anxiety and Depression Scale (HADS). Presence of acne impaired the quality of life of 89.4% of the cohabitants. The FDLQI scores of cohabitants were significantly associated with the DLQI scores of the patients (rp = 0.294; p = 0.044). Anxiety and depression levels in cohabitants were significantly higher than in controls (p < 0.01). In conclusion, acne may have a negative impact on quality of life and psychological well-being of patients and their cohabitants.

Secukinumab versus ustekinumab for skin clearance in patients with moderate to severe psoriasis after a year of treatment: Real-world practice.

A descriptive retrospective, study comparing the first 29 patients who received ustekinumab at our unit following its approval in September 2009 with 30 patients who received secukinumab after its marketing in Spain in November 2015 was conducted. The secukinumab treatment group showed higher whitening rates and a higher percentage of patients reached a psoriasis area and severity index (PASI) 75 response (89.65 vs. 73.33%, p = .108) than those in the ustekinumab treatment group at Week 52. The number of patients achieving a PASI 90 response was particularly remarkable and statistically significant (82.75 vs. 43.33%, p = .002). Better PASI 75 response rates were also observed in the secukinumab group than in the ustekinumab group after 52 weeks in biologic-naïve patients (89 vs. 72%, p = .586) and among those previously treated with one line (92 vs. 100%, p = 1.00) or with two or more previous biologic lines (88 vs. 62%, p = .336). These differences were greater in the number of patients reaching a PASI 90 response in the secukinumab group than in the ustekinumab group in biologic-naïve patients (78 vs. 63%, p = .642) and in those previously treated with one (92 vs. 50%, p = .083) or with two or more treatment lines (75 vs. 31%, p = .080). These regular-practice results overlap or surpass those obtained in the CLEAR clinical trial.

Correction to: Determinants of Influenza Mortality Trends: Age-Period-Cohort Analysis of Influenza Mortality in the United States, 1959-2016.

First, we use Lexis surfaces based on Serfling models to highlight influenza mortality patterns as well as to identify lingering effects of early-life exposure to specific influenza virus subtypes (e.g., H1N1, H3N2).

Determinants of Influenza Mortality Trends: Age-Period-Cohort Analysis of Influenza Mortality in the United States, 1959-2016.

This study examines the roles of age, period, and cohort in influenza mortality trends over the years 1959-2016 in the United States. First, we use Lexis surfaces based on Serfling models to highlight influenza mortality patterns as well as to identify lingering effects of early-life exposure to specific influenza virus subtypes (e.g., H1N1, H3N2). Second, we use age-period-cohort (APC) methods to explore APC linear trends and identify changes in the slope of these trends (contrasts). Our analyses reveal a series of breakpoints where the magnitude and direction of birth cohort trends significantly change, mostly corresponding to years in which important antigenic drifts or shifts took place (i.e., 1947, 1957, 1968, and 1978). Whereas child, youth, and adult influenza mortality appear to be influenced by a combination of cohort- and period-specific factors, reflecting the interaction between the antigenic experience of the population and the evolution of the influenza virus itself, mortality patterns of the elderly appear to be molded by broader cohort factors. The latter would reflect the processes of physiological capital improvement in successive birth cohorts through secular changes in early-life conditions. Antigenic imprinting, cohort morbidity phenotype, and other mechanisms that can generate the observed cohort effects, including the baby boom, are discussed.