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The weathering hypothesis proposes that marginalized people experience faster biologic aging due to cumulative stress which translates to chronic disease disparities. We assessed telomere length (TL) differences, an aging biomarker, by sexual orientation (bisexual, gay/lesbian, straight) among 102,258 individuals enrolled in the Resource for Genetic Epidemiology Research on Aging Cohort during 2008 through 2011 (mean age of 60.6 years, 58% female, and 7.6% bisexual/gay/lesbian). We used linear models to estimate differences in telomere length, stratified by sex/gender and adjusted for age (at salivary sample) and socio-demographic variables and Kitagawa-Blinder-Oaxaca decomposition to quantify contributions of participant factors on TL differences. Among females, there was no significant difference in age-adjusted telomere length by sexual orientation after adjustment for socio-demographics (ref: straight; bisexual 0.007, 95%CI: -0.03 to 0.04; lesbian: 0.005, 95%CI: -0.02 to 0.03). Among males, only gay (-0.04, 95%CI: -0.06 to -0.02) but not bisexual (-0.02, 95%CI: -0.06 to 0.02) men had significantly shorter age-adjusted telomere length compared to straight men after adjusting for socio-demographic variables. Decomposition analysis identified ever smoking and marital status as significant drivers of the gay-straight disparity. Studies confirming our findings are needed and the implications of shorter telomeres on gay men's health requires further investigation.
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Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterised by recurrent painful nodules, abscesses, fistulas and scarring. The primary distinguishing factor in the complex, yet still not fully understood, pathogenesis is an inflammation occurring within the hair follicle, followed by an immune response leading to further development of the skin lesions seen in HS. The treatment of patients with HS is very difficult due to the complexity of the lesions and the frequent tendency to recurrence, which also has a negative impact on the psychological state of patients and directly translates into a reduced quality of life. This review article addresses the pathogenesis, clinical presentation of HS and, in particular, explores the new therapeutic options available.
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BACKGROUND: The appropriate response to mass causality biological events requires well-established preparedness and providing a surge capacity. In such a situation, a practical solution is to convert large public venues into shelter hospitals. Due to the lack of a guideline for the transformation of a large public center into a hospital, the present study collected the design criteria for the transformation of public buildings into shelter hospitals in response to biological events such as epidemics or mass causality biological accidents. METHODS: The keywords were searched in Scopus, Web of Science, and PubMed databases until November 2021. This systematic review was conducted using terms related to mass causality biological accidents, shelter hospitals, and design criteria. RESULTS: Of 1802 extracted articles, duplicates (n = 280) and unrelated publications (n = 1342) were left out in the initial evaluation. Among 180 remained papers, 29 records satisfied our criteria after reviewing abstracts and full texts. Most of the included studies were related to the transformation of public venues into hospitals in response to the coronavirus disease 2019 (COVID-19) pandemic. The investigated themes included site selection, layout and structure, waste and wastewater management, ventilation, communication, food and medicine delivery, humanitarians and social supports, post-treatment care, and Management measures. CONCLUSIONS: In summary, large public venues are highly recommended alternatives for surge capacity in response to mass causality biological accidents. However, the main challenges for using these centers are the provision of basic requirements such as water and electricity, ventilation, and available space.
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COVID-19 , Humanos , COVID-19/epidemiología , Arquitectura y Construcción de Hospitales/métodos , Arquitectura y Construcción de Hospitales/normas , Refugio de Emergencia/estadística & datos numéricos , Planificación en Desastres/métodosRESUMEN
Chronic rhinosinusitis with nasal polyps (CRSwNP) significantly impacts quality of life and often presents therapeutic challenges, with biologics like dupilumab showing promise in managing severe, uncontrolled cases. The aim of this study was to assess the influence of overweight on the effectiveness of dupilumab in patients with uncontrolled CRSwNP. This retrospective study analyzed treatment outcomes of 75 CRSwNP patients receiving dupilumab, categorizing them into underweight/normal-weight (BMI ≤ 24.9 kg/m2) and overweight/obese (BMI ≥ 25 kg/m2) groups. Outcome measures included changes in nasal polyp score (NPS) and sinonasal outcome test (SNOT-22) scores. Results demonstrated that the underweight/normal-weight group experienced significantly greater improvements in NPS and a higher rate of total NPS improvement compared to the overweight/obese group. While SNOT-22 scores improved in both groups, no significant differences were observed. Among patients with comorbid asthma, the underweight/normal-weight subgroup also showed significantly better outcomes, including greater reductions in both NPS and SNOT-22 scores. Multiple regression analysis identified BMI as an independent prognostic factor for NPS outcomes. The findings suggest that overweight/obesity adversely affects the response to dupilumab in CRSwNP, emphasizing the need for personalized treatment strategies considering BMI.
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Anticuerpos Monoclonales Humanizados , Índice de Masa Corporal , Pólipos Nasales , Sobrepeso , Rinitis , Sinusitis , Humanos , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/complicaciones , Masculino , Femenino , Sinusitis/tratamiento farmacológico , Sinusitis/complicaciones , Anticuerpos Monoclonales Humanizados/uso terapéutico , Estudios Retrospectivos , Persona de Mediana Edad , Rinitis/tratamiento farmacológico , Rinitis/complicaciones , Enfermedad Crónica , Sobrepeso/complicaciones , Sobrepeso/tratamiento farmacológico , Adulto , Resultado del Tratamiento , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Anciano , Calidad de Vida , RinosinusitisRESUMEN
The epidermal growth factor (EGF) receptor (EGFR) is activated by the binding of one of seven EGF-like ligands to its ectodomain. Ligand binding results in EGFR dimerization and stabilization of the active receptor conformation subsequently leading to activation of downstream signaling. Aberrant activation of EGFR contributes to cancer progression through EGFR overexpression/amplification, modulation of its positive and negative regulators, and/or activating mutations within EGFR. EGFR targeted therapeutic antibodies prevent dimerization and interaction with endogenous ligands by binding the ectodomain of EGFR. However, these antibodies have had limited success in the clinic, partially due to EGFR ectodomain resistance mutations, and are only applicable to a subset of patients with EGFR-driven cancers. These limitations suggest that alternative EGFR targeted biologics need to be explored for EGFR-driven cancer therapy. To this end, we analyze the EGFR interfaces of known inhibitory biologics with determined structures in the context of endogenous ligands, using the Rosetta macromolecular modeling software to highlight the most important interactions on a per-residue basis. We use this analysis to identify the structural determinants of EGFR targeted biologics. We suggest that commonly observed binding motifs serve as the basis for rational design of new EGFR targeted biologics, such as peptides, antibodies, and nanobodies.
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Receptores ErbB , Receptores ErbB/química , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Receptores ErbB/genética , Humanos , Productos Biológicos/química , Productos Biológicos/farmacología , Productos Biológicos/metabolismo , Modelos Moleculares , Unión Proteica , Sitios de Unión , Diseño de Fármacos , LigandosRESUMEN
Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder of unknown etiology characterized by systemic inflammation, high fever, salmon-colored skin rash, arthralgia, and arthritis. Patients with AOSD may also present with elevated inflammatory markers, hyperferritinemia, anemia, leukocytosis, hepatosplenomegaly, and lymphadenopathy. Glucocorticoids and biological disease-modifying anti-rheumatic drugs, including the anti-interleukin-1 agent anakinra, are used in the management of AOSD. This retrospective single-center study included patients with AOSD who were registered at our tertiary center, and received anakinra treatment. The primary outcome of our study was the proportion of patients who achieved complete remission of disease-related clinical and laboratory complications. The glucocorticoid treatment profiles of the included patients before and after anakinra treatment were also analyzed. The occurrence of serious and non-serious adverse events was recorded to analyze the safety profile of anakinra. Thirty-four patients with AOSD, including 25 females (73.5%), were enrolled in the study. Twelve patients (35.3%) achieved complete remission and 14 patients (41.2%) achieved partial remission after anakinra treatment. Eight patients (23.5%) did not response to anakinra. Anakinra significantly decreased the number of patients receiving glucocorticoid treatment [33 (97%) vs. 22 (64.7%), p < 0.001] and the mean daily glucocorticoid dose [19 ± 13.5 mg vs. 4.6 ± 5.8 mg, p < 0.001]. Mild adverse events occurred in 11 patients (32.3%) with injection site reactions being the most common. One patient (2.9%) was diagnosed with tuberculosis within the treatment period. Anakinra is an effective and generally safe option for biological treatment initiation in the management of AOSD.
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BACKGROUND: Temporary eosinophilia is a potential adverse reaction of monoclonal antibody therapies in the treatment of a variety of type 2 inflammatory conditions, including asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). The pathophysiology, epidemiology, and clinical significance of eosinophilia and eosinophilic adverse reactions following the initiation of biologic therapy are unclear. OBJECTIVES: To describe the postmarketing, eosinophilic adverse reactions with clinical significance in patients treated with the 3 biologic therapies approved by the U.S. Food and Drug Administration (FDA) for CRSwNP: dupilumab, omalizumab, and mepolizumab. METHODS: The FDA Adverse Event Reporting System (FAERS) Public Dashboard was searched for eosinophilic adverse reactions related to dupilumab, omalizumab, and mepolizumab treatments from November 2004 to December 2022. Data regarding each of the eosinophilic adverse reactions were extracted and analyzed. RESULTS: A total of 218, 270, and 134 reports of eosinophilic adverse reactions were reported among patients who were treated with dupilumab, omalizumab, and mepolizumab, respectively. The most common eosinophilic adverse reaction was eosinophilic granulomatosis with polyangiitis (338 patients), followed by eosinophilic respiratory tract reactions (158 patients). The most common indication for biological treatment among the reaction groups was asthma. CONCLUSIONS: Eosinophilic adverse reactions are rare but consequential complications of biological treatment. They are more common among patients treated for asthma and chronic rhinosinusitis with nasal polyposis. Measuring and monitoring blood eosinophil levels may be appropriate in specific clinical instances when patients are started on different biologic therapies for type 2 inflammatory conditions.
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Background: Rotator cuff repair is one of the most frequently performed procedures in orthopedic surgery. However, considering the limited healing potential of rotator cuff tendons, several augmentation strategies have evolved to enhance tendon healing. The purpose of this article was to present a new surgical technique called Bio-Ravioli. Methods: Patients with repairable full-thickness posterosuperior rotator cuff tear and a moderate-to-high risk of healing failure were chosen as candidates for the Bio-Ravioli procedure. It is a biologic augmentation strategy to increase healing potential of arthroscopic rotator cuff repair by use of a biologic graft fixed at the bone-tendon interface. The Bio-Ravioli consists of microfragmented autologous subacromial bursal tissue enveloped in a patch of compressed autologous long head of biceps tendon tissue. The rotator cuff is then repaired to the bone and over the graft using a transosseus equivalent configuration. Conclusion: The Bio-Ravioli technique represents an easy and reliable way to increase the healing potential at the bone-tendon interface by using autologous mesenchymal stem cells from different sources: subacromial bursa and long head of the biceps tendon.
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INTRODUCTION: Monoclonal antibodies (mAbs) and other biological agents are being increasingly approved in the last years with very different indications. Their highly heterogeneous immunosuppressive effects, mechanisms of action and pharmacokinetics require comprehensive individualized vaccination schedules. AREAS COVERED: Vaccination for immunocompromised patients. Prevention and treatment with mAbs and other biological therapies. EXPERT OPINION: Current recommendations on vaccine schedules for patients under mAbs or other biological treatments are based on expert opinions and are not individualized according to each vaccine and treatment. No studies are focusing on the high heterogeneity of these agents, that are exponentially developed and used for many different indications. Recent paradigm changes in vaccine development (boosted by the COVID-19 pandemic) and in the mAbs use for prophylactic purposes (changing 'vaccination' by 'immunization' schedules) has been witnessed in the last years. We aimed at collecting all mAbs used for treatment or prevention, approved as of 1 January 2024, by the EMA. Based on available data on mAbs and vaccines, we propose a comprehensive guide for personalizing vaccination. Recent vaccine developments and current population strategies (e.g. zoster vaccination or prophylactic nirsevimab) are discussed. This review aims to be a practical guideline for professionals working in vaccine consultations for immunosuppressed patients.
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OBJECTIVES: There is no consensus on the therapeutic strategy of rheumatologists for patients with spondyloarthritis (SpA) and concomitant fibromyalgia (FM).The main aim of this study was to identify, in a population of rheumatologists practicing in Normandy, France, the determinants associated with their decision to prescribe a first biologic DMARD (bDMARD) in patients with Spa/FM. Specific objectives were to evaluate professional prescribing practices to identify a set of criteria likely to contribute to the therapeutic decision of rheumatologists, and to validate the relevance of these criteria. METHOD: This is a cross-sectional survey-based study using a mixed (qualitative and quantitative) method. The quantitative approach was web-based and conducted among rheumatologists in Normandy. RESULTS: The qualitative study allowed us to identify a set of criteria likely to contribute to the therapeutic decision of rheumatologists. In the quantitative study, 54/113 rheumatologists filled the questionnaire. Four criteria were considered by all respondents to contribute to their decision to prescribe a first bDMARD: arthritis on physical examination, extra-articular manifestations, systemic inflammation and structural damage on imaging. CONCLUSIONS: The determinants associated with the decision of rheumatologists to prescribe a first bDMARD in patients with SpA/FM were mostly objective, in line with the recommendations in the literature. Most criteria were more related to an approach aimed at ensuring the diagnosis of SpA than evaluating its activity or severity.
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Background: Ustekinumab (UST) is an effective treatment option in Crohn's disease (CD) and ulcerative colitis (UC). However, it still remains unclear if therapeutic drug monitoring could be helpful to guide clinicians. Objectives: The aim of our study was to analyze the relationship between UST through levels (USTTL) and clinical outcomes in real-world inflammatory bowel disease (IBD) patients. Design: We performed a unicentric retrospective study including patients with IBD under UST treatment with at least one level determination. Methods: The following variables were analyzed at the initiation of UST and at each USTTL measurement: clinical response and remission using the Harvey-Bradshaw Index (HBI) for CD and the Partial Mayo Score (pMayo) for UC; biochemical response and remission using fecal calprotectin and C-reactive protein, among others. Two periods were considered: P1 (time between induction and the first determination of USTTL) and P2 (time between USTTL1 and the second determination of USTTL). Results: We included 125 patients, 117 with CD. In P1, 62.4% of patients were on subcutaneous maintenance, and the median USTTL1 was 3.1 µg/mL (1.6-5.3). In 44.8% of CD patients (48/117), clinical remission was achieved, with USTTL1 significantly higher than those who did not achieve remission (3.7 µg/mL (2.3-5.4) vs 2.3 µg/mL (1.1-5.2); p = 0.04). In the 46 patients with two determinations, statistically significant differences were found between variables in P2 versus P1: clinical remission (73.9% vs 21.7%; p = 0.001); USTTL (7.2 µg/mL (4.7-11.7) vs 3.4 µg/mL (1.9-6.4); p < 0.001), HBI (4 (4-4.3) vs 8 (4-9); p < 0.001), pMayo (1 (1-3.3) vs 4.5 (3-5); p = 0.042), and corticosteroid use (26.1% vs 41.3%; p = 0.024). Receiver-Operating-Characteristic (ROC) curves were calculated for clinical remission in P2, with USTTL cutoff value of 6.34 µg/mL for clinical remission and a high rate of intensified patients (98%). Conclusion: High serum levels of UST were associated with clinical remission during treatment for IBD under intensification treatment, with a cutoff point of 6.3 µg/mL.
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Psoriasis, a chronic inflammatory skin disease, presents unique challenges when co-occurring with HIV. Tildrakizumab, an IL-23p19 inhibitor, has demonstrated efficacy in treating moderate-to-severe psoriasis. This retrospective case series reports three individuals living with HIV and psoriasis treated with tildrakizumab. Clinical outcomes, including Psoriasis Area and Severity Index (PASI) and HIV viral load, were recorded over a year. All three patients achieved significant clinical improvements with tildrakizumab, with PASI scores improving by over 95%. No adverse effects were reported, and HIV viral loads remained undetectable. Tildrakizumab appears to be a safe and effective treatment option for psoriasis in individuals living with HIV, providing significant benefits without compromising HIV control.
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The development of new large molecule drug therapies along with the innovation of biologic-device combination products such as prefilled syringes, autoinjectors and pen injectors have significantly impacted the treatment of new diseases and has improved the process of administering parenteral medicines. To support the regulatory approval of a new biologic-device combination products or subsequent chemistry, manufacturing and control changes impacting a combination product, sponsor companies must thoroughly assess the potential impact to product quality, safety and efficacy. In this report, a risk-based process to determine the potential impact to product quality, safety, and efficacy as well as corresponding regulatory actions supporting a chemistry, manufacturing and control change is presented. The risk assessment includes the standardized assessment of a) chemistry, manufacturing and control risk factors, potential responses and appropriately weighted scoring; b) pharmacokinetic risk factors, potential responses and appropriately weighted scoring; and c) the use of a 2-dimensional risk grid to combine the chemistry, manufacturing and control risks and pharmacokinetic risks to provide a regulatory recommendation. Three case studies (two clinical case studies and a post-approval case study) are provided to demonstrate the assessment process and capabilities.
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Productos Biológicos , Inyecciones Subcutáneas/instrumentación , Medición de Riesgo , Humanos , Productos Biológicos/farmacocinética , Productos Biológicos/administración & dosificación , Factores de RiesgoRESUMEN
Purpose: This article aims to present a case report of a patient with Follicular occlusion triad (FOT) who achieved successful disease control with adalimumab combined with isotretinoin and provide a comprehensive review of the current research progress on biologic therapies for FOT.Methods: We report a case of a 22-year-old female patient diagnosed with FOT, who was treated with adalimumab combined with isotretinoin after failing to respond to conventional therapies. A systematic literature review was conducted to summarize the current research progress on biologic therapies for FOT, including TNF-α inhibitors, IL-17 inhibitors, IL-12/IL-23 inhibitors, IL-23 inhibitors, IL-1 inhibitors, and other novel biologic agents.Results: The patient achieved significant improvement in skin lesions, pain, and quality of life after three months of treatment with adalimumab combined with isotretinoin, without experiencing severe adverse reactions. The literature review revealed that adalimumab and secukinumab are the two FDA-approved biologics for FOT, while others, such as bimekizumab, infliximab, anakinra, and bermekimab, have shown promise in clinical studies.Conclusions: Biologic therapies have revolutionized FOT management, providing effective options for patients unresponsive to conventional treatments. As our understanding of FOT pathogenesis and the mechanisms of action of biologics grows, further advancements in biologic therapies for FOT are expected.
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Adalimumab , Fármacos Dermatológicos , Quimioterapia Combinada , Isotretinoína , Humanos , Adalimumab/uso terapéutico , Femenino , Adulto Joven , Isotretinoína/uso terapéutico , Fármacos Dermatológicos/uso terapéutico , Resultado del Tratamiento , Terapia BiológicaRESUMEN
Background Rheumatoid arthritis and psoriatic arthritis patients have dysregulated immune system parameters that may increase infection risk at baseline. In addition, treatment of these conditions with immunosuppressive medications may lead to the development of secondary immunodeficiency (SID). Our objective was to assess SID in a cohort on immunosuppressive medications. We hypothesized that SID is clinically detectable by assessing immune parameters and polysaccharide and protein-based vaccination responses. Methodology A prospective cohort study of 42 subjects on immunosuppressive medications was assessed. Analysis included immunoglobulin levels, lymphocyte subsets, and two-step response to diphtheria, tetanus, and 23-valent Streptococcus pneumoniae vaccinations. Exclusions included primary immunodeficiency, malignancy, pregnancy, neutropenia, immunoglobulin replacement, prior B-cell-depleting medication or chemotherapy, use of non-immunosuppressive medication, or recent use of glucocorticoids. Suboptimal vaccine response was defined as an abnormal response based on standard criteria for each vaccine. Results Low IgM levels (below 50 mg/dL) occurred in seven (17%) subjects and IgG (below 650 mg/dL) in three (7%) subjects. Impaired lymphocyte subsets were uncommon. In total, 33 (78%) subjects completed the two-step vaccination assessment. Overall, 29 of 33 (88%) subjects demonstrated suboptimal response to pneumococcal vaccination, 10 (30%) demonstrated suboptimal response to diphtheria, and four (12%) to tetanus. Two (6%) subjects demonstrated suboptimal response to all vaccinations. Finally, 31 (94%) subjects demonstrated suboptimal response to at least one vaccination. Conclusions SID may develop, is clinically detectable, and most notably demonstrated in suboptimal responses to polysaccharide vaccinations, especially against S. pneumoniae.
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Background: Extracorporeal shockwave therapy (ESWT) is a noninvasive treatment modality that is used in the treatment of chronic Achilles tendinopathy (AT). Purposes: To (1) retrospectively assess outcomes after ESWT for both noninsertional AT (NAT) and insertional AT (IAT) at >1-year follow-up and (2) identify potential predictors of outcomes. Study Design: Cohort study; Level of evidence, 3. Methods: Chart review was conducted to identify patients who underwent ESWT for AT with a minimum of 1-year follow-up. Data collected and assessed included patient demographic characteristics, pathological characteristics including the location of AT (NAT or IAT), presence of a Haglund deformity, and severity of tendon degeneration on magnetic resonance imaging (MRI), in addition to treatment characteristics including number of sessions and intensity of ESWT. The Victorian Institute of Sports Assessment-Achilles (VISA-A) and visual analog scale (VAS) pain scores were obtained before ESWT, 6 months after ESWT, and at final follow-up. Failures were also recorded, which were defined as no improvement in VISA-A or VAS scores or need for surgical intervention. Linear regression was performed to identify potential predictors of inferior subjective clinical outcomes and failures. Survival analysis was conducted using Kaplan-Meier curves. Results: The study included 52 patients with IAT and 34 patients with NAT. The mean follow-up in the NAT cohort was 22.3 ± 10.2 months and the mean follow-up in the IAT cohort was 26.8 ± 15.8 months. Improvements in VISA-A and VAS scores were observed in the NAT cohort at 6-month follow-up and at final follow-up (P < .05). Improvements in VISA-A and VAS scores were recorded in the IAT cohort at 6-month follow-up, which subsequently deteriorated at final follow-up. In the NAT cohort, the failure rate at 6-month follow-up was 11.8%, which increased to 29.4% at final follow-up. In the IAT cohort, the failure rate at 6-month follow-up was 32.7%, which increased to 59.6% at final follow-up. Predictors of inferior subjective clinical outcomes and failures in the NAT cohort included pre-ESWT subjective clinical score, male sex, presence of a cardiovascular risk factor, and more severe MRI grading of tendinopathy. Predictors of inferior subjective clinical outcomes and failures in the IAT cohort included pre-ESWT subjective clinical score and more severe MRI grading of tendinopathy. Conclusion: Superior subjective clinical outcomes together with a lower failure rate were maintained for >1 year in the NAT cohort compared with the IAT cohort, calling into question the long-term benefit of ESWT for patients with IAT.