Differences In Disease Progression Research Articles

Association of NOTCH3 Variant Risk Category With 2-Year Clinical and Radiologic Small Vessel Disease Progression in Patients With CADASIL.

Pathogenic variants in NOTCH3 are the main cause of hereditary cerebral small vessel disease (SVD). SVD-associated NOTCH3 variants have recently been categorized into high risk (HR), moderate risk (MR), or low risk (LR) for developing early-onset severe SVD. The most severe NOTCH3-associated SVD phenotype is also known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to investigate whether NOTCH3 variant risk category is associated with 2-year progression rate of SVD clinical and neuroimaging outcomes in CADASIL. A single-center prospective 2-year follow-up study was performed of patients with CADASIL. Clinical outcomes were incident stroke, disability (modified Rankin Scale), and executive function (Trail Making Test B given A t-scores). Neuroimaging outcomes were mean skeletonized mean diffusivity (MSMD), normalized white matter hyperintensity volume (nWMHv), normalized lacune volume (nLV), and brain parenchymal fraction (BPF). Cox regression and mixed-effect models, adjusted for age, sex, and cardiovascular risk factors, were used to study 2-year changes in outcomes and differences in disease progression between patients with HR-NOTCH3 and MR-NOTCH3 variants. One hundred sixty-two patients with HR (n = 90), MR (n = 67), and LR (n = 5) NOTCH3 variants were included. For the entire cohort, there was 2-year mean progression for MSMD (β = 0.20, 95% CI 0.17-0.23, p = 7.0 × 10-24), nLV (β = 0.13, 95% CI 0.080-0.19, p = 2.1 × 10-6), nWMHv (β = 0.092, 95% CI 0.075-0.11, p = 8.8 × 10-20), and BPF (β = -0.22, 95% CI -0.26 to -0.19, p = 3.2 × 10-22), as well as an increase in disability (p = 0.002) and decline of executive function (β = -0.15, 95% CI -0.30 to -3.4 × 10-5, p = 0.05). The HR-NOTCH3 group had a higher probability of 2-year incident stroke (hazard ratio 4.3, 95% CI 1.4-13.5, p = 0.011), and a higher increase in MSMD (β = 0.074, 95% CI 0.013-0.14, p = 0.017) and nLV (β = 0.14, 95% CI 0.034-0.24, p = 0.0089) than the MR-NOTCH3 group. Subgroup analyses showed significant 2-year progression of MSMD in young (n = 17, β = 0.014, 95% CI 0.0093-0.019, p = 1.4 × 10-5) and premanifest (n = 24, β = 0.012, 95% CI 0.0082-0.016, p = 1.1 × 10-6) individuals. In a trial-sensitive time span of 2 years, we found that patients with HR-NOTCH3 variants have a significantly faster progression of major clinical and neuroimaging outcomes, compared with patients with MR-NOTCH3 variants. This has important implications for clinical trial design and disease prediction and monitoring in the clinic. Moreover, we show that MSMD is a promising outcome measure for trials enrolling premanifest individuals.

#901 Natural history of idiopathic nephrotic syndrome: the UK National RaDaR Idiopathic Nephrotic Syndrome Cohort

Abstract Background and Aims Idiopathic nephrotic syndrome (INS) is an important class of proteinuric renal disease leading to kidney failure (KF). Here we describe the natural history of INS and congenital nephrotic syndrome (NS) using the UK National Registry of Rare Kidney Diseases Idiopathic Nephrotic Syndrome (RaDaR-INS) Cohort, including retrospective and prospective data from 4610 patients with NS not attributable to glomerulonephritis or systemic disorders recruited from 107 adult and paediatric kidney units across the UK since 2010. Method Participant eligibility of RaDaR-INS Cohort patients included ≥12 months observation from disease onset and no KF (CKD stage 5 or on renal replacement therapy) at or prior to disease onset. Disease onset date was defined as first database occurrence of kidney biopsy, primary diagnosis or protein-creatinine ratio (PCR) ≥1.5 g/g. Participants were sub-categorized into those with a genetic diagnosis (INS-genetic), biopsy-proven FSGS (FSGS-biopsy), biopsy–proven minimal change disease (MCD-biopsy) and those with no genetic or biopsy-proven diagnosis (INS-no genetic or biopsy diagnosis). Participants with a biopsy-proven MCD diagnosis and a subsequent biopsy proven FSGS diagnosis were included in both MCD-biopsy and FSGS-biopsy categories and formed a category of their own (MCD progressing to FSGS). Longitudinal proteinuria, assessed as time-average protein-to-creatinine ratio (TA-PCR), and eGFR slope were calculated over the full duration of follow-up or until KF. Kidney survival was calculated from disease onset to event (KF or death) and censored at last follow-up. Results Of the 4066 patients meeting eligibility, median age at disease onset was 28 years (IQR 6-51), with children (<18 yrs) representing 39% of the study population. Median proteinuria was 6.4 g/g (IQR 3.1-10.8; n = 923), while mean eGFR was 118 mL/min/1.73 m2 (SD 49; n = 240) and 69 mL/min/1.73 m2 (SD 34; n = 906) for children and adults, respectively. Median follow-up duration was 8.2 yrs (IQR 4.3-13.1) with KF/death events occurring in 30% of patients. Mean TA-PCR was greater in children than adults (5.0 g/g (SD 13.9) vs. 1.9 g/g (SD 2.5), as was annual rate of loss of eGFR (−7.4 mL/min/1.73 m2 (SD 21.8) vs. −3.1 mL/min/1.73 m2 (SD 10.2)). Characteristics at disease onset and clinical outcomes of the INS cohort sub-categories are presented in Fig. 1. Kaplan Meier survival plots of each sub-category, and further divided into children and adults, illustrate the poor survival probability for patients with FSGS, particularly INS-genetic patients who are predominantly diagnosed in childhood (Fig. 2). While INS with no genetic or biopsy diagnosis presenting in childhood exhibits disease course and outcomes similar to MCD-biopsy patients, those diagnosed in adulthood have a more rapid disease course similar to FSGS-biopsy patients. Conclusion The RaDaR-INS cohort represents a large study population with lengthy follow-up data. These analyses illustrate the difference in disease progression and survival rates for INS patients with different causes or histological descriptions, highlighting in particular an unmet need for effective treatments for patients with nephrotic syndrome and FSGS.

Sex differences in amino acid composition in a rodent model of ARPKD, the PCK rat

Polycystic Kidney Disease (PKD) is a severe, genetically inherited disease that leads to renal failure. Like several other chronic kidney diseases, male sex is a risk factor for accelerated PKD. Rat models of both Autosomal Recessive and Dominant forms of PKD (PCK and Han:SPRD rats, respectively) exhibit sex differences in disease progression. Previous studies have found that amino acids (AAs) and peptides are predominant constituents of cystic fluid. We hypothesized that AA homeostasis in male and female cystic fluid would demonstrate sexual dimorphism, and these differences may provide essential information about the progression of cystogenesis. We quantified the AAs in cystic fluid, plasma, and urine in PCK and control Sprague Dawley (SD) rats (only plasma and urine for SD rats). Of the 42 AAs that were measured, only asparagine, serine, aspartic acid, glutamic acid, beta-alanine, cystathionine, and leucine were NOT significantly different between SD and PCK plasma values. Interestingly, only 18 AAs were significantly different in urine of PCK rats compared to SD rats. In SD rats, between sexes, 26 AAs were significantly different in plasma and 5 were significantly different in urine. Among PCK rats, 13 AAs in plasma, 9 AAs in urine, and 4 AAs in cystic fluid were significantly different between sexes. The 4 AAs that differed between male and female cystic fluid were 1-methylhistidine, 3-methylhistidine, ethanolamine, and taurine. Moreover, taurine was the most abundant AA in cystic fluid. Taurine concentrations in both plasma (165 ± 9 vs. 128 ± 4 μM, N=6, p=0.003) and cystic fluid (7508 ± 469 vs. 4557 ± 788 μM, N=6, p=0.01) were significantly different between sexes in the PCK rats (male vs. female, respectively). Urine values for the PCK rats (9705 ± 1863 vs. 7570 ± 1631 μM, N=6) were not significantly different in males and females; however, the average urinary taurine excretion in PCK rats was nearly 4-fold greater than SD rats (8637 ± 1223 vs. 2219 ± 465 μM, N=12, p<0.0001). There were no significant differences in taurine concentrations between SD male and female rat plasma (202 ± 17 vs. 194 ± 7.0 μM, N=6) or urine (2044 ± 614 vs. 2395 ± 752 μM, N=6). Western blot of the taurine transporter, TauT, detected bands at 50 and 75 kDa, and both bands were significantly reduced by ~50% in PCK kidneys compared to SD kidneys. Lastly, immunolabeling in PCK kidney sections demonstrated that TauT is present at the apical membrane of cyst epithelia. These results point to a potential role for AAs, and specifically for taurine in cystogenesis, which likely varies by sex in diseased, but not healthy kidneys. R00 HL153686, BX004024, R01 DK126720, R01 DK129227. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Large phenotypic diversity by genotype in patients with GNE myopathy: 10years after the establishment of a national registry in Japan.

GNE myopathy is an ultra-rare autosomal recessive distal myopathy caused by pathogenic variants of the GNE gene, which encodes a key enzyme in sialic acid biosynthesis. The present study aimed to examine the long-term progression of GNE myopathy, genotype-phenotype correlations, and complications to provide useful information for predicting patient progression and designing clinical trials using a large collection of registry data over a 10-year period. We analyzed 220 Japanese patients with GNE myopathy from a national registry in Japan. Diagnoses were confirmed by genetic curators based on genetic analysis reports. We analyzed registration sheets and annually updated items completed by attending physicians. In total, 197 of 220 participants (89.5%) carried p.D207V or p.V603L in at least one allele. The median disease duration to loss of ambulation was estimated to be 10 years in p.V603L homozygotes (n = 48), whereas more than 90% of p.D207V/p.V603L compound heterozygotes were estimated to be ambulatory even 20 years after disease onset according to Kaplan-Meier analysis (p < 0.001). Moreover, participants with a younger age of onset lost ambulation earlier regardless of genotype. A decline in respiratory function was observed as the disease progressed, particularly in p.V603L homozygotes, whereas none of the p.D207V/p.V603L compound heterozygotes showed a decline. The present study demonstrated large differences in disease progression and respiratory function between genotypes. Moreover, age of onset was found to be an indicator of disease severity regardless of genotype in GNE myopathy patients. These results may help stratify patients in clinical trials and predict disease progression.

P076 Exploring the correlation between body mass index and fracture risk in men

Abstract Background/Aims There has been an increase in interest in identifying patients with high risk of fracture, due to the high mortality. In De Laet et al. (2005) meta-analysis on 60000 women and men, which analysed the effect of body mass index (BMI), bone mineral density (BMD), age and gender on risk of any fracture; low BMI is linked to significantly higher fracture risk (two-fold at BMI of 20) when compared with a BMI 25. On the same comparison, high BMI (30) reduced risk of fractures by 17% (RR 0.83). This was significant in women, but not in men. No newer large-scale study focused on the correlation between BMI and fracture risks in men. Therefore, we set out to investigate the relationship between BMI and different fractures in male patients. Methods 5388 male patients referred for DEXA scan in the North West of England between 2004 and 2019 were included in the analysis. Logistic regression is performed for age, BMI, and BMD using R-4.3.1 for Windows. Results Prior to adjusting for BMD, low BMI is a significant risk factor for femur fracture. On the other hand, low BMI is a protective factor against tibia-fibula fractures. There was no significant correlation detected in spine, rib, humerus, forearm and elbow fractures. After adjusting for BMD, higher BMI is associated with significantly higher odds of humerus, tibia-fibula and wrist fractures, but no statistically significant association with spine, ribs and femur fractures. Conclusion Our results show the correlation between BMI, adjusted for BMD, and different fracture site. Our findings corroborated with previous literature, suggesting that BMI is likely a risk factor that is dependent on BMD. Furthermore, we highlighted that higher BMI is a protective factor for some fractures whilst being a risk factor for others. It is unclear whether the difference between the fracture types are due to the mechanism of fracture or the difference in disease progression at the different fracture sites - this is a potential area for future research. Disclosure M.H. Nguyen: None. M. Bukhari: None.

Long-Term Follow-Up of the LEAP Study: Early Versus Delayed Levodopa in Early Parkinson's Disease.

The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years. The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow-up visits were performed 3 and 5 years after baseline. We assessed the between-group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose. A total of 321 patients completed the 5-year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups. We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Prevalence and disease disability in immigrants with multiple sclerosis in Malmö, southern Sweden

BackgroundMultiple sclerosis (MS) is the most common chronic demyelinating disease of the central nervous system and the major non-traumatic cause of permanent disability in young adults. Several migration studies have been performed over the years suggesting a pattern of higher disease disability in certain ethnic groups. To our knowledge, differences in disease progression in immigrants have not been studied in Sweden before. Thus, the aims of our study were to estimate the prevalence of multiple sclerosis among first-generation immigrants in the City of Malmö and to compare differences in disease severity with the native population. MethodsAll persons with multiple sclerosis living in Malmö on prevalence day 31 Dec 2010 were included. Cases were classified according to the country of birth into Scandinavians, Western and non-Western. ResultsThe crude prevalence was 100/100,000 (95% CI, 80–124) among first-generation immigrants, 154/100,000 (95% CI, 137–173) among individuals with Scandinavian background, 123/100,000 (95% CI, 94–162) in the Western group and 76/100,000 (95% CI, 53–108) in the non-Western group. The mean Multiple Sclerosis Severity Score (MSSS) value among Scandinavians was 4.2 (SD 3.5), whereas the figures in the immigrant group were 4.6 (SD 3.3) and 5.2 (SD 3.7) among Westerns respectively non-Westerns, which differences were not statistically significant. When adjusting for gender, age at onset and initial disease course, the mean MSSS difference between the non-Western and the Scandinavian individuals was 1.7 (95% CI 0.18–3.3, p = 0.030). There were no differences on time to diagnosis or the time from diagnosis to treatment initiation between the three groups. ConclusionsWe found a lower prevalence among Western and non-Western first-generation immigrants compared to the Scandinavian population and a more severe disease in non-Western immigrants than in Scandinavians.

Abstract 7340: Investigating the function and impact of UBASH3B in head and neck squamous cell carcinoma and its implications for racial health disparities

Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the top cancers with significant cancer health disparities among racial and ethnic groups. African Americans (AAs) with HNSCC demonstrate worse overall survival compared to European Americans (EAs). While the reasons behind this disparity are multifaceted, recent findings suggest that biological features in HNSCC may contribute to differences in disease progression. However, race-related biological factors in HNSCC have been relatively little explored. We have identified the gene UBASH3B, a protein tyrosine phosphatase that plays a role in the stabilization of the Epidermal Growth Factor Receptor (EGFR). High expression of UBASH3B in AAs is associated with significantly worse overall survival compared to high expression in EAs and low expression in AAs. This study seeks to examine the role of UBASH3B in HNSCC and determine its impact on tumorigenesis. We hypothesize that the upregulation of UBASH3B in AAs contributes to the survival disparity by promoting tumor progression through EGFR signaling. Preliminary data using The Cancer Genome Atlas (TCGA) shows overexpression of UBASH3B in tumor samples of both AAs and EAs HNSCC samples. Plus, the overexpression of UBASH3B is associated with perineural invasion. Additionally, among AA-HNSCC patients, advanced T-stage is associated with increased UBASH3B expression. Elucidating the role UBASH3B plays in tumorigenesis will give us a further understanding of HNSCC in African Americans and can serve as a potential therapeutic target for new treatment options, as well as the biomarkers for the detection of the high-risk group. Citation Format: Madeleine Ndahayo, Vera Mukhina, Ishita Gupta, Daria A. Gaykalova. Investigating the function and impact of UBASH3B in head and neck squamous cell carcinoma and its implications for racial health disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7340.

Comparing Molnupiravir to Nirmatrelvir/Ritonavir (Paxlovid) in the Treatment of Mild-to-Moderate COVID-19 in Immunocompromised Cancer Patients.

Nirmatrelvir/Ritonavir has been shown to reduce the risk of COVID-19 progression by 88% compared to placebo, while Molnupiravir reduced it by 31%. However, these two agents have not been compared head-to-head. We therefore compared the safety and efficacy of both agents for the treatment of mild-to-moderate COVID-19 in immunocompromised cancer patients. We identified 240 cancer patients diagnosed with COVID-19 and treated with Molnupiravir or Nirmatrelvir/Ritonavir. Patients were matched using a 1:2 ratio based on age group (18-64 years vs. ≥65) and type of cancer. The collected data included demographics, comorbidities, and treatment outcome. Both groups had comparable characteristics and presenting symptoms. However, dyspnea was more prevalent in the Molnupiravir group, while sore throat was more prevalent in the Nirmatrelvir/Ritonavir group. The rate of disease progression was comparable in both groups by univariate and multivariable analysis. Treatment with Molnupiravir versus Nirmatrelvir/Ritonavir revealed no significant difference in disease progression by multivariable analysis (adjusted OR = 1.31, 95% CI: 0.56-3.14, p = 0.70). Patients who received Nirmatrelvir/Ritonavir, however, were significantly more prone to having drug-drug interactions/adverse events (30% vs. 0%, p < 0.0001). In the treatment of mild-to-moderate COVID-19 in cancer patients, Molnupiravir was comparable to Nirmatrelvir/Ritonavir in preventing progression to severe disease/death and rebound events, and it had a superior safety profile.

Role of Female Sex Hormones in ADPKD Progression and a Personalized Approach to Contraception and Hormonal Therapy.

This review navigates the intricate relationship between gender, hormonal influences, and the progression of autosomal dominant polycystic kidney disease (ADPKD), highlighting the limited literature on this crucial topic. The study explores the impact of female sex hormones on liver and renal manifestations, uncovering gender-specific differences in disease progression. Actually, hormonal therapy in women with ADPKD remains a challenging issue and is a source of concern regarding its potential impact on disease outcomes, particularly at the hepatic level. Notably, women with ADPKD exhibit a slower renal disease progression compared to men, attributed to hormonal dynamics. This review sheds light on the role of estrogen in regulating pathways of the renin-angiotensin-aldosterone system, revealing its complex interplay and implications for cardiovascular and renal health. Therapeutic considerations for fertile women with ADPKD, including contraception options, are discussed, emphasizing the necessity for personalized approaches. In the postmenopausal phase, the review evaluates the role of hormonal replacement therapy, considering its potential benefits and risks in the context of ADPKD. The review concludes by underscoring the imperative need for tailored treatment approaches for ADPKD patients, considering individual risks and benefits. The scarcity of literature underlines the call for further research to enhance our understanding of optimal hormonal therapies in the context of ADPKD, ultimately paving the way for innovative and personalized therapeutic interventions.

Hepatitis B surface antigen positivity is associated with poor short- and long-term outcomes in patients with diffuse large B-cell lymphoma who received CHOP or R-CHOP.

The development of diffuse large B-cell lymphoma (DLBCL) is closely related to the host infection status. China is a highly endemic area for hepatitis B virus (HBV) infection. It is not clear whether HBV infection has a consistent effect on the prognostic implications of patients with DLBCL in different treatment settings. We conducted a cohort study of 692 patients with DLBCL receiving three or more cycles of treatment with a CHOP or R-CHOP regimen from the First Hospital of Jilin University between July 2011 and July 2022. The patients were divided into two groups based on their hepatitis B surface antigen (HBsAg) status: HBsAg-positive (n = 84, 12.1%) and HBsAg-negative (n = 608, 87.9%) groups. Tumor specimens from 180 patients with primary DLBCL were collected for next-generation sequencing (NGS). The HBsAg-positive group had more frequent abnormal liver function (P= 0.003), hypoalbuminemia (P < 0.001), incidence of > 2 extranodal organs (P= 0.011), and spleen involvement (P < 0.001) than the HBsAg-negative group. HBsAg-positive patients had lower complete response (CR) and overall response rates (ORR) rates (all the p values < 0.05), in either the CHOP group or R-CHOP group. Among patients receiving R-CHOP, the rates of disease progression within 12 and 24 months were higher in the HBsAg-positive group than in the HBsAg-negative group (P=0.018, P=0.029). However, no significant difference in disease progression was observed between HBsAg-positive and HBsAg-negative patients in the CHOP group(P > 0.05). HBsAg positivity (OS: HR [95% CI] = 2.511 [1.214-5.192], P = 0.013) was only associated with poorer OS in the CHOP group. Whereas in the R-CHOP group, HBsAg positivity was associated with both poorer OS and PFS (OS: HR [95% CI] = 1.672 [1.050-2.665], P = 0.030; PFS: HR [95% CI] = 1.536 [1.013-2.331], P = 0.043). Additionally, HBsAg-positive patients with DLBCL also had a higher prevalence of mutations in MYC, ATM, PTPN6, and epigenetically regulated genes. These findings suggest that HBsAg-positive DLBCL patients may represent a distinct subgroup with a poorer prognosis. The standard therapies may be insufficient and new therapeutic strategies should be developed based on a better understanding of the underlying mechanisms of chemoresistance.

The role of rapid syndromic diagnostic testing of gastrointestinal pathogens as a clinical decision support tool in a pediatric emergency department

PurposeThis study aimed to investigate the role of rapid syndromic diagnostic testing of gastrointestinal pathogens as a clinical decision support tool in a pediatric emergency department (ED) by comparing clinical decision and patient outcome parameters pre- and post-implementation.MethodsThis was a big data analytical study of children < 18 years old without any underlying diseases, that visited the ED with acute moderate to severe diarrhea during a 34-month period from 2018 to 2022 using Seoul St. Mary’s hospital’s healthcare corporate data warehouse to retrieve demographic, clinical, and laboratory parameters. Outcome measures pre- and post-implementation of a rapid syndromic multiplex gastrointestinal panel (GI panel) were compared.ResultsA total of 4,184 patients’ data were included in the analyses. Broad spectrum antibiotics were prescribed at a significantly lower rate to patients presenting with acute infectious diarrhea at discharge from the ED (9.9% vs 15.8%, P < 0.001) as well as upon admission (52.2% vs 66.0%, P < 0.001) during the post-implementation period compared to the pre-implementation period. Although the duration of ED stay was found to be significantly longer (6.5 vs 5.5 h, P < 0.0001), the rate of ED revisit due to persistent or aggravated symptoms was significantly lower (Δ in intercept, β = -0.027; SE = 0.013; P = 0.041), and the admission rate at follow up after being discharged from the ED shown to be significantly lower during the post-implementation period compared to the pre-implementation period (0.8% vs. 2.1%, P = 0.001, respectively). No significant difference in disease progression was observed (P = 1.000).ConclusionUsing the GI panel in the ED was shown to decrease broad spectrum antibiotic prescribing practices and reduce revisits or admission at follow up by aiding clinical decisions and improving patient outcome.

Benefits of aHSCT over alemtuzumab in patients with multiple sclerosis besides disability and relapses: Sustained improvement in cognition and quality of life

BackgroundAutologous hematopoietic stem cell transplantation (aHSCT) exhibits promising results for multiple sclerosis (MS) in the short term. We investigated the long-term outcome differences in disease progression and cognitive impairment after aHSCT and alemtuzumab treatment. Methods20 patients receiving aHSCT and 21 patients treated with alemtuzumab between 2007 and 2020 were included in this monocentric observational cohort study. The primary objective was to compare the outcome of both groups with regards to achieving No Evidence of Disease Activity (NEDA-3), defined by the absence of relapses, EDSS progression, and MRI activity. Secondary endpoints in the study included the assessment of neurocognitive functioning, quality of life (QoL), Multiple Sclerosis Functional Composite (MSFC), and EDSS improvement. ResultsBaseline characteristics between both groups were comparable, except for a longer disease duration in the alemtuzumab group of 11.3 years compared to 5.4 years in aHSCT-treated patients (p = 0.002) and a longer mean follow-up time in the aHSCT cohort of 9.0 (range 2.8–15.7) years compared to 5.9 years (range 0.9–9.2) in alemtuzumab patients. NEDA-3 was more frequently observed in the aHSCT group with 75.0 % and 55.0 % at five and 10 years, respectively, than in the alemtuzumab group with only 40.0 % at five years (p = 0.012). Relapse free survival was higher in the aHSCT group (p < 0.001). None of the aHSCT-treated patients showed new T2-lesions six months after therapy initiation until the end of the observational period in contrast to 35.0 % of the alemtuzumab-treated patients showing new T2-lesions (95 %CI 14.2–98.9, p = 0.002). aHSCT-treated patients showed significantly improved cognitive performance in five out of 12 cognitive tests whereas alemtuzumab treated patients deteriorated in four out of 12 tests. Quality of life remained on a constant level for up to 10 years in patients receiving aHSCT with improved scores for the subscale fatigue (p = 0.013). ConclusionaHSCT seems to be superior to alemtuzumab in maintaining long-term NEDA-3 status, improving cognition and stabilizing quality of life for up to 10 years.

Sex Differences in Infective Endocarditis: A Systematic Review.

Despite the advancement in medicine, there is still a lack of understanding of the sex disparities in disease onset, progression, treatment, and outcome. In some life-threatening acute conditions, despite most patients with these illnesses being males, females have a significantly higher chance of mortality. This can be due to the differences in disease progression or healthcare disparities in managing the illness between the sexes. Treatment of illnesses tends to be more conservative for women without an explanation, but this disparity is due to the healthcare provider. Infective endocarditis (IE) is an acute life-threatening condition where bacteria latch onto and seed damaged endocardium, with some preliminary information reporting differences between the sexes. This paper aims to evaluate the sex disparities in the incidence, age, comorbidities, etiology, risk factors, manifestations, treatment, and outcomes of IE. From 2003-2023, 21584 articles were found that focused on the sex differences in IE and, through PRISMA guidelines, were narrowed down to 34 publications. There are significant differences between the sexes in IE, such as a significantly higher incidence of IE in males, who also tend to be older and have their native aortic valves involved, compared to younger females who have their mitral valve involved. Comorbidities also vary between the sexes; females tend to have atrial fibrillation, chronic kidney disease, psychiatric disorders, and taking immunosuppressants compared to males who suffer from chronic liver disease, underlying valve disease, and peripheral artery disease, contributing to the ease of developing IE. While the most common microorganism leading to IE is Staphylococcus aureus, females were more likely to have culture-negative IE, and men were more likely to be infected with Streptococcus viridans. Major manifestations in IE are fever and vegetation along the closure of the valves in the heart, where females were more likely to have vegetation on the mitral and aortic valves. At the same time, males were more likely to have it on the tricuspid valve. On par with sex disparities in health, females usually took longer to seek medical help than males despite the advancement of symptoms and deterioration. Females were also treated conservatively through antibiotic management, whereas males were more likely to advance to surgical treatment, leading to a longer hospital stay. While there was no true difference in the in-hospital mortality rate, the 30-day and 1-year mortality were significantly increased in females. These differences provide a range of starting points for various research to further educate physicians on sex disparities, such as why males have a higher incidence of infective endocarditis and determining whether it's hormones and basic metabolites, possibly limiting those who develop the infection. Another important point is treating females with IE; the antibiotic doses are standard, but whether they advance to surgical treatment is mostly up to the provider. Some providers deny surgical treatment despite all indications, but it could also be females denying surgery as they tend to leave against medical advice. This review is crucial in developing the next steps to sex disparity in IE, which may lead to better outcomes for males and females.

IPSC‐derived hindbrain spheroids to evaluate drug responses targeting neuropsychiatric symptoms in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD), a neurodegenerative disorder, is the most common cause of dementia. The gradual deterioration of brain function eventually leads to death. Almost all AD patients eventually suffer from neuropsychiatric symptoms (NPS; e.g., agitation, depression) whose emergence correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain spheroids containing serotonergic neurons using induced Pluripotent Stem Cells (iPSCs) from healthy volunteers or AD patients with and without NPS. The spheroids can be used to study AD, NPS, and to evaluate individual differences in disease progression, NPS development, and/or pharmacological treatment response.MethodHuman peripheral blood mononuclear cells from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain spheroids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of serotonin (5‐HT) secreted in the extracellular environment. To assess patient‐specific treatment effects, spheroids were treated with different concentrations of escitalopram oxalate, a medication widely prescribed for the treatment of NPS.ResultHindbrain spheroids containing serotonergic neurons were successfully generated and characterized from these 6 individual iPSC lines. Changes in 5‐HT levels before and after treatment with escitalopram were dose‐dependent and variable across patients.ConclusionIt is possible to generate hindbrain spheroids from human iPSCs to study inter‐patient variability using a precision medicine approach. Since hindbrain spheroids from different people respond differently to the application of escitalopram in vitro this may reveal subgroups of AD patients who may be more or less likely to benefit from the drug in vivo. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment with escitalopram.

Correlates of Skeletal Muscle Mass and Differences Between Novel Subtypes in Recent-Onset Diabetes.

Low skeletal muscle mass (SMM) is associated with long-standing diabetes but little is known about SMM in newly diagnosed diabetes. We aimed to identify correlates of SMM in recent-onset diabetes and to compare SMM between novel diabetes subtypes. SMM was normalized to body mass index (SMM/BMI) in 842 participants with known diabetes duration of less than 1 year from the German Diabetes Study (GDS). Cross-sectional associations between clinical variables, 79 biomarkers of inflammation, and SMM/BMI were assessed, and differences in SMM/BMI between novel diabetes subtypes were analyzed with different degrees of adjustment for confounders. Male sex and physical activity were positively associated with SMM/BMI, whereas associations of age, BMI, glycated hemoglobin A1c, homeostatic model assessment for β-cell function, and estimated glomerular filtration rate with SMM/BMI were inverse (all P < .05; model r2 = 0.82). Twenty-three biomarkers of inflammation showed correlations with SMM/BMI after adjustment for sex and multiple testing (all P < .0006), but BMI largely explained these correlations. In a sex-adjusted analysis, individuals with severe autoimmune diabetes had a higher SMM/BMI whereas individuals with severe insulin-resistant diabetes and mild obesity-related diabetes had a lower SMM/BMI than all other subtypes combined. However, differences were attenuated after adjustment for the clustering variables. SMM/BMI differs between diabetes subtypes and may contribute to subtype differences in disease progression. Of note, clinical variables rather than biomarkers of inflammation explain most of the variation in SMM/BMI.

T regulatory lymphocytes specific for SARS-CoV-2 display increased functional plasticity

The study of phenotypic and functional characteristics of immune cells involved in host response to SARS-CoV-2 is relevant for understanding COVID-19 pathogenesis and individual differences in disease progression. We have analyzed chemokine receptor expression in SARS-CoV-2-specific CD4+ T lymphocytes from vaccinated donors, and have found an increase of CCR9+ and CCR6+ cells. CCR9+ specific CD4+ cells are enriched in T regulatory (Treg) lymphocytes. These cells specifically show heterogeneous regulatory activity, associated with different profiles of CCR9/CCR6 expression, individual differences in IL-10 and IL-17 production, and variable FoxP3 and Notch4 expression. A higher heterogeneity in FoxP3 is selectively observed in convalescent individuals within vaccinated population. Accordingly, SARS-CoV-2-specific CD4+ lymphocytes from COVID-19 patients are also enriched in CCR9+ and CCR6+ cells. CCR6+ specific Treg lymphocytes are mainly increased in critically ill individuals, indicating a preferential role for these cells in lung injury pathogenesis. We provide experimental evidence for a SARS-CoV-2-specific Treg population with increased plasticity, which may contribute to the differential pathogenic response against SARS-CoV-2 among individuals, and underlie the development of autoimmune conditions following SARS-CoV-2 infection.

Pores of the internal limiting membrane: A common finding in vitreo-maculopathies.

To describe presence and distribution of pores of the inner limiting membrane (ILM) in eyes with vitreo-maculopathies. ILM specimens were harvested from 117 eyes of 117 patients during vitrectomy with membrane peeling from eyes with vitreomacular traction syndrome, idiopathic and secondary epiretinal gliosis, and idiopathic full-thickness macular hole (FTMH). All specimens were processed as flat-mounts for immunocytochemistry and examined by phase-contrast, interference and fluorescence microscopy. Demographic and clinical data were correlated. ILM pores were found in all vitreo-maculopathies. They were identified in 47 (40.2%) of 117 eyes being most evident with anti-laminin. In eyes with FTMH >400μm, pores were seen in more than half of all eyes. They occur as numerous and uniformly distributed defects of the flat mounted ILM with a mean diameter of 9.5 ± 2.4 µm. Edges of ILM pores are round with an irregular contour and no specific cellular pattern. Pores were distinguished from retinal vessel thinning and iatrogenic artefacts. Contrary to previous reports, ILM pores are a common finding in vitreo-maculopathies easily visible with anti-laminin staining. Further studies are needed to clarify whether their presence correlates with differences in disease progression or imaging before and after vitrectomy with ILM peeling.

Gender and sex in the development and progression of renal diseases

Sex-based disparities in nephrology have been a historically understudied area. In nephrology, gender differences exist with regard to the epidemiology, evolution and prognosis of chronic kidney disease (CKD). In some cases, these differences run contrary to the general population trends. We discuss such gender and sex disparities, including differing impact of traditional and novel risk factors, as well as hormonal factors, all of them potentially influencing propensity, progression and biochemical and psychological aspects of CKD. The factors involved in this gender disparity may include diet, kidney and glomerular size, differences in glomerular hemodynamics, and the direct effects of sex hormones. The progression rate of many renal diseases is affected by sex. In polycystic kidney disease, membranous nephropathy, immunoglobulin A nephropathy, and “chronic renal disease of unknown etiology”, men progress at a faster rate to end-stage renal failure than women do. In many, but not all, animal models of renal disease, estrogens slow progression rate. Animal and experimental studies have tried to offer further mechanistic explanations for gender differences in disease progression. It has been suggested that the gender dimorphism of CKD progression may represent the effects of the interaction of circulating steroids with specific kidney receptors. Endogenous estrogens have in general been considered to have anti-fibrotic and anti-apoptotic effects on the kidney. On the other hand, the faster decline of kidney function in men has been attributed to the specific pro-apoptotic and pro-fibrotic properties of androgens.

Genotype–phenotype associations in Alström syndrome: a systematic review and meta-analysis

BackgroundAlström syndrome (ALMS; #203800) is an ultrarare monogenic recessive disease. This syndrome is associated with variants in the ALMS1 gene, which encodes a centrosome-associated protein involved in the regulation of...