High Burden Research Articles

Fecal proteolytic profiling of pediatric inflammatory bowel disease: A pilot study.

Colonoscopy is the gold standard for diagnosing inflammatory bowel disease (IBD). However, this invasive procedure has a high burden for pediatric patients. Previous research has shown elevated fecal amino acid concentrations in children with IBD versus controls. We hypothesized that this finding could result from increased proteolytic activity. Therefore, the aim of this study was to investigate whether fecal protease-based profiling was able to discriminate between IBD and controls. Protease activity was measured in fecal samples from patients with IBD (Crohn's disease (CD) n = 19; ulcerative colitis (UC) n = 19) and non-IBD controls (n = 19) using a fluorescence resonance energy transfer (FRET)-peptide library. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of each FRET-peptide substrate. Screening the FRET-peptide library revealed an increased total proteolytic activity (TPA), as well as degradation of specific FRET-peptides specifically in fecal samples from IBD patients. Based on level of significance (p < .001) and ROC curve analysis (AUC > 0.85), the fluorogenic substrates W-W, A-A, a-a, F-h, and H-y showed diagnostic potential for CD. The substrates W-W, a-a, T-t, G-v, and H-y showed diagnostic potential for UC based on significance (p < .001) and ROC analysis (AUC > 0.90). None of the FRET-peptide substrates used was able to differentiate between protease activity in fecal samples from CD versus UC. This study showed an increased fecal proteolytic activity in children with newly diagnosed, treatment-naïve, IBD. This could lead to the development of novel, noninvasive biomarkers for screening and diagnostic purposes.

Secukinumab in adult patients with lichen planus: Efficacy and safety results from the randomised, placebo-controlled, proof-of-concept PRELUDE study.

Patients with lichen planus (LP) refractory to available therapies often experience a high disease burden; representing a population with a clear unmet need for new treatments. To evaluate the efficacy and safety of secukinumab 300 mg over 32 weeks in adult patients with biopsy-proven cutaneous LP (CLP), mucosal LP (MLP) or lichen planopilaris (LPP), inadequately controlled by topical corticosteroids. PRELUDE was a, randomised, double-blind, placebo-controlled, Phase 2 proof-of-concept study that enrolled patients with CLP, MLP or LPP. Eligible patients were randomised to eithersecukinumab 300 mg every 4 weeks for 32 weeks (SECQ4W), or placebo for 16 weeks followed by secukinumab 300 mg every 2 weeks (SECQ2W) for 16 weeks. The primary endpoint was achievement of the newly designed Investigator's Global Assessment (IGA) score ≤2 at Week 16. Overall, 111 patients were randomised (n=37 each) to CLP, MLP and LPP cohorts. As the proof-of-concept criteria were not met for any of the 3 cohorts, the primary objective was not met. A numerically higher proportion of patients achieved IGA ≤2 response at Week 16 with SECQ4W vs. placebo in the MLP (37.5% [95% credibility interval (Crl): 20.3-57.2] vs. 23.1% [95% Crl: 6.5-49.2]) and LPP cohorts (37.5% [95% Crl: 20.2-57.3] vs. 30.8% [95% Crl: 10.8-57.6]). In the LPP cohort, a sustained response for IGA ≤2 from Week 16 to Week 32 was achieved with SECQ4W (Week 16: 37.5%; Week 32: 45.8%), and a substantial improvement was observed in IGA ≤2 response in patients of this cohort switching from placebo (Week 16: 30.8%) to SECQ2W after Week 16 (Week 32: 63.6%). The safety profile was consistent with the known profile of secukinumab and showed no new or unexpected signals. PRELUDE is the first randomised controlled basket trial evaluating interleukin-17A inhibition with secukinumab across 3 subtypes of LP. Secukinumab was well-tolerated and safe, showing different response rates across the 3 subtypes, with numerical IGA improvements in MLP and LPP, and no response in CLP. The study raises the question of a differential role of interleukin-17A across LP subtypes. The novel IGA score showed significant correlation with patient as well as physician reported outcome measurements. NCT04300296.

Associations between Posttraumatic Stress Disorder and Diabetes in Vietnam-Era Women Veterans in the HealthViEWS Study.

Background: Posttraumatic stress disorder (PTSD) is associated with incident diabetes. However, past studies have often included predominantly male samples, despite important sex and gender differences in diabetes. To address this limitation, this study examined the association between PTSD and diabetes in older Veteran women, a population with a high burden of PTSD. Materials and Methods: Data were collected from 4,105 women (Mage = 67.4 years), participating in the Health of Vietnam-Era Veteran Women's Study (HealthViEWS; Department of Veterans Affairs Cooperative Studies Program #579). Participants completed self-report measures of demographics, health conditions, and health behaviors. Information on military service was obtained through service records. A structured clinical interview was conducted by telephone to assess current and lifetime PTSD and other mental health disorders. Weighted descriptive and logistic regression analyses were used to examine associations between PTSD and diabetes. Results: The prevalence of diabetes was 28.4% among women with current full PTSD compared to 23.4%, 17.6%, and 17.5% for current subthreshold, remitted, and no PTSD. In unadjusted analyses, women with current full and subthreshold PTSD were 1.87 [1.49; 2.33] and 1.44 [1.11; 1.85] times more likely to have diabetes compared to women with no PTSD. Remitted PTSD was not associated with increased odds of diabetes. Effects were attenuated but remained significant after adjustment for relevant covariates. Conclusions: Vietnam-era women with current PTSD, including subthreshold symptoms, had a greater likelihood of diabetes compared to women without PTSD. These findings suggest that women with PTSD may benefit from increased diabetes prevention efforts.

In situ ascending aortic thrombus in a patient with metastatic lung adenocarcinoma and no aortic atherosclerosis or cisplatin exposure: a case report

BackgroundAn ascending aortic thrombus is exceedingly rare. Two instances have been reported in the setting of lung cancer, but only after cisplatin use, which is associated with hypercoagulability. We present the first case of a patient with lung cancer who developed an ascending aortic thrombus without structural risk factors or chemotherapy use.CaseA 60-year-old white female with significant smoking history presented with several weeks of malaise. A chest computed tomography scan revealed a 2.2-cm right upper lobe mass. As an outpatient, right hilar lymph node immunohistochemistry (IHC) samples via endobronchial ultrasound confirmed thyroid transcription factor-1 adenocarcinoma. After the procedure, the patient endorsed dyspnea and was advised to go to the emergency department. A chest computed tomography angiography identified a new 2.4 × 1.1 × 1.1 cm thrombus within the proximal aortic arch. No pulmonary emboli or intrapulmonary shunts were identified. A hypercoagulable workup was negative. Transthoracic echocardiogram was without left ventricular thrombus, akinesis or hypokinesis, left atrial dilation, or intracardiac shunts. A lower extremity ultrasound was negative for deep vein thrombosis. Given the procedural risk, thrombectomy was deferred. The patient was transitioned to enoxaparin, and a repeat computed tomography for resolution is in process.ConclusionTo our knowledge, this is the only case detailing an in situ ascending aortic thrombus in the setting of lung cancer, without structural risk factors, chemotherapy use, or other hypercoagulable comorbidities. Optimal management for an aortic thrombus and malignant disease is less clear. Clinicians should be vigilant for unusual arterial thromboses in patients with high metastatic burden.

The safety and efficacy of the Stryker OptaBlate™ Bone Tumor Ablation system for vertebral body metastases

BackgroundMetastatic spinal lesions are a significant cause of morbidity and decreased quality of life in those with a high tumor burden. Despite treatment modalities such as medical therapy (e.g., chemotherapy, steroids), spinal augmentation procedures, and radiation therapy, many patients still experience refractory back pain due to neoplastic infiltration of the vertebral body and/or pathologic compression fractures. With the aim to address refractory pain in patients who have exhausted conventional treatment options, Stryker developed the OptablateTM Bone Tumor Ablation system (BTA; Stryker Corporation, Kalamazoo, MI), which delivers radiofrequency energy to pathologic vertebral body lesions. In this preliminary single-institution study, we characterize the use of the BTA system in 11 patients undergoing kyphoplasty for pathologic spinal lesions with the goal to demonstrate the impact of this novel technology on refractory pain in this challenging clinical setting.MethodsA single-center retrospective chart review was performed on all patients identified as those receiving tumor ablation/kyphoplasty for spinal neoplasms using the OptablateTM BTA system performed by a single surgeon at the University of Oklahoma Medical Center. Sex, age, primary lesion type, presenting symptomatology, spinal level, time of follow-up, and outcome were obtained from the electronic medical record (EMR).ResultsEleven patients (4 males, 7 females) with a mean age of 62 (range, 38–82) years had an average follow-up time of 6 months. Presenting symptoms attributed to spinal pathology included back pain (n = 11, 100%), pathologic fracture (n = 6, 55%), and lower extremity weakness (n = 3, 27%). A total of 20 lesions were ablated at 12 vertebral levels. Eight patients (73%) had improved pain. No complications were reported.ConclusionThis preliminary study documents the safety of the BTA system, in addition to its diverse use across many levels. The majority of patients reported improvement in their pain. Further study is required to fully characterize the use of the BTA system in those with neoplastic spinal pathology.

Identification of DNA methylation characteristics associated with metastasis and prognosis in colorectal cancer

Colorectal cancer (CRC) is prone to metastasis and recurrence after surgery, which is one of the main causes for its poor treatment and prognosis. Therefore, it is essential to identify biomarkers associated with metastasis and recurrence in CRC. DNA methylation has a regulatory role in cancer metastasis, tumor immune microenvironment (TME), and prognosis and may be one of the most valuable biomarkers for predicting CRC metastasis and prognosis. We constructed a diagnostic model and nomogram that can effectively predict CRC metastasis based on the differential methylation CpG sites (DMCs) between metastatic and non-metastatic CRC patients. Then, we identified 17 DMCs associated with progression free survival (PFS) of CRC and constructed a prognostic model. The prognosis model based on 17 DMCs can predict the PFS of CRC with medium to high accuracy. The results of immunohistochemical analysis indicated that the protein expression levels of the genes involved in prognostic DMCs were different between normal and colorectal cancer tissues. According to the results of immune-related analysis, we found that the low-risk patients had better immunotherapy response. In addition, high risk scores were negatively correlated with high tumor mutation burden (TMB) levels, and patients with low TMB levels in the high-risk group had the worst PFS. Our work shows the clinical value of DNA methylation in predicting CRC metastasis and PFS, as well as their correlation with TME, immunotherapy, and TMB, which helps understand the changes of DNA methylation in CRC metastasis and improving the treatment and prognosis of CRC.

Psychosocial and supportive care concerns of young women living with advanced breast cancer: baseline findings from a prospective virtual support intervention study.

Adolescent and young adults (AYAs) with metastatic breast cancer (MBC) experience high physical and psychosocial burdens compounded by a disrupted life trajectory. We sought to determine the psychosocial and supportive care concerns of this population to better understand and address unmet needs. AYAs diagnosed with MBC (18-39years) participating in a prospective interventional study (Young, Empowered, and Strong) at Dana-Farber Cancer Institute completed an electronic survey following enrollment. Measures evaluated sociodemographics, health behaviors, quality of life, and symptoms, among others. We used two-sided Fisher's exact tests to determine associations between concerns (e.g., cancer progression, side effects, lifestyle, finances, fertility) and demographic variables. Among 77 participants enrolled from 9/2020-12/2022, average age at MBC diagnosis and survey was 35.9 (range: 22-39) and 38.3years (range: 27-46), respectively. Most were non-Hispanic white (83.8%) and 40.3% reported their diagnosis caused some financial problems. Many were concerned about fertility (27.0%), long-term treatment side effects (67.6%), exercise (61.6%), and diet (54.1%). Select concerns varied significantly by age, race/ethnicity, and education. Younger women at survey reported greater concern about familial cancer risk (p = 0.028). Women from minority racial/ethnic groups more frequently reported issues talking about their cancer to family/friends (p = 0.040) while those with more education were more frequently concerned with long-term effects of cancer on their health (p = 0.021). Young women living with MBC frequently report psychosocial, health, and cancer management concerns. Tailoring supportive care and communications to address prevalent concerns including disease progression and treatment side effects may optimize wellbeing.

Crizanlizumab in adult patients with sickle cell disease: a retrospective German analysis

IntroductionThe marketing authorization for crizanlizumab (Adakveo®), indicated for the prevention of recurrent vaso-occlusive crises (VOCs) in sickle cell patients (pts) aged ≥16, was revoked by the European Medicines Agency (EMA) as the STAND study did not demonstrate a significant difference between crizanlizumab and placebo in annualized rates of VOCs.MethodsThis is a retrospective, monocentric analysis of adult pts with sickle cell disease (SCD) (age (median) 29 years, range 19-42, annual VOC rate 3, range 1-5, homozygous SCD (HbS/S) 50.0% (4/8)) receiving crizanlizumab as monotherapy at the University Hospital of Essen between Dec 2020 to May 2023 (observation time (median) 17.5 months, range 4.8-27.3). The results were compared to hydroxycarbamide (HC)-treated pts at maximum tolerated dose (MTD).ResultsAt 6, 9, and 12 months, mean VOC rate was 1.5 (range 0-3; N=6), 1.8 (range 0-3; N=5) and 4.0 (range 3-5; N=3), indicating a time-dependent increase in VOCs in crizanlizumab-treated pts (6-9 months: p=0.039; 6-12 months: p=0.008) (mean VOC rate in HC-treated pts: 6 months: 0.38, range 0-1 (N=8); 9 months: 0.50, range 0-2 (N=8); 12 months: 0.63, range 0-3 (N=8)). Serious adverse events were mandatory in 7 pts, resulting in 12 inpatient-admissions (acute chest syndrome (N=2), VOC-related pain crisis (N=9), infusion-related VOC (N=1)).ConclusionThese findings, together with the high economic burden of crizanlizumab in contrast to HC, do further support the revocation of crizanlizumab in Europe in our opinion. Physicians should consider the potential risks when making a therapeutic decision regarding the use of crizanlizumab outside of Europe.

Case report: Is severe toxicity the price to pay for high sensitivity to checkpoint inhibitors immunotherapy in desmoplastic melanoma?

BackgroundDesmoplastic melanoma (DM) is a rare subtype of melanoma characterized by high immunogenicity which makes it particularly suitable for immune checkpoint inhibitors (ICIs) treatment.Case presentationWe report the case of a 53-year-old man with metastatic DM successfully treated with the combination of anti-CTLA-4 and anti-PD-1 antibodies, who developed serious immune-related adverse events (irAEs). The primary tumor was characterized by absent PD-L1 expression and no-brisk lymphocytes infiltration. NGS showed absence of BRAF mutation, a high tumor mutational burden, and an UV-induced DNA damage signature. Metastatic lesions regressed rapidly after few cycles of ICIs until complete response, however the patient developed serious irAEs including hypothyroidism, adrenal deficiency, and acute interstitial nephritis which led to the definitive suspension of treatment. Currently, the patient has normal renal functionality and no disease relapse after 26 months from starting immunotherapy, and after 9 months from its definitive suspension.ConclusionEfficacy and toxicity are two sides of the same coin of high sensitivity to ICIs in DM. For this reason, these patients should be closely monitored during ICIs therapy to promptly identify serious side effects and to correctly manage them.

Regional differentiation of the tax burden on personal income in Canada

The income of citizens reflects the degree of economic development of the country, and in the regional aspect – the degree of economic development of each region. Canada is very similar to Russia in its geographical location, nature and climate, so the standard of living of the population in this country is of interest. One of its indicators is the income of citizens. The state’s approach to personal income taxation reflects the general socio-economic policy in the country. The study analysed the tax burden on personal income in the provinces of Canada in 2000–2022, determined the dynamics of this indicator for the period under review, and identified the existence of correlation between the amount of income and the tax burden on it in the regional aspect. The results obtained found that in Canada, there is a conditional division into eastern provinces with a traditionally high tax burden, western provinces with a national average tax burden, and northern territories with a relatively low tax burden. A certain inverse relationship between the amount of citizens’ income and the tax burden on it has been established. In regions with high incomes, the tax burden is usually lower, and in regions with low incomes, it is generally higher. However, there are regions that are exceptions, which shows the relative financial independence of regional authorities in Canada. The dynamics of the tax burden on personal income in the analysed period reflected the impact of the crises of 2008 and 2020 when it decreased. This fact demonstrates the sensitive response of regional governments to the changing economic situation.

A single subcutaneous dose of eprinomectin (Eprecis®) is effective against common gastrointestinal nematodes and lungworms in experimentally infected lactating goats

BackgroundThe health and productivity of dairy goats continue to be impacted by gastrointestinal nematodes (GIN) and lungworms (LW). Eprinomectin (EPN) is frequently selected for treatment because it is generally effective and does not require a milk withdrawal period. However, some factors, such as lactation, can have an impact on EPN pharmacokinetics and potentially its efficacy. To evaluate whether this can alter the efficacy of Eprecis® 2%, an eprinomectin injectable solution, a study was performed in lactating goats using the dose currently registered in cattle, sheep and goats (0.2 mg/kg).MethodsThis study was a blinded, randomized, controlled trial performed according to the VICH guidelines. Eighteen (18) worm-free lactating goats were included and experimentally challenged on day 28 with a mixed culture of infective gastrointestinal and lung nematode larvae (Haemonchus contortus, Trichostrongylus colubriformis, Teladorsagia circumcincta, Dictyocaulus filaria). At D-1, fecal samples were collected to confirm patent infection in all animals. On D0, the goats were randomly allocated into two groups of nine goats; group 1 was treated with Eprecis® 2% at 0.2 mg/kg BW by subcutaneous injection, while group 2 remained untreated. Fecal samples for egg counts were collected from all animals on days 3, 5, 7, 9, 11 and 14. On D14, all goats were killed, and the abomasum, small intestine and lungs were removed, processed and subsampled to record the number and species of worms.ResultsThe treatment was well tolerated. After treatment, the arithmetic mean FEC decreased in the treated group and remained < 5 EPG until the end of the study, while the arithmetic mean FEC in the control group remained > 849.0 EPG. At D14, goats in the treated group had very limited or zero total worm counts, whereas all animals from the control group had a high worm burden. The measured efficacy was 100.0% against H. contortus and T. colubriformis, 99.9% against T. circumcincta and 98.0% against D. filaria.ConclusionsEprinomectin (Eprecis®, 20 mg/ml), administered at the label dose (0.2 mg/kg), is highly effective against gastrointestinal nematodes and lungworms in lactating goats.Graphical abstract

Disability and costs of ischemic heart disease attributable to the consumption of trans fatty acids in Brazil.

To estimate the disability and costs of the Brazilian Unified Health System (SUS) for ischemic heart disease (IHD) attributable to trans fatty acid (TFA) consumption in 2019. This ecological study used secondary data from the Global Burden of Disease (GBD) Study 2019 to estimate the years lived with disability (YLDs) from IHD attributable to TFA in Brazil in 2019. Data on direct costs (purchasing power parity: 1 Int$ = R$ 2.280) were obtained from the Hospital and Ambulatory Information Systems of the SUS. Moreover, the total costs in each state were divided by the resident population in 2019 and multiplied by 10,000 inhabitants. The relationship between the socio-demographic index (SDI), disease, and economic burden was investigated. Brazil and its 27 states. Adults aged ≥ 25 years of both sexes. IHD attributable to TFA consumption resulted in 11,165 YLDs (95% uncertainty interval [UI]: 932-18,462) in 2019 in Brazil. A total of Int$ 54,546,227 (95% UI: 4,505,792-85,561,810) was spent in the SUS in 2019 due to IHD attributable to TFA, with the highest costs of hospitalizations, for males and individuals aged ≥ 50 years or over. The highest costs were observed in Sergipe (Int$ 6,508/10,000; 95% UI: 576-10,265), followed by the two states from the South. Overall, as the SDI increases, expenditures increase. TFA consumption results in a high disease and economic IHD burden in Brazil, reinforcing the need for more effective health policies, such as industrial TFA elimination, following the international agenda.

Gut microbiota, blood metabolites, and left ventricular diastolic dysfunction in US Hispanics/Latinos

BackgroundLeft ventricular diastolic dysfunction (LVDD) is an important precursor of heart failure (HF), but little is known about its relationship with gut dysbiosis and microbial-related metabolites. By leveraging the multi-omics data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a study with population at high burden of LVDD, we aimed to characterize gut microbiota associated with LVDD and identify metabolite signatures of gut dysbiosis and incident LVDD.ResultsWe included up to 1996 Hispanic/Latino adults (mean age: 59.4 years; 67.1% female) with comprehensive echocardiography assessments, gut microbiome, and blood metabolome data. LVDD was defined through a composite criterion involving tissue Doppler assessment and left atrial volume index measurements. Among 1996 participants, 916 (45.9%) had prevalent LVDD, and 212 out of 594 participants without LVDD at baseline developed incident LVDD over a median 4.3 years of follow-up. Using multivariable-adjusted analysis of compositions of microbiomes (ANCOM-II) method, we identified 7 out of 512 dominant gut bacterial species (prevalence > 20%) associated with prevalent LVDD (FDR-q < 0.1), with inverse associations being found for Intestinimonas_massiliensis, Clostridium_phoceensis, and Bacteroide_coprocola and positive associations for Gardnerella_vaginali, Acidaminococcus_fermentans, Pseudomonas_aeruginosa, and Necropsobacter_massiliensis. Using multivariable adjusted linear regression, 220 out of 669 circulating metabolites with detection rate > 75% were associated with the identified LVDD-related bacterial species (FDR-q < 0.1), with the majority being linked to Intestinimonas_massiliensis, Clostridium_phoceensis, and Acidaminococcus_fermentans. Furthermore, 46 of these bacteria-associated metabolites, mostly glycerophospholipids, secondary bile acids, and amino acids, were associated with prevalent LVDD (FDR-q < 0.1), 21 of which were associated with incident LVDD (relative risk ranging from 0.81 [p = 0.001, for guanidinoacetate] to 1.25 [p = 9 × 10−5, for 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4)]). The inclusion of these 21 bacterial-related metabolites significantly improved the prediction of incident LVDD compared with a traditional risk factor model (the area under the receiver operating characteristic curve [AUC] = 0.73 vs 0.70, p = 0.001). Metabolite-based proxy association analyses revealed the inverse associations of Intestinimonas_massilliensis and Clostridium_phoceensis and the positive association of Acidaminococcus_fermentans with incident LVDD.ConclusionIn this study of US Hispanics/Latinos, we identified multiple gut bacteria and related metabolites linked to LVDD, suggesting their potential roles in this preclinical HF entity.E59jTaJp--U2oUtePgjZu8Video

Serving Those Who Served: Enhancing Colorectal Surgery Care for Veterans

AbstractThe Department of Veterans Affairs (VA) is the largest provider of integrated health care services in the United States and its mission is to honor veterans by providing timely, effective, and high-quality health care that improves individuals' health and functionality. The VA provides comprehensive primary and specialty care, including colorectal surgery services, to eligible veterans who suffer from a disproportionately high burden of medical comorbidities and often belong to vulnerable populations, including individuals of low socioeconomic status, those who identify as lesbian, gay, bisexual, transgender, and questioning, racial minorities, and those suffering from severe mental health illness. There are many challenges to caring for a population of veterans with benign and malignant colorectal disease due to both patient and system level factors. Despite these challenges, the VA has demonstrated a commitment to ensuring culturally competent, equitable, and inclusive care and to conducting research that establishes evidence-based best practices in the management of colorectal diseases. These efforts have led to outcomes for patients undergoing care for colorectal diseases within the VA that are par with or better than civilian outcomes. The VA is uniquely positioned on a system level to provide nationwide efforts that improve care delivery and serve those who served.

High Prevalence of Psychological Comorbidities and Functional Neurological Symptoms in Women With Urinary Retention.

Chronic idiopathic urinary retention (CIUR) in young women is poorly understood and a probable etiology is established only in around 40%, most commonly a primary disorder of external urethral sphincter relaxation, sometimes referred to as Fowler's syndrome. A high prevalence of psychological and functional comorbidities is reported, however these have been poorly characterized. Women consecutively referred for the assessment and management of CIUR were evaluated cross-sectionally for 13 psychological/behavioral domains using a structured clinical interview: depression, anxiety, post-traumatic stress disorder (PTSD), other psychiatric history, functional neurological disorder, other functional syndromes, childhood and adult trauma, personality disorder, and self-harm (ever/current). A total of 91 women (mean age [SD]: 34 [11] years) were evaluated. Women with Fowler's syndrome (n = 69) were younger (mean age [SD]: 32 [9] vs 40 [13] years) than women without Fowler's syndrome and reported shorter mean duration of urinary symptoms (mean [SD]: 5 [6] vs 10 [9]). A high prevalence of psychiatric and psychological comorbidities was reported (97%) including current depression (77%), current anxiety (78%), and PTSD (32%). A high prevalence of functional neurological disorder (56%) and other functional symptoms (65%) was also reported. Self-harm was reported in (14%) and personality disorder in 16%. Childhood trauma was reported in 35% of women. Young women with CIUR report a high burden of psychiatric disorders, affective symptoms, trauma, PTSD, self-harm, and functional neurological disorder, particularly in those with Fowler's syndrome. These factors can undermine the engagement with health care professionals and affect management and should therefore be addressed during the urological assessment.

Functional characterization of helminth-associated Clostridiales reveals covariates of Treg differentiation

BackgroundParasitic helminths influence the composition of the gut microbiome. However, the microbiomes of individuals living in helminth-endemic regions are understudied. The Orang Asli, an indigenous population in Malaysia with high burdens of the helminth Trichuris trichiura, display microbiotas enriched in Clostridiales, an order of spore-forming obligate anaerobes with immunogenic properties. We previously isolated novel Clostridiales that were enriched in these individuals and found that a subset promoted the Trichuris life cycle. In this study, we aimed to further characterize the functional properties of these bacteria.ResultsClostridiales isolates were profiled for their ability to perform 57 enzymatic reactions and produce short-chain fatty acids (SCFAs) and hydrogen sulfide, revealing that these bacteria were capable of a range of activities associated with metabolism and host response. Consistent with this finding, monocolonization of mice with individual isolates identified bacteria that were potent inducers of regulatory T-cell (Treg) differentiation in the colon. Comparisons between variables revealed by these studies identified enzymatic properties correlated with Treg induction and Trichuris egg hatching.ConclusionWe identified Clostridiales species that are sufficient to induce high levels of Tregs. We also identified a set of metabolic activities linked with Treg differentiation and Trichuris egg hatching mediated by these newly isolated bacteria. Altogether, this study provides functional insights into the microbiotas of individuals residing in a helminth-endemic region.-EyM7p7tfAvrAjtAePB85JVideo

Characteristics and Neural Mechanisms of Sleep-Wake Disturbances After Traumatic Brain Injury.

Sleep-wake disturbances (SWDs) are one of the most common complaints following traumatic brain injury (TBI). The high prevalence and socioeconomic burden of SWDs post-TBI have only been recognized in the past decade. Common SWDs induced by TBI include excessive daytime sleepiness (EDS), hypersomnia, insomnia, obstructive sleep apnea (OSA), and circadian rhythm sleep disorders. Sleep disturbances can significantly compromise quality of life, strain interpersonal relationships, diminish work productivity, exacerbate other clinical conditions, and impede the rehabilitation process of TBI patients. Consequently, the prompt regulation and enhancement of sleep homeostasis in TBI patients is of paramount importance. Although studies have shown that abnormal neural network function, neuroendocrine changes, disturbance of sleep-wake regulators, and immune inflammatory responses related to brain structural damage induced by TBI are involved in the development of SWDs, the exact neuropathological mechanisms are still poorly understood. Therefore, we systematically review the current clinical and experimental studies on the characteristics and possible neural mechanisms of post-TBI SWDs. Elucidating the neural underpinnings of post-TBI SWDs holds the potential to diversify and enhance therapeutic approaches for these conditions. Such advancements could hasten the recuperation of TBI patients and ameliorate their overall quality of life. It is our aspiration that departments specializing in neurosurgery, rehabilitation, and neuropsychiatry will be able to recognize and address these conditions promptly, thereby facilitating the healing journey of affected individuals.

The performance of single and combination test strategies using visual inspection, cytology, high-risk HPV DNA and HPV16/18 to screen South African women with and without HIV-infection

BackgroundCervical cancer screening strategies should ideally be informed by population-specific data. Strategies recommended for secondary prevention, are often inadequately studied in populations with high cervical disease burdens. This report describes the test performance measured against CIN2 + /CIN3 + histology in HIV-positive women (HPW) and HIV-negative women (HNW) with the aim to determine the most effective strategies to identify South African women at risk.MethodsPrimary screening using visual inspection, cytology and HPV DNA (cobas®) was performed in two South African provinces on 456 HPW and 639 HNW participating in the multicentric DiaVACCS trial. Histology was obtained for 91.7% screen-positive and 42.7% screen-negative participants, and unavailable histology was determined by multiple imputation to adjust for verification bias. Cross-sectional test performance was calculated for single and combination test strategies with and without intermediate risk categories using different cut-offs. Minimum acceptability for sensitivity and specificity, treatment and follow-up numbers were considered to evaluate strategies.ResultsThe only single test to reach acceptability in HPW was cytology (LSIL) [sensitivity 71.2%; specificity 90.5%; treatment 33.4%]; in HNW only HPV (hr) qualified [sensitivity 68.2%; specificity 85.2%; treatment 23.5%]. The universally best performing strategy which also resulted in smaller treatment numbers without intermediate risk group was primary HPV(hr), with treatment of both HPV(16/18) and cytology (ASCUS +) [HPW: sensitivity 73.6%; specificity 89.7%; treatment 34.7%. HNW: sensitivity 59.1%; specificity 93.6%; treatment 13.9%].DNA testing for hrHPV (any) and hrHPV (16/18) was the best universally acceptable strategy with an intermediate risk category (early follow-up) in HPW [sensitivity 82.1%; specificity 96.4%; treatment 17.1%; follow-up 31.4%] and HNW [sensitivity 68.2%; specificity 96.7%; treatment 7.6%; follow-up 15.9%]. In comparison, using both HPV (16/18) and cytology (ASCUS +) as secondary tests in hrHPV positive women, decreased follow-up [HPW 13.8%, HNW 9.6%], but increased treatment [HPW 34.7%, HNW 13.9%].ConclusionUsing hrHPV (any) as primary and both HPV16/18 and cytology as secondary tests, was universally acceptable without an intermediate risk group. Strategies with follow-up groups improved screening performance with smaller treatment numbers, but with effective management of the intermediate risk group as prerequisite.

Stratification of arrhythmic risk in patients admitted for acute coronary syndrome: the role of the machine learning-derived PRAISE score

Abstract Funding Acknowledgements None. Background Patients with acute coronary syndrome (ACS) have a high arrhythmic burden, and either ventricular and supraventricular arrhythmias are very common during hospitalization[1]. Patients who develop arrhythmias show higher mortality and worse prognosis. The PRAISE (Prediction of Adverse Events Following an Acute Coronary Syndrome) score is a machine-learning based model for predicting 1-year all cause death, recurrent acute myocardial infarction and major bleedings in patients after ACS[2]. To date, its role to predict arrhythmic complications in ACS remains unknown. Purpose We hypothesized that patients with higher PRAISE score have a higher arrhythmic burden. Aim was to evaluate in a prospective protocol the PRAISE score capability for identifying patients with ACS at higher risk of arrhythmic complications during in-hospital stay. Methods A total of 365 consecutive patients admitted to our cardiac intensive care unit for ACS and undergoing percutaneous coronary intervention were enrolled. All patient was monitored by continuous electrocardiogram during hospitalization. The PRAISE score was obtained for each patient &amp;lt;24 hours from admission. Patients were divided into 2 groups based on the results of the PRAISE score for all-cause of death as patients without high PRAISE score (e.g. with low to intermediate risk, n=350) and patients with high PRAISE score (e.g. with high risk, n=15). The occurrence of atrial fibrillation (AF) and ventricular arrhythmias (VAs) up to discharge was recorded. AF was defined by detection of at least one episode of uncoordinated atrial electrical activation and irregular R-R intervals, in absence of distinct repeating P waves and with irregular atrial activations lasting at least 5 minutes. We considered as VAs all episodes of ventricular non-sustained tachycardia, sustained ventricular tachycardia and ventricular fibrillation. Results ROC curve analysis indicated a significant relationship between high PRAISE score and risk of both in-hospital AF (AUC 0.89, 95%CI 0.82-0.94, p=0.0001) and VAs (AUC 0.69, 95%CI 0.64-0.75, p=0.0001). A high PRAISE score had a specificity of 99% for AF and 92% for VAs. By Kaplan-Meier analysis, patients with high PRAISE score more frequently developed AF (30% vs 4% in those without high score; log rank p=0.00001) and VAs (77% vs 35%; log rank p=0.00001). Multivariate analysis showed that a high PRAISE score was an independent predictor of both AF (HR 4.08, 95%CI 1.14-14.58, p=0.030) and VAs (HR 2.36, 95%CI 1.08-5.14, p=0.030). Conclusions In patients hospitalized for ACS, the PRAISE score has a comprehensive capability to identify with high specificity those patients prone to develop arrhythmic events during hospitalization. This may be important in order to stratify patients with higher arrhythmic risk in whom individualized strategies may improve the clinical outcome.Baseline features of the populationKaplan-Meier anaysis

Molecular alterations in claudin 18 suppressed and non-suppressed gastric adenocarcinomas to guide targeted therapies

ABSTRACT Background Gastric adenocarcinoma represents an aggressive type of cancer and an important cause of cancer mortality. Progress in gastric cancer therapeutics has resulted from a better understanding of the molecular pathogenesis of the disease and introduction of targeted therapies, but most gastric cancer patients still rely on non-targeted chemotherapy as the mainstay of treatment for advanced disease. Methods An analysis of publicly available series from The Cancer Genome Atlas (TCGA) gastric cancer cohort was undertaken to delineate the clinical and genomic landscape of gastric cancers with suppressed expression of claudin 18 compared with cancers with non-suppressed claudin 18. Claudin 18 suppressed cancers were defined as having an mRNA expression z-score relative to normal samples (log RNA Seq V2) of less than −1. Claudin 18 non-suppressed cancers were defined as having an mRNA expression z-score relative to normal samples (log RNA Seq V2) above 0.5. Results Gastric cancers with claudin 18 mRNA suppression represented 7.7% of the gastric adenocarcinomas of TCGA cohort, while non-suppressed cancers represented 46.6% of the cases. The two groups did not differ in clinical and genomic characteristics, such as mean age, histology, grade, and stage. The mutation landscape of claudin 18 suppressed cases included high mutation rates of TP53, of genes of the WNT/β-catenin pathway and of ubiquitin ligase FBXW7. Moreover, a subset of both claudin 18 suppressed and non-suppressed cancers displayed mutations in Mismatch Repair (MMR) associated genes or a high tumor mutation burden (TMB). At the mRNA expression level, claudin 18 suppressed gastric cancers showed up-regulation of EMT core transcription factor Snail 2 and down-regulation of genes of HLA cluster. The survival of gastric cancer patients with claudin 18 mRNA suppression was not significantly different compared with patients with non-suppressed claudin 18. Conclusion Sub-sets of gastric cancers with claudin 18 mRNA suppression displayed characteristics of potential therapeutic interest, such as mutations in WNT and PI3K pathways and MMR defects. These may guide the development of alternative targeted therapies, in this sub-set of gastric cancers which are not candidates for claudin 18 targeting therapies.