bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and health outcomes: a drug-target Mendelian randomization study and a phenome-wide association study
Authors: Yang Guoyi , Schooling C. Mary
Published: July 2023

Background

Asialoglycoprotein receptor 1 (ASGR1) is emerging as a potential drug target to reduce low-density lipoprotein (LDL)-cholesterol and coronary artery disease (CAD) risk. Here, we investigated genetically mimicked ASGR1 inhibitors on all-cause mortality and any possible adverse effects.

Methods

We conducted a drug-target Mendelian randomization study to assess genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and 25a priorioutcomes relevant to lipid traits, CAD, and possible adverse effects, i.e. liver function, cholelithiasis, adiposity and type 2 diabetes. We also performed a phenome-wide association study of 1951 health-related phenotypes to identify any novel effects. Associations found were compared with those for currently used lipid modifiers, assessed using colocalization, and replicated where possible.

Results

Genetically mimicked ASGR1 inhibitors were associated with a longer lifespan (3.31 years per standard deviation reduction in LDL-cholesterol, 95% confidence interval 1.01 to 5.62). Genetically mimicked ASGR1 inhibitors were inversely associated with apolipoprotein B (apoB), triglycerides (TG) and CAD risk. Genetically mimicked ASGR1 inhibitors were positively associated with alkaline phosphatase, gamma glutamyltransferase, erythrocyte traits, insulin-like growth factor 1 (IGF-1) and C-reactive protein (CRP), but were inversely associated with albumin and calcium. Genetically mimicked ASGR1 inhibitors were not associated with cholelithiasis, adiposity or type 2 diabetes. Associations with apoB and TG were stronger for ASGR1 inhibitors compared with currently used lipid modifiers, and most non-lipid effects were specific to ASGR1 inhibitors. The probabilities for colocalization were > 0.80 for most of these associations, but were 0.42 for lifespan and 0.30 for CAD. These associations were replicated using alternative genetic instruments and other publicly available genetic summary statistics.

Conclusions

Genetically mimicked ASGR1 inhibitors reduced all-cause mortality. Beyond lipid-lowering, genetically mimicked ASGR1 inhibitors increased liver enzymes, erythrocyte traits, IGF-1 and CRP, but decreased albumin and calcium.
Dobutamine-induced alternations in cerebral blood flow of healthy adults: a 3D pseudocontinuous arterial spin labeling study
Authors: Zhang Tingting , Niu Haijun , Liu Yawen , Cai Linkun , Liu Dong , Zhao Erwei , Li Min , Liu Wenjuan , Li Jing , Qiao PengGang , Zheng Wei , Ren Pengling , Wang Zhenchang
Published: July 2023

Background

It is unclear whether dobutamine, commonly used clinically in echocardiography and short-term congestive heart failure treatment for promoting increased myocardial contractility, affects brain microcirculatory behavior. Cerebral microcirculation plays an important role in ensuring adequate oxygen transport. Therefore, we investigated the effects of dobutamine on cerebral hemodynamics.

Methods

Forty-eight healthy volunteers without cardiovascular or cerebrovascular disease underwent MRI to obtain cerebral blood flow (CBF) maps using 3D pseudocontinuous arterial spin labeling before and during the dobutamine stress test. Additionally, cerebrovascular morphology was obtained based on 3D-time-off-light (3D-TOF) magnetic resonance angiography (MRA). Electrocardiogram, heart rate (HR), respiration rate (RR), blood pressure, and blood oxygen were simultaneously recorded before and during dobutamine injection and during recovery (not during MRI). The anatomic features of the circle of Willis and the basilar artery (BA) diameter were assessed on MRA images by two radiologists with extensive neuroimaging experience. Binary logistic regression was used to test for the independent determinants of CBF changes.

Results

HR, RR, systolic (SBP), and diastolic blood pressure (DBP) significantly increased after dobutamine infusion. Blood oxygen levels remained similar. Compared to the CBF in the resting state, the CBF values exhibited significantly lower CBF levels in both grey matter and white matter. Furthermore, compared with the CBF in the resting state, that in the stress state was decreased in the anterior circulation, mainly in the frontal lobe (voxel level P < 0.001, pixel level P < 0.05). Logistic regression showed that body mass index (BMI; odds ratio [OR] 5.80, 95% confidence interval [CI] 1.60–21.01, P = 0.008], resting SBP (OR 0.64, 95% CI 0.45–0.92, P = 0.014), and BA diameter (OR 11.04, 95% CI 1.05–116.53, P = 0.046) were significantly associated with frontal lobe CBF changes.

Conclusions

Dobutamine-induced stress significantly decreased CBF in the frontal lobe anterior circulation. Individuals with a high BMI and low SBP during the dobutamine stress test are more likely to have a stress-induced CBF decrease. Thus, attention should be paid to blood pressure, BMI, and cerebrovascular morphology of patients undergoing dobutamine stress echocardiography or those receiving intensive care or anesthesia.
Progressive trajectories of schizophrenia across symptoms, genes, and the brain
Authors: Jiang Sisi , Huang Huan , Zhou Jingyu , Li Hechun , Duan Mingjun , Yao Dezhong , Luo Cheng
Published: July 2023

Background

Schizophrenia is characterized by complex psychiatric symptoms and unclear pathological mechanisms. Most previous studies have focused on the morphological changes that occur over the development of the disease; however, the corresponding functional trajectories remain unclear. In the present study, we aimed to explore the progressive trajectories of patterns of dysfunction after diagnosis.

Methods

Eighty-six patients with schizophrenia and 120 healthy controls were recruited as the discovery dataset. Based on multiple functional indicators of resting-state brain functional magnetic resonance imaging, we conducted a duration-sliding dynamic analysis framework to investigate trajectories in association with disease progression. Neuroimaging findings were associated with clinical symptoms and gene expression data from the Allen Human Brain Atlas database. A replication cohort of patients with schizophrenia from the University of California, Los Angeles, was used as the replication dataset for the validation analysis.

Results

Five stage-specific phenotypes were identified. A symptom trajectory was characterized by positive-dominated, negative ascendant, negative-dominated, positive ascendant, and negative surpassed stages. Dysfunctional trajectories from primary and subcortical regions to higher-order cortices were recognized; these are associated with abnormal external sensory gating and a disrupted internal excitation–inhibition equilibrium. From stage 1 to stage 5, the importance of neuroimaging features associated with behaviors gradually shifted from primary to higher-order cortices and subcortical regions. Genetic enrichment analysis identified that neurodevelopmental and neurodegenerative factors may be relevant as schizophrenia progresses and highlighted multiple synaptic systems.

Conclusions

Our convergent results indicate that progressive symptoms and functional neuroimaging phenotypes are associated with genetic factors in schizophrenia. Furthermore, the identification of functional trajectories complements previous findings of structural abnormalities and provides potential targets for drug and non-drug interventions in different stages of schizophrenia.
Neutralizing antibody levels associated with injectable and aerosolized Ad5-nCoV boosters and BA.2 infection
Authors: Wang Fuzhen , Huang Baoying , Deng Yao , Zhang Shaobai , Liu Xiaoqiang , Wang Lei , Liu Qianqian , Zhao Li , Tang Lin , Wang Wenling , Wang Xiaoqi , Ye Fei , Hu Weijun , Yang Haitao , Wang Siquan , Ren Jiao , Liu Xiaoyu , Wang Cangning , Guan Xuhua , Wang Ruize , Zheng Yan , Zhang Xianfeng , Zheng Hui , Wu Dan , An Zhijie , Xu Wenbo , Rodewald Lawrence E. , Gao George F. , Yin Zundong , Tan Wenjie
Published: July 2023

Background

Several COVID-19 vaccines are in widespread use in China. Few data exist on comparative immunogenicity of different COVID-19 vaccines given as booster doses. We aimed to assess neutralizing antibody levels raised by injectable and inhaled aerosolized recombinant adenovirus type 5 (Ad5)-vectored COVID-19 vaccine as a heterologous booster after an inactivated COVID-19 vaccine two-dose primary series.

Methods

Using an open-label prospective cohort design, we recruited 136 individuals who had received inactivated vaccine primary series followed by either injectable or inhaled Ad5-vectored vaccine and measured neutralizing antibody titers against ancestral SARS-CoV-2 virus and Omicron BA.1 and BA.5 variants. We also measured neutralizing antibody levels in convalescent sera from 39 patients who recovered from Omicron BA.2 infection.

Results

Six months after primary series vaccination, neutralizing immunity against ancestral SARS-CoV-2 was low and neutralizing immunity against Omicron (B.1.1.529) was lower. Boosting with Ad5-vectored vaccines induced a high immune response against ancestral SARS-CoV-2. Neutralizing responses against Omicron BA.5 were ≥ 80% lower than against ancestral SARS-CoV-2 in sera from prime-boost subjects and in convalescent sera from survivors of Omicron BA.2 infection. Inhaled aerosolized Ad5-vectored vaccine was associated with greater neutralizing titers than injectable Ad5-vectored vaccine against ancestral and Omicron SARS-CoV-2 variants.

Conclusions

These findings support the current strategy of heterologous boosting with injectable or inhaled Ad5-vectored SARS-CoV-2 vaccination of individuals primed with inactivated COVID-19 vaccine.
Family history and breast cancer risk for Asian women: a systematic review and meta-analysis
Authors: Wang Heran , MacInnis Robert J. , Li Shuai
Published: July 2023

Background

Studies of women of European ancestry have shown that the average familial relative risk for first-degree relatives of women with breast cancer is approximately twofold, but little is known for Asian women. We aimed to provide evidence for the association between family history and breast cancer risk for Asian women by systematically reviewing published literature.

Methods

Studies reporting the familial relative risk of breast cancer for Asian women were searched in three online databases and complemented by a manual search. Odds ratios (ORs) for the association between family history and breast cancer risk were pooled across all included studies and by subgroups in terms of the type of family history, age, menopausal status and geographical region.

Results

The pooled OR for women who have a first-degree relative with breast cancer was 2.46 (95% confidence interval [CI]: 2.03, 2.97). There was no evidence that the familial risk differed by the type of affected relative (mother versus sisters), the woman’s age (< 50 years versus ≥ 50 years), menopausal status (pre versus post) and geographical region (East and Southeast Asia versus other regions) (all P > 0.3). The pooled ORs for women of Asian ancestry with a family history in any relative were similar for those living in non-Asian countries (2.26, 95% CI: 1.42, 3.59) compared with those living in Asian countries (2.18, 95% CI: 1.85, 2.58).

Conclusions

Family history of breast cancer is associated with an approximately twofold relative risk of breast cancer for Asian women, which is of similar magnitude to that observed for women of European ancestry. This implies that similar familial factors are implicated in breast cancer risk between women of European and Asian ancestries. Genetic factors are likely to play a substantial role in explaining the breast cancer familial risk for Asian women, as similar risks were observed across different living environments and cultures.
Evaluation of post-acute care and one-year outcomes among Medicare beneficiaries with hip fractures: a retrospective cohort study
Authors: Riester Melissa R. , Beaudoin Francesca L. , Joshi Richa , Hayes Kaleen N. , Cupp Meghan A. , Berry Sarah D. , Zullo Andrew R.
Published: July 2023

Background

Post-acute care (PAC) services after hospitalization for hip fracture are typically provided in skilled nursing facilities (SNFs), inpatient rehabilitation facilities (IRFs), or at home via home health care (HHC). Little is known about the clinical course following PAC for hip fracture. We examined the nationwide burden of adverse outcomes by PAC setting in the year following discharge from PAC for hip fracture.

Methods

This retrospective cohort included Medicare Fee-for-Service beneficiaries > 65 years who received PAC services in U.S. SNFs, IRFs, or HHC following hip fracture hospitalization between 2012 and 2018. Individuals who had a fall-related injury (FRI) during PAC or received PAC services in multiple settings were excluded. Primary outcomes included FRIs, all-cause hospital readmissions, and death in the year following discharge from PAC. Cumulative incidences and incidence rates for adverse outcomes were reported by PAC setting. Exploratory analyses examined risk ratios and hazard ratios between settings before and after inverse-probability-of-treatment-weighting, which accounted for 43 covariates.

Results

Among 624,631 participants (SNF, 67.78%; IRF, 16.08%; HHC, 16.15%), the mean (standard deviation) age was 82.70 (8.26) years, 74.96% were female, and 91.30% were non-Hispanic White. Crude incidence rates (95%CLs) per 1000 person-years were highest among individuals receiving SNF care for FRIs (SNF, 123 [121, 123]; IRF, 105 [102, 107]; HHC, 89 [87, 91]), hospital readmission (SNF, 623 [619, 626]; IRF, 538 [532, 544]; HHC, 418 [414, 423]), and death (SNF, 167 [165, 169]; IRF, 47 [46, 49]; HHC, 55 [53, 56]). Overall, rates of adverse outcomes generally remained higher among SNF care recipients after covariate adjustment. However, inferences about the group with greater adverse outcomes differed for FRIs and hospital readmissions based on risk ratio or hazard ratio estimates.

Conclusions

In this retrospective cohort study of individuals hospitalized for hip fracture, rates of adverse outcomes in the year following PAC were common, especially among SNF care recipients. Understanding risks and rates of adverse events can inform future efforts to improve outcomes for older adults receiving PAC for hip fracture. Future work should consider calculating risk and rate measures to assess the influence of differential time under observation across PAC groups.
Social and environmental determinants influencing injection drug use and HIV risk among two sister cities on the US–Mexico border: a comparative cross-sectional study, 2016–2018
Authors: Lechuga Julia , Ramos Rebeca , Ludwig-Barron Natasha , Perez Gilberto , Ramos Maria Elena , Ferreira-Pinto João B. , Cordero Jacquelin I. , Sauceda John , Salazar Jorge
Published: July 2023

The economic, social, cultural and political milieus that influence injection drug-related HIV risk behaviors along the US–Mexico border in the previous decade have been studied comparing cities on an East–West axis. In an effort to inform interventions targeting factors beyond the individual level, we used a cross-sectional study design comparing people who inject drugs during 2016–2018, living on a North–South axis, in two cities—Ciudad Juárez, Chihuahua, Mexico and El Paso, Texas, USA—situated at the midpoint of the 2000 US–Mexico borderland stretch. We conceptualize injection drug use and its antecedents and consequences as influenced by factors operating at various levels of influence. Results of analysis comparing samples recruited from each border city indicated significant differences in demographic, socioeconomic, micro- and macro-level factors that affect risk. Similarities emerged in individual-level risk behaviors and some dynamics of risk at the drug use site most frequented to use drugs. In addition, analyses testing associations across samples indicated that different contextual factors such as characteristics of the drug use sites influenced syringe sharing. In this article, we reflect on the potential tailored interventions needed to target the context of HIV transmission risk among people who use drugs and reside in binational environment.
Time interval between hCG administration and oocyte retrieval and ART outcomes: an updated systematic review and meta-analysis
Authors: Gan Runxin , Huang Xi , Zhao Jing , Zhang Qiong , Huang Chuan , Li Yanping
Published: July 2023

Research question

To explore whether prolonged hCG-ovum pickup interval improves assisted reproductive technology outcomes.

Design

CENTRAL, CNKI, Cochrane Systematic Reviews, EMBASE, MEDLINE, PUBMED, and Web of Science up to May 13 2023 were searched for studies reporting associations between hCG-ovum pickup intervals and assisted reproductive technology outcomes. Intervention types included short (≤ 36 h) and long (> 36 h) hCG-ovum pickup intervals in assisted reproductive technology cycles. All outcomes were based upon only fresh embryo transfers. Primary outcome is defined as the clinical pregnancy rate. Data were pooled using random-effects models. Heterogeneity was assessed using the I 2 statistics.

Results

Twelve studies were included in the meta-analysis, including five retrospective cohort studies, one prospective cohort study, and six randomized or quasi-randomized controlled trials. The short and long interval groups had similar oocyte maturation rates, fertilization rate and high-quality embryo rate (OR, 0.69; 95% CI, 0.45–1.06; I 2 = 91.1%, OR, 0.88; 95% CI, 0.77–1.0; I 2 = 44.4% and OR, 1.05; 95% CI, 0.95–1.17; I 2 = 8.6%, respectively). The clinical pregnancy rates in the long retrieval group were significantly higher than in the short retrieval group (OR, 0.66; 95% CI, 0.45–0.95; I 2 = 35.4%). The groups had similar miscarriage and live birth rates (OR, 1.92; 95% CI, 0.66–5.60; I 2 = 0.0% and OR, 0.50; 95% CI, 0.24–1.04; I 2 = 0.0%, respectively).

Conclusions

The clinical pregnancy rates can be increased by prolonging the hCG-ovum pickup interval, which would help us develop more reasonable time schedules for fertility centers and patients.

Meta-analysis registration

PROSPERO CRD42022310006 (28 Apr 2022).
Predictors of pulmonary embolism in hospitalized patients with COVID-19
Authors: Bahk Jeeyune , Rehman Abdul , Ho Kam Sing , Narasimhan Bharat , Baloch Hafiza Noor Ul Ain , Zhang Jiafang , Yip Rowena , Lookstein Robert , Steiger David J
Published: July 2023

Background

High venous thromboembolism (VTE) rates have been described in critically ill patients with COVID-19. We hypothesized that specific clinical characteristics may help differentiate hypoxic COVID-19 patients with and without a diagnosed pulmonary embolism (PE).

Methods

We performed a retrospective observational case-control study of 158 consecutive patients hospitalized in one of four Mount Sinai Hospitals with COVID-19 between March 1 and May 8, 2020, who received a Chest CT Pulmonary Angiogram (CTA) to diagnose a PE. We analyzed demographic, clinical, laboratory, radiological, treatment characteristics, and outcomes in COVID-19 patients with and without PE.

Results

92 patients were negative (CTA-), and 66 patients were positive for PE (CTA+). CTA + had a longer time from symptom onset to admission (7 days vs. 4 days, p = 0.05), higher admission biomarkers, notably D-dimer (6.87 vs. 1.59, p < 0.0001), troponin (0.015 vs. 0.01, p = 0.01), and peak D-dimer (9.26 vs. 3.8, p = 0.0008). Predictors of PE included time from symptom onset to admission (OR = 1.11, 95% CI 1.03–1.20, p = 0.008), and PESI score at the time of CTA (OR = 1.02, 95% CI 1.01–1.04, p = 0.008). Predictors of mortality included age (HR 1.13, 95% CI 1.04–1.22, p = 0.006), chronic anticoagulation (13.81, 95% CI 1.24–154, p = 0.03), and admission ferritin (1.001, 95% CI 1-1.001, p = 0.01).

Conclusions

In 158 hospitalized COVID-19 patients with respiratory failure evaluated for suspected PE, 40.8% patients had a positive CTA. We identified clinical predictors of PE and mortality from PE, which may help with early identification and reduction of PE-related mortality in patients with COVID-19.
Artificial intelligence for the prevention and prediction of colorectal neoplasms
Authors: Tokutake Kohjiro , Morelos-Gomez Aaron , Hoshi Ken-ichi , Katouda Michio , Tejima Syogo , Endo Morinobu
Published: July 2023

Background

Colonoscopy is a useful as a cancer screening test. However, in countries with limited medical resources, there are restrictions on the widespread use of endoscopy. Non-invasive screening methods to determine whether a patient requires a colonoscopy are thus desired. Here, we investigated whether artificial intelligence (AI) can predict colorectal neoplasia.

Methods

We used data from physical exams and blood analyses to determine the incidence of colorectal polyp. However, these features exhibit highly overlapping classes. The use of a kernel density estimator (KDE)-based transformation improved the separability of both classes.

Results

Along with an adequate polyp size threshold, the optimal machine learning (ML) models’ performance provided 0.37 and 0.39 Matthews correlation coefficient (MCC) for the datasets of men and women, respectively. The models exhibit a higher discrimination than fecal occult blood test with 0.047 and 0.074 MCC for men and women, respectively.

Conclusion

The ML model can be chosen according to the desired polyp size discrimination threshold, may suggest further colorectal screening, and possible adenoma size. The KDE feature transformation could serve to score each biomarker and background factors (health lifestyles) to suggest measures to be taken against colorectal adenoma growth. All the information that the AI model provides can lower the workload for healthcare providers and be implemented in health care systems with scarce resources. Furthermore, risk stratification may help us to optimize the efficiency of resources for screening colonoscopy.
Childhood-Onset ANCA- Associated Vasculitis: single center experience from Central California
Authors: Singh Deepika , Sukumaran Sukesh
Published: July 2023

Background

Childhood-onset ANCA-associated vasculitides (AAV) are characterized by necrotizing inflammation and include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Pediatric data is scare and there have been no prior studies examining the characteristics of pediatric AAV in Central California.

Methods

This retrospective study comprised AAV patients ≤18 years of age, diagnosed between 2010 and 2021, in Central California. We analyzed initial presentation including demographics, clinical, laboratory characteristics, treatment, and initial outcomes.

Results

Of 21 patients with AAV, 12 were categorized as MPA and 9 with GPA. Median age at diagnosis was 13.7 years in MPA cohort and 14 years in GPA. MPA cohort were majority females (92% versus 44%). 57% of the cohort were racial/ethnic minority including Hispanics (n = 9), Asians (n = 2), multiracial (n = 1) and 43% were white (n = 9). MPA patients were more frequently Hispanic (67%), meanwhile GPA patients were frequently white (78%). Median duration of symptoms prior to diagnosis was 14 days in MPA cohort and 21 days in GPA cohort. Renal involvement was frequent (100% in MPA and 78% in GPA). GPA cohort had frequent ear, nose and throat (ENT) involvement (89%). All patients were ANCA positive. All Hispanic patients were MPO positive, meanwhile 89% of white patients were PR3 positive. MPA cohort tended towards more severe disease with 67% requiring ICU admission and 50% requiring dialysis. Two deaths were reported in MPA cohort, related to Aspergillus pneumonia and pulmonary hemorrhage. In MPA cohort, 42% received cyclophosphamide in combination with steroids and 42% received rituximab in combination with steroids. GPA patients received cyclophosphamide, either with steroids alone (78%) or in combination with steroids and rituximab (22%).

Conclusions

Microscopic polyangiitis was the most frequent AAV subtype with female preponderance, shorter duration of symptoms at onset and higher proportion of racial/ ethnic minority patients. Hispanic children demonstrated frequent MPO positivity. Trends towards higher rates of ICU requirement and need for dialysis upon initial presentation was noted in MPA. Patients with MPA received rituximab more frequently. Future prospective studies are needed to understand differences in presentation and outcomes in childhood onset AAV between diverse racial-ethnic groups.
Diesel Exhaust Particle (DEP)-induced glucose intolerance is driven by an intestinal innate immune response and NLRP3 activation in mice
Authors: Bosch Angela J. T. , Rohm Theresa V. , AlAsfoor Shefaa , Low Andy J. Y. , Baumann Zora , Parayil Neena , Noreen Faiza , Roux Julien , Meier Daniel T. , Cavelti-Weder Claudia
Published: July 2023

Background

We previously found that air pollution particles reaching the gastrointestinal tract elicit gut inflammation as shown by up-regulated gene expression of pro-inflammatory cytokines and monocyte/macrophage markers. This inflammatory response was associated with beta-cell dysfunction and glucose intolerance. So far, it remains unclear whether gut inflammatory changes upon oral air pollution exposure are causally linked to the development of diabetes. Hence, our aim was to assess the role of immune cells in mediating glucose intolerance instigated by orally administered air pollutants.

Methods

To assess immune-mediated mechanisms underlying air pollution-induced glucose intolerance, we administered diesel exhaust particles (DEP; NIST 1650b, 12 µg five days/week) or phosphate-buffered saline (PBS) via gavage for up to 10 months to wild-type mice and mice with genetic or pharmacological depletion of innate or adaptive immune cells. We performed unbiased RNA-sequencing of intestinal macrophages to elucidate signaling pathways that could be pharmacologically targeted and applied an in vitro approach to confirm these pathways.

Results

Oral exposure to air pollution particles induced an interferon and inflammatory signature in colon macrophages together with a decrease of CCR2− anti-inflammatory/resident macrophages. Depletion of macrophages, NLRP3 or IL-1β protected mice from air pollution-induced glucose intolerance. On the contrary, Rag2-/- mice lacking adaptive immune cells developed pronounced gut inflammation and glucose intolerance upon oral DEP exposure.

Conclusion

In mice, oral exposure to air pollution particles triggers an immune-mediated response in intestinal macrophages that contributes to the development of a diabetes-like phenotype. These findings point towards new pharmacologic targets in diabetes instigated by air pollution particles.
Overview of patients’ cohorts in the French National rare disease registry
Authors: Pichon Thibaut , Messiaen Claude , Soussand Louis , Angin Céline , Sandrin Arnaud , Elarouci Nabila , Jannot Anne-Sophie ,   on behalf of the BNDMR infrastructure team
Published: July 2023

In France, all patients followed by Rare Disease (RD) expert centers have to be registered in the National Rare Disease Registry (BNDMR). This database collects a minimum data set including diagnosis coded using the Orphanet nomenclature. Overall, 753,660 patients were recorded from 2007 to March 2022 including 493,740 with at least one rare disease diagnosis. Among these rare disease diagnoses, 1,300 diagnoses gathered between 10 and 70 patients and 792 gathered more than 70 patients, corresponding to more than one patient per million inhabitants. A total of 47 rare disease diagnoses with point prevalence or incidence reported in the literature below 1/1,000,000 have more than 70 patients in the BNDMR, suggesting larger BNDMR cohorts than expected from reported literature. As a conclusion, our national RD registry is a great resource to facilitate patients’ recruitment in clinical research and a better understanding of RD natural history and epidemiology.
Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease
Authors: Yu Shan P. , Jiang Michael Q. , Shim Seong S. , Pourkhodadad Soheila , Wei Ling
Published: July 2023

Stroke and late-onset Alzheimer’s disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity and NMDAR-mediated Ca2+influx are essential for neuronal function and cell survival. An ischemic insult, however, can cause rapid increases in glutamate concentration and excessive activation of NMDARs, leading to swift Ca2+overload in neuronal cells and acute excitotoxicity within hours and days. On the other hand, mild upregulation of NMDAR activity, commonly seen in AD animal models and patients, is not immediately cytotoxic. Sustained NMDAR hyperactivity and Ca2+dysregulation lasting from months to years, nevertheless, can be pathogenic for slowly evolving events, i.e. degenerative excitotoxicity, in the development of AD/ADRD. Specifically, Ca2+influx mediated by extrasynaptic NMDARs (eNMDARs) and a downstream pathway mediated by transient receptor potential cation channel subfamily M member (TRPM) are primarily responsible for excitotoxicity. On the other hand, the NMDAR subunit GluN3A plays a “gatekeeper” role in NMDAR activity and a neuroprotective role against both acute and chronic excitotoxicity. Thus, ischemic stroke and AD share an NMDAR- and Ca2+-mediated pathogenic mechanism that provides a common receptor target for preventive and possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs and was approved by the Federal Drug Administration (FDA) for symptomatic treatment of moderate-to-severe AD with variable efficacy. According to the pathogenic role of eNMDARs, it is conceivable that MEM and other eNMDAR antagonists should be administered much earlier, preferably during the presymptomatic phases of AD/ADRD. This anti-AD treatment could simultaneously serve as a preconditioning strategy against stroke that attacks ≥ 50% of AD patients. Future research on the regulation of NMDARs, enduring control of eNMDARs, Ca2+homeostasis, and downstream events will provide a promising opportunity to understand and treat the comorbidity of AD/ADRD and stroke.
Gastro-intestinal lesions are not relatable to diarrhoea or specific pathogens in post-weaning diarrhoea (PWD) in pigs
Authors: Blirup-Plum Sophie Amalie , Jensen Henrik Elvang , Nielsen Søren Saxmose , Pankoke Karen , Hansen Mette Sif , Pedersen Ken Steen , Eriksen Esben Østergaard , Nielsen Jens Peter , Olsen John Elmerdahl , Kudirkiene Egle , Larsen Lars Erik , Goecke Nicole Bakkegård , Barington Kristiane
Published: July 2023

Background

Post-weaning diarrhoea (PWD) is a multifactorial condition and the most well documented infectious cause is enterotoxigenicEscherichia coli. The objective of the study was to investigate possible associations between pathological manifestations and pathogens in pigs with and without PWD. The study was conducted as a case–control study and included a total of 173 pigs from 9 different commercial intensive indoor production herds in eastern Denmark.

Results

Based on clinical examination, a total of 89 piglets with PWD (cases) and 84 piglets without PWD (controls) were included. Most of the pigs (n = 105/173) presented gastric lesions, which were more frequently observed in the control group. The odds of gastric ulcers were lower among pigs with PWD compared to pigs without PWD with an odds ratio (OR) of 0.2 (0.0; 0.7). Abnormal content in the colon was associated with PWD, with an OR of 6.5 (3.2; 14.3). No apparent association was found between lesions and the various pathogens or a combination of these. The odds of neutrophilic granulocyte infiltration were lower in the jejunum among pigs with PWD (OR 0.3 [0.1; 0.6]) compared to pigs without PWD. The association between neutrophilic granulocyte infiltration in jejunum and PWD differed between the herds (P = 0.03). Furthermore, the associations between PWD and hyperleukocytosis (P = 0.04) or infiltration of eosinophilic granulocytes (P = 0.04) in ileum were also herd dependent. Histopathology revealed several lesions not relatable to PWD.

Conclusion

The association between lesions and specific pathogens or PWD is more complex than anticipated.
Celiac disease in autism spectrum disorder: data from an Italian child cohort
Authors: Zambrano Stefania , Parma Barbara , Morabito Valeria , Borini Silvia , Romaniello Roberta , Molteni Massimo , Mani Elisa , Selicorni Angelo
Published: July 2023

Background

In recent decades some studies described the frequent co-occurrence of celiac disease autoimmunity and overt celiac disease in patients with autism. Therefore, it was suggested that celiac disease could play a possible role in the etiopathogenesis of autism spectrum disorder. However, several other studies have not confirmed this association. The aim of the present study was to elucidate the potential association between autism spectrum disorder and celiac disease.

Methods

We prospectively collected data from an Italian cohort of 223 children at the time of their clinical diagnosis of autism spectrum disorder in the 2019–2020 period. A serological celiac disease screening was performed and data were available for 196 patients; male (M):female (F) ratio = 4.4:1; median age = 3.6 years; age range = 1.6–12.8 years. Full-blown celiac disease was established according to the diagnostic algorithm of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) 2012 or 2019 guidelines. Fisher’s exact test was used to compare the celiac disease seroprevalence and prevalence in our autism spectrum disorder cohort and in the Italian healthy pediatric population studied by Gatti et al. to highlight the possible differences between the two groups.

Results

A not statistically significant difference between the celiac disease seroprevalence in our autism spectrum disorder cohort (4.08%) and Gatti’s Italian healthy group (2.22%) was found, p = 0.0810; OR = 1.871. A similar result emerged for overt celiac disease prevalences (2.24% versus 1.58%, respectively), p = 0.2862; OR = 1.431.

Conclusions

Our data validates a weakness of association between autism spectrum disorder and celiac disease. On the basis of our results, a regular screening for CD in patients with ASD is not recommended to a greater extent than in the general population.
Prognostic and predictive value of endothelial dysfunction biomarkers in sepsis-associated acute kidney injury: risk-stratified analysis from a prospective observational cohort of pediatric septic shock
Authors: Atreya Mihir R. , Cvijanovich Natalie Z. , Fitzgerald Julie C. , Weiss Scott L. , Bigham Michael T. , Jain Parag N. , Schwarz Adam J. , Lutfi Riad , Nowak Jeffrey , Allen Geoffrey L. , Thomas Neal J. , Grunwell Jocelyn R. , Baines Torrey , Quasney Michael , Haileselassie Bereketeab , Alder Matthew N. , Goldstein Stuart L. , Stanski Natalja L.
Published: July 2023

Background

Sepsis-associated acute kidney injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based risk strata, and develop prediction models to identify those at highest risk of SA-AKI.

Methods

Secondary analyses of prospective observational cohort of pediatric septic shock. Primary outcome of interest was the presence of ≥ Stage II KDIGO SA-AKI on day 3 based on serum creatinine (D3 SA-AKI SCr). Biomarkers including those prospectively validated to predict pediatric sepsis mortality (PERSEVERE-II) were measured in Day 1 (D1) serum. Multivariable regression was used to test the independent association between endothelial markers and D3 SA-AKI SCr. We conducted risk-stratified analyses and developed prediction models using Classification and Regression Tree (CART), to estimate risk of D3 SA-AKI among prespecified subgroups based on PERSEVERE-II risk.

Results

A total of 414 patients were included in the derivation cohort. Patients with D3 SA-AKI SCr had worse clinical outcomes including 28-day mortality and need for CRRT. Serum soluble thrombomodulin (sTM), Angiopoietin-2 (Angpt-2), and Tie-2 were independently associated with D3 SA-AKI SCr. Further, Tie-2 and Angpt-2/Tie-2 ratios were influenced by the interaction between D3 SA-AKI SCr and risk strata. Logistic regression demonstrated models predictive of D3 SA-AKI risk performed optimally among patients with high- or intermediate-PERSEVERE-II risk strata. A 6 terminal node CART model restricted to this subgroup of patients had an area under the receiver operating characteristic curve (AUROC) 0.90 and 0.77 upon tenfold cross-validation in the derivation cohort to distinguish those with and without D3 SA-AKI SCr and high specificity. The newly derived model performed modestly in a unique set of patients (n = 224), 84 of whom were deemed high- or intermediate-PERSEVERE-II risk, to distinguish those patients with high versus low risk of D3 SA-AKI SCr.

Conclusions

Endothelial dysfunction biomarkers are independently associated with risk of severe SA-AKI. Pending validation, incorporation of endothelial biomarkers may facilitate prognostic and predictive enrichment for selection of therapeutics in future clinical trials among critically ill children.

Graphical abstract
The CBIT + TMS trial: study protocol for a two-phase randomized controlled trial testing neuromodulation to augment behavior therapy for youth with chronic tics
Authors: Conelea Christine , Greene Deanna J. , Alexander Jennifer , Houlihan Kerry , Hodapp Sarah , Wellen Brianna , Francis Sunday , Mueller Bryon , Hendrickson Tim , Tseng Angela , Chen Mo , Fiecas Mark , Lim Kelvin , Opitz Alexander , Jacob Suma
Published: July 2023

Background

Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment for tic disorders that aims to improve controllability over tics that an individual finds distressing or impairing. However, it is only effective for approximately half of patients. Supplementary motor area (SMA)-directed neurocircuitry plays a strong role in motor inhibition, and activity in this region is thought to contribute to tic expression. Targeted modulation of SMA using transcranial magnetic stimulation (TMS) may increase CBIT efficacy by improving patients' ability to implement tic controllability behaviors.

Methods

The CBIT + TMS trial is a two-phase, milestone-driven early-stage randomized controlled trial. The trial will test whether augmenting CBIT with inhibitory, non-invasive stimulation of SMA with TMS modifies activity in SMA-mediated circuits and enhances tic controllability in youth ages 12–21 years with chronic tics. Phase 1 will directly compare two rTMS augmentation strategies (1 Hz rTMS vs. cTBS) vs. sham in N = 60 participants. Quantifiable, a priori “Go/No Go Criteria” guide the decision to proceed to phase 2 and the selection of the optimal TMS regimen. Phase 2 will compare the optimal regimen vs. sham and test the link between neural target engagement and clinical outcomes in a new sample of N = 60 participants.

Discussion

This clinical trial is one of few to date testing TMS augmentation of therapy in a pediatric sample. The results will provide insight into whether TMS is a potentially viable strategy for enhancing CBIT efficacy and reveal potential neural and behavioral mechanisms of change.

Trial registration

ClinicalTrials.gov NCT04578912. Registered on October 8, 2020.
Awareness of celiac disease among the public in Kuwait: a cross-sectional survey
Authors: Qasem Wafaa A. , Roumi Ali Al , Al Mojil Khaled , Sakijha Hind , AlMughamis Nouf
Published: July 2023

Objective

Health literacy levels among the general population predict better health outcomes and uptake of health services. Inequities in health literacy and uptake of health services are often observed in deprived neighborhoods. There is a paucity of data on literacy regarding celiac disease in Kuwait. Therefore, the present survey aims to address this paucity of data.

Results

We conducted a survey of 350 respondents in six governates of Kuwait. Although around 51% of respondents were aware of peanut allergy and gluten sensitivity, less than 15% were aware of celiac disease. More than 40% of respondents reported that a gluten-free diet should be promoted for everyone. Better awareness regarding CD was associated with Kuwaiti nationality, higher education levels and higher age. Among different governates, residents of Al-Asimah reported the highest awareness levels, while the rest of the governates did not differ significantly. While eating behavior did not significantly predict awareness regarding CD.
Plasma apolipoprotein E levels, isoform composition, and dimer profile in relation to plasma lipids in racially diverse patients with Alzheimer’s disease and mild cognitive impairment
Authors: Giannisis Andreas , Al-Grety Asma , Carlsson Henrik , Howell Jennifer C. , Hu William T. , Kultima Kim , Nielsen Henrietta M.
Published: July 2023

Background

The APOEε4-promoted risk of Alzheimer’s disease (AD) is lower in Black/African-Americans (B/AAs), compared to non-Hispanic whites (NHWs). Previous studies reported lower plasma apolipoprotein E (apoE) levels in NHW APOEε4-carriers compared to non-carriers, and low plasma apoE levels were directly associated with an increased risk of AD and all dementia. We further showed that APOEε3/ε3 AD patients exhibited reduced plasma apoE dimers compared to corresponding control subjects. Whether plasma apoE levels and apoE dimer formation differ between races/ethnicities and therefore may help explain AD risk racial disparity remains to be elucidated.

Methods

Using mass spectrometry, we determined total plasma apoE and apoE isoform levels in a cohort of B/AAs (n = 58) and NHWs (n = 67) including subjects with normal cognition (B/AA: n = 25, NHW: n = 28), mild cognitive impairment (MCI) (B/AA: n = 24, NHW: n = 24), or AD dementia (B/AA: n = 9, NHW: n = 15). Additionally, we used non-reducing western blot analysis to assess the distribution of plasma apoE into monomers/disulfide-linked dimers. Plasma total apoE, apoE isoform levels, and % apoE monomers/dimers were assessed for correlations with cognition, cerebrospinal fluid (CSF) AD biomarkers, sTREM2, neurofilament light protein (NfL), and plasma lipids.

Results

Plasma apoE was predominantly monomeric in both racial groups and the monomer/dimer distribution was not affected by disease status, or correlated with CSF AD biomarkers, but associated with plasma lipids. Plasma total apoE levels were not related to disease status and only in the NHW subjects we observed lower plasma apoE levels in the APOEε4/ε4-carriers. Total plasma apoE levels were 2.6-fold higher in B/AA compared to NHW APOEε4/ε4 subjects and associated with plasma high-density lipoprotein (HDL) in NHW subjects but with low-density lipoprotein levels (LDL) in the B/AA subjects. Higher plasma apoE4 levels, exclusively in APOEε3/ε4 B/AA subjects, were linked to higher plasma total cholesterol and LDL levels. In the controls, NHWs and B/AAs exhibited opposite associations between plasma apoE and CSF t-tau.

Conclusions

The previously reported lower APOEε4-promoted risk of AD in B/AA subjects may be associated with differences in plasma apoE levels and lipoprotein association. Whether differences in plasma apoE levels between races/ethnicities result from altered APOEε4 expression or turnover, needs further elucidation.
Primary and secondary tumors of the peritoneum: key imaging features and differential diagnosis with surgical and pathological correlation
Authors: Miguez González Javier , Calaf Forn Francesc , Pelegrí Martínez Laura , Lozano Arranz Pilar , Oliveira Caiafa Rafael , Català Forteza Jordi , Palacio Arteaga Lina Maria , Losa Gaspà Ferrán , Ramos Bernadó Isabel , Barrios Sánchez Pedro , Ayuso Colella Juan Ramón
Published: July 2023

Peritoneal malignancies represent a diagnostic challenge for abdominal radiologists, oncologists, surgeons and pathologists in multidisciplinary teams, who must address their differential diagnosis, staging and treatment. In this article, we explain the pathophysiology of these processes and lay out the role of different imaging techniques in their evaluation. Then, we review the clinical and epidemiological aspects, the main radiological features and the therapeutic approaches for each primary and secondary peritoneal neoplasm, with surgical and pathological correlation. We further describe other rare peritoneal tumors of uncertain origin and a variety of entities that may mimic peritoneal malignancy. Finally, we summarize the key imaging findings of each peritoneal neoplasm to facilitate an accurate differential diagnosis that may impact patient management.

Clinical relevance statement

Imaging plays an essential role in the evaluation of peritoneal malignancies, assessing their extension, detecting unfavorable sites of involvement and facilitating an accurate differential diagnosis, helping to choose the best therapeutic approach.

Graphical abstract
Photon-counting CT allows better visualization of temporal bone structures in comparison with current generation multi-detector CT
Authors: Hermans Robert , Boomgaert Lukas , Cockmartin Lesley , Binst Joke , De Stefanis Rashèl , Bosmans Hilde
Published: July 2023

Purpose

To compare photon-counting CT (PCCT) and multi-detector CT (MDCT) for visualization of temporal bone anatomic structures.

Methods

Thirty-six exams of temporal bones without pathology were collected from consecutive patients on a MDCT, and another 35 exams on a PCCT scanner. Two radiologists independently scored visibility of 14 structures for the MDCT and PCCT dataset, using a 5-point Likert scale, with a 2-month wash-out period. For MDCT, the acquisition parameters were: 110 kV, 64 × 0.6 mm (slice thickness reconstructed to 0.4 mm), pitch 0.85, quality ref. mAs 150, and 1 s rotation time; for PCCT: 120 kV, 144 × 0.2 mm, pitch 0.35, IQ level 75, and 0.5 s rotation time. Patient doses were reported as dose length product values (DLP). Statistical analysis was done using the Mann–Whitney U test, visual grading characteristic (VGC) analysis, and ordinal regression.

Results

Substantial agreement was found between readers (intraclass correlation coefficient 0.63 and 0.52 for MDCT and PCCT, resp.). All structures were scored higher for PCCT (p < 0.0001), except for Arnold’s canal (p = 0.12). The area under the VGC curve was 0.76 (95% CI, 0.73–0.79), indicating a significantly better visualization on PCCT. Ordinal regression showed the odds for better visualization are 354 times higher (95% CI, 75–1673) in PCCT (p < 0.0001). Average (range) of DLP was 95 (79–127) mGy*cm for MDCT and 74 (50–95) mGy*cm for PCCT (p < 0.001).

Conclusion

PCCT provides a better depiction of temporal bone anatomy than MDCT, at a lower radiation dose.

Graphical Abstract

Critical relevance statement

PCCT provides a better depiction of temporal bone anatomy than MDCT, at a lower radiation dose.

Key points

PCCT allows high-resolution imaging of temporal bone structures.

Compared to MDCT, the visibility of normal temporal bone structures is scored better with PCCT.

PCCT allows to obtain high-quality CT images of the temporal bones at lower radiation doses than MDCT.