Miracle-dz/UniFAR-FTUs huggingface dataset:
Decreased Interleukin-1 Family Cytokine Production in Patients with Nontuberculous Mycobacterial Lung Disease

Upon MAC stimulation, the production of IL-1 family cytokines and IL-10 by PBMCs of NTMPD patients was attenuated compared with that of healthy household contacts. Upon MAC stimulation, the expression of TLR2 and TWIK2 (one of the two-pore domain K+ channels) was attenuated in PBMCs of NTMPD patients compared with that of healthy household contacts. ABSTRACT Nontuberculous mycobacteria (NTM) cause pulmonary disease in individuals without obvious immunodeficiency. This study was initiated to gain insight into the immunological factors that predispose persons to NTM pulmonary disease (NTMPD). Blood was obtained from 15 pairs of NTMPD patients and their healthy household contacts. Peripheral blood mononuclear cells (PBMCs) were stimulated with the Mycobacterium avium complex (MAC). A total of 34 cytokines and chemokines were evaluated in plasma and PBMC culture supernatants using multiplex immunoassays, and gene expression in the PBMCs was determined using real-time PCR. PBMCs from NTMPD patients produced significantly less interleukin-1β (IL-1β), IL-18, IL-1α, and IL-10 than PBMCs from their healthy household contacts in response to MAC. Although plasma RANTES levels were high in NTMPD patients, they had no effect on IL-1β production by macrophages infected with MAC. Toll-like receptor 2 (TLR2) and TWIK2 (a two-pore domain K+ channel) were impaired in response to MAC in PBMCs of NTMPD patients. A TLR2 inhibitor decreased all four cytokines, whereas a two-pore domain K+ channel inhibitor decreased the production of IL-1β, IL-18, and IL-1α, but not IL-10, by MAC-stimulated PBMCs and monocytes. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. A reduced monocyte ratio might contribute to the attenuated production of IL-1 family cytokines by PBMCs of NTMPD patients in response to MAC stimulations. Collectively, our findings suggest that the attenuated IL-1 response may increase susceptibility to NTM pulmonary infection through multiple factors, including impaired expression of the TLR2 and TWIK2 and reduced monocyte ratio. IMPORTANCE Upon MAC stimulation, the production of IL-1 family cytokines and IL-10 by PBMCs of NTMPD patients was attenuated compared with that of healthy household contacts. Upon MAC stimulation, the expression of TLR2 and TWIK2 (one of the two-pore domain K+ channels) was attenuated in PBMCs of NTMPD patients compared with that of healthy household contacts. The production of IL-1 family cytokines by MAC-stimulated PBMCs and MAC-infected monocytes of healthy donors was reduced by a TLR2 inhibitor and two-pore domain K+ channel inhibitor. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. Collectively, our data suggest that defects in the expression of TLR2 and TWIK2 in human PBMCs or monocytes and reduced monocyte ratio are involved in the reduced production of IL-1 family cytokines, and it may increase susceptibility to NTM pulmonary infection.
Brainnetome atlas of preadolescent children based on anatomical connectivity profiles

Abstract During the preadolescent period, when the cerebral thickness, curvature, and myelin are constantly changing, the brain's regionalization patterns underwent persistent development, contributing to the continuous improvements of various higher cognitive functions. Using a brain atlas to study the development of these functions has attracted much attention. However, the brains of children do not always have the same topological patterns as those of adults. Therefore, age-specific brain mapping is particularly important, serving as a basic and indispensable tool to study the normal development of children. In this study, we took advantage of longitudinal data to create the brain atlas specifically for preadolescent children. The resulting human Child Brainnetome Atlas, with 188 cortical and 36 subcortical subregions, provides a precise period-specific and cross-validated version of the brain atlas that is more appropriate for adoption in the preadolescent period. In addition, we compared and illustrated for regions with different topological patterns in the child and adult atlases, providing a topologically consistent reference for subsequent research studying child and adolescent development.
A systematic review and clinical atlas on mucocutaneous presentations of the current monkeypox outbreak: With a comprehensive approach to all dermatologic and nondermatologic aspects of the new and previous monkeypox outbreaks

Monkeypox is a zoonotic disease, endemic in central and west African regions, and has re‐emerged, currently causing an outbreak as of May 2022. In this systematic review, we aimed to characterize the current face of the disease, with a detailed categorization of mucocutaneous, as well as systemic symptoms of the disease. We searched four main online databases with the keywords “monkeypox” and “Orthopoxvirus”. A total of 46 articles were included, with a cumulative number of 1984 confirmed cases. Patients were predominantly men who have sex with men, who were mostly in their 30s, with a history of unprotected sexual contact or international travel. Among mucocutaneous manifestations, anogenital lesions were the most commonly observed, followed by lesions on the limbs, face, trunk, and palms or soles. Among lesion types, vesiculopustular, pustular or pseudo‐pustular, vesicular‐umbilicated and papular lesions were the most common, mainly presenting asynchronously, with less than 10 lesions on each patient. Almost all patients also reported systemic manifestations, namely fever, lymphadenopathy, fatigue, myalgia, headaches, pharyngitis, and proctitis. Sexual contact is the main pathway of transmission in the current outbreak, with viral shedding in bodily fluids playing a key role. We've compared these idiosyncratic findings of the new outbreak with previous outbreaks. We've also gathered and categorized images from our included studies to make a “clinical atlas” for this “new” face of monkeypox, which can be of utmost importance for clinicians to be familiarized with, and have a clear picture of monkeypox for their differential diagnoses.
Impact of preoperative magnetic resonance imaging on surgery and eligibility for intraoperative radiotherapy in early breast cancer

We looked at the usefulness of magnetic resonance imaging (MRI) in decision-making and surgical management of patients selected for intraoperative radiotherapy (IORT). We also compared lesion size measurements in different modalities (ultrasound (US), mammogram (MMG), MRI) against pathological size as the gold standard. 63 patients eligible for IORT based on clinical and imaging criteria over a 34-month period were enrolled. All had MMG and US, while 42 had additional preoperative MRI for locoregional preoperative staging. Imaging findings and pathological size concordances were analysed across the three modalities. MRI changed the surgical management of 5 patients (11.9%) whereby breast-conserving surgery (BCS) and IORT was cancelled due to detection of satellite lesion, tumor size exceeding 30mm and detection of axillary nodal metastases. Ten of 42 patients (23.8%) who underwent preoperative MRI were subjected to additional external beam radiotherapy (EBRT); 7 due to lymphovascular invasion (LVI), 2 due to involved margins, and 1 due to axillary lymph node metastatic carcinoma detected in the surgical specimen. Five of 21 (23.8%) patients without prior MRI were subjected to additional EBRT post-surgery; 3 had LVI and 2 had involved margins. The rest underwent BCS and IORT as planned. MRI and MMG show better imaging-pathological size correlation. Significant increase in the mean ‘waiting time’ were seen in the MRI group (34.1 days) compared to the conventional imaging group (24.4 days). MRI is a useful adjunct to conventional imaging and impacts decision making in IORT. It is also the best imaging modality to determine the actual tumour size.
Sleep facilitates spatial memory but not navigation using the Minecraft Memory and Navigation task

Significance Sleep facilitates hippocampal-dependent memories, and the hippocampus uniquely supports the spatial acquisition and representation of environments. However, sleep’s contribution to how specific locations within environments (spatial memory) are retained and the movements to them (navigation) have had mixed findings, possibly due to task designs, familiarity of environments, or measurements. Additionally, prior research has not been able to disentangle the contributions of sleep to spatial memory from navigation. To meet this need, we developed the Minecraft Memory and Navigation (MMN) task to study how spatial memory and navigation changes over time and during sleep. Our findings support the role of sleep in retaining precise spatial relationships within a cognitive map. However, they do not support the role of sleep in navigation.
Body Mass Index Trajectories Across the Adult Life Course and Pancreatic Cancer Risk.

BACKGROUND Body mass index (BMI) during adulthood has been associated with pancreatic ductal adenocarcinoma (PDAC), however patterns of body size across the adult life course have not been studied extensively. We comprehensively evaluated the association between adiposity across adulthood and PDAC. METHODS We conducted a prospective analysis of 269,480 (162,735 males, 106,745 females) NIH-AARP Diet and Health Study participants, aged 50-71years (1995-1996) who self-reported height and weight history. Participants were followed through December 31, 2011. We examined associations between BMI (kg/m2) at ages 18, 35, 50, and 50-71 (baseline) years, their trajectories determined from latent-class trajectory modeling, and incident PDAC. Cox proportional hazard models were used to calculate multivariable adjusted hazards ratios (HR) and 95% confidence intervals (CI). RESULTS During up to 15.2 years of follow-up, 3,092 (2,020 males, 1,072 females) incident PDAC cases were identified. BMI at all four ages were significantly associated with increased PDAC (per 5-unit increase, HRs = 1.09 to 1.13) with higher magnitude associations in males than females at ages ≥ 35 (P-interaction < 0.05). Four BMI trajectories were created. Compared to normal-weight-maintainers, normal-to-overweight, normal-to-obese class I, and overweight-to-severely obese trajectories had HRs (95% CI) of 1.15 (1.06-1.25), 1.39 (1.25-1.54), and 1.48 (1.18-1.87), respectively (P-interaction by sex = 0.07). CONCLUSIONS High BMI and BMI trajectories that result in overweight or obesity during adulthood were positively associated with PDAC, with stronger associations among those with early onset adiposity and male sex. Avoidance of excess body weight throughout the life course may prevent PDAC.
Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy.

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for pediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with e developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers' global impression, serum inflammatory markers, and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a "responder," defined as ≥ 2 of: > 50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement, or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (p < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (p < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (p < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.
Levodopa Response in Patients With Early Parkinson Disease

Background and Objectives The Levodopa in EArly Parkinson's Disease (LEAP) study enabled us to conduct post hoc analyses concerning the effects of levodopa in patients with early Parkinson disease. Methods The LEAP study was a double-blind, placebo-controlled, randomized, delayed-start trial in which patients with early Parkinson disease were randomized to receive levodopa/carbidopa 300/75 mg daily for 80 weeks (early-start group) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed-start group). We analyzed the effect of levodopa with the Unified Parkinson's Disease Rating Scale on bradykinesia, rigidity, and tremor. At week 80, participants answered 3 questions regarding motor response fluctuations. Results A total of 222 patients were randomized to the early-start group (mean ± SD age at baseline 64.8 ± 8.7 years; 71% male) and 223 to the delayed-start group (mean ± SD age at baseline 65.5 ± 8.8 years; 69% male). The difference between the early- and delayed-start groups in mean change from baseline to week 4, expressed as Hedges g effect size, was −0.33 for bradykinesia, −0.29 for rigidity, and −0.25 for tremor (for all symptoms indicating a small effect in favor of the early-start group); from baseline to week 22, respectively, −0.49, −0.36, and −0.44 (small to medium effect); and from baseline to week 40, respectively, −0.32, −0.19, and −0.27 (small effect). At 80 weeks, fewer patients in the early-start group (46 of 205 patients, 23%) experienced motor response fluctuations than patients in the delayed-start group (81 of 211, 38%; p < 0.01). Discussion In patients with early Parkinson disease, levodopa improves bradykinesia, rigidity, and tremor to the same order of magnitude. For all 3 symptoms, effects were larger at 22 weeks compared with 4 weeks. At 80 weeks, there were fewer patients with motor response fluctuations in the group that had started levodopa earlier. Classification of Evidence This study provides Class II evidence that the effect of levodopa on bradykinesia, rigidity, and tremor is larger after 22 weeks compared with 4 weeks of treatment. Trial Registration Information ISRCTN30518857, EudraCT number 2011-000678-72.
Identifying and eliminating the problem with Einstein's cosmological constant

Title of Dissertation: Identifying and Eliminating the Problem with Einstein’s Cosmological Constant Zachary Myers, Doctor of Philosophy, 2005 Dissertation directed by: Professor Jeffrey Bub – Department of Philosophy and Professor James Mattingly – Department of Philosophy The cosmological constant, Λ, was first introduced into Einstein’s field equations in the early 20th century. It was introduced as a quantity of outward-pushing energy in space that would counteract the contracting force of gravity thereby keeping the universe in a balanced and static state. Einstein willingly removed it once the universe was observed to be dynamic rather than static. However, as the decades have gone by, Λ has maintained its supporters and has continually been reintroduced to solve problems in cosmology. Presently, there is good reason to believe that Λ or something like it is indeed present in our universe. In the 1960s, in an effort to provide a physical basis for Λ, particle physicists turned to quantum vacuum energy and have since estimated a value for Λ to be ~10 110 erg/cm3, which happens to be significantly greater than its observationally constrained value of ~10-10 erg/cm3. This discrepancy of 120 orders of magnitude has come to be known as the cosmological constant problem. Any effort to resolve the inconsistency must also account for the various observations we attribute to Λ, such as cosmic inflation and cosmic acceleration. To date, there are two basic approaches to resolving the cosmological constant problem that we may call the Identity approach and the Eliminativist approach. The Identity approach entails that vacuum energy is responsible for all the relevant observations and the problem is to be solved by some cancellation mechanism within the internal components of the vacuum. The Eliminativist approach explicitly rejects the reality and cosmological efficacy of vacuum energy, seeks alternative explanations for the observations and eliminates the cosmological constant problem by eliminating the cosmological constant. The benefit of having a crisis between these two views at this particular stage in cosmology’s history is that they can be tested against each other in an experimental situation. Whatever the outcome of the experiments, we will be clearer about the work needed to resolve the cosmological constant problem once and for all. IDENTIFYING AND ELIMINATING THE PROBLEM WITH EINSTEIN’S COSMOLOGICAL CONSTANT
C-peptide Targets and Patient-centered Outcomes of Relevance to Cellular Transplantation for Diabetes

Background C-peptide levels are a key measure of beta-cell mass following islet transplantation, but threshold values required to achieve clinically relevant patient-centered outcomes are not yet established. Methods. We conducted a cross-sectional retrospective cohort study evaluating patients undergoing islet transplantation at a single center from 1999 to 2018. Cohorts included patients achieving insulin independence without hypoglycemia, those with insulin dependence without hypoglycemia, and those with recurrent symptomatic hypoglycemia. Primary outcome was fasting C-peptide levels at 6 to 12 mo postfirst transplant; secondary outcomes included stimulated C-peptide levels and BETA-2 scores. Fasting and stimulated C-peptide and BETA-2 cutoff values for determination of hypoglycemic freedom and insulin independence were evaluated using receiver operating characteristic curves. Results. We analyzed 192 patients, with 122 (63.5%) being insulin independent without hypoglycemia, 61 (31.8%) being insulin dependent without hypoglycemia, and 9 (4.7%) experiencing recurrent symptomatic hypoglycemia. Patients with insulin independence had a median (interquartile range) fasting C-peptide level of 0.66 nmol/L (0.34 nmol/L), compared with 0.49 nmol/L (0.25 nmol/L) for those being insulin dependent without hypoglycemia and 0.07 nmol/L (0.05 nmol/L) for patients experiencing hypoglycemia (P < 0.001). Optimal fasting C-peptide cutoffs for insulin independence and hypoglycemia were ≥0.50 nmol/L and ≥0.12 nmol/L, respectively. Cutoffs for insulin independence and freedom of hypoglycemia using stimulated C-peptide were ≥1.2 nmol/L and ≥0.68 nmol/L, respectively, whereas optimal cutoff BETA-2 scores were ≥16.4 and ≥5.2. Conclusions. We define C-peptide levels and BETA-2 scores associated with patient-centered outcomes. Characterizing these values will enable evaluation of ongoing clinical trials with islet or stem cell therapies.
Increased all-cause mortality following occupational injury: a comparison of two states

Objectives To measure the impact of lost-time occupational injuries on all-cause mortality in Washington State and, using the same data elements and study design, to determine whether the estimated impact was similar to previous estimates for New Mexico. Methods We linked injuries in the Washington workers’ compensation system with Social Security Administration data on earnings and mortality. We estimated Cox survival models of mortality for women and men with lost-time compared with medical-only injuries, adjusting for age, pre-injury earnings and industry. We used quantitative bias analysis to account for confounding by pre-injury smoking and obesity. Results The estimated mortality HR was 1.24 for women (95% CI 1.21 to 1.28) and 1.22 for men (95% CI 1.20 to 1.24). After adjusting for unmeasured pre-injury smoking and obesity, the estimated HR for women was 1.10, 95% simulation interval (SI) 1.00 to 1.21; for men, it was 1.15, 95% SI 1.04 to 1.27. Conclusions All-cause mortality for Washington workers with lost-time injuries was higher than for those with medical-only injuries. Estimated HRs for Washington were consistent with those previously estimated for New Mexico, a less populous state with lower median wages and a different workers’ compensation insurance mechanism. This suggests that the relationship between workplace injury and long-term mortality may be generalisable to other US states. These findings support greater efforts to enhance safety and to investigate factors that improve postinjury employment opportunities and long-term health. This association should be examined in additional locations, with different study conditions, or using additional data on pre-injury risk factors.
Mass distribution and structural parameters of Small Magellanic Cloud star clusters

In this work we estimate, for the first time, the total masses and mass function slopes of a sample of 29 young and intermediate-age SMC clusters from CCD Washington photometry. We also derive age, interstellar reddening and structural parameters for most of the studied clusters by employing a statistical method to remove the unavoidable field star contamination. Only these 29 clusters out of 68 originally analysed cluster candidates present stellar overdensities and coherent distribution in their colour-magnitude diagrams compatible with the existence of a genuine star cluster. We employed simple stellar population models to derive general equations for estimating the cluster mass based only on its age and integrated light in the B, V, I, C and T1 filter. These equations were tested against mass values computed from luminosity functions, showing an excellent agreement. The sample contains clusters with ages between 60 Myr and 3 Gyr and masses between 300 and 3000 Mo distributed between ~0.5 deg. and ~2 deg. from the SMC optical centre. We determined mass function slopes for 24 clusters, of which 19 have slopes compatible with that of Kroupa IMF (2.3 +/- 0.7), considering the uncertainties. The remaining clusters - H86-188, H86-190, K47, K63 and NGC242 - showed flatter MFs. Additionally, only clusters with masses lower than ~1000 Mo and flatter MF were found within ~0.6 deg. from the SMC rotational centre.