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The article discusses various aspects of automated reasoning proof certificates, and it mentions the use of automated reasoning tools to find computer hardware and software-related bugs and security vulnerabilities. According to the article, formal proof certificates help improve trustworthiness. Satisfiability Modulo Theories (SMT), the efficient production of proofs, and SMT solvers are also assessed.

Invasive aspergillosis (IA) is a rare but fatal disease among liver transplant recipients (LiTRs). We performed a multicenter 1:2 case-control study comparing LiTRs diagnosed with proven/probable IA and controls with no invasive fungal infection. We included 62 IA cases and 124 matched controls. Disseminated infection occurred only in 8 cases (13%). Twelve-week all-cause mortality of IA was 37%. In multivariate analyses, systemic antibiotic usage (adjusted odds ratio [aOR], 4.74; P= .03) and history of pneumonia (aOR, 48.7; P= .01) were identified as independent risk factors associated with the occurrence of IA. Moreover, reoperation (aOR, 5.99; P= .01), systemic antibiotic usage (aOR, 5.03; P= .04), and antimold prophylaxis (aOR, 11.9; P= .02) were identified as independent risk factors associated with the occurrence of early IA. Among IA cases, Aspergilluscolonization (adjusted hazard ratio [aHR], 86.9; P< .001), intensive care unit stay (aHR, 3.67; P= .02), disseminated IA (aHR, 8.98; P< .001), and dialysis (aHR, 2.93; P= .001) were identified as independent risk factors associated with 12-week all-cause mortality, while recent receipt of tacrolimus (aHR, 0.11; P= .001) was protective. Mortality among LiTRs with IA remains high in the current era. The identified risk factors and protective factors may be useful for establishing robust targeted antimold prophylactic and appropriate treatment strategies against IA.

The article highlights several nonprofit arts organizations in Kentucky that promote access to culture and the arts, including the Kentucky Symphony Orchestra, the Grand Theatre in Frankfort, and the Pine Mountain Settlement School. Topics include nonprofit funding strategies, community engagement through arts and education, and the preservation of historic venues and traditions.

Astrocytes are the most abundant cell type in the mammalian brain and provide structural and metabolic support to neurons, regulate synapses and become reactive after injury and disease. However, a small subset of astrocytes settles in specialized areas of the adult brain where these astrocytes instead actively generate differentiated neuronal and glial progeny and are therefore referred to as neural stem cells1–3. Common parenchymal astrocytes and quiescent neural stem cells share similar transcriptomes despite their very distinct functions4–6. Thus, how stem cell activity is molecularly encoded remains unknown. Here we examine the transcriptome, chromatin accessibility and methylome of neural stem cells and their progeny, and of astrocytes from the striatum and cortex in the healthy and ischaemic adult mouse brain. We identify distinct methylation profiles associated with either astrocyte or stem cell function. Stem cell function is mediated by methylation of astrocyte genes and demethylation of stem cell genes that are expressed later. Ischaemic injury to the brain induces gain of stemness in striatal astrocytes7. We show that this response involves reprogramming the astrocyte methylome to a stem cell methylome and is absent if the de novo methyltransferase DNMT3A is missing. Overall, we unveil DNA methylation as a promising target for regenerative medicine.

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Background: Noradrenergic signaling declines in Parkinson’s disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that ß-acting drugs slow PD progression.Objective: The primary objective was to compare the safety and effects of 3 ß-adrenoceptor (ß-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of ß-AR acting drugs in HVs and PD-patients.Methods: In Part A, HVs received single doses of 32?mg salbutamol, 160µg clenbuterol, 60?mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20µg on Day 1, 40µg on Day 2, 80µg on Days 3–7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests.Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral ß2-AR effects were observed with clenbuterol.Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of ß2-ARs in the CNS.

Noradrenergic signaling declines in Parkinson’s disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that β-acting drugs slow PD progression. The primary objective was to compare the safety and effects of 3 β-adrenoceptor (β-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of β-AR acting drugs in HVs and PD-patients. In Part A, HVs received single doses of 32 mg salbutamol, 160μg clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20μg on Day 1, 40μg on Day 2, 80μg on Days 3–7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests. Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral β2-AR effects were observed with clenbuterol. This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of β2-ARs in the CNS. This research aimed to explore how three different drugs affect brain function. These drugs are salbutamol, clenbuterol, and pindolol and work in the brain by stimulating specific brain cells that can improve aspects like memory and coordination. The main question was to see how safe these drugs were and how they impact the brain function after one dose in healthy people, and after multiple doses in both healthy people and those with Parkinson’s disease. Parkinson’s disease is a condition where brain cells start to die, which affects different areas of the brain, including movement function, as well as memory and attention. This research matters because finding drugs that affect the brain function could improve the lives of people with Parkinson’s disease. The study was conducted in three parts. In the first part, healthy volunteers took one dose of each of the three drugs— salbutamol, clenbuterol, and pindolol— as well as a placebo (a harmless pill that has no effect). The researchers tested the participants’ brain functions using various tasks including memory tests and eye response measurements. In the second and third part, healthy people and people with Parkinson’s disease took the drug that performed best in healthy volunteers for seven days. In the first part, a single dose of clenbuterol was safe and improved memory and attentions tasks in healthy people, and therefore was chosen for further testing in the second and third part. In these parts, multiple doses of clenbuterol were safe and helped improve memory and attention tasks in healthy people, with similar positive trends seen in people with Parkinson’s disease. The study suggests that clenbuterol might help improve brain function by activating specific receptors in the brain. These results are important because they suggest that clenbuterol could be a potential treatment to help improve brain function in people with Parkinson’s disease. However, more research is needed to fully understand its effects and to confirm these findings.

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson’s disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF). Exploratory outcomes were changes in clinical scales and biomarker-based target engagement as measured by seed amplification assays. Twenty patients were randomized 7:3 (UB-312:placebo) into 300/100/100 μg or 300/300/300 μg (weeks 1, 5 and 13) intramuscular prime-boost dose groups. Safety was similar across groups; adverse events were mostly mild and transient. Two patients experienced three serious adverse events in total, one possibly treatment related; all resolved without sequalae. Anti-αSyn antibodies in serum from 12/13 and CSF from 5/13 patients who received three UB-312 doses confirmed immunogenicity. Mean serum titers (in log-dilution factor) increased from baseline by 1.398 and 1.354, and peaked at week 29 at 2.520 and 2.133, for 300/100/100 μg and 300/300/300 μg, respectively. CSF titers were 0 at baseline and were 0.182 and 0.032 at week 21, respectively. Exploratory analyses showed no statistical differences in clinical scales but a significant reduction of αSyn seeds in CSF of a subset of UB-312-treated patients. These data support further UB-312 development. ClinicalTrials.gov:NCT04075318.

The classic conception of pain etiology in rheumatologic disease is nociceptive pain—tissue injury and inflammation signaling through peripheral and central nerve fibers. But this can be mixed with other pain etiologies, including nociplastic, which is augmented pain experience due to central sensitization. The pain of fibromyalgia (FM) is nociplastic, occurs in 10% to 30% of patients with rheumatologic disease, and its presence can influence disease severity assessment. The objective of our study was to (1) ascertain the prevalence of FM and widespread pain (WP) in the CorEvitas psoriatic arthritis (PsA) registry as assessed by the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS) questionnaires; (2) characterize the demographic and clinical factors associated with FM and WP; and (3) ascertain the association of FM and WP on the Clinical Disease Activity in Psoriatic Arthritis (cDAPSA) score and other disease activity measures. PsA registry patients completing the WPI/SSS questionnaires since May 2020, at their most recent visit recorded in the registry, were analyzed. The analysis included 1,823 patients with PsA; 11.1% fulfilled the FM definition and 20.6% fulfilled the WP definition. Several factors were associated with the FM definition, including female sex, depression and/or anxiety, impaired function, increased body mass index, and increased number of comorbidities. cDAPSA, patient pain and global assessment, and tender joint count were twice as severe in patients with FM compared to those without. FM prevalence is elevated in PsA and is associated with elevated disease measures, confounding reliable disease assessment for treat‐to‐target goals. Identification of FM as an influential contextual factor in disease assessment is recommended.

•No formal training program exists for intraoperative cholangiography interpretation.•Novel training program based on perceptual learning principles significantly improved surgical residents' intraoperative cholangiography interpretation and confidence.•Combined simulator-based and perceptual learning training enhanced residents' confidence and efficiency in intraoperative cholangiography interpretation.

Loss of muscle quantity and function is associated with frailty and reduced quality of life. Sonography is a simple option to quantify muscle mass, which could be included into routine diagnostic workup. This study was designed to prospectively evaluate sonographic measurement and to compare it with established measurements of muscle quantity and function. Between March 2020 and May 2022, 723 patients were enrolled in the study. Psoas muscle area index (PMAI) and psoas muscle thickness height index (PMTI) were quantified. Thigh muscle thickness indices (TMTI) were either measured without compression (fTMTI) or under compression (cTMTI). Variation coefficient (VC) as well as intra‐ and inter‐observer reliability were analyzed. The reliability and reproducibility of the sonographic morphometry were assessed using two examiners. Sonographic morphometry was compared with established measurements of muscle using computed tomography and hand grip strength, respectively. In 156 patients, sonographic indices were compared with corresponding CT indices. Of the 723 patients included, sonographic indices were compared with hand strength in 429 patients. Interobserver and intraobserver variability showed better results for the femur indices than for the psoas indices (correlation coefficient: 0.8697/0.9118 vs 0.7502/0.7319). Psoas muscle indices correlated best with the reference standard of the SMI. The optimal cut‐off for each muscle index for determining muscle loss according to the SMI and hand grip strength was calculated. Sonography can simplify muscle measurement and should be used in the future. Sonographic muscle indices have the potential to simplify evaluation, especially in risk groups such as patients with liver cirrhosis or other wasting disorders.

Hybrid battery cells that combine a garnet-type Li7La3Zr2O12(LLZO) solid electrolyte with other solid, polymer or liquid electrolytes are increasingly investigated. In such cells with layered electrolytes, ensuring a low-resistive heteroionic interface between neighboring electrolytes is crucial for preventing major additional overpotentials during operation. Electrochemical impedance spectroscopy is frequently used to extract such parameters, usually on multilayer symmetrical model cells that contain the different electrolytes stacked in series. Unfortunately, the impedance contributions of the heteroionic interfaces often overlap with those of the electrolyte|electrode interfaces, necessitating the use of sophisticated four-point cells that probe the electrochemical potential away from the polarization source. In this work, an alternative solution to this problem is demonstrated by taking advantage of the inherent fast charge transfer kinetics of LLZO with its parent metal electrode. The “resistance-free” nature of a reversible Li|LLZO interface enables a precise evaluation of the heteroionic interface impedance in symmetric two-point cells of the type Li|LLZO|electrolyte|LLZO|Li with negligible electrode contribution. This is exemplified for symmetric multilayer cells containing tantalum-doped LLZO and a poly(ethylene oxide) (PEO)-based dry polymer electrolyte. Validation and comparison of impedance data with results from symmetric four-point cells and two-point cells with ion-blocking electrodes demonstrate the advantage of the proposed method. Overall, this study presents a simple and reliable method for studying heteroionic interface impedances in LLZO-containing multilayer cells.

The objective of this study was to compare the effectiveness of a second tumor necrosis factor inhibitor (TNFi) versus a non‐TNFi biologic following discontinuation of a TNFi for patients with polyarticular‐course juvenile idiopathic arthritis (pJIA). Using the Childhood Arthritis and Rheumatology Research Alliance Registry, patients with pJIA who started receiving a second biologic following a first TNFi were identified. Patients were required to have no active uveitis on the index date and a visit six months after the index date. Outcome measures included Clinical Juvenile Arthritis Disease Activity Score with a maximum of 10 active joints (cJADAS10), cJADAS10 inactive disease (ID; ≤2.5) and cJADAS10 minimal disease activity (MiDA; ≤5). Multiple imputation was used to account for missing data. Adjusted odds ratios (aORs) were calculated using propensity score quintiles to compare outcomes at six months following second biologic initiation. There were 216 patients included, 84% initially received etanercept, and most patients stopped receiving it because of its ineffectiveness (74%). A total of 183 (85%) started receiving a second TNFi, and 33 (15%) started receiving a non‐TNFi. Adalimumab was the most common second biologic received (71% overall, 84% of second TNFi), and tocilizumab was the most common non‐TNFi second biologic received (9% overall, 58% of non‐TNFi). There was no difference between receiving TNFi versus non‐TNFi in cJADAS10 ID (29% vs 25%; aOR 1.23, 95% confidence interval [CI] 0.47–3.20) or at least MiDA (43% vs 39%; aOR 1.11, 95% CI 0.47–2.62) at six months. Most patients with pJIA started receiving TNFi rather than non‐TNFi as their second biologic, and there were no differences in disease activity at six months.

Serum creatinine is used as initial test to derive eGFR and confirmatory testing with serum cystatin C is recommended when creatinine‐based eGFR is considered less accurate due to deviant muscle mass. Low muscle mass is associated with increased risk of premature mortality. However, the associations of serum creatinine and cystatin C with muscle mass and mortality remain unclear and require further investigation to better inform clinical decision‐making. We included 8437 community‐dwelling adults enrolled in the Dutch PREVEND study and 5033 in the US NHANES replication cohort. Associations of serum creatinine and/or cystatin C with muscle mass surrogates and mortality were quantified with linear and Cox proportional hazards regression, respectively. Missing observations in covariates were multiply imputed using Substantive Model Compatible Fully Conditional Specification. Mean (SD) age of PREVEND and NHANES participants (50% and 48% male) were 49.8 (12.6) and 48.7 (18.7) years, respectively. Median (Q1–Q3) serum creatinine and cystatin C were 71 (61–80) and 80 (62–88) μmol/L and 0.87 (0.78–0.98) and 0.91 (0.80–1.10) mg/L, respectively. Higher serum creatinine was associated with greater muscle mass, while serum cystatin C was not associated with muscle mass. Adjusting both markers for each other strengthened the positive relationship between serum creatinine and muscle mass and revealed an inverse association between serum cystatin C and muscle mass. In the PREVEND cohort, 1636 (19%) deaths were registered over a median follow‐up of 12.9 (5.8–16.3) years with a 10‐year mortality rate (95% CI) of 7.6% (7.1–8.2%). In the NHANES, 1273 (25%) deaths were registered over a median follow‐up of 17.9 (17.3–18.5) years with a 10‐year mortality rate of 13.8% (12.8–14.7%). Both markers were associated with increased mortality. Notably, when adjusted for each other, higher serum creatinine was associated with decreased mortality, while the association between serum cystatin C and increased mortality strengthened. The shapes of the associations in the PREVEND study and NHANES were almost identical. The strong association between serum creatinine and muscle mass challenges its reliability as GFR marker, necessitating a more cautious approach in its clinical use. The minimal association between serum cystatin C and muscle mass supports its increased use as a more reliable alternative in routine clinical practice.

The article offers information on the importance of critical thinking in various contexts, including scientific research, social media use, societal decision-making, and academic environments. Topics include the role of critical thinking in analyzing information, learning new concepts, and problem-solving, as well as its significance in quality assurance processes in scientific research.

Polar and chiral crystal symmetries confer a variety of potentially useful functionalities upon solids by coupling otherwise noninteracting mechanical, electronic, optical, and magnetic degrees of freedom. We describe two phases of the 3D perovskite, CsSnBr3, which emerge below 85 K due to the formation of Sn(II) lone pairs and their interaction with extant octahedral tilts. Phase II (77 K < T< 85 K, space group P21/m) exhibits ferroaxial order driven by a noncollinear pattern of lone pair-driven distortions within the plane normal to the unique octahedral tilt axis, preserving the inversion symmetry observed at higher temperatures. Phase I (T< 77 K, space group P21) additionally exhibits ferroelectric order due to distortions along the unique tilt axis, breaking both inversion and mirror symmetries. This polar and chiral phase exhibits second harmonic generation from the bulk and pronounced electrostriction and negative thermal expansion along the polar axis (Q22≈ 1.1 m4C–2; αb= −7.8 × 10–5K–1) through the onset of polarization. The structures of phases I and II were predicted by recursively following harmonic phonon instabilities to generate a tree of candidate structures and subsequently corroborated by synchrotron X-ray powder diffraction and polarized Raman and 81Br nuclear quadrupole resonance spectroscopies. Preliminary attempts to suppress unintentional hole doping to allow for ferroelectric switching are described. Together, the polar symmetry, small band gap, large spin–orbit splitting of Sn 5p orbitals, and predicted strain sensitivity of the symmetry-breaking distortions suggest bulk samples and epitaxial films of CsSnBr3or its neighboring solid solutions as candidates for bulk Rashba effects.

Assemblies of peptides and proteins through specific intermolecular interactions set the basis for macroscopic materials found in nature. Peptides provide easily tunable hydrogen-bonding interactions, which can lead to the formation of ordered structures such as highly stable β-sheets that can form amyloid-like supramolecular peptide nanofibrils (PNFs). PNFs are of special interest, as they could be considered as mimics of various fibrillar structures found in nature. In their ability to serve as supramolecular scaffolds, they could mimic certain features of the extracellular matrix to provide stability, interact with pathogens such as virions, and transduce signals between the outside and inside of cells. Many PNFs have been reported that reveal rich bioactivities. PNFs supporting neuronal cell growth or lentiviral gene transduction have been studied systematically, and their material properties were correlated to bioactivities. However, the impact of the structure of PNFs, their dynamics, and stabilities on their unique functions is still elusive. Herein, we provide a microscopic view of the self-assembled PNFs to unravel how the amino acid sequence of self-assembling peptides affects their secondary structure and dynamic properties of the peptides within supramolecular fibrils. Based on sequence truncation, amino acid substitution, and sequence reordering, we demonstrate that peptide–peptide aggregation propensity is critical to form bioactive β-sheet-rich structures. In contrast to previous studies, a very high peptide aggregation propensity reduces bioactivity due to intermolecular misalignment and instabilities that emerge when fibrils are in close proximity to other fibrils in solution. Our multiscale simulation approach correlates changes in biological activity back to single amino acid modifications. Understanding these relationships could lead to future material discoveries where the molecular sequence predictably determines the macroscopic properties and biological activity. In addition, our studies may provide new insights into naturally occurring amyloid fibrils in neurodegenerative diseases.

The design of bifunctional compounds is a promising approach toward the development of strong analgesics with reduced side effects. We here report the optimization of the previously published lead peptide KGFF09, which contains opioid receptor agonist and neuropeptide FF receptor antagonist pharmacophores and is shown to induce potent antinociception and reduced side effects. We evaluated the novel hybrid peptides for their in vitroactivity at MOP, NPFFR1, and NPFFR2 and selected four of them (DP08/14/32/50) for assessment of their acute antinociceptive activity in mice. We further selected DP32and DP50and observed that their antinociceptive activity is mostly peripherally mediated; they produced no respiratory depression, no hyperalgesia, significantly less tolerance, and strongly attenuated withdrawal syndrome, as compared to morphine and the recently FDA-approved TRV130. Overall, these data suggest that MOP agonist/NPFF receptor antagonist hybrids might represent an interesting strategy to develop novel analgesics with reduced side effects.

IMPORTANCE: A recent randomized clinical trial concluded that discontinuing medium-efficacy therapy might be a reasonable option for older patients with nonactive multiple sclerosis (MS), but there is a lack of data on discontinuing high-efficacy therapy (HET). In younger patients, the discontinuation of natalizumab and fingolimod is associated with a risk of rebound of disease activity. OBJECTIVE: To determine whether discontinuing HET in patients 50 years and older with nonactive MS is associated with an increased risk of relapse compared with continuing HET. DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study used data from 38 referral centers from the French MS registry (Observatoire Français de la Sclérose en Plaques [OFSEP] database). Among 84704 patients in the database, data were extracted for 1857 patients 50 years and older with relapsing-remitting MS treated by HET and with no relapse or magnetic resonance imaging activity for at least 2 years. After verification of the medical records, 1620 patients were classified as having discontinued HET or having remained taking treatment and were matched 1:1 using a dynamic propensity score (including age, sex, disease phenotype, disability, treatment of interest, and time since last inflammatory activity). Patients were included from February 2008 to November 2021, with a mean (SD) follow-up of 5.1 (2.9) years. Data were extracted in June 2022. EXPOSURES: Natalizumab, fingolimod, rituximab, and ocrelizumab. MAIN OUTCOMES AND MEASURES: Time to first relapse. RESULTS: Of 1620 included patients, 1175 (72.5%) were female, and the mean (SD) age was 54.7 (4.8) years. Among the 1452 in the HET continuation group and 168 in the HET discontinuation group, 154 patients in each group were matched using propensity scores (mean [SD] age, 57.7 [5.5] years; mean [SD] delay since the last inflammatory activity, 5.6 [3.8] years; mean [SD] follow-up duration after propensity score matching, 2.5 [2.1] years). Time to first relapse was significantly reduced in the HET discontinuation group compared with the HET continuation group (hazard ratio, 4.1; 95% CI, 2.0-8.5; P &lt; .001) but differed between HETs, with a hazard ratio of 7.2 (95% CI, 2.1-24.5; P = .001) for natalizumab, 4.5 (95% CI, 1.3-15.5; P = .02) for fingolimod, and 1.1 (95% CI, 0.3-4.8; P = .85) for anti-CD20 therapy. CONCLUSION AND RELEVANCE: As in younger patients, in patients 50 years and older with nonactive MS, the risk of relapse increased significantly after stopping HETs that impact immune cell trafficking (natalizumab and fingolimod). There was no significant increase in risk after stopping HETs that deplete B-cells (anti-CD20 therapy). This result may inform decisions about stopping HETs in clinical practice.

Indiana was the first state to pass legislation severely restricting access to abortion care following the Dobbs v. Jackson Women’s Health Organizationdecision. Indiana Senate Enrolled Act 1 (SEA 1) outlaws all abortions with few exceptions. Indiana University Health (IU Health), the largest and only academic health system in the state, has a unique relationship with the Indiana University School of Medicine and a vision to improve the health of Indiana residents. IU Health employed the Hospital Incident Command System model to create a plan to ensure its patients continue to have access to safe, high-quality family planning, maternal, and neonatal care services and that clinicians are protected against criminal penalties and threats to personal safety. This article provides an overview of the Incident Command structure used to rapidly work across many disciplines, tackle complex issues, respond to concerns, and design and implement changes. The article also outlines the key considerations and decisions made by Incident Command leaders, such as where abortions that met the new law’s criteria should be performed, changes to clinical workflows and protocols, and the creation of a rapid response team. The article then examines the operational, legal, and clinical challenges encountered by clinicians and health care team members, including a lack of peer support or idea sharing with other health systems in the state; accurate estimation of abortion, live birth, and neonatal intensive care unit volumes; and ambiguity in the law and lack of guidance from the state government. Recommendations regarding communication with clinicians and other health care team members and engaging information technology early are offered for health systems and medical schools that may face legislative barriers to health care delivery in the future. Finally, IU Health’s commitment to tracking the impact of SEA 1 on patients, clinicians, employees, and the state is outlined.

This article compares the 2019 BLEU model bilateral investment treaty with the older 2002 version. After an overview of the BLEU’s role as a major actor in international investment law, the authors argue that the changes introduced by the 2019 Model BIT reflect the EU’s policy towards foreign investment protection. The drafters of the 2019 Model BIT were inspired by the EU-Canada Comprehensive Economic and trade Agreement and the European Commission’s proposal to establish a Multilateral Investment Court. The 2019 Model BIT marks a shift from liberalization of foreign direct investment (FDI) to the protection of the sovereign powers, in particular the State’s right to regulate, and the curtailing of investment protection presented as a response to the investment protection system’s misuse and abuse by investors. By placing certain limitations to substantive standards of protection, placing strong emphasis of sustainable development objectives and advocating a reform of the investor-State dispute settlement (ISDS), the 2019 BLEU Model BIT puts forward a vision for the future of investment protection that departs from the Washington Consensus of economic liberalization but also enables the investment protection system to survive in the face of the so-called backlash against ISDS and the criticism of civil society.

Since the nineteenth century, economists have worked with models which posit extrinsic factors, such as the subject’s income and the income of others, as determinants of happiness and discontent. In the discipline of psychology, however, self-actualization theory stresses instead the importance of intrinsic values as determinants of subjective well-being. This paper tests empirically the hypothesis that self-actualization theory and intrinsic values can explain differences in happiness at the nationallevel. Its novelty is that, instead of measuring the causal relationship from extrinsic rewards to happiness, it measures the causal relationship from preoccupation withintrinsic rewards to happiness. Multiple regressions tested the correlation at the national level between countries’ reported happiness and focus on extrinsic/intrinsic values. Backwards stepwise regressions selected “valuing hard work” and “valuing imagination” as indicators of a preoccupation with extrinsic and intrinsic values respectively. The data used were collected between 2010 and 2019 and the sample consisted of all 49 countries for which data were available. The analysis found that, after accounting for per capita incomes, a preoccupation with extrinsic values was negatively correlated with happiness (p = 0.009), the feeling of having enough money (p = 0.011), life satisfaction (p = 0.001) and the feeling of having an ideal job (p = 0.001). Meanwhile, a preoccupation with intrinsic values was positively correlated with the feeling of having enough money (p = 0.002), with life satisfaction (p = 0.021) and the feeling of having an ideal job (p = 0.000). As a specific application of this finding, it is shown that countries of the former socialist bloc exhibit (i) a comparatively low preoccupation with intrinsic values/self-actualization (ii) lower levels of happiness than their incomes would predict, and (iii) a higher responsiveness of happiness to income than other countries. This novel application of self-actualization theory to the country level, underpinned by powerful regression results, suggests that strengthening a nation’s preoccupation with intrinsic values could be an element of national policy and international development cooperation.

Contrast-enhanced magnetic resonance imaging (MRI) is the imaging modality routinely used to follow up patients who have undergone surgical resection of brain meningiomas. There are growing concerns about the massive use of gadolinium-based contrast agents (GBCA). Our aim was to evaluate the performance of a new imaging protocol, performed without GBCA injection, in the detection of tumoral residue or local recurrence after surgery of parafalcine and convexity meningiomas.

A review is offered for the Frazier History Museum located in Louisville, Kentucky.

Tons of skaters from the US flock to Barcelona every year to pillage its plentiful spots, hit the beach, explore the culinary landscape and party their buns off. However, most [...]

Owen Gingerich’s previously unpublished autobiographical sketch of his astronomical education, from his teenage years up through graduate school at Harvard, is presented with an introduction and notes by the editors.

Responsible for many essential functions of life, human skin is made up of many components, each of which undergoes significant functional changes with aging and photodamage. Wound healing was previously thought to be defective in the elderly given the higher presence of chronic wounds and the longer time required for re-epithelialization of acute wounds. However, these notions have been challenged in recent research, which has shown that wound healing in the elderly is delayed but not defective. Poor healing of chronic wounds in older populations is more often attributable to comorbid conditions rather than age alone.

For many years, the European Forum for Good Clinical Practice (EFGCP) Children Medicines Working Party has organised a Paediatric conference annually. In the past, this event was organised jointly with the European Medicines Agency who was used to host it, along with the Drug Information Association (DIA). This conference is the opportunity for all involved in paediatric drug development, i.e., regulators, HTA bodies, patients’ representatives, academia and industry, to share learnings and raise awareness about new regulatory requirements of interest to optimise paediatric drug development. The theme of the 2021 conference was “Challenges and Solutions – the path forward”while in 2022 it focused on “Progress made and Continuing Challenges”. Because of the COVID-19 pandemic these two conferences were organised virtually. However, this has not impacted the attendance and value of the conference, since because of a broad and attractive agenda there was a wide stakeholder participation, which provided a compendious overview of the leading issues to improve children’s access to innovative medicines.

This study investigates Late Holocene environmental changes in Central Cameroon induced by the combined effects of climate and human impact. For this purpose, sediments from lakes Dang, Massote, Fonjak and Ngaoundaba were studied through lithologic analysis including mineralogical composition and organic geochemistry combined with radiocarbon dates. From these analyses, the sediments at the base of lakes Massote and Dang cores are respectively dated to 4680–3530 and 4220–3580 cal yr BP, whereas the sediments of lakes Fonjak and Ngaoundaba seem to be younger, respectively dated to 3210–3000 and 1870–1740 cal yr BP. Lake sedimentation is dominated by organic matter (OM) poor deposits (OM < 3%) in the lower sections and OM-rich deposits (OM: 5–54%) in the upper sections. This shift from OM-poor to OM-rich sedimentation induced by climate variations occurred at ∼2800–2400 cal yr BP. The mineral assemblage is predominantly composed of kaolinite with minor contributions from chlorite, smectite, chlorite/smectite, illite/smectite, quartz, K-feldspar, gibbsite, plagioclase, siderite, hematite and goethite. These sediments are clastic, except for Lake Fonjak core sediments which correspond to peat intercalated with carbonate clay and clastic deposits. Age-depth models suggest that the sedimentation rate was 0.2 mm yr-1for lakes Dang and Massote before ∼690–560 cal yr BP and ∼660–470 cal yr BP, respectively. Thereafter, it increased to 0.8 mm yr-1in Lake Dang and 0.7 mm yr-1in Lake Massote. Finally, Late Holocene environment changes in Central Cameroon consisted of the shift of open water lakes to marshy fringes with abundant vegetation induced by human activities and facilitated by increasing seasonality.

BackgroundWe assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors.MethodsIn this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability.Results16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well.ConclusionA clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell’s criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.

Background: Pediatric regulations enacted in both Europe and the USA have disrupted the pharmaceutical industry, challenging business and drug development processes, and organizational structures. Over the last decade, with science and innovation evolving, industry has moved from a reactive to a proactive mode, investing in building appropriate structures and capabilities as part of their business strategy to better tackle the challenges and opportunities of pediatric drug development. Methods: The EFGCP Children’s Medicines Working Party and the IQ Pediatric working group have joined their efforts to survey their member company representatives to understand how pharmaceutical companies are organized to fulfill their regulatory obligations and optimize their pediatric drug development programs. Results: Key success factors and recommendations for a fit-for-purpose Pediatric Expert Group (PEG) were identified. Conclusion: Pediatric structures and expert groups were shown to be important to support optimization of the development of pediatric medicines.

Time series arise in many different applications in the form of sensor data, stocks data, videos, and other time-related information. Analysis of this data typically requires searching for similar time series in a database. Dynamic Time Warping (DTW) is a widely used high-quality distance measure for time series. As DTW is computationally expensive, efficient algorithms for fast computation are crucial.In this paper, we propose a novel filter-and-refine DTW algorithm called Anticipatory DTW. Existing algorithms aim at efficiently finding similar time series by filtering the database and computing the DTW in the refinement step. Unlike these algorithms, our approach exploits previously unused information from the filter step during the refinement, allowing for faster rejection of false candidates. We characterize a class of applicable filters for our approach, which comprises state-of-the-art lower bounds of the DTW.Our novel anticipatory pruning incurs hardly any over-head and no false dismissals. We demonstrate substantial efficiency improvements in thorough experiments on synthetic and real world time series databases and show that our technique is highly scalable to multivariate, long time series and wide DTW bands.

Objectives: Autistic individuals frequently experience mental health concerns, and there are few strengths-based programs available within community settings. This study examined the initial outcomes of the Autism Mentorship Program (AMP), a mentoring program for autistic youth and adults. Methods: Fourteen autistic youth and 14 autistic adults were paired in one-to-one mentoring relationships, and they met weekly for mentoring sessions. Seventeen parents of autistic youth also participated in this study. A mixed methods design was used to assess social and emotional outcomes and acceptability of AMP. Data were collected via online surveys and standardized rating scales before AMP, following eight weeks of programming, and following AMP. Data were analyzed using descriptive methods and Hedge’s g. Results: Results indicated strong uptake and satisfaction with the program and mentoring relationships. Mentee outcomes included increased pride in their autistic identities (g= .28) and improvements in self-awareness, social connectedness, and communication skills. Parents of mentees reported increases in quality of life (g= .49), life satisfaction (g= .60), and pride in autistic identity (g= .80) for their child. Mentors reported improvements in quality of life (g= .58), internalizing (g=  − .12) and externalizing symptoms (g= -.06), leadership, communication skills, social connectedness, and social skills (g= .19). Conclusions: Initial results indicate that AMP has the potential to benefit autistic mentors and mentees. Additional research is needed regarding mentoring for autistic individuals.

Lange wirbelsäulenchirurgische Eingriffe stellen eine starke körperliche und geistige Belastung für den Chirurgen dar, deren Ausmaß von der Art und Dauer des Eingriffs, äußeren Umständen und der Rolle des Chirurgen abhängt. Die Studie umfasste 101 unterschiedlich schwierige Operationen, die als erster Operateur durchgeführt oder als Assistent begleitet wurden. Mithilfe eines Trainingscomputers, einer Personenwaage und eines Thermometers wurden die OP-Dauer, die Herzfrequenz, der Verlust an Körperflüssigkeit, die Umgebungstemperatur und der Kalorienverbrauch registriert und ausgewertet. Die durchschnittliche und maximale Herzfrequenz als Operateur (124 spm) waren signifikant höher als beim Assistieren (99 spm). Die subjektive psychische Belastung in den unterschiedlichen Schwierigkeitsgraden resultierte in einem Anstieg stressrelevanter Kreislaufparameter. Der durchschnittliche Gewichtsverlust während der OP betrug 0,82 kg Körpergewicht (0–2,3 kg). Der durchschnittliche Gewichtsverlust pro Stunde bei einer durchschnittlichen Raumtemperatur von 20,4 °C betrug 1,12 % beim Operateur und 0,59 % beim Assistenten. Mit steigender Komplexität und OP-Dauer tritt beim Operateur eine größere physische und psychische Belastung als beim Assistenten auf. Die während und nach der OP registrierten Kreislaufreaktionen sind vergleichbar mit denen durch Sport. Während mehrstündiger Eingriffe kommt es zu einer mäßigen Dehydratation, bei der laut Literatur mit einer negativen Beeinflussung kognitiver und motorischer Fähigkeiten gerechnet werden muss. Die Ergebnisse legen nahe, dass ein Ausgleich des Flüssigkeitsverlusts und die Anwendung von Entspannungstechniken während einer OP dazu beitragen können, mögliche Risiken durch eine herabgesetzte Leistungsfähigkeit zu minimieren. Requirements for orthopaedic spine surgeons include occupational skills, concentration, physical fitness and psychological stress resistance, depending on the attending surgeon’s or the resident’s position. This study measured and evaluated stress-relevant cardiovascular parameters during 101 spinal surgical procedures of a 40-year old fellowship-trained spine surgeon with 12 years of practice. A training computer, personal scales and a thermometer were used to record the duration of surgery, heart rate, weight loss and calorie burning. The average maximum heart rate as an attending surgeon (124 bpm) was significantly higher than the resident’s heart rate (99 bmp). A higher stress level resulted in an increasingly higher average maximum heart rate according to the duration of surgery. The mean loss of body fluids at an average room temperature of 20.4 C after surgery was 0.82 kg (0 to 2.3 kg). The mean loss of body weight was calculated as 1.12% of the attending surgeon versus 0.59% of the resident. Increasing complexity, longer duration and a higher potential of intraoperative complications arouse a strong response from the attending surgeon. The observed cardiovascular parameters are similar to those of a moderate to intense workout such as cycling. Long lasting surgeries result in a weight loss equivalent to a mild dehydration ranging from 2 to 5% of body fluids. Increasing dehydration will eventually worsen cognitive, visual and motor skills. Results of this study suggest early rehydration and utilization of mental relaxation techniques to minimize risks during prolonged, complex spine surgeries.

The increasing frequency of antibiotic-resistant bacteria is a constant threat to global human health. Therefore, the pathogens of the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Enterobacterspp.) are among the most relevant causes of hospital infections responsible for millions of deaths every year. However, little has been explored about the danger of microorganisms resistant to biocides such as antiseptics and disinfectants. Widely used in domestic, industrial, and hospital environments, these substances reach the environment and can cause selective pressure for resistance genes and induce cross-resistance to antibiotics, further aggravating the problem. Therefore, it is necessary to use innovative and efficient strategies to monitor the spread of genes related to resistance to biocides. Whole genome sequencing and bioinformatics analysis aiming to search for sequences encoding resistance mechanisms are essential to help monitor and combat these pathogens. Thus, this work describes the construction of a bioinformatics tool that integrates different databases to identify gene sequences that may confer some resistance advantage about biocides. Furthermore, the tool analyzed all the genomes of Brazilian ESKAPE isolates deposited at NCBI and found a series of different genes related to resistance to benzalkonium chloride, chlorhexidine, and triclosan, which were the focus of this work. As a result, the presence of resistance genes was identified in different types of biological samples, environments, and hosts. Regarding mobile genetic elements (MGEs), around 52% of isolates containing genes related to resistance to these compounds had their genes identified in plasmids, and 48.7% in prophages. These data show that resistance to biocides can be a silent, underestimated danger spreading across different environments and, therefore, requires greater attention.

Climate change threatens the role of European forests as a long-term carbon sink. Assisted migration aims to increase the resilience of forest tree populations to climate change, using species-specific climatic limits and local adaptations through transferring seed provenances. We modelled assisted migration scenarios for seven main European tree species and analysed the effects of species and seed provenance selection, accounting for environmental and genetic variations, on the annual above-ground carbon sink of regrowing juvenile forests. To increase forest resilience, coniferous trees need to be replaced by deciduous species over large parts of their distribution. If local seed provenances are used, this would result in a decrease of the current carbon sink (40 TgC yr−1) by 34–41% by 2061–2080. However, if seed provenances adapted to future climates are used, current sinks could be maintained or even increased to 48–60 TgC yr−1.

Light electric vehicles (LEV) are seen as an effective solution for reducing the carbon emissions in the transportation sector thanks to their light weight and low energy requirement. Integrated photovoltaic (PV) panels on LEVs have great potential because a higher portion of the energy demands can be covered by PV panels compared to heavier vehicles. Integrated PV panels on LEVs are constrained by the surface shape and available area, which results in panels facing different angles. In this work, we assess the effectiveness of such integrated PV panels based on simulations with meteorological data and measurements from a real prototype on an electric scooter. It is shown that the measured PV power correlates well with the simulated data. A number of design options such as the number of PV panels and the angle of the panels are evaluated through simulations and we compare seasonal and regional differences. Based on the assessment, we make design suggestions for cost-effective and energy-efficient integrated PV panels on LEVs. Results indicate that with the right design and favorable circumstances, the integrated PV panels can generate more energy over a day than is consumed by the LEV in one day.

Introduction: The aim of this work is to evaluate secukinumab vs. placebo in a challenging-to-treat and smaller US patient subpopulation of the international FUTURE 2–5 studies in patients with psoriatic arthritis (PsA). Methods: Data were pooled from US patients enrolled in the phase 3 FUTURE 2–5 studies (NCT01752634, NCT01989468, NCT02294227, and NCT02404350). Patients received secukinumab 300 or 150 mg with subcutaneous loading dose, secukinumab 150 mg without subcutaneous loading dose, or placebo. Categorical efficacy and health-related quality-of-life (QoL) outcomes and safety were evaluated at week 16. Subgroup analyses were performed based on tumor necrosis factor inhibitor (TNFi) status and body mass index (BMI). For hypothesis generation, odds ratios (ORs) for American College of Rheumatology (ACR) 20/50/70 and Psoriasis Area and Severity Index (PASI) 75/90/100 responses by treatment were estimated using logistic regression without adjustment for multiple comparisons. Results: Of 2148 international patients originally randomized, 279 US patients were included in this pooled analysis. Mean BMI was > 30 kg/m2and 55.2% had prior TNFi treatment. ORs for ACR20/50/70 significantly favored patients receiving secukinumab 300 mg and 150 mg with loading dose vs. placebo (P&lt; 0.05), but not those receiving secukinumab 150 mg without loading dose vs. placebo. For PASI75, ORs favored all secukinumab groups over placebo (P&lt; 0.05); for PASI90 and PASI100, only the secukinumab 300-mg group was significantly favored over placebo (P&lt; 0.05). Conclusions: In this challenging sub-population of US patients with PsA, secukinumab provided rapid improvements in disease activity and QoL. Patients with PsA and active psoriasis might benefit more from secukinumab 300 mg than 150 mg.

Single-cell bisulfite sequencing (scBS) is a technique that enables the assessment of DNA methylation at single-base pair and single-cell resolution. The analysis of large datasets obtained from scBS requires preprocessing to reduce the data size, improve the signal-to-noise ratio and provide interpretability. Typically, this is achieved by dividing the genome into large tiles and averaging the methylation signals within each tile. Here we demonstrate that this coarse-graining approach can lead to signal dilution. We propose improved strategies to identify more informative regions for methylation quantification and a more accurate quantitation method than simple averaging. Our approach enables better discrimination of cell types and other features of interest and reduces the need for large numbers of cells. We also present an approach to detect differentially methylated regions between groups of cells and demonstrate its ability to identify biologically meaningful regions that are associated with genes involved in the core functions of specific cell types. Finally, we present the software tool MethSCAn for scBS data analysis (https://anders-biostat.github.io/MethSCAn).

Es wird über den Fall einer hochgradigen Deformität der thorakolumbalen Wirbelsäule nach Resektion eines Sarkoms berichtet. Nach adjuvanter Radiatio bestand ein ausgedehnter Strahlenschaden im Bereich der Haut mit chronischer Fistelung. Es erfolgte die Korrektur über eine Closing-Wedge-Osteotomie von L3 und Verlängerung der vorhandenen dorsalen Instrumentierung (Th10-L4) auf Th8 und das Os ileum. Am Folgetag erfolgte eine Weichteildeckung durch eine freie Latissimus-dorsi-Lappenplastik, welche an eine arterio-venöse Gefäßschleife in der Axilla angeschlossen wurde. Durch dieses interdisziplinäre Vorgehen konnte eine nahezu vollständige Korrektur und eine sichere Weichteildeckung erreicht werden. This article presents the case of a high-grade deformity of the thoraco-lumbar spine. The patient suffered from a sarcoma that was radically resected. Due to adjuvant radiation, the patient suffered from a radiation injury with chronic fistula. In a two-stage approach, the deformity was corrected by a closing-wedge osteotomy of L3 with elongation of the present dorsal spondylodesis (Th10-L4) to Th8 and the iliac bone. Soft-tissue reconstruction was achieved by a free latissimus dorsi flap that was anastomosed to an axillary arterio-venous loop. The presented interdisciplinary approach allowed an almost complete correction of the deformity and stable soft-tissue coverage.

Introduction: To understand factors leading to biologic switches and to develop a readily usable model with data collected in clinical care at preceding visits, with the overall aim to predict the probability of switching biologic at a subsequent clinic visit in patients with rheumatoid arthritis (RA). Methods: Participants were adults with RA participating in the CorEvitas RA registry. The study matched patients who switched biologics or targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs) with control patients who had not switched biologics/tsDMARDs; the cohort was divided into a training and test set for prediction model development and validation. Using the training set, the best subset regression, lasso, and elastic net methods were used to determine the best potential models. Area under the ROC curve (AUC) was used for the final selection of the best model, and estimated coefficients of this model were applied to the test dataset to predict switching. Results: A total of 5050 patients were included, of whom 3016 were in the training set and 2034 were in the test dataset. The average age was 59.6 years, the majority were female (3998, 79.2%), and the average duration of RA at the time of switch or control visit was 12.8 years. The final model included prior Clinical Disease Activity Index (CDAI) by category, prior patient pain measurement, change in CDAI from baseline, age group, and number of prior biologics, all of which were significantly associated with switching biologics. The AUC was 0.690 for this model with the training dataset. The model was then applied to the test data with similar performance; the AUC was 0.687. Conclusion: We have developed a simple model to determine the probability of switching biologics for RA at the following clinic visit. This model could be used in practice to provide clinicians with more information about their patient’s trajectory and likelihood of switching to a new biologic.