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Introduction Cytokines might play a key role in the pathophysiology of major depressive disorder (MDD). The speed of onset of depressive episodes has been discussed as an important clinical parameter in MDD. The aim of this study was to investigate a potential influence of the speed of onset of the depressive episode on cytokine serum levels. Method Serum level of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ) granulocyte and monocyte colony stimulating factor (GM-CSF) were measured in a total of 92 patients with MDD that did not respond to at least one previous antidepressant treatment. Patients were retrospectively divided in two groups: Faster (≤4 weeks) and slower (>4 weeks) onset of the depressive episode defined as the time passing from the first depressive symptoms to a full-blown depressive episode by using information from a clinical interview. Results We found significantly lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with a faster onset compared to patients with a slower onset of the depressive episodes. Furthermore, lower cytokine serum levels of IL-2, IL-8, IL-10 and IFN-γ were found in patients with a shorter duration (less than 6 months) compared to a longer duration (6–24 months) of the current depressive episode. This effect on cytokines was independent from the effect of the speed of onset of the depressive episode. Conclusions Patients with faster onset of the depressive episode might represent a biological subtype of MDD with lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ.

The synthesis, photophysical, and electrochemical properties of selectively mono-, bis- and tris-dimethylamino- and trimethylammonium-substituted bis-triarylborane bithiophene chromophores are presented along with the water solubility and singlet oxygen sensitizing efficiency of the cationic compounds Cat1+ , Cat2+ , Cat(i)2+ , and Cat3+ . Comparison with the mono-triarylboranes reveals the large influence of the bridging unit on the properties of the bis-triarylboranes, especially those of the cationic compounds. Based on these preliminary investigations, the interactions of Cat1+ , Cat2+ , Cat(i)2+ , and Cat3+ with DNA, RNA, and DNApore were investigated in buffered solutions. The same compounds were investigated for their ability to enter and localize within organelles of human lung carcinoma (A549) and normal lung (WI38) cells showing that not only the number of charges but also their distribution over the chromophore influences interactions and staining properties.

Silver diamine fluoride (SDF) is a dental biomaterial used to arrest dental caries. To better understand SDF’s mechanism of action, we examined the localization of silver within the tissues of SDF-treated teeth. Carious primary teeth fixed within 2 min of SDF application (SDF-minutes, n = 3), at 3 wk after SDF application in vivo (SDF-weeks, n = 4), and at 2 y after multiple SDF applications in vivo (SDF-multiple, n = 1) were investigated in this study. Carious primary teeth without SDF application (no-SDF, n = 3) served as controls. Mineral density and structural analyses were performed via micro–X-ray computed tomography and scanning electron microscopy. Elemental analyses were performed through X-ray fluorescence microprobe and energy-dispersive X-ray spectroscopic techniques. SDF-treated teeth revealed higher X-ray–attenuated surface and subsurface regions within carious lesions, and similar regions were not present in no-SDF teeth. Regions of higher mineral density correlated with regions of silver abundance in SDF-treated teeth. The SDF penetration depth was approximated to 0.5 ± 0.02 mm and 0.6 ± 0.05 mm (mean ± SD) for SDF-minutes and SDF-weeks specimens, respectively. A higher percentage of dentin tubular occlusion by silver or calcium phosphate particles was observed in primary teeth treated with SDF-weeks as compared with SDF-minutes. Elemental analysis also revealed zinc abundance in carious lesions and around the pulp chamber. SDF-weeks teeth had significantly increased tertiary dentin than SDF-minutes and no-SDF teeth. These results suggest that SDF treatment on primary teeth affected by caries promotes pathologic biomineralization by altering their physicochemical properties, occluding dentin tubules, and increasing tertiary dentin volume. These seemingly serendipitous effects collectively contribute to the cariostatic activity of SDF.

Exercise interventions may influence adverse effects experienced during hospitalization for hematopoietic stem cell transplantation (HSCT). Adherence to exercise interventions is challenging. This review aimed to synthesize the literature to identify exercise interventions implemented during hospitalization for HSCT, including intervention characteristics, adherence, barriers and facilitators, and behavior change techniques using the behavior change technique taxonomy. A review of PubMed, CINAHL, PsycINFO, and Embase was completed. The sample included 19 studies. Exercise interventions demonstrated heterogeneity in prescription components, definitions, measures, and reporting of adherence. Barriers and facilitators of adherence to exercise were reported infrequently. Behavior change techniques most frequently used in studies reporting adherence rates of ≥75% included instruction on how to perform the behavior, graded tasks, and adding objects to the environment. The heterogeneity in definitions and measures of adherence limit forming conclusions to identify barriers and facilitators and determine which behavior change techniques increase adherence to exercise during HSCT.

BACKGROUND: The prevalence of atrial fibrillation(AF) and diabetes mellitus is rising to epidemic proportions. We aimed to assess the impact of diabetes on the management and outcomes of patients with AF.METHODS: The EORP-AF General Long-Term Registry is a prospective, observational registry from 250 centres across 27 European countries. Outcomes of interest were as follows: i)rhythm control interventions; ii)quality of life; iii)healthcare resource utilisation; and iv)major adverse events.RESULTS: Of 11,028 patients with AF, the median age was 71 (63-77) years and 2537 (23.0%) had diabetes. Median follow-up was 24 months. Diabetes was related to increased use of anticoagulation but less rhythm control interventions. Using multivariable analysis, at 2-year follow-up, patients with diabetes were associated with greater levels of anxiety (p = 0.038) compared to those without diabetes. Overall, diabetes was associated with worse health during follow-up, as indicated by Health Utility Score and Visual Analogue Scale. Healthcare resource utilisation was greater with diabetes in terms of length of hospital stay (8.1 (±8.2) vs. 6.1 (±6.7) days); cardiology and internal medicine/general practitioner visits; and emergency room admissions. Diabetes was an independent risk factor of major adverse cardiovascular event (MACE; HR 1.26 [95% CI, 1.04-1.52]), all-cause mortality (HR 1.28 [95% CI, 1.08-1.52]), and cardiovascular mortality (HR 1.41 [95% CI, 1.09-1.83]).CONCLUSION: In this contemporary AF cohort, diabetes was present in 1 in 4 patients and it served as an independent risk factor for reduced quality of life, greater healthcare resource utilisation and excess MACE, all-cause mortality and cardiovascular mortality. There was increased use of anticoagulation therapy in diabetes but with less rhythm control interventions.

Families (and sometimes courts) make important decisions regarding child physical custody arrangements post-separation, and shared parenting arrangements are increasingly common in most developed countries. Shared arrangements may be differentially associated with parental satisfaction, and these associations may vary across countries. Using data from surveys of separated mothers in Wisconsin and Finland, the present study explores this possibility and is guided by three aims: (a) to identify child and family characteristics associated with sole and shared child placements 6 or more years after separation; (b) to estimate associations of children's post-separation placements with maternal satisfaction with placements and expense sharing; (c) to examine whether the relationship between post-separation placement and maternal satisfaction varies by mothers' earnings and the quality of parents' relationships. We find that Finnish mothers with shared placement are more satisfied with their placement than are their counterparts with sole placement, while we find the inverse is true for Wisconsin mothers. Moreover, parental satisfaction with shared placement, overall and relative to sole placement, varies greatly depending on the quality of a mother's relationship with the other parent; and differences in relationship quality in Wisconsin and Finland may help explain the difference in satisfaction with shared placement in the two locations. In both Finland and Wisconsin, we find mothers with shared placement are more satisfied with the way expenses are shared between parents than are mothers with sole placement. Associations between placement and satisfaction are robust to extensive controls for child and maternal characteristics.父母分居之后，家庭(有时是法院)对儿童实际生活地的安置做出重要决定，在大多数发达国家，共同监护抚养孩子的安置越来越普遍。父母共同承担抚养孩子的安排可能与父母的满意度有不同的联系，这些联系在不同的国家可能有所不同。本研究利用威斯康星州和芬兰分居母亲的调查数据，探讨了这种可能性，并以三个目标为指导:(a) 确定与分居后6年或更长时间内单独和共同安置儿童有关的儿童和家庭特征；(b) 评估儿童分居后的安置与母亲对安置和费用分摊的满意度的关联；(c) 研究分居后安置与母亲方面满意度之间的关系是否因母亲的收入和父母关系的质量而变化。笔者发现，在芬兰与只安置在跟母亲一起的情况相比，父母共同抚育两处安置的母亲对她们的安置更满意，而威斯康星州的母亲则是相反的情况。此外，父母对共同监护抚养安置的满意度，无论是整体还是相对于单独一方安置而言，都有很大差异，这取决于母亲与另一方父母的关系质量；威斯康星州和芬兰的关系质量差异可能有助于解释父母共同抚养安置满意度的差异。在芬兰和威斯康星州，我们发现与母亲单独安置相比，共同抚育安置的母亲对父母之间分担费用的方式更加满意。安置情况和满意度之间的关系是强相关的，主要是针对儿童和母亲特征的拓展性控制而言。.

The metabolic pathways controlling naive CD8+ T (Tn) cell maturation following thymic egress remain mostly undefined. This is important because immature Tn are a major component of peripheral immune tolerance in newborns and under lymphopenia. In this study we demonstrate that TMRM, a mitochondrial membrane potential marker, could be applied to rapidly identify an immature Tn cell population in the periphery. Applying this marker to perform metabolic and proteomic analysis, we show that immature Tn cells maintain accelerated methionine cycle in respect to mature Tn. This unique metabolic state was associated with restricted Tbx21 locus and diminished immune response in vitro and in vivo. Following our findings, we demonstrate that inhibition of methionine cycle leads to rapid functional maturation of Tn and recovery of immune response to stimuli. Our work provides insight into the way the rate of methionine cycling regulates T cell maturation, opening a path for metabolic manipulation of immune tolerance.

Ring-shaped hexameric helicases are an essential class of enzymes that unwind duplex nucleic acids to support a variety of cellular processes. Because of their critical roles in cells, hexameric helicase dysfunction has been linked to DNA damage and genomic instability. Biochemical characterization of hexameric helicase activity and regulation in vitro is necessary for understanding enzyme function and aiding drug discovery efforts. In this chapter, we describe protocols for characterizing mechanisms of helicase loading, activation, and unwinding using the model replicative hexameric DnaB helicase and its cognate DnaC loading factor from E. coli.

Botulism is a very rare disease in Switzerland, with less than one case per year, an incidence of 0.01 cases for 100,000 inhabitants. Indeed, over the past ten years, 9 cases have been reported to Public Health registry. Foodborne botulism (FB) is caused by ingestion of preformed botulinum neurotoxin. Characteristic features should be rapidly recognized, and prompt treatment should be administered to avoid further progression towards respiratory failure and death. We report the case of a patient who developed gastrointestinal symptoms just after a sandwich consumption followed by rapidly progressive cranial nerve impairment, truncal muscle weakness in a descending pattern and respiratory failure requiring mechanical ventilation. The diagnosis of foodborne botulism was delayed due to differential diagnosis considerations. Specific antitoxin therapy was administered immediately after firm clinical conviction of botulism, without waiting for serologic results that later confirmed the diagnosis. As expected, muscle weakness recovery was slow, with persistent chronic deficits nine years later. This case highlights differential diagnosis issues of botulism. These include acute neuromuscular disorders such as myasthenia gravis, Guillain-Barré syndrome, or tick-borne encephalitis. The importance of careful medical history and repeated clinical evaluation to avoid misdiagnosis can be lifesaving. Our case highlights the typical warning signs.

Purpose: Despite favorable outcomes, up to 20% of patients with human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) will experience recurrence. Monitoring circulating tumor tissue modified viral (TTMV)-HPV DNA during post-treatment surveillance has emerged as a tool that has demonstrated >95% positive predictive value (PPV) for detecting recurrence. Here we describe a large real-world population with detailed clinical follow-up, permitting determination of the longitudinal negative predictive value (NPV) of the assay. Patients and methods: This IRB-approved, retrospective observational cohort study included 312 patients across five U.S. centers who were ≥3 months post-treatment for HPV-driven OPSCC. Patients had one or more TTMV-HPV DNA results (NavDx®, Naveris Laboratories) obtained during surveillance between February 2020 and January 2021. A baseline TTMV-HPV DNA test was not required. HPV status was assessed by p16 immunohistochemistry or HPV PCR/ISH. Test results were correlated with physician-reported exam and imaging findings to assess disease status in follow-up. Results: The cohort was mostly male (85%), had a median age of 61 (range: 27-81), included smokers (50%), and 282 (90%) had involved nodes (N1: 204, N2: 70, N3: 8) at initial staging. Curative-intent treatment involved surgery with or without another modality in 54% of cases (169/312). Median follow-up time was 23.5 months, and 39 patients (12.5%) had documented recurrence. Most patients had >1 TTMV-HPV DNA test result ≥3 months post-treatment (231, 74%), with 48 (15%) having 5 or more tests. Among patients with multiple negative surveillance tests, the median time between tests was 126 days (4.2 months, range: 0.37-24.2). The first TTMV-HPV DNA surveillance test was most often performed within the first year post-treatment (195, 63%). Across 812 test results, the NPV was 99.5%. There were 4 false negative tests among patients with confirmed p16-positive (3/4) or HPV PCR-positive (1/4) biopsy-proven recurrence. One of these patients had a subsequent positive TTMV-HPV DNA test during salvage immunotherapy. Only one of these patients had baseline TTMV-HPV DNA testing available, which showed a low positive Conclusion: Our findings further support the clinical potential of monitoring circulating TTMV-HPV DNA during post-treatment surveillance. We demonstrate a very high assay NPV correlated with physician-reported outcomes. TTMV-HPV DNA can be used to assist in surveillance and could inform imaging needs and future practice guidelines for HPV-driven head and neck cancer survivors. Citation Format: Glenn J. Hanna, Scott Roof, James Jabalee, Eleni M. Rettig, Rocco M. Ferrandino, Sida Chen, Marshall Posner, Krzysztof J. Misiukiewicz, Eric M. Genden, Raymond L. Chai, John Sims, Elaine Thrash, Scott J. Stern, Adam Raben, Lydia I. Clements, Abie H. Mendelsohn, Charlotte Kuperwasser, Catherine Del Vecchio Fitz, Barry M. Berger. Negative predictive value of circulating tumor tissue modified viral HPV DNA for identifying recurrence among patients treated for HPV-driven oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3360.

The faithful and timely copying of DNA by molecular machines known as replisomes depends on a disparate suite of enzymes and scaffolding factors working together in a highly orchestrated manner. Large, dynamic protein–nucleic acid assemblies that selectively morph between distinct conformations and compositional states underpin this critical cellular process. In this article, we discuss recent progress outlining the physical basis of replisome construction and progression in eukaryotes.

Salt-inducible kinases (SIKs) are key metabolic regulators. The imbalance in SIK function is associated with the development of diverse cancers, including breast, gastric, and ovarian cancers. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based p21-activated kinase (PAK) inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets, MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.

Background The enormous health impact of the COVID-19 pandemic has refocused attention on measures to optimize immune function and vaccine response. Dietary deficiencies of micronutrients can weaken adaptive immunity. The aim of this review was to examine links between micronutrients, immune function and COVID-19 infection, with a focus on nutritional risks in subgroups of the Swiss population. Methods Scoping review on the associations between selected micronutrients (vitamins D and C, iron, selenium, zinc, and n-3 PUFAs) and immunity, with particular reference to the Swiss population. These nutrients were chosen because previous EFSA reviews have concluded they play a key role in immunity. Results The review discusses the available knowledge on links between sufficient nutrient status, optimal immune function, and prevention of respiratory tract infections. Because of the rapid spread of the COVID-19 pandemic, controlled intervention studies of micronutrients in the context of COVID-19 infection are now underway, but evidence is not yet available to draw conclusions. The anti-inflammatory properties of n-3 PUFAs are well established. In Switzerland, several subgroups of the population are at clear risk of nutrient deficiencies; e.g., older adults, multiple comorbidities, obesity, pregnancy, and institutionalized. Low intakes of n-3 PUFA are present in a large proportion of the population. Conclusion There are clear and strong relationships between micronutrient and n-3 PUFA status and immune function, and subgroups of the Swiss population are at risk for deficient intakes. Therefore, during the COVID-19 pandemic, as a complement to a healthy and balanced diet, it may be prudent to consider supplementation with a combination of moderate doses of Vitamins C and D, as well as of Se, Zn and n-3 PUFA, in risk groups., Clinical Nutrition ESPEN, 43, ISSN:2405-4577

BACKGROUND The US Preventive Services Task Force (USPSTF) includes multitarget stool DNA (mt-sDNA) testing as a colorectal cancer (CRC) screening option in average-risk individuals, but data on colonoscopy outcomes after positive mt-sDNA tests in community settings are needed. AIM The aim of this study was to investigate colonoscopy outcomes and quality following positive mt-sDNA in the population-based New Hampshire Colonoscopy Registry. METHODS We compared colonoscopy outcomes and quality between age-matched, sex-matched, and risk-matched patients from 30 endoscopy practices with and without a preceding positive mt-sDNA test. Main outcomes were colonoscopy findings of CRC, advanced noncancerous neoplasia, nonadvanced neoplasia, or normal examination. Quality measures included withdrawal time, bowel preparation quality, examination completion, and percentage of average-risk individuals with normal colonoscopies receiving a USPSTF-recommended 10 year rescreening interval. RESULTS Individuals with positive mt-sDNA tests (N=306, average age 67.0 y; 61.8% female) were significantly more likely than colonoscopy-only patients (N=918, 66.2 y; 61.8% female) to have CRC (1.3% vs. 0.4%) or advanced noncancerous neoplasia (27.1% vs. 8.2%) (P

With the current COVID-19 pandemic, we all realized how important interactions are. Interactions are everywhere. At the cellular level, protein interactions play a key role and their ensemble, also called interactome, is often referred as the basic building blocks of life. Given its importance, the maintenance of the integrity of the interactome is a real challenge in the cell. Many events during evolution can disrupt interactomes and potentially result in different characteristics for the organisms. However, the molecular underpinnings of changes in interactions at the cellular level are still largely unexplored. Among the perturbations, hybridization puts in contact two different interactomes, which may lead to many changes in the protein interaction network of the hybrid, including gains and losses of interactions. We recently investigated the fate of the interactomes after hybridization between yeast species using a comparative proteomics approach. A large-scale conservation of the interactions was observed in hybrids, but we also noticed the presence of proteostasis-related changes. This suggests that, despite a general robustness, small differences may accumulate in hybrids and perturb their protein physiology. Here, we summarize our work with a broader perspective on the importance of interactions.

Amino acid (AA) metabolism is severely disturbed in critically ill ICU patients. To be able to make a more scientifically based decision on the type of protein or AA nutrition to deliver in ICU patients, comprehensive AA phenotyping with measurements of plasma concentrations and whole body production (WBP) is needed. Therefore, we studied ICU patients and matched control subjects using a novel pulse isotope method to obtain in-depth metabolic analysis. In 51 critically ill ICU patients (SOFA~6.6) and 49 healthy controls, we measured REE and body composition/phase-angle using BIA. In the postabsorptive state, we collected arterial (ized) blood for CRP and AA. Then, we administered an 8 mL solution containing 18 stable AA tracers as a pulse and calculated WBP. Enrichments: LC-MS/MS and statistics: t-test, ANCOVA. Compared to healthy, critically ill ICU patients had lower phase-angle (p 0.00001), and higher CRP (p 0.0001). Most AA concentrations were lower in ICU patients (p 0.0001), except tau-methylhistidine and phenylalanine. WBP of most AA were significantly (p 0.0001) higher with increases in glutamate (160%), glutamine (46%), and essential AA. Remarkably, net protein breakdown was lower. There were only weak relationships between AA concentrations and WBP. Critically ill ICU patients (SOFA 8-16) had lower values for phase angle (p = 0.0005) and small reductions of most plasma AA concentrations, but higher tau-methylhistidine (p = 0.0223) and hydroxyproline (p = 0.0028). Remarkably, the WBP of glutamate and glutamine were lower (p 0.05), as was their clearance, but WBP of tau-methylhistidine (p = 0.0215) and hydroxyproline (p = 0.0028) were higher. Our study in critically ill ICU patients shows that comprehensive metabolic phenotyping was able to reveal severe disturbances in specific AA pathways, in a disease severity dependent way. This information may guide improving nutritional compositions to improve the health of the critically ill patient. CLINICAL TRIAL REGISTRY: Data are from the baseline measurements of study NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092) and NCT03628365 (URL: https://clinicaltrials.gov/ct2/show/NCT03628365).

Reaching the goals set by the Health Care Payment and Learning Action Network requires an unyielding and unrelenting focus on encouraging providers to adopt advanced alternative payment models (APMs). Many of these models will continue to be voluntary because they either are in early stages or have not yet proven their effectiveness. The models that have proven their effectiveness should become permanent, comprising the new way that providers are paid in the Medicare program. Either way, getting today's high performers into those programs and keeping them engaged to continue to innovate and set new benchmarks is as important as attracting and improving the performance of poorer performers. That will require a shift in Medicare's policy on pricing and evaluating APMs.

Growing evidence shows diminished response to mRNA-based SARS-CoV‑2 vaccination in kidney transplant recipients. We aimed to investigate the seroconversion rate after a 3rd and 4th dose of mRNA vaccination in kidney transplant recipients without prior antibody response to two or three vaccination doses.This retrospective study included 324 prevalent kidney transplant recipients of a single tertiary transplantation center of which 157 remained seronegative, defined as anti-spike-RBD-IgG antibody titer 7.1 BAU/ml, after two doses of mRNA-based SARS-CoV‑2 vaccination. Maintenance immunosuppression was not changed. The median patient age was 60.6 years (IQR 51.4-68.1 years), 66.9% were male. Positivity for anti-spike-RBD-IgG (≥ 7.1 BAU/ml) was measured 4-5 weeks after administration of a 3rd and 4th vaccine dose.Seroconversion rates were 63.9% after a 3rd dose and 29.3% after a 4th dose of vaccine. Cumulative prevalence of seropositivity was 51.5% after 2 doses, 80.5% after 3 doses and 84.2% after 4 doses.In conclusion, seroconversion can be achieved in the majority of the kidney transplant recipients by administrating three or four doses of mRNA vaccine without changing maintenance immunosuppression.