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Hearing and balance rely on small sensory hair cells that reside in the inner ear. To explore dynamic changes in the abundant proteins present in differentiating hair cells, we used nanoliter-scale shotgun mass spectrometry of single cells, each ~1 picoliter, from utricles of embryonic day 15 chickens. We identified unique constellations of proteins or protein groups from presumptive hair cells and from progenitor cells. The single-cell proteomes enabled the de novo reconstruction of a developmental trajectory using protein expression levels, revealing proteins that greatly increased in expression during differentiation of hair cells (e.g., OCM, CRABP1, GPX2, AK1, GSTO1) and those that decreased during differentiation (e.g., TMSB4X, AGR3). Complementary single-cell transcriptome profiling showed corresponding changes in mRNA during maturation of hair cells. Single-cell proteomics data thus can be mined to reveal features of cellular development that may be missed with transcriptomics. [ABSTRACT FROM AUTHOR]

Because of their individual vulnerabilities, treatment decisions for older patients can be difficult. Geriatric assessment (GA) may help to select patients for systemic treatment, but its value is still unproven. Older cancer patients (≥65 years of age) with and without complex GA followed by discussion in the geriatric-oncologic conference, who had been treated in palliative intention with standard combination chemotherapy at the Evang. Kliniken Essen-Mitte, were retrospectively evaluated. All patients had been orally informed about the treatment options and had chosen chemotherapy beside supportive care. To reduce selection bias, the method of propensity-score matching was performed. Patient groups treated in the years 2011–2013 (without GA, group 1) and in the years 2014–2015 (with GA, group 2) were compared regarding different toxicity endpoints. The primary endpoint of the study was defined as numbers of patients with unplanned admission to the hospital or death during first-line chemotherapy and GA should reduce these events by 15%. Overall, 114 patients were evaluated in both groups. The median age was 74 years. Patients suffered from gastrointestinal carcinomas (47%), lung cancer (28%), breast cancer (12%), and other cancer types (3%). Consequently, most patients were treated with platinum-based (41%), fluoropyrimidine-based (35%), or anthracycline-based (13%) combination chemotherapy. In group 2, the events were numerically lower for all toxicity endpoints. The need for a premature stop of treatment was 54.4% in group 1 compared to 29.8% in group 2 (p < 0.01) and also the treatment-related mortality was significantly lower in group 2 (17.5% vs. 5.3%; p = 0.04). The primary endpoint, the rate of unplanned hospital admission, and death was 49.1% versus 35.1% (difference 14.0%), which did not reach the predefined border of 15%. There was a nonsignificant overall survival benefit in the group with GA (22.6 vs. 18.4 months). GA appears useful to better select older patients with advanced cancer for combination chemotherapy. The significant reduction of mortality during chemotherapy justifies the efforts and costs which need to be expended. To evaluate the effect of GA on overall survival, prospective trials are required. [ABSTRACT FROM AUTHOR]

This contribution investigates the influence of outgassing processes on the vibration behavior of a hydrodynamic bearing supported turbocharger rotor. The examined rotor is supported radially by floating rings with outer squeeze-film damping and axially by thrust bearings. Due to the highly nonlinear bearing properties, the rotor can be excited via the lubricating film, which results in subsynchronous vibrations known as oil-whirl and oil-whip phenomena. A significant influence on the occurrence of oil-whip phenomena is attributed to the bearing stiffness and damping, which depend on the kinematic state of the supporting elements, the thermal condition, and the occurrence of outgassing processes. For modeling the bearing behavior, the Reynolds equation with mass-conserving cavitation regarding the two-phase model and the three-dimensional (3D) energy as well as heat conduction equation is solved. To evaluate the impact of cavitation, run-up simulations are carried out assuming a fully (half-Sommerfeld) or partially filled lubrication gap. The resulting rotor responses are compared with the shaft motion measurement. Also, the normalized eccentricity, the minimum lubricant fraction, and the thermal bearing condition are discussed. [ABSTRACT FROM AUTHOR]

Purpose: The management of perforated diverticulitis with generalized peritonitis is still controversial and no preferred standardized therapeutic approach has been determined. We compared surgical outcomes between Hartmann's procedure (HP) and primary anastomosis (PA) in patients with Hinchey III and IV perforated diverticulitis. Methods: Multicenter retrospective analysis of 131 consecutive patients with Hinchey III and IV diverticulitis operated either with HP or PA from 2015 to 2018. Postoperative morbidity was compared after adjustment for known risk factors in a multivariate logistic regression. Results: Sixty-six patients underwent HP, while PA was carried out in 65 patients, 35.8% of those were defunctioned. HP was more performed in older patients (74.6 vs. 61.2 years, p <.001), with Hinchey IV diverticulitis (37% vs. 7%, p <.001) and in patients with worse prognostic scores (P-POSSUM Physiology Score, p <.001, Charlson Comorbidity Index p <.001). Major morbidity and mortality were higher in HP compared to PA (30.3% vs. 9.2%, p =.002 and 10.6% vs. 0%, p =.007, respectively) with lower stoma reversal rate (43.9% vs. 86.9%, p <.001). In a multivariate logistic regression, PA was independently associated with lower postoperative morbidity and mortality (OR 0.24, 95% CI 0.06–0.96, p =.044). Conclusions: In comparison to PA, HP is associated with a higher morbidity, higher mortality, and a lower stoma reversal rate. Although a higher prevalence of risk factors in HP patients may explain these outcomes, a significant increase in morbidity and mortality persisted in a multivariate logistic regression analysis that was stratified for the identified risk factors. [ABSTRACT FROM AUTHOR]

Leptin is a homeostatic regulatory element that signals the presence of adipocyte energy stores, reduces food intake, and increases energy expenditure. Similarly, serotonin (5- HT), a signaling molecule found in both the central and peripheral nervous systems, also controls food intake. Using neuronal tract-tracing, pharmacological and optogenetics approaches, and in vivo microdialysis, combined with behavioral endpoints, we tested the hypothesis that leptin controls food intake not only by activating hypothalamic leptin receptors (LepRs), but also through activation of LepRs expressed by serotonergic raphe neurons that send projections to the arcuate (ARC). We show that microinjection of leptin directly into the dorsal raphe nucleus (DRN) reduces food intake in rats. This effect is mediated by LepR expressing neurons in the DRN as selective optogenetic activation of these neurons at either their DRN cell bodies or their ARC terminals reduces food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing LepRs that send projections to the ARC. Finally, by utilizing in vivo microdialysis, we show that leptin administration to the DRN increases 5-HT efflux into the ARC, and specific antagonism of the 5-HT2C receptors in the ARC diminishes the leptin anorectic effect. Overall, this study identifies a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, identifying a new level of interaction between leptin and serotonin to control food intake. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior, as well as opens alternative routes for the treatment of eating disorders., (© 2024 by the American Diabetes Association.)

Improving the quality of malaria clinical case management in health facilities is key to improving health outcomes in patients. The U.S. President's Malaria Initiative Impact Malaria Project has supported implementation of the Outreach Training and Supportive Supervision (OTSS) approach in 11 African countries to improve the quality of malaria care in health facilities through the collection and analysis of observation-based data on health facility readiness and health provider competency in malaria case management. We conducted a secondary analysis of longitudinal data collected during routine supervision in Cameroon (April 2021-March 2022), Mali (October 2020-December 2021), and Niger (November 2020-September 2021) using digitized checklists to assess how service readiness affects health worker competencies in managing patients with fever correctly and providing those with confirmed uncomplicated malaria cases with appropriate treatment and referral. Linear or logistic regression analyses were conducted to assess the effect of facility readiness and its components on observed health worker competencies. All countries demonstrated significant associations between health facility readiness and malaria case management competencies. Data from three rounds of OTSS visits in Cameroon, Mali, and Niger showed a statistically significant positive association between greater facility readiness scores (including the availability of commodities, materials, and trained staff) and health worker competency in case management. These findings provide evidence that health worker performance is likely affected by the tools and training available to them. These results reinforce the need for necessary tools and properly trained staff if high-quality malaria case management services are to be delivered at health facilities.

Background: Seasonal malaria chemoprevention (SMC) consists of the intermittent administration of a 3 day course of anti-malarial medications during the months of highest malaria risk in the Sahel region, where malaria transmission is highly seasonal. SMC is an effective intervention to reduce episodes of uncomplicated and severe malaria in children. However, morbidity cannot be lowered without adherence to medications. The objective of this study was to examine SMC medication adherence and to identify the attitudes and practices of caregivers during the 2020 SMC campaign in the Dosso region., Methods: This study was conducted based on data from independent monitoring using random cluster sampling. Adherence levels and the attitudes and practices of caregivers were evaluated using data from caregivers' self-reports and analysed according to Bernard Vrijens' taxonomy., Results: At the initiation of treatment phase, 99% of children (N = 2296) received their first administration of medication, with 90% of caregivers (N = 1436) knowing that the medications help prevent malaria. However, only 56% of caregivers (N = 1856) reported that treatment initiation took place under direct observation by the distributor. At the implementation of treatment phase, 90% of children (N = 2132) took their medication on the second day and 84% (N = 1068) took it the third day. "Forgetting," "not having time," and "the mother's absence" were the main reasons caregivers gave to explain discontinuation of the 3 day course of medication., Conclusion: This simple, low-cost survey demonstrated that coverage of SMC and adherence by caregivers to completing the full 3 day medication course was high. The survey also showed that knowledge, attitudes, and practices of some caregivers regarding adherence to medications during the SMC campaign could be improved. Expanding distributors' training, developing and providing them with tools for interpersonal communication, and strengthening supervision could lead to even higher adherence., (© 2022. The Author(s).)

Background: Growing consideration in quality of life (QoL) has changed the therapeutic strategy in patients suffering from diverticular disease. Patients' well-being plays a crucial role in the decision-making process. However, there is a paucity of studies investigating patients' or surgery-related factors influencing the postoperative gastrointestinal function. The aim of this study was to investigate in a predictive model patients or surgical variables that allow better estimation of the postoperative gastrointestinal QoL., Methods: This observational study retrospectively analyzed patients undergoing elective laparoscopic sigmoidectomy for diverticulitis between 2004 and 2017. The one-time postoperative QoL was assessed with the gastrointestinal quality of life index (GIQLI) in 2019. A linear regression model with stepwise selection has been applied to all patients and surgery-related variables., Results: Two hundred seventy-two patients with a mean age of 62.30 ± 9.74 years showed a mean GIQLI of 116.39±18.25 at a mean follow-up time of 90.4±33.65 months. Women (n=168) reported a lower GIQLI compared to male (n=104; 112.85±18.79 vs 122.11±15.81, p<0.001). Patients with pre-operative cardiovascular disease (n=17) had a worse GIQLI (106.65 ±22.58 vs 117.08±17.66, p=0.010). Finally, patients operated less than 5 years ago (n=63) showed a worse GIQLI compared to patients operated more than 5 years ago (n=209; 111.98±19.65 vs 117.71±17.63, p=0.014)., Conclusions: Female gender and the presence of pre-operative cardiovascular disease are predictive for a decreased postoperative gastrointestinal QoL. Furthermore, patients' estimation of gastrointestinal functioning seems to improve up to 5 years after surgery., (© 2021. The Author(s).)

Introduction: Immunotherapy is the new standard of care in advanced nonsmall cell lung cancer (NSCLC). Recently published data show that treatment discontinuation after 12 months of nivolumab treatment is associated with shorter survival. Therefore, the ideal duration of immunotherapy remains unclear, and finding markers of beneficial outcomes is of great importance. Here, we determine the proportion of complete metabolic responses (CMR) in patients who have not progressed after 24 months of immunotherapy., Methods: This is a retrospective analysis of 45 patients with positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose imaging for assessment of residual metabolic activity after at least 24 months. CMR was defined as uptake in tumor lesions below background levels, using mediastinum as a reference. Results Out of 45 patients, 29 patients had a CMR (64%). CMR was observed more frequently in non-first-line patients. Patients with CMR were younger (median 65.7 vs 75.5, p=0.03). Fourteen patients with CMR have discontinued therapy and have not progressed until time of analysis; however, median follow-up was only 5.6 (range 0.8-17.0) months., Conclusion: After a minimum of 24 months of palliative immunotherapy for NSCLC, CMR occurred in almost two thirds of patients. Potentially, achievement of CMR might identify patients, for whom palliative immunotherapy may be safely discontinued., Competing Interests: Competing interests: MM reports personal fees from Boehringer-Ingelheim, Bristol-Myers Squibb, MSD Sharp & Dohme, Roche and Takeda. LK is a consultant for AAA and BTG and received fees from Sanofi, all outside of the submitted work. LU is a speaker for Bayer Healthcare, a speaker for Siemens Healthcare and has received research grants from Siemens Healthcare outside of the submitted work. KH reports personal fees from Bayer, personal fees and others from Sofie Biosciences, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from BTG, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from ymAbs, outside the submitted work. WPF is a consultant for Endocyte and BTG, and he received fees from RadioMedix, Bayer, and Parexel outside of the submitted work. MF has received speaker’s honoraria and participated as PI in clinical trials of AstraZeneca, Roche, MSD, and BMS. DCC reports personal fees, non-financial support and others from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai, MSD Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Platin-containing regimes are currently considered as state-of-the-art therapies in malignant pleural mesotheliomas (MPM) but show dissatisfying response rates ranging from 6 to 16% only. Still, the reasons for the rather poor efficacy remain largely unknown. A clear stratification of patients based on new biomarkers seems to be a promising approach to enhance clinical management, which would be a long-needed improvement for MPM patients but does not seem likely soon unless new biomarkers can be validated. Twenty-four formalin-fixed, paraffin-embedded (FFPE) tumour specimens were subjected to a miRNA expression screening of 800 important miRNAs using digital quantification via the nCounter technique (NanoString). We defined a small subset of miRNAs regulating the key enzymes involved in the repair of platin-associated DNA damage. Particularly, the TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main miRNA targets within this context. The TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main players for risk stratification in patients suffering from this severe disease. Taking the specific molecular profile of the tumour into account can help to enhance the clinical management prospectively and to smooth the way to better response prediction.

Purpose: 25% of all lung cancer cases are neuroendocrine (NELC) including typical (TC) and atypical carcinoid (AC), large-cell neuroendocrine (LCNEC) and small cell lung cancer (SCLC). Prognostic and predictive biomarkers are lacking., Experimental Design: Sixty patients were used for nCounter mRNA expression analysis of the folic-acid metabolism (ATIC, DHFR, FOLR1, FPGS, GART, GGT1, SLC19A1, TYMS) and DNA-repair (ERCC1, MLH1, MSH2, MSH6, XRCC1). Phenotypic classification classified tumors (either below or above the median expression level) with respect to the folic acid metabolism or DNA repair., Results: Expression of FOLR1, FPGS, MLH1 and TYMS (each p<0.0001) differed significantly between all four tumor types. FOLR1 and FPGS associated with tumor differentiation (both p<0.0001), spread to regional lymph nodes (FOLR1 p=0.0001 and FPGS p=0.0038), OS and PFS (FOLR1 p<0.0050 for both and FPGS p<0.0004 for OS). Phenotypic sorting revealed the Ft-phenotype to be the most prominent expression profile in carcinoids, whereas SCLC presented nearly univocal with the fT and LCNEC with fT or ft. These results were significant for tumor subtype (p<0.0001)., Conclusions: The assessed biomarkers and phenotypes allow for risk stratification (OS, PFS), diagnostic classification and enhance the biological understanding of the different subtypes of neuroendocrine tumors revealing potential new therapy options and clarifying known resistance mechanisms.