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Policymakers must make management decisions despite incomplete knowledge and conflicting model projections. Little guidance exists for the rapid, representative, and unbiased collection of policy-relevant scientific input from independent modeling teams. Integrating approaches from decision analysis, expert judgment, and model aggregation, we convened multiple modeling teams to evaluate COVID-19 reopening strategies for a mid-sized United States county early in the pandemic. Projections from seventeen distinct models were inconsistent in magnitude but highly consistent in ranking interventions. The 6-mo-ahead aggregate projections were well in line with observed outbreaks in mid-sized US counties. The aggregate results showed that up to half the population could be infected with full workplace reopening, while workplace restrictions reduced median cumulative infections by 82%. Rankings of interventions were consistent across public health objectives, but there was a strong trade-off between public health outcomes and duration of workplace closures, and no win-win intermediate reopening strategies were identified. Between-model variation was high; the aggregate results thus provide valuable risk quantification for decision making. This approach can be applied to the evaluation of management interventions in any setting where models are used to inform decision making. This case study demonstrated the utility of our approach and was one of several multimodel efforts that laid the groundwork for the COVID-19 Scenario Modeling Hub, which has provided multiple rounds of real-time scenario projections for situational awareness and decision making to the Centers for Disease Control and Prevention since December 2020.

Abstract Background Chronic non-healing wounds pose a global health challenge. Under optimized conditions, skin wounds heal by the formation of scar tissue. However, deregulated cell activation leads to persistent inflammation and the formation of granulation tissue, a type of premature scar tissue without epithelialization. Regenerative cells from the wound periphery contribute to the healing process, but little is known about their cellular fate in an inflammatory, macrophage-dominated wound microenvironment. Methods We examined CD45−/CD31−/CD34+ preadipocytes and CD68+ macrophages in human granulation tissue from pressure ulcers (n=6) using immunofluorescence, immunohistochemistry, and flow cytometry. In vitro, we studied macrophage-preadipocyte interactions using primary human adipose-derived stem cells (ASCs) exposed to conditioned medium harvested from IFNG/LPS (M1)- or IL4/IL13 (M2)-activated macrophages. Macrophages were derived from THP1 cells or CD14+ monocytes. In addition to confocal microscopy and flow cytometry, ASCs were analyzed for metabolic (OXPHOS, glycolysis), morphological (cytoskeleton), and mitochondrial (ATP production, membrane potential) changes. Angiogenic properties of ASCs were determined by HUVEC-based angiogenesis assay. Protein and mRNA levels were assessed by immunoblotting and quantitative RT-PCR. Results CD45−/CD31−/CD34+ preadipocytes were observed with a prevalence of up to 1.5% of total viable cells in human granulation tissue. Immunofluorescence staining suggested a spatial proximity of these cells to CD68+ macrophages in vivo. In vitro, ASCs exposed to M1, but not to M2 macrophage secretome showed a pro-fibrotic response characterized by stress fiber formation, elevated alpha smooth muscle actin (SMA), and increased expression of integrins ITGA5 and ITGAV. Macrophage-secreted IL1B and TGFB1 mediated this response via the PI3K/AKT and p38-MAPK pathways. In addition, ASCs exposed to M1-inflammatory stress demonstrated reduced migration, switched to a glycolysis-dominated metabolism with reduced ATP production, and increased levels of inflammatory cytokines such as IL1B, IL8, and MCP1. Notably, M1 but not M2 macrophages enhanced the angiogenic potential of ASCs. Conclusion Preadipocyte fate in wound tissue is influenced by macrophage polarization. Pro-inflammatory M1 macrophages induce a pro-fibrotic response in ASCs through IL1B and TGFB1 signaling, while anti-inflammatory M2 macrophages have limited effects. These findings shed light on cellular interactions in chronic wounds and provide important information for the potential therapeutic use of ASCs in human wound healing.

BackgroundHead and neck squamous cell carcinomas (HNSCC) are highly heterogeneous tumors. In the harsh tumor microenvironment (TME), metabolic reprogramming and mitochondrial dysfunction may lead to immunosuppressive phenotypes. Aerobic glycolysis is needed for the activation of cytotoxic T-cells and the absence of glucose may hamper the full effector functions of cytotoxic T-cells. To test the effect of mitochondrial dysfunction on cytotoxic T cell function, slice cultures (SC) of HNSCC cancer were cultivated under different metabolic conditions.MethodsTumor samples from 21 patients with HNSCC were collected, from which, SC were established and cultivated under six different conditions. These conditions included high glucose, T cell stimulation, and temporarily induced mitochondrial dysfunction (MitoDys) using FCCP and oligomycin A with or without additional T cell stimulation, high glucose and finally, a control medium. Over three days of cultivation, sequential T cell stimulation and MitoDys treatments were performed. Supernatant was collected, and SC were fixed and embedded. Granzyme B was measured in the supernatant and in the SC via immunohistochemistry (IHC). Staining of PD1, CD8/Ki67, and cleaved­caspase­3 (CC3) were performed in SC.ResultsHematoxylin eosin stains showed that overall SC quality remained stable over 3 days of cultivation. T cell stimulation, both alone and combined with MitoDys, led to significantly increased granzyme levels in SC and in supernatant. Apoptosis following T cell stimulation was observed in tumor and stroma. Mitochondrial dysfunction alone increased apoptosis in tumor cell aggregates. High glucose concentration alone had no impact on T cell activity and apoptosis. Apoptosis rates were significantly lower under conditions with high glucose and MitoDys (p=0.03).ConclusionStimulation of tumor-infiltrating lymphocytes in SC was feasible, which led to increased apoptosis in tumor cells. Induced mitochondrial dysfunction did not play a significant role in the activation and function of TILs in SC of HNSCC. Moreover, high glucose concentration did not promote cytotoxic T cell activity in HNSCC SC.

Abstract Quantitative reverse transcription polymerase chain reaction (qRT‐PCR) of BCR‐ABL1 transcript level is an essential part of routine disease monitoring in patients with chronic myeloid leukemia. One patient sample (e13a2 transcript detected by nested PCR) attracted attention by revealing an aberrantly spliced BCR‐ABL1 transcript variant e13a1. The last 38 base pairs (bp) of BCR exon 13 were replaced by a 37 bp insertion of the ABL1 intron 1–2/exon 1 sequence. The rare aberrant BCR‐ABL1 fusion transcript can cause discrepancies in molecular diagnostics. This scenario highlights the importance of an individual characterization of the BCR‐ABL1 fusion sequence in case of unclear qRT‐PCR results.

BackgroundStandardization and digitalization are getting more and more essential in surgery. Surgical procedure manager (SPM®) is a freestanding computer serving as a digital supporter in the operating room. SPM® navigates step-by-step through surgery by providing a checklist for each individual step.MethodsThis was a single center, retrospective study at the Department for General and Visceral Surgery at Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin. Patients who underwent ileostomy reversal without SPM® in the period of January 2017 until December 2017 were compared to patients who were operated with SPM® in the period of June 2018 until July 2020. Explorative analysis and multiple logistic regression were performed.ResultsOverall, 214 patients underwent ileostomy reversal: 95 patients without SPM® vs. 119 patients with SPM®. Ileostomy reversal was performed by head of department/attendings in 34.1%, by fellows in 28.5% and by residents in 37.4%; p = 0.91. Postoperative intraabdominal abscess emerged more often in patients without SPM®: ten (10.5%) patients vs. four (3.4%) patients; p = 0.035. Multiple logistic regression showed a risk reduction for intraabdominal abscess {Odds ratio (OR) 0.19 [95% confidence interval (CI) 0.05–0.71]; p = 0.014} and for bowel perforation [OR 0.09 (95% CI 0.01–0.93); p = 0.043] in the group with use of SPM® in ileostomy reversal.ConclusionsSPM® may reduce postoperative complications in ileostomy reversal such as intraabdominal abscess and bowel perforation. SPM® may contribute to patient safety.

We determined the relative expression levels of the receptors TrkA, TrkB, TrkC, and p75NTR and ligands BDNF, NT-3, NGF, and NT-4 with RNAseq analysis on fetal human inner ear samples, located TrkB and TrkC proteins, and quantified BDNF with in situ hybridization on histological sections between gestational weeks (GW) 9 to 19. Spiral ganglion neurons (SGNs) and satellite glia appear to be the main source of BDNF and synthesis peaks twice at GW10 and GW15–GW17. Tonotopical gradients of BDNF revert between GW8 and GW15 and follow a maturation and innervation density gradient in SGNs. NT-3/TrkC follows the same time course of expression as BDNF/TrkB. Immunostaining reveals that TrkB signaling may act mainly through satellite glia, Schwann cells, and supporting cells of Kölliker's organ, while TrkC signaling targets SGNs and pillar cells in humans. The NT-4 expression is upregulated when BDNF/NT-3 is downregulated, suggesting a balancing effect for sustained TrkB activation during fetal development. The mission of neurotrophins expects nerve fiber guidance, innervation, maturation, and trophic effects. The data shall serve to provide a better understanding of neurotrophic regulation and action in human development and to assess the transferability of neurotrophic regenerative therapy from animal models. [ABSTRACT FROM AUTHOR]

BackgroundTemperature-taking behaviors vary with levels of circulating infectious illness; however, little is known about how these behaviors differ by demographic characteristics. Populations with higher perceived risks of illness are more likely to adopt protective health behaviors. ObjectiveWe investigated differences in temperature-taking frequency and the proportion of readings that were feverish among demographic groups (age, gender, urban/rural status) over influenza offseason; influenza season; and waves 1, 2, and 3 of the COVID-19 pandemic. MethodsUsing data from smart thermometers collected from May 1, 2019, to February 28, 2021, across the United States, we calculated the frequency of temperature-taking and the proportion of temperature readings that were feverish. Mixed-effects negative binomial and mixed-effects logistic regression analyses were performed to identify demographic characteristics associated with temperature-taking frequency and the proportion of feverish readings, respectively. Separate models were fit over five study periods: influenza offseason (n=122,480), influenza season (n=174,191), wave 1 of COVID-19 (n=350,385), wave 2 (n=366,489), and wave 3 (n=391,578). ResultsBoth temperature-taking frequency and the proportion of feverish readings differed by study period (ANOVA P

Abstract Background Surgical closure of anal fistulas with rectal advancement flaps is an established standard method, but it has a high degree of healing failure in some cases. The aim of this study was to identify risk factors for anal fistula healing failure after advancement flap placement between patients with cryptoglandular fistulas and patients with Crohn’s disease (CD). Methods From January 2010 to October 2020, 155 rectal advancement flaps (CD patients = 55, non-CD patients = 100) were performed. Patients were entered into a prospective database, and healing rates were retrospectively analysed. Results The median follow-up period was 189 days (95% CI: 109–269). The overall complication rate was 5.8%. The total healing rate for all rectal advancement flaps was 56%. CD patients were younger (33 vs. 43 years, p

This is a case of a female toddler presenting with a minor injury to the right lower extremity with progressively worsening erythema and oedema. Initial workup revealed elevated inflammatory markers and imaging with significant soft tissue gas. The overall clinical presentation was highly suggestive of a necrotising soft tissue infection. The patient was expeditiously managed with fluid resuscitation, intravenous antibiotics and admission to intensive care. The patient required multiple operative interventions for excisional debridement of grossly necrotic soft tissue and fascia with eventual achievement of healthy wound margins amenable to reconstruction with skin grafting. [ABSTRACT FROM AUTHOR]

Abstract Background Adipose-derived stem cells (ASC) and adipocytes are involved in numerous physiological and pathophysiological conditions, which have been extensively described in subcutaneous and visceral fat depots over the past two decades. However, much less is known about ASC and adipocytes outside classical fat tissue depots and their necessity in tissue remodeling after injury. Therefore, we investigated the etiology of adipocytes in human granulation tissue and define their possible role wound healing. Methods Identification of human wound tissue adipocytes was determined by immunohistochemical staining of granulation tissue sections from patients undergoing surgical debridement. Stromal cell fractions from granulation tissue and subcutaneous fat tissue were generated by collagenase type II-based protocols. Pro- and anti-inflammatory wound bed conditions were mimicked by THP1- and CD14+ monocyte-derived macrophage models in vitro. Effects of macrophage secretome on ASC differentiation and metabolism were determined by immunoblotting, flow cytometry, and microscopy assessing early and late adipocyte differentiation states. Functional rescuing experiments were conducted by lentiviral transduction of wildtype PPARG, IL1RA, and N-chlorotaurine (NCT) treatment. Results Single and clustered adipocyte populations were detected in 11 out of 13 granulation tissue specimens and single-cell suspensions from granulation tissue showed adipogenic differentiation potential. Pro-inflammatory signaling by IFNG/LPS-stimulated macrophages (M (IFNG/LPS)) inhibited the maturation of lipid droplets in differentiated ASC. In contrast, anti-inflammatory IL4/IL13-activated macrophages (M (IL4/IL13)) revealed minor effects on adipocyte development. The M (IFNG/LPS)-induced phenotype was associated with a switch from endogenous fatty acid synthesis to glycolysis-dominated cell metabolism and increased pro-inflammatory cytokine production. Impaired adipogenesis was associated with increased, but seemingly non-functional, CEBPB levels, which failed to induce downstream PPARG and CEBPA. Neither transgenic PPARG overexpression, nor inhibition of IL1B was sufficient to rescue the anti-adipogenic effects induced by IFNG/LPS-activated macrophages. Instead, macrophage co-treatment during stimulation with NCT, a mild oxidant produced by activated granulocytes present in human wounds in vivo, significantly attenuated the anti-adipogenic effects. Conclusions In conclusion, the appearance of adipocytes in wound tissue indicates a prevailing anti-inflammatory environment that could be promoted by NCT treatment and may be associated with improved healing outcomes. Graphical abstract

Introduction. Rural Appalachia is endemic to issues such as substance abuse, poverty, and lack of community support, all of which negatively influence health outcomes. The incidence of pediatric trauma as it relates to substance abuse is of concern in the region, where the rate of positive drug screens in pediatric trauma cases is higher than national average. Methods. The West Virginia statewide pediatric trauma database was analyzed in a retrospective cohort study for the years 2009-2019. Variables of interest included injury severity (assessed using Abbreviated Injury Scale (AIS)), drug screening results, and various measures of patient outcome. Results. The sample was divided into 2009-2016 presentations (n=3,356) and 2017-2019 presentations (n=1,182). Incidence of critical (AIS 5) head injuries (p=0.007) and serious (AIS 3) neck injuries (p=0.001) increased as time progressed. Days requiring ventilation increased from 3.1 in 2009–2016 to 6.3 in 2017–2019 (p

The measurement and simulation data, their preparation and the simulation setup published in this co-submission are related to the article “Simulation of metal cutting with cutting fluid using the Finite-Pointset-Method” [1]. Wet and dry turning experiments were conducted at the Institute for Machine Tools and Factory Management(IWF), Berlin, Germany. Required adaptions of the used software MESHFREE were performed at Fraunhofer ITWM, Kaiserslautern, Germany. Both institutes collaboratively developed and validated the orthogonal cutting simulation model using the Finite-Pointset-Method (FPM).In this paper all measurement and simulation data and their preparation methods are presented in detail. This includes the preparation methods of process forces, analysis of chip morphology images as well as measured contact lengths on tool rake faces. Moreover, the experimental and simulation data are provided at the Mendeley Data repository [2]. Hence the reader can use the data for own validations and analysis.Furthermore, the used simulation model files are completely published at the Mendeley Data repository. It allows the reader to retrace all settings. In addition, this enables to repeat the simulations and to simulate other process parameter combinations according to own interests.

Objective Purpose of this study is to analyse the visual outcomes, the complication and eye retention rate as well as tumour control data of patients treated with proton beam radiation therapy (PBRT) for iris melanoma.Methods Retrospective case series and review based on patients’ records. All tumours were categorised according to the American Joint Committee of Cancer staging criteria for primary iris melanoma und underwent either sectorial or whole anterior segment PBRT.Results Thirteen cases were identified of which five received PBRT of the whole anterior segment and eight received sectorial PBRT. Local tumour control after a mean follow-up of 25 months was 92%. Complications after PBRT included cataract (46%), secondary glaucoma (31%), superficial keratitis (15%) and madarosis (8%). Complications were more common in patients necessitating irradiation of the entire anterior segment than in patients which received sectorial irradiation. Eye retention was achieved in all cases. No statistically significant difference in the mean best corrected visual acuity (BCVA) and intraocular pressure (IOP) was found before and after treatment. Comparison of mean BCVA and IOP between different treatment groups (complete anterior segment vs sectorial irradiation) at the last follow-up visit were also not significantly different. No patient developed metastatic disease during follow-up.Conclusion PBRT is a safe and vision preserving therapeutic modality for iris melanoma. Complete irradiation of the anterior segment is associated with higher complication rates.

Objectives: The COVID-19 pandemic and its associated restrictions have resulted in delayed diagnoses across various tumor entities, including rectal cancer. Our hypothesis was based on the expectation of a reduced number of primary operations due to higher tumor stages compared to the control group. Methods: In a single-center retrospective study conducted from 1 March 2018 to 1 March 2022, we analyzed 120 patients with an initial diagnosis of rectal cancer. Among them, 65 patients were part of the control group (pre-COVID-19), while 55 patients were included in the study group (during the COVID-19 pandemic). We compared tumor stages, treatment methods, and complications, presenting data as absolute numbers or mean values. Results: Fewer primary tumor resections during the COVID-19 pandemic (p = 0.010), as well as a significantly lower overall number of tumor resections (p = 0.025) were seen compared to the control group. Twenty percent of patients in the COVID-19 group received their diagnosis during lockdown periods. These patients presented significantly higher tumor stages (T4b: 27.3% vs. 6.2%, p = 0.025) compared to the control group prior to the pandemic. In addition, more patients with angiolymphatic invasion (ALI) were identified in the COVID-19 group following neoadjuvant treatment compared to the control group (p = 0.027). No differences were noted between the groups regarding complications, stoma placement, or conversion rates. Conclusions: The COVID-19 pandemic, particularly during lockdown, appears to have contributed to delayed diagnoses, resulting in higher tumor stages and a decreased number of surgeries. The quality of rectal cancer treatment can be maintained under pandemic conditions. [ABSTRACT FROM AUTHOR]

Abstract Stress comprises three sequential stages: the event (stressor), which leads to an initial effect on a focal organism (stress), followed by the organism's ultimate response (recovery or not). Using this framework, we test how the duration and timing of a stressor individually and interactively affect the initial and asymptotic organism outcomes. We applied either long or short water restrictions either early or later in the life of Lepidium sativum. While several of these water restriction treatments caused a noticeable initial effect, all were able to recover fully, except for those exposed to a long early water restriction. While long early stressors led to decreased height, a growth model revealed that both long and short early stressors changed the rate of growth and prolonged the inflection point, findings that would have been missed had effect and response not been analyzed separately. Both the stressor and the magnitude of the initial effect in part explained the change in the growth model parameter estimates. Overall, timing, duration, and, more importantly, the interaction of these two temporal aspects of stress significantly affects an organism's initial response to a stressor and its ability to ultimately recover from stress. Our findings highlight the importance of explicitly studying the interactions of stressor aspects and of examining the immediate stress effects, as well as long‐term responses.