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Abstract Background Residual fibroglandular breast tissue (RFGT) following a mastectomy is associated with the remaining of occult breast cancer at the time of mastectomy as well as an increased local recurrence risk thereafter. Despite its oncologic implications, data on measures to prevent RFGT are lacking. Therefore, in a first step knowledge of risk factors for RFGT is of uttermost importance in order to allow identification of patients at risk and subsequently adaption of the surgical treatment and potentially prevention of RFGT a priori. Methods We performed a systematic literature review in PubMed using the MESH terms [residual fibroglandular breast tissue], [residual breast tissue], [mastectomy] and [risk factor] followed by a retrospective data analysis including all patients with a mastectomy treated at the Department of Obstetrics and Gynecology of the Medical University of Vienna, Austria, between 01.01.2015 and 26.02.2020 in order to identify risk factors of RFGT following a mastectomy. The primary aim of the study was to assess a potential difference in RFGT volume between the different types of mastectomy. The secondary objectives of the study were to identify other potential risk factors for RFGT as well as to compare the skin and subcutaneous fat tissue thickness pre- to postoperatively. Results Significantly higher RFGT volumes were observed following a nipple-sparing mastectomy (NSM) compared to a skin-sparing mastectomy (SSM) and radical mastectomy (RME) (p

Abstract In 2020, the novel severe acute respiratory syndrome coronavirus outbreak emerged as a public health emergency. Three years later, we are still assessing the effects caused by the coronavirus disease (COVID‐19) and by the lifestyle changes due to prevention measures, like social isolation. Here, we assessed the profile of both the anxiety screening scores and anthropometric variables in the university community, associated with the isolation due to the COVID‐19 pandemic. We analyzed social and epidemiological associated factors for anxiety and weight change to address and better identify the physical and mental conditions aggravated during the pandemic. This is a cross‐sectional study based on the 7‐item Generalized Anxiety Disorder Scale questionnaire applied virtually to university students and professors in the State of Rio de Janeiro (n = 480). In our population cohort, we showed that the majority of individuals showed moderate to severe anxiety and increased body weight during the COVID‐19 pandemic. The major demographic associated factors for higher anxiety levels were young age, female gender, and low family income. The main modifiable associated factors for both anxiety and weight gain were the negative changes in living habits. In addition, there was a trend toward severe anxiety and greater weight change in people with increased time in social isolation. In view of these results, we suggest that bad habits, adopted during the COVID‐19 pandemic, were the main reason for the high anxiety levels found in the studied population.

Landsat and Sentinel-2 data archives provide ever-increasing amounts of satellite data. However, the availability of usable observations greatly varies spatially and temporally. Pixel-based compositing that generates temporally equidistant cloud-free synthetic images can mitigate temporal variability, by constructing uninterrupted time series using different compositing windows. Here, we evaluated the feasibility of using compositing windows ranging from five days to one year for 1984–2021 Landsat and 2015–2021 Sentinel 2 time series to derive uninterrupted time series across Europe. We considered separate and joint use of both data archives and analyzed the spatio-temporal availability of composites during each calendar year and pixel-specific growing season across a variety of time windows and hypothesizing data interpolation. Our results demonstrated opportunities and limitations in the available data records to support medium- and long-term analyses requiring uninterrupted time series of composites with sub-annual temporal resolution. Spatial disparities across different compositing windows provide guidance on the feasibility of workflows relying on different data densities and on the challenges in wall-to-wall analyses. The feasibility of consistent time series based on composites with sub-monthly aggregation periods was mostly limited to the combined Landsat and Sentinel-2 archives after 2015, yet in some geographies requires interpolation of up to 50% of data.

The enteric nervous system (ENS), a collection of neural cells contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the neural crest and remains largely unchanged thereafter. Here, we show that the lineage composition of maturing ENS changes with time, with a decline in the canonical lineage of neural-crest derived neurons and their replacement by a newly identified lineage of mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility which can be reversed by GDNF supplementation. Transcriptomic analyses of human gut tissues show reduced GDNF-RET signaling in patients with intestinal dysmotility which is associated with reduction in neural crest-derived neuronal markers and concomitant increase in transcriptional patterns specific to mesoderm-derived neurons. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS.

Summary: Upon proinflammatory challenges, endothelial cell surface presentation of the leukocyte receptor P-selectin, together with the stabilizing co-factor CD63, is needed for leukocyte capture and is mediated via demand-driven exocytosis from the Weibel-Palade bodies that fuse with the plasma membrane. We report that neutrophil recruitment to activated endothelium is significantly reduced in mice deficient for the endolysosomal cation channel TPC2 and in human primary endothelial cells with pharmacological TPC2 block. We observe less CD63 signal in whole-mount stainings of proinflammatory-activated cremaster muscles from TPC2 knockout mice. We find that TPC2 is activated and needed to ensure the transfer of CD63 from endolysosomes via Weibel-Palade bodies to the plasma membrane to retain P-selectin on the cell surface of human primary endothelial cells. Our findings establish TPC2 as a key element to leukocyte interaction with the endothelium and a potential pharmacological target in the control of inflammatory leukocyte recruitment.

„Wir müssen endlich im großen Stil abschieben“. Diese Aussage, wirkmächtig platziert auf dem Spiegel-Cover vom 21. Oktober 2023, stammt nicht von einem oder einer derjenigen Politiker:innen, von denen es unmittelbar zu erwarten gewesen wäre. Obwohl Forderungen nach Abschiebungen im „großen Stil“ eigentlich eine klare politische Heimat am rechten Rand haben, stammt sie von einem Sozialdemokraten, Olaf Scholz. Für viele Beobachter:innen aus den Rechts- und Sozialwissenschaften kommt dieses Spiegel-Cover dennoch nicht überraschend, sondern fügt sich nahtlos ein in die Chronologie des Rechtsrucks der deutschen Politik und Gesellschaft.

Abstract Background Residual fibroglandular breast tissue (RFGT) following a mastectomy has been claimed to be associated with the occurrence of an in-breast local recurrence (IBLR) or new primary tumor (NP). Yet, scientific evidence proving this assumption is lacking. The primary aim of the study was to verify whether RFGT following a mastectomy is a risk factor for an IBLR or NP. Methods This retrospective analysis included all patients that underwent a mastectomy and were followed up at the Department of Obstetrics and Gynecology of the Medical University of Vienna between 01.01.2015 and 26.02.2020. RFGT volume (assessed on magnetic resonance imaging) was correlated with the prevalence of an IBLR and a NP. Results A total of 105 patients (126 breasts) following a therapeutic mastectomy were included. After a mean follow-up of 46.0 months an IBLR had occurred in 17 breasts and a NP in 1 breast. A significant difference in RFGT volume was observed between the disease-free cohort and the subgroup with an IBLR or NP (p = .017). A RFGT volume of ≥ 1153 mm3 increased the risk by the factor 3.57 [95%CI 1.27; 10.03]. Conclusions RFGT volume is associated with an increased risk for an IBLR or NP.

Background: Cataracts resulting from equine recurrent uveitis (ERU) or other forms of uveitis are usually associated with rapid progression. ERU is the most common ocular disease cause of blindness and cause of cataracts in horses. The necessity for the posterior capsulorhexis (PC) during phacoemulsification (PE) is controversial. This study aimed to evaluate vision and complications after PE combined with pars plana vitrectomy (PPV) in horses with uveitis-associated cataracts and compare the PE technique with and without posterior capsulorhexis. Methods: Thirty-two eyes of 28 horses with uveitis-associated cataracts aged 14 months to 19.6 years were treated with PE-PPV under identical conditions. Twenty-three eyes of 21 horses were affected by an ERU-associated (ERU group), and nine eyes of 7 horses were affected by cataracts related to uveitis with pathogenesis different to ERU (non-ERU group). PE-PPV was performed in 12 eyes of 10 horses (PC group) and 20 eyes of 18 horses without posterior capsulorhexis (NPC group). Follow-up examination was performed at a mean of 1.7 ± 1.8 years postoperatively (range: 1 month–6.4 years). Results: In the period up to 1 month postoperatively, 17/20 (85%) NPC-eyes and 8/12 (67%) PC-eyes (total: 25/32 [78%]) were visual. From 1–6 months postoperatively, 16/20 (80%) NPC-eyes and 7/12 (58.3%) PC-eyes (total: 23/32 [72%]), and from 6–12 months, 7/11 (63.6%) NPC-eyes and 3/8 (37.5%) PC-eyes (total: 10/19 [52.6%]) were visual. From 12–18 months postoperatively, 3/7 (42.9%) NPC-eyes and 2/9 (22.2%) PC-eyes (total: 5/16 [31.3%]), and from 18–24 months, 3/8 (37.5%) NPC-eyes and 1/8 (12.5%) PC-eyes (total: 4/16 [25%]) were visual. After 24 months postoperatively, 2/7 (28.6%) NPC-eyes and 1/8 (12.5%) PC-eyes (total: 3/15 [20%]) were visual. Despite the higher number of visual eyes in the NPC group at each time point, differences were not significant. No obvious differences regarding postsurgical vision were observed between the ERU- and non-ERU groups at each time point. In the overall population, a significant decrease in the number of eyes with postoperative active uveitis was observed during the follow-up examinations (p < 0.001). A significant increase in the number of eyes that were blind due to retinal detachment was observed in the overall patient population as the examination period progressed (p < 0.001). Retinal detachment was the sole long-term cause of blindness. Conclusions: In horses diagnosed with uveitis-associated cataracts and treated with PE-PPV, no persistent active uveitis was observed in the present study during follow-up examinations. However, the proportion of eyes that were blind due to retinal detachment increased. Whilst PE-PPV may prevent postsurgical persistent active uveitis and remove lens opacity, the prognosis for a visual outcome is guarded. A superior outcome in postsurgical vision was observed in the NPC group. However, caution is required when interpreting these results due to several factors that affect the independent comparison of the surgical groups.

To advance probiotic research, a comprehensive understanding of bacterial interactions with human physiology at the molecular and cellular levels is fundamental. Lacticaseibacillus rhamnosus LGG® is a bacterial strain that has long been recognized for its beneficial effects on human health. Probiotic effector molecules derived from LGG®, including secreted proteins, surface-anchored proteins, polysaccharides, and lipoteichoic acids, which interact with host physiological processes have been identified. In vitro and animal studies have revealed that specific LGG® effector molecules stimulate epithelial cell survival, preserve intestinal barrier integrity, reduce oxidative stress, mitigate excessive mucosal inflammation, enhance IgA secretion, and provide long-term protection through epigenetic imprinting. Pili on the cell surface of LGG® promote adhesion to the intestinal mucosa and ensure close contact to host cells. Extracellular vesicles produced by LGG® recapitulate many of these effects through their cargo of effector molecules. Collectively, the effector molecules of LGG® exert a significant influence on both the gut mucosa and immune system, which promotes intestinal homeostasis and immune tolerance.

Abstract Purpose IMpassion130 led to the approval of atezolizumab plus nab-paclitaxel as first-line treatment for patients with unresectable locally advanced or metastatic triple-negative, PD-L1 immune-cell positive breast cancer (BC) by the European Medicines Agency (EMA). The objective of the present study was to investigate the implementation, safety and efficacy of this combination in the initial phase after approval. Methods A retrospective data analysis including all BC patients who received atezolizumab and nab-paclitaxel between 1.1.2019 and 31.10.2020 at the Department of Obstetrics and Gynecology and the Department of Medicine 1, respectively, at the Medical University of Vienna, Austria, was performed. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Maier product-limit method. Owing to the retrospective nature of this study, all statistics must be considered exploratory. Results In total 20 patients were included in the study. Median follow-up was 7.1 months (IQR 5.2–9.1). Median PFS was 3.0 months (SE = .24; 95% CI [2.5; 3.5]). Median OS was 8.94 months (SE = 2.34, 95%CI [4.35; 13.53]). No new safety signals were observed. Conclusion The present study showed a considerably shorter PFS (3.0 vs. 7.5 months) and OS (8.94 vs. 25.0 months) than IMpassion130 putatively owing to the use of atezolizumab in later treatment lines, more aggressive tumors and a study population with higher morbidity compared to the pivotal trial.

Abstract Background Pancreatic neuroendocrine neoplasms (PanNENs) fall into two subclasses: the well-differentiated, low- to high-grade pancreatic neuroendocrine tumors (PanNETs), and the poorly-differentiated, high-grade pancreatic neuroendocrine carcinomas (PanNECs). While recent studies suggest an endocrine descent of PanNETs, the origin of PanNECs remains unknown. Methods We performed DNA methylation analysis for 57 PanNEN samples and found that distinct methylation profiles separated PanNENs into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA alterations and immunohistochemistry of cell-type markers PDX1, ARX, and SOX9 were utilized to further characterize PanNECs and their cell of origin in the pancreas. Results Phylo-epigenetic and cell-type signature features derived from alpha, beta, acinar, and ductal adult cells suggest an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin. Conclusions Our study provides a robust and clinically applicable method to clearly distinguish PanNECs from G3 PanNETs, improving patient stratification.

Recent evidence on the association between vitamin D and cognition in mentally healthy individuals is inconsistent. Furthermore, the link between vitamin D and cognitive ability in individuals with bipolar disorder has not been studied yet. Thus, we aimed to investigate the association between 25-hydroxyvitamin D (25(OH)D), 24,25 dihydroxyvitamin D (24,25(OH)2D, the vitamin D metabolite ratio (VMR) and cognition in a cohort of euthymic patients with bipolar disorder. Vitamin D metabolites were measured simultaneously by liquid-chromatography tandem mass-spectrometry in serum samples from 86 outpatients with bipolar disorder and 93 healthy controls. Neither the inactive precursor 25(OH)D, nor the primary vitamin D catabolite 24,25(OH)2D, or the vitamin D metabolite ratio were significantly associated with the domains “attention”, “memory”, or “executive function” in individuals with bipolar disorder and healthy controls. Further, no vitamin D deficiency effect or interaction group × vitamin D deficiency was found in the cognitive domain scores. In summary, the present study does not support vitamin D metabolism as a modulating factor of cognitive function in euthymic BD patients. Considering the current study’s cross-sectional design, future research should expand these results in a longitudinal setting and include additional aspects of mental health, such as manic or depressive symptoms, long-term illness course and psychopharmacological treatment.

BackgroundLiver metastases are common in patients with breast cancer, and determining the factors associated with such metastases may improve both their early detection and treatment. Given that liver function protein level changes in these patients have not been determined, the aim of our study was to investigate liver function protein level changes over time, spanning 6 months before the detection of liver metastasis to 12 months after.MethodsWe retrospectively studied 104 patients with hepatic metastasis from breast cancer who were treated at the Departments of Internal Medicine I and the Department of Obstetrics and Gynecology at the Medical University of Vienna between 1980 and 2019. Data were extracted from patient records.ResultsAspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, lactate dehydrogenase and alkaline phosphatase were significantly elevated when compared to normal range 6 months before the detection of liver metastases (pConclusionLiver function protein levels should be considered as potential indicators when screening for liver metastasis in patients with breast cancer. With the new treatment options available, it could lead to prolonged life.

Accumulation of advanced glycation end products (AGEs), particularly in long-lived extracellular matrix proteins, has been implicated in pathogenesis of diabetic complications and in aging. Knowledge about specific locations of AGEs and their precursors within protein primary structure is critical for understanding their physiological and pathophysiological impact. However, the information on specific AGE sites is lacking. Here, we identified sequence positions of four major AGEs, carboxymethyllysine, carboxyethyllysine, 5-hydro-5-methyl imidazolone, and 5-hydro-imidazolone, and an AGE precursor fructosyllysine within the triple helical region of collagen I from cortical bone of human femurs. The presented map provides a basis for site-specific quantitation of AGEs and other non-enzymatic post-translational modifications and identification of those sites affected by aging, diabetes, and other diseases such as osteoporosis; it can also help in guiding future studies of AGE impact on structure and function of collagen I in bone.

Abstract The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective and block at least two of the three human isoforms. We have now identified the first highly potent and isoform-selective TRPML1 antagonist, the steroid 17β-estradiol methyl ether (EDME). Two analogs of EDME, PRU-10 and PRU-12, characterized by their reduced activity at the estrogen receptor, have been identified through systematic chemical modification of the lead structure. EDME and its analogs, besides being promising new small molecule tool compounds for the investigation of TRPML1, selectively affect key features of TRPML1 function: autophagy induction and transcription factor EB (TFEB) translocation. In addition, they act as inhibitors of triple-negative breast cancer cell migration and invasion.

Abstract Background Disruptions of brain-gut axis have been implicated in the progression of a variety of gastrointestinal (GI) disorders and central nervous system (CNS) diseases and injuries, including traumatic brain injury (TBI). TBI is a chronic disease process characterized by persistent secondary injury processes which can be exacerbated by subsequent challenges. Enteric pathogen infection during chronic TBI worsened cortical lesion volume; however, the pathophysiological mechanisms underlying the damaging effects of enteric challenge during chronic TBI remain unknown. This preclinical study examined the effect of intestinal inflammation during chronic TBI on associated neurobehavioral and neuropathological outcomes, systemic inflammation, and dysautonomia. Methods Dextran sodium sulfate (DSS) was administered to adult male C57BL/6NCrl mice 28 days following craniotomy (Sham) or TBI for 7 days to induce intestinal inflammation, followed by a return to normal drinking water for an additional 7 to 28 days for recovery; uninjured animals (Naïve) served as an additional control group. Behavioral testing was carried out prior to, during, and following DSS administration to assess changes in motor and cognitive function, social behavior, and mood. Electrocardiography was performed to examine autonomic balance. Brains were collected for histological and molecular analyses of injury lesion, neurodegeneration, and neuroinflammation. Blood, colons, spleens, mesenteric lymph nodes (mLNs), and thymus were collected for morphometric analyses and/or immune characterization by flow cytometry. Results Intestinal inflammation 28 days after craniotomy or TBI persistently induced, or exacerbated, respectively, deficits in fine motor coordination, cognition, social behavior, and anxiety-like behavior. Behavioral changes were associated with an induction, or exacerbation, of hippocampal neuronal cell loss and microglial activation in Sham and TBI mice administered DSS, respectively. Acute DSS administration resulted in a sustained systemic immune response with increases in myeloid cells in blood and spleen, as well as myeloid cells and lymphocytes in mesenteric lymph nodes. Dysautonomia was also induced in Sham and TBI mice administered DSS, with increased sympathetic tone beginning during DSS administration and persisting through the first recovery week. Conclusion Intestinal inflammation during chronic experimental TBI causes a sustained systemic immune response and altered autonomic balance that are associated with microglial activation, increased neurodegeneration, and persistent neurological deficits.

ABSTRACT West Nile virus (WNV) is a major cause of viral encephalitis in the United States. WNV infection of the brain leads to neuroinflammation characterized by activation of microglia, the resident phagocytic cells of the central nervous system (CNS). In this study, depletion of CNS microglia using the CSF1R antagonist PLX5622 increased the viral load in the brain and decreased the survival of mice infected with WNV (strain TX02). PLX5622 was also used in ex vivo brain slice cultures (BSCs) to investigate the role of intrinsic neuroinflammatory responses during WNV infection. PLX5622 effectively depleted microglia (>90% depletion) from BSCs resulting in increased viral titers (3 to 4-fold increase in PLX5622-treated samples) and enhanced virus-induced caspase 3 activity and cell death. Microglia depletion did not result in widespread alterations in cytokine and chemokine production in either uninfected or WNV infected BSCs. The results of this study demonstrated how microglia contribute to limiting viral growth and preventing cell death in WNV infected BSCs but were not required for the cytokine/chemokine response to WNV infection. This study highlighted the importance of microglia in the protection from neuroinvasive WNV infection and demonstrated that microglia responses were independent of WNV-induced peripheral immune responses. IMPORTANCE WNV infections of the CNS are rare but can have devastating long-term effects. There are currently no vaccines or specific antiviral treatments, so a better understanding of the pathogenesis and immune response to this virus is crucial. Previous studies have shown microglia to be important for protection from WNV, but more work is needed to fully comprehend the impact these cells have on neuroinvasive WNV infections. This study used PLX5622 to eliminate microglia in an ex vivo brain slice culture (BSC) model to investigate the role of microglia during a WNV infection. The use of BSCs provided a system in which immune responses innate to the CNS could be studied without interference from peripheral immunity. This study will allow for a better understanding of the complex nature of microglia during viral infections and will likely impact the development of new therapeutics that target microglia.

Oil in water emulsions are an important class of soft material that are used in the food, cosmetic, and biomedical industries. These materials are formed through the use of emulsifiers that are able to stabilize oil droplets in water. Historically emulsifiers have been developed from lipids or from large biomolecules such as proteins. However, the ability to use short peptides, which have favorable degradability and toxicity profiles is seen as an attractive alternative. In this work, we demonstrate that it is possible to design emulsifiers from short (tetra) peptides that have tunability (i.e., the surface activity of the emulsion can be tuned according to the peptide primary sequence). This design process is achieved by applying coarse grain molecular dynamics simulation to consecutively reduce the molecular search space from the 83,521 candidates initially considered in the screen to four top ranking candidates that were then studied experimentally. The results of the experimental study correspond well to the predicted results from the computational screening verifying the potential of this screening methodology to be applied to a range of different molecular systems.

Although great strides have been made in the pathophysiological understanding, diagnosis and management of cardiogenic shock (CS), morbidity and mortality in patients presenting with the condition remain high. Acute MI is the commonest cause of CS; consequently, most existing literature concerns MI-associated CS. However, there are many more phenotypes of patients with acute heart failure. Medical treatment and mechanical circulatory support are well-established therapeutic options, but evidence for many current treatment regimens is limited. The issue is further complicated by the fact that implementing adequately powered, randomized controlled trials are challenging for many reasons. In this review, the authors discuss the history, landmark trials, current topics of medical therapy and mechanical circulatory support regimens, and future perspectives of CS management.

Therapy-induced senescence reflects a biological effector principle that is underrecognized in lesion-focused cancer precision medicine. Here the authors utilize mouse lymphoma genetics to functionally dissect senescence and cross-species apply a novel senescence-based prognosticator to lymphoma patients.

Bone is a dynamic tissue that adapts to changes in its mechanical environment. Mechanical stimuli pressurize interstitial fluid in the lacunar-canalicular system within the bone matrix, causing fluid shear stress (FSS) across bone embedded, mechano-sensitive osteocytes. Therefore, modeling this mechanical stimulus in vitro is vital for identifying mechano-transduction cascades that contribute to the regulation of mechano-responsive proteins, such as the Wnt/β-catenin antagonist, sclerostin, which is reduced in response to FSS. Recently, we reported the rapid post-translational degradation of sclerostin protein in bone cells following FSS. Given the fundamental nature of sclerostin to bone physiology and the nuances of studying its rapid post-translational control, here, we detail our FSS protocol, and adaptations that can be made, to stimulate Ocy454 osteocyte-like cells to study sclerostin protein in vitro. While this protocol is optimized for detecting sclerostin degradation by western blot, this protocol can be adapted to examine transcriptional changes with RT-qPCR, cellular dynamics with live cell imaging, or secreted factors in the FSS buffer. This protocol utilizes 3D-printed FSS tips that are compatible with commercially available 96-well plates, allowing for high experimental accessibility, versatility, and throughput. However, this protocol can be adapted for any FSS chamber. It can also be combined with pharmacological inhibitors or genetic manipulations to interrogate the role of specific cellular components. In all, this experimental set-up and protocol is highly adaptable to allow for many experimental outcomes to examine many aspects of cell mechano-transduction.

The decline in the mass and function of bone and muscle is an inevitable consequence of healthy aging with early onset and accelerated decline in those with chronic disease. Termed osteo-sarcopenia, this condition predisposes the decreased activity, falls, low-energy fractures, and increased risk of co-morbid disease that leads to musculoskeletal frailty. The biology of osteo-sarcopenia is most understood in the context of systemic neuro-endocrine and immune/inflammatory alterations that drive inflammation, oxidative stress, reduced autophagy, and cellular senescence in the bone and muscle. Here we integrate these concepts to our growing understanding of how bone and muscle senses, responds and adapts to mechanical load. We propose that age-related alterations in cytoskeletal mechanics alter load-sensing and mechano-transduction in bone osteocytes and muscle fibers which underscores osteo-sarcopenia. Lastly, we examine the evidence for exercise as an effective countermeasure to osteo-sarcopenia.

(1) Background: Perioperative Antibiotics for acute complicated appendicitis are a standard of care. While there are plenty of trials for pediatric patients, data for elderly patients are scarce. The goal of our study was to evaluate whether elderly patients carry more resistant bacteria and thus have less favorable outcomes after an appendectomy that may warrant intensified perioperative antibiotic treatment (2) We present a retrospective single-center matched pair (139 patients each) analysis of perioperative and microbiological outcomes of an elderly appendicitis cohort (i.e., older than 60 years) compared with a younger adult cohort (i.e., ≤60 years). Both groups were matched one for one according to gender, duration of symptoms, c-reactive protein at presentation and whether they presented with uncomplicated or complicated appendicitis. (3) Results: After matching, complicated appendicitis was present in 76.3% of both groups. Elderly patients more frequently received preoperative diagnostic CT (p < 0.001) than the young. Both operative strategy (laparoscopic appendectomy in 92.1% each) and duration of surgery (57 vs. 56 min) were equal in both groups. Postoperative antibiotics were prescribed in ~57% for a median of 3 days in both groups and antibiotic selection was similar. The incidence of surgical site infections was higher in the young (12.2% vs. 7.9%) yet not significant. There was no difference in culture positivity or bacterial spectrum and the elderly cohort did not present with increased resistant bacterial isolates. (4) Conclusions: While overall resistant bacterial strains were rare, perioperative outcomes between the young and the elderly did not differ and did neither warrant longer nor intensified antibiotic treatment.

Direct support professionals (DSPs) play a large social role in the lives of people with developmental disabilities (DD) and have the potential to influence their health behaviors. Six qualitative focus groups (n = 48) were conducted with DD community agency administrators, DSPs, family members and adults with DD to better understand the perceived role of DSPs in the health promotion efforts of those with DD. Findings from this study suggest that DSPs experience several barriers when trying to promote the health of those with DD, one of which is fear of violating the rights of people with DD. Future work should identify ways to overcome the barriers experienced by DSPs, so that they can better assist people with DD with health promotion efforts.

Abstract Background Diagnosis and treatment decisions in cancer increasingly depend on a detailed analysis of the mutational status of a patient’s genome. This analysis relies on previously published information regarding the association of variations to disease progression and possible interventions. Clinicians to a large degree use biomedical search engines to obtain such information; however, the vast majority of scientific publications focus on basic science and have no direct clinical impact. We develop the Variant-Information Search Tool (VIST), a search engine designed for the targeted search of clinically relevant publications given an oncological mutation profile. Results VIST indexes all PubMed abstracts and content from ClinicalTrials.gov. It applies advanced text mining to identify mentions of genes, variants and drugs and uses machine learning based scoring to judge the clinical relevance of indexed abstracts. Its functionality is available through a fast and intuitive web interface. We perform several evaluations, showing that VIST’s ranking is superior to that of PubMed or a pure vector space model with regard to the clinical relevance of a document’s content. Conclusion Different user groups search repositories of scientific publications with different intentions. This diversity is not adequately reflected in the standard search engines, often leading to poor performance in specialized settings. We develop a search engine for the specific case of finding documents that are clinically relevant in the course of cancer treatment. We believe that the architecture of our engine, heavily relying on machine learning algorithms, can also act as a blueprint for search engines in other, equally specific domains. VIST is freely available at https://vist.informatik.hu-berlin.de/

Abstract Background The decreasing cost of obtaining high-quality calls of genomic variants and the increasing availability of clinically relevant data on such variants are important drivers for personalized oncology. To allow rational genome-based decisions in diagnosis and treatment, clinicians need intuitive access to up-to-date and comprehensive variant information, encompassing, for instance, prevalence in populations and diseases, functional impact at the molecular level, associations to druggable targets, or results from clinical trials. In practice, collecting such comprehensive information on genomic variants is difficult since the underlying data is dispersed over a multitude of distributed, heterogeneous, sometimes conflicting, and quickly evolving data sources. To work efficiently, clinicians require powerful Variant Information Systems (VIS) which automatically collect and aggregate available evidences from such data sources without suppressing existing uncertainty. Methods We address the most important cornerstones of modeling a VIS: We take from emerging community standards regarding the necessary breadth of variant information and procedures for their clinical assessment, long standing experience in implementing biomedical databases and information systems, our own clinical record of diagnosis and treatment of cancer patients based on molecular profiles, and extensive literature review to derive a set of design principles along which we develop a relational data model for variant level data. In addition, we characterize a number of public variant data sources, and describe a data integration pipeline to integrate their data into a VIS. Results We provide a number of contributions that are fundamental to the design and implementation of a comprehensive, operational VIS. In particular, we (a) present a relational data model to accurately reflect data extracted from public databases relevant for clinical variant interpretation, (b) introduce a fault tolerant and performant integration pipeline for public variant data sources, and (c) offer recommendations regarding a number of intricate challenges encountered when integrating variant data for clincal interpretation. Conclusion The analysis of requirements for representation of variant level data in an operational data model, together with the implementation-ready relational data model presented here, and the instructional description of methods to acquire comprehensive information to fill it, are an important step towards variant information systems for genomic medicine.

The downregulation of sclerostin in osteocytes mediates bone formation in response to mechanical cues and parathyroid hormone (PTH). To date, the regulation of sclerostin has been attributed exclusively to the transcriptional downregulation of the Sost gene hours after stimulation. Using mouse models and rodent cell lines, we describe the rapid, minute-scale post-translational degradation of sclerostin protein by the lysosome following mechanical load and PTH. We present a model, integrating both new and established mechanically and hormonally activated effectors into the regulated degradation of sclerostin by lysosomes. Using a mouse forelimb mechanical loading model, we find transient inhibition of lysosomal degradation or the upstream mechano-signaling pathway controlling sclerostin abundance impairs subsequent load-induced bone formation by preventing sclerostin degradation. We also link dysfunctional lysosomes to aberrant sclerostin regulation using human Gaucher disease iPSCs. These results reveal how bone anabolic cues post-translationally regulate sclerostin abundance in osteocytes to regulate bone formation.

This paper explores the policing of vices and offers a critical inquiry into the affective politics of policing practices seen through police and state ethnography, political anthropology, and the ‘affective turn’ in social and cultural theory. It shows how the moral worlds of policing sex work and performing raids in the red-light ‘milieu’ are constituted in the making of boundaries through visual, olfactory, somatosensory, and auditory sensations, which can be understood as normative performances in the realm of morality. Police officers do not engage in a neutral gaze but transform the sensuous into sensations that enact these normative distinctions between the ‘normal’ and the ‘abnormal’ – the morally questionable red-light ‘milieu.’ These practices can be read in regard to a morality that is conveyed in and through the officers’ sensational performances in an observingly affective and somatic manner. Morality not simply is but is being done—and performing affects and sensations plays a significant role in the making of moral worlds in the realm of policing. Raiding the red-light ‘milieu’ is a performance on disorder and order, on what is normal and what is not, and thus a deeply political practice that reveals how order- and boundary-making operates through basic sensations and feelings, of the sensuous, the aesthetic, and the somatic.