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An assessment of the pathoanatomic parameters of the arthritic glenohumeral joint (GHJ) has the potential to identify discriminating metrics to differentiate glenoid types in shoulders with primary glenohumeral osteoarthritis (PGHOA). The aim was to identify the morphometric differences and threshold values between glenoid types including normal and arthritic glenoids with the various types in the Walch classification. We hypothesized that there would be clear morphometric discriminators between the various glenoid types and that specific numeric threshold values would allow identification of each glenoid type.The computed tomography scans of 707 shoulders were analyzed: 585 obtained from shoulders with PGHOA and 122 from shoulders without glenohumeral pathology. Glenoid morphology was classified according to the Walch classification. All computed tomography scans were imported in a dedicated automatic 3D-software program that referenced measurements to the scapular body plane. Glenoid and humeral modeling was performed using the best-fit sphere method, and the root-mean-square error was calculated. The direction and orientation of the glenoid and humerus described glenohumeral relationships.Among shoulders with PGHOA, 90% of the glenoids and 85% of the humeral heads were directed posteriorly in reference to the scapular body plane. Several discriminatory pathoanatomic parameters were identified: GHJ narrowing3 mm was a discriminatory metric for type A glenoids. Posterior humeral subluxation70% discriminated type B1 from normal GHJs. The root-mean-square error was a discriminatory metric to distinguish type B2 from type A, type B3, and normal GHJs. Type B3 glenoids differed from type A2 by greater retroversion (13°) and subluxation (71%). The type C glenoid retroversion inferior limit was 21°, whereas normal glenoids never presented with retroversion16°.Pathoanatomic metrics with the identified threshold values can be used to discriminate glenoid types in shoulders with PGHOA.

Cervical cancer therapy is still a major clinical challenge, as patients substantially differ in their response to standard treatments, including chemoradiotherapy (CRT). During cervical carcinogenesis, T‐helper (Th)‐17 cells accumulate in the peripheral blood and tumor tissues of cancer patients and are associated with poor prognosis. In this prospective study, we find increased Th17 frequencies in the blood of patients after chemoradiotherapy and a post‐therapeutic ratio of Th17/CD4+ T cells > 8% was associated with early recurrence. Furthermore, Th17 cells promote resistance of cervical cancer cells toward CRT, which was dependent on the AKT signaling pathway. Consistently, patients with high Th17 frequencies in pretherapeutic biopsies exhibit lower response to primary CRT. This work reveals a key role of Th17 cells in CRT resistance and elevated Th17 frequencies in the blood after CRT correspond with early recurrence. Our results may help to explain individual treatment responses of cervical cancer patients and suggest evaluation of Th17 cells as a novel predictive biomarker for chemoradiotherapy responses and as a potential target for immunotherapy in cervical cancer., This study demonstrates that chemoradiotherapy‐treated patients with cervical cancer have increased frequencies of Th17 cells. Th17 frequency was associated with early cancer relapse. Additionally, high pretherapeutic Th17 amounts in situ were correlated to a failed response to chemoradiotherapy. Our work suggests that the evaluation of Th17 cells could serve as a novel predictive biomarker for chemoradiotherapy responses and a potential target for immunotherapy in patients with cervical cancers.

Background Given the increasing rates of childhood obesity in Alaska Native children and the understanding that the most effective interventions are informed by and reflect the cultural knowledge of the community in which they are implemented, this project sought to gather the wisdom of local Yup’ik and Cup’ik Elders in the Yukon-Kuskokwim region of Alaska around how to maintain a healthy diet and active lifestyle. Methods Perspectives were sought through the use of semi-structured focus groups, which were completed in person in twelve communities. All conversations were recorded, translated, transcribed, and analyzed using a qualitative approach, where key themes were identified. Results Elders provided a clear and consistent recollection of what their life looked like when they were young and expressed their perspectives related to maintaining a healthy and traditional lifestyle. The key themes the Elders discussed included an emphasis on the nutritional and cultural benefits of traditional foods; concerns around changing dietary patterns such as the consumption of processed foods and sugar sweetened beverages; and concerns on the time and use of screens. Elders also expressed a desire to help younger generations learn traditional subsistence practices. Conclusions The risk of obesity in Alaska Native children is high and intervention efforts should be grounded in local knowledge and values. The perspectives from Yup’ik and Cup’ik Elders in the Yukon-Kuskokwim Delta area of Alaska provide a better understanding on local views of how to maintain a healthy diet, physical activities, and traditional values.

Aims The aim of this study was to describe a quantitative 3D CT method to measure rotator cuff muscle volume, atrophy, and balance in healthy controls and in three pathological shoulder cohorts. Methods In all, 102 CT scans were included in the analysis: 46 healthy, 21 cuff tear arthropathy (CTA), 18 irreparable rotator cuff tear (IRCT), and 17 primary osteoarthritis (OA). The four rotator cuff muscles were manually segmented and their volume, including intramuscular fat, was calculated. The normalized volume (NV) of each muscle was calculated by dividing muscle volume to the patient’s scapular bone volume. Muscle volume and percentage of muscle atrophy were compared between muscles and between cohorts. Results Rotator cuff muscle volume was significantly decreased in patients with OA, CTA, and IRCT compared to healthy patients (p < 0.0001). Atrophy was comparable for all muscles between CTA, IRCT, and OA patients, except for the supraspinatus, which was significantly more atrophied in CTA and IRCT (p = 0.002). In healthy shoulders, the anterior cuff represented 45% of the entire cuff, while the posterior cuff represented 40%. A similar partition between anterior and posterior cuff was also found in both CTA and IRCT patients. However, in OA patients, the relative volume of the anterior (42%) and posterior cuff (45%) were similar. Conclusion This study shows that rotator cuff muscle volume is significantly decreased in patients with OA, CTA, or IRCT compared to healthy patients, but that only minimal differences can be observed between the different pathological groups. This suggests that the influence of rotator cuff muscle volume and atrophy (including intramuscular fat) as an independent factor of outcome may be overestimated. Cite this article: Bone Jt Open 2021;2(7):552–561.

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe complication of mainly antiresorptive drugs. We evaluated the frequency of dentoalveolar pathologies in patients scheduled for antiresorptive therapy in a ‘real-world’ setting, also including patients with poor oral health potentially requiring tooth extractions and/or other dentoalveolar surgery. This approach is in contrast to the setting of recent randomized trials with restrictive exclusion criteria. Patients & methods: We prospectively included patients suffering from solid tumors with osseous metastases or multiple myeloma. Screening for dentoalveolar pathologies was done prior to initiation of antiresorptive therapy at the specialized MRONJ clinic of the University Hospital for Cranio-Maxillofacial and Oral Surgery, Innsbruck, Austria. Results: 119 subjects could be included. In 76 patients (63.9%), a dental focus was revealed including deep caries (24.4% of patients), chronic apical periodontitis (26.9%), periodontal disease (45.8%), root remnants (16%), jaw cysts (2.5%), partially impacted teeth (5.0%) and peri-implantitis (5.0%). Conclusion: Considering the high number of dentoalveolar pathologies (63.9%), systematic dental focus screening prior to initiation of antiresorptive therapy is of utmost importance to lower the risk for MRONJ.

Background: At our craniofacial center patients are routinely admitted to a regular ward, or floor, rather an intensive care unit (ICU) after uncomplicated craniosynostosis surgery. In this study, we review the safety of our postoperative placement policy, examining the rate of transfer from floor to ICU. Methods: The charts of patients who underwent craniosynostosis surgery from 2009 through 2017 at a single children’s hospital were reviewed. Postoperative hospital courses were characterized as preoperatively-planned ICU admission, perioperatively-planned ICU admission, or primary floor admission. The primary outcome was transfer from floor to ICU. Secondary outcomes included duration of hospitalization. Results: Chart review yielded 420 patients. Three hundred sixty-eight (88%) were admitted directly to the floor and 52 (12.0%) directly to an ICU. Of patients admitted to the floor, 2 (0.5%) were transferred to an ICU. Twenty-four patients with syndromic and 20 patients with multisutural craniosynostosis were admitted to the floor. Only 1 patient from each group (the same patient; 4.2% and 5.0%, respectively), was transferred to an ICU. Thirty-two ICU admissions were preoperatively planned and 20 were perioperatively planned. Reasons for preoperatively planned ICU admission included significant comorbidities and type of surgery. Reasons for perioperatively planned ICU admissions included significant intraoperative adverse events, excessive blood loss, and failure of clearance from the post-anesthesia care unit (PACU). Patients admitted to the ICU had a statistically significant longer mean length of hospitalization (4.8 days vs 2.7 days) than did patients admitted to the floor. Conclusions: Most postoperative craniosynostosis surgery patients—including patients with syndromic and/or multisutural synostosis—are managed safely on the floor at our center. Some patients still need postoperative ICU admission, but are easily identified preoperatively, intraoperatively, or in the PACU. Our findings should be applicable to other large craniofacial centers.

Food insecurity continues to be high despite the increasing use of emergency food assistance. Research shows that food insecurity among food pantry clients is over 50-70%. Despite the high rates, there remains the paradox of people who are both food insecure and obese. Limited research has examined links between obesity, food insecurity, and food pantry clients. This cross-sectional study examined the relationship between food security, weight, and sociodemographic factors of clients at the largest food pantry in Alaska. On-site surveys were completed with 148 clients between February and March of 2018. Descriptive statistics, chi-square models, and a multivariate logistic regression were used to describe participants and determine any associations. Alaska food pantry clients are primarily over 45 years old, work at least part time, and make less than $25,000 per year. A majority of participants (n = 148) were either overweight or obese (69.6%) and food insecure (88.4%). No significant associations were found between weight and food security status. Despite the lack of statistical significance, results help understand pantry clients' demographic, food security, and weight status. Providing emergency food assistance and addressing underlying causes of food insecurity or obesity, such as the ability to access healthy food, are needed first steps.

Background: PITX2 DNA methylation has been shown to predict outcomes in high-risk breast cancer patients after anthracycline-based chemotherapy. To determine its prognostic versus predictive value, the impact of PITX2 DNA methylation on outcomes was studied in an untreated cohort vs. an anthracycline-treated triple-negative breast cancer (TNBC) cohort. Material and Methods: The percent DNA methylation ratio (PMR) of paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time PCR test. Patient samples of routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue and clinical data from 144 TNBC patients of 2 independent cohorts (i.e., 66 untreated patients and 78 patients treated with anthracycline-based chemotherapy) were analyzed. Results: The risk of 5- and 10-year overall survival (OS) increased continuously with rising PITX2 DNA methylation in the anthracycline-treated population, but it increased only slightly during 10-year follow-up time in the untreated patient population. PITX2 DNA methylation with a PMR cutoff of 2 did not show significance for poor vs. good outcomes (OS) in the untreated patient cohort (HR = 1.55; p = 0.259). In contrast, the PITX2 PMR cutoff of 2 identified patients with poor (PMR >2) vs. good (PMR ≤2) outcomes (OS) with statistical significance in the anthracycline-treated cohort (HR = 3.96; p = 0.011). The results in the subgroup of patients who did receive anthracyclines only (no taxanes) confirmed this finding (HR = 5.71; p = 0.014). Conclusion: In this hypothesis-generating study PITX2 DNA methylation demonstrated predominantly predictive value in anthracycline treatment in TNBC patients. The risk of poor outcome (OS) correlates with increasing PITX2 DNA methylation.

Primary aldosteronism is a frequent form of endocrine hypertension caused by aldosterone overproduction from the adrenal cortex. Regulation of aldosterone biosynthesis has been studied in rodents despite differences in adrenal physiology with humans. We, therefore, investigated pig adrenal steroidogenesis, morphology, and transcriptome profiles of the zona glomerulosa (zG) and zona fasciculata in response to activation of the renin-angiotensin-aldosterone system by dietary sodium restriction. Six-week-old pigs were fed a low- or high-sodium diet for 14 days (3 pigs per group, 0.4 g sodium/kg feed versus 6.8 g sodium/kg). Plasma aldosterone concentrations displayed a 43-fold increase ( P =0.011) after 14 days of sodium restriction (day 14 versus day 0). Low dietary sodium caused a 2-fold increase in thickness of the zG ( P CYP11B ( P

OBJECTIVEA standardized guideline for treatment of posthemorrhagic hydrocephalus in premature infants is still missing. Because an early ventriculoperitoneal shunt surgery is avoided due to low body weight and fragility of the patients, the neurosurgical treatment focuses on temporary solutions for CSF diversion as a minimally invasive approach. Neuroendoscopic lavage (NEL) was additionally introduced for early elimination of intraventricular blood components to reduce possible subsequent complications such as shunt dependency, infection, and multiloculated hydrocephalus. The authors report their first experience regarding neurodevelopmental outcome after NEL in this patient cohort.METHODSIn a single-center retrospective cohort study with 45 patients undergoing NEL, the authors measured neurocognitive development at 2 years with the Bayley Scales of Infant Development, 2nd Edition, Mental Developmental Index (BSID II MDI) and graded the ability to walk with the Gross Motor Function Classification System (GMFCS). They further recorded medication with antiepileptic drugs (AEDs) and quantified ventricular and brain volumes by using 3D MRI data sets.RESULTSForty-four patients were alive at 2 years of age. Eight of 27 patients (30%) assessed revealed a fairly normal neurocognitive development (BSID II MDI ≥ 70), 28 of 36 patients (78%) were able to walk independently or with minimal aid (GMFCS 0–2), and 73% did not require AED treatment. Based on MR volume measurements, greater brain volume was positively correlated with BSID II MDI (rs = 0.52, 95% CI 0.08–0.79) and negatively with GMFCS (rs = −0.69, 95% CI −0.85 to −0.42). Based on Bayesian logistic regression, AED treatment, the presence of comorbidities, and also cerebellar pathology could be identified as relevant risk factors for both neurodevelopmental outcomes, increasing the odds more than 2-fold—but with limited precision in estimation.CONCLUSIONSNeuromotor outcome assessment after NEL is comparable to previously published drainage, irrigation, and fibrinolytic therapy (DRIFT) study results. A majority of NEL-treated patients showed independent mobility. Further validation of outcome measurements is warranted in an extended setup, as intended by the prospective international multicenter registry for treatment of posthemorrhagic hydrocephalus (TROPHY).

Background Recent studies have shown variations in glenoid bone density in asymmetric wear patterns but have yet to analyze non-arthritic or concentrically worn glenoids. Questions/Purposes The purpose of this study is to characterize and compare subchondral glenoid bone densities in both non-arthritic and A1, A2, B1, B2 and B3 osteoarthritic glenoids, as well as to assess uniformity in symmetric and asymmetric erosion wear patterns. Methods In all, 150 computerized tomography (CT) scans containing equal numbers of non-arthritic (N), A1, A2, B1, B2 and B3 glenoids were segmented semi-automatically. Each reconstructed glenoid was divided first into anterior and posterior quadrants, and then further subdivided into four quadrants. Volumes of interest (VOI) were defined at depths of 0–2.5 mm (Zone A), 2.5–5 mm (Zone B) and 5–7.5 mm (Zone C). Average bone densities were measured at each VOI depth and in each quadrant. Results Osteoarthritic glenoids had higher mean bone densities than N glenoids. Mean bone densities were uniform amongst all quadrants for N glenoids, but not for osteoarthritic glenoids. In A1 glenoids, the antero-superior quadrant was less dense in Zone C. A2 glenoids had increased bone density measured posteriorly in Zones B and C. In B1 and B2 glenoids, Zones B and C demonstrated increased bone densities of posterior quadrants compared to anterior quadrants. B3 glenoids presented similar results as A1 and A2 glenoids. Cystic changes were more pronounced in anterior quadrants of A2, B1, B2 and B3 glenoids. Conclusion This study demonstrates that osteoarthritic glenoids have greater bone density than non-arthritic glenoids, independent of depth of interest. It also confirms that N glenoids have uniform erosion wear patterns and that B1 and B2 glenoids have irregular wear patterns. It is the first study to reveal that A1, A2 and B3 glenoids, though geometrically symmetrical, have irregular bony densities similar to B2 glenoids. These findings have clinical implications for reaming the glenoid and implant fixation. Level of evidence Basic Science, Anatomy, Imaging.

Short- and mid-term outcomes after massive cuff tear repair are well reported, but there is no documentation of the clinical and structural outcomes at 20 years of follow-up. The hypothesis of the present study was that at 20 years, deterioration of the shoulder would have occurred and led to a substantial number of reoperations.The authors retrospectively recalled all 127 patients operated for massive rotator cuff tears in 1994 at 6 different centers. At the 20-year follow-up, 26 patients died and 35 were lost to follow-up. Thirteen (10.2%) had been reoperated. This left 53 patients for personal clinical assessment. Forty-nine consented to standardized radiographic evaluation for assessment of osteoarthritis, 36 patients underwent magnetic resonance imaging, allowing assessment of tendon healing, atrophy, and fatty infiltration (FI) of the cuff muscles.The final Constant-Murley score (CS) was 68 ± 17.7 (range, 8-91) vs. 44 ± 15.3 (range, 13-74) preoperatively (P.05). The final Subjective Shoulder Value (SSV) was 73% ± 23% (range, 0-100). Retears (Sugaya IV and V) were found in 17 cases (47%). Nine patients (17%) had cuff tear arthropathy (Hamada stage 4). The CS and SSV for the shoulders with FI stages III or IV were significantly inferior (53 ± 19 points and 65% ± 14% respectively) than for those with FI stages 0-II (respectively, 71.6 ± 6 points and 73% ± 4%) (P.05).Twenty years after surgical repair of massive rotator cuff tears, the functional scores remain satisfactory, and the rate of revision is low.

Introduction The use of regional anesthesia techniques continues to expand in a wide variety of surgical procedures as the benefits and safety are increasingly appreciated. Limb-lengthening procedures are often associated with significant postoperative pain and high opioid requirements which may impact patient’s recovery and increase risk of chronic pain and long-term opioid use. Methods The current study retrospectively reviews our experience utilizing a novel peripheral nerve catheter (PNC) protocol for postoperative pain management in patients undergoing elective limb-lengthening procedures. We measure total opioid consumption following 48 hrs in the postoperative period between groups. Results A total of 70 patients were included from which 41 received general plus regional anesthesia (RA) and 29 were managed with general anesthesia alone (NORA). Postoperative pain needs were calculated as morphine equivalents (ME). There were no differences in the demographic characteristics between the groups. Over the first 48 postoperative hours, opioid use was 0.5 mg/kg ME (IQR 0.3, 0.9) in the RA group versus 1.7 mg/kg ME (IQR 1.1, 3.1) in the NORA group (p

The opioid crisis in the United States has been pandemic. As such, anesthesia providers are frequently faced with patients who have a history of opioid abuse or are currently receiving chronic therapy for such disorders. The chronic administration of medications such as buprenorphine-naloxone can impact the choice of perioperative anesthesia and pain control. Furthermore, the postoperative administration of opioids may lead to relapse in patients with a history of opioid abuse. We present a 26-year-old male with a history of opioid abuse on maintenance therapy with buprenorphine-naloxone, who presented for median sternotomy, cardiopulmonary bypass, and pulmonary valve replacement. The perioperative implications of buprenorphine-naloxone and implementation of multimodal analgesia are discussed, along with options to decrease or eliminate the perioperative use of opioids.

Glioblastomas are malignant tumors of the central nervous system hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. The source of the dynamic reorganization within the spatial context of these tumors remains elusive. Here, we characterized glioblastomas in-depth by spatially resolved transcriptomics, metabolomics and proteomics. By deciphering regional shared transcriptional programs across patients, we infer that glioblastomas are organized by spatial segregation of lineage states and adapt to inflammatory or metabolic stimuli reminiscent of reactive transformation in mature astrocytes. Integration of metabolic imaging and image mass cytometry uncovered locoregional tumor-host interdependence resulting in spatially exclusive adaptive transcriptional programs. Inferring copy-number alterations emphasizes a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. A model of glioblastoma stem cells implanted into human and rodent neocortical tissue mimicking various environments confirmed that transcriptional states originate from dynamic adaptation to various environments. Funding: DHH is funded by the Else Kroner-Fresenius Foundation. The work is part of the MEPHISTO project (PI: DHH and DD), funded by BMBF (iGerman Ministry of Education and Research) (project number: 031L0260B). The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) supports the work of AW (project number: SFB 824 C04). VR, KJ and UGH funded by BMBF (Bundes Ministerium fur Bildung und Forschung) (project number: FMT 13GW0230A), US was supported by the Fordergemeinschaft Kinderkrebszentrum Hamburg. We thank Dietmar Pfeifer for here helpful advice. We thank Biorender.com. We thank Stella Maria Carro for her support and the provision of her laboratory facilities and equipment. Declaration of Interest: No potential conflicts of interest were disclosed by the authors. Ethical Approval: The local ethics committee of the University of Freiburg approved the data evaluation, imaging procedures and experimental design (protocol 100020/09 and 472/15_160880).

Asymptomatic anthracosis is the accumulation of black carbon particles in adult human lungs. It is a common occurrence, but the pathophysiologic significance of anthracosis is debatable. Using in situ high mass resolution matrix-assisted laser desorption/ionization (MALDI) fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging analysis, we discovered noxious carbon-bound exogenous compounds, such as polycyclic aromatic hydrocarbons (PAH), tobacco-specific nitrosamines, or aromatic amines, in a series of 330 patients with lung cancer in highly variable and unique patterns. The characteristic nature of carbon-bound exogenous compounds had a strong association with patient outcome, tumor progression, the tumor immune microenvironment, programmed death-ligand 1 (PD-L1) expression, and DNA damage. Spatial correlation network analyses revealed substantial differences in the metabolome of tumor cells compared with tumor stroma depending on carbon-bound exogenous compounds. Overall, the bioactive pool of exogenous compounds is associated with several changes in lung cancer pathophysiology and correlates with patient outcome. Given the high prevalence of anthracosis in the lungs of adult humans, future work should investigate the role of carbon-bound exogenous compounds in lung carcinogenesis and lung cancer therapy. Significance: This study identifies a bioactive pool of carbon-bound exogenous compounds in patient tissues associated with several tumor biological features, contributing to an improved understanding of drivers of lung cancer pathophysiology.

Background EGFR amplification occurs in about 1% of metastatic colorectal cancers (mCRCs) but is not routinely tested as a prognostic or predictive biomarker for patients treated with anti-EGFR monoclonal antibodies. Herein, we aimed to characterize the clinical and molecular landscape of EGFR-amplified mCRC. Methods In this multinational cohort study, we compared clinical data of 62 patients with EGFR-amplified vs 1459 EGFR nonamplified mCRC, as well as comprehensive genomic data of 35 EGFR-amplified vs 439 EGFR nonamplified RAS/BRAF wild-type and microsatellite stable (MSS) tumor samples. All statistical tests were 2-sided. Results EGFR amplification was statistically significantly associated with left primary tumor sidedness and RAS/BRAF wild-type status. All EGFR-amplified tumors were MSS and HER2 nonamplified. Overall, EGFR-amplified samples had higher median fraction of genome altered compared with EGFR-nonamplified, RAS/BRAF wild-type MSS cohort. Patients with EGFR-amplified tumors reported longer overall survival (OS) (median OS = 71.3 months, 95% confidence interval [CI] = 50.7 to not available [NA]) vs EGFR-nonamplified ones (24.0 months; 95% CI = 22.8 to 25.6; hazard ratio [HR] = 0.30, 95% CI = 0.20 to 0.44; P < .001; adjusted HR = 0.46, 95% CI = 0.30 to 0.69; P < .001). In the subgroup of patients with RAS/BRAF wild-type mCRC exposed to anti-EGFR-based therapy, EGFR amplification was again associated with better OS (median OS = 54.0 months, 95% CI = 35.2 to NA, vs 29.1 months, 95% CI = 27.0 to 31.9, respectively; HR = 0.46, 95% CI = 0.28 to 0.76; P = .002). Conclusion Patients with EGFR-amplified mCRC represent a biologically defined subgroup and merit dedicated clinical trials with novel and more potent EGFR-targeting strategies beyond single-agent monoclonal antibodies.

While self-reported Coronavirus Disease 2019 (COVID-19) symptom checklists have been extensively used during the pandemic, they have not been sufficiently validated from a psychometric perspective. We, therefore, used advanced psychometric modelling to explore the construct validity and internal consistency of an online self-reported COVID-19 symptom checklist and suggested adaptations where necessary. Fit to the Rasch model was examined in a sample of 1638 Austrian citizens who completed the checklist on up to 20 days during a lockdown. The items’ fatigue’, ‘headache’ and ‘sneezing’ had the highest likelihood to be affirmed. The longitudinal application of the symptom checklist increased the fit to the Rasch model. The item ‘cough’ showed a significant misfit to the fundamental measurement model and an additional dependency to ‘dry cough/no sputum production’. Several personal factors, such as gender, age group, educational status, COVID-19 test status, comorbidities, immunosuppressive medication, pregnancy and pollen allergy led to systematic differences in the patterns of how symptoms were affirmed. Raw scores’ adjustments ranged from ±0.01 to ±0.25 on the metric scales (0 to 10). Except for some basic adaptations that increases the scale’s construct validity and internal consistency, the present analysis supports the combination of items. More accurate item wordings co-created with laypersons would lead to a common understanding of what is meant by a specific symptom. Adjustments for personal factors and comorbidities would allow for better clinical interpretations of self-reported symptom data.

Background The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC). Methods Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided. Results In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P Conclusions EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.

Background: Total shoulder arthroplasty (TSA) and hemiarthroplasty (HA) have shown good clinical outcomes in primary avascular necrosis of the humeral head (PANHH) both in short and long terms. The purpose of this study was to assess the complications, the clinical and radiological outcomes of shoulder arthroplasty in young patients with PANHH. Methods: One hundred and twenty-seven patients aged under 60 years old and suffering from PANHH were operated with arthroplasty. Patients were assessed clinically and radiographically before surgery with a minimum of 2 years of follow up (FU). Results: HA was performed on 108 patients (85%). Two patients were revised for painful glenoid wear after 2 and 4 years. TSA was performed on 19 patients (15%). Five TSA had to be revised for glenoid loosening (n = 4) or instability (n = 1). Revision rate was 26% with TSA and 2% with HA. There were no significant differences between HA and TSA in terms of clinical outcomes. Conclusions: With a mean FU of 8 years, HA and TSA improved clinical outcomes of patients with PANHH. HA revisions for painful glenoid wear were rare (2%). The revision rate was excessively high with TSA (26%).

Progression to metastatic disease remains the main cause of cancer death. Yet, the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we present MSK-MET, an integrated pan-cancer cohort of tumor genomic and clinical outcome data from more than 25,000 patients. We analyzed this dataset to identify associations between tumor genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma and HR-positive breast ductal carcinoma, but not in others, such as colorectal adenocarcinoma, pancreatic adenocarcinoma and high-grade serous ovarian cancer. We also identified specific somatic alterations associated with increased metastatic burden and specific routes of metastatic spread. Our data offer a unique resource for the investigation of the biological basis for metastatic spread and highlight the crucial role of chromosomal instability in cancer progression.

Graphical abstract The CR780RGD-NPs can easily penetrate the blood-brain-barrier and actively target the brain tumor, where the strong optoacoustic generation from CR780RGD-NPs can be efficiently monitored by multispectral optoacoustic tomography (MSOT)., Contrast enhancement in optoacoustic (photoacoustic) imaging can be achieved with agents that exhibit high absorption cross-sections, high photostability, low quantum yield, low toxicity, and preferential bio-distribution and clearance profiles. Based on advantageous photophysical properties of croconaine dyes, we explored croconaine-based nanoparticles (CR780RGD-NPs) as highly efficient contrast agents for targeted optoacoustic imaging of challenging preclinical tumor targets. Initial characterization of the CR780 dye was followed by modifications using polyethylene glycol and the cancer-targeting c(RGDyC) peptide, resulting in self-assembled ultrasmall particles with long circulation time and active tumor targeting. Preferential bio-distribution was demonstrated in orthotopic mouse brain tumor models by multispectral optoacoustic tomography (MSOT) imaging and histological analysis. Our findings showcase particle accumulation in brain tumors with sustainable strong optoacoustic signals and minimal toxic side effects. This work points to CR780RGD-NPs as a promising optoacoustic contrast agent for potential use in the diagnosis and image-guided resection of brain tumors.

Cases of foreign body ingestion in the forensic literature are mainly described in children or psychiatric patients. Postmortem imaging can detect most foreign bodies, but its sensitivity depends, among other things, on the type of item and its location. In some cases, the ingestion of foreign bodies can remain unnoticed and have serious consequences for the patient. We describe the case of a patient who died in a psychiatric seclusion room with no obvious cause and for whom a forensic autopsy was requested. Further investigations showed the existence of a subdural hematoma associated with a midline shift, secondary to a skull fracture that was considered to be the cause of death. Toxicological analyses identified in blood several drugs, including diazepam (24 ng/mL) and its major metabolite nordazepam (24 ng/mL), propranolol (57 ng/mL), paliperidone (9 ng/mL), and loxapine (620 ng/mL). The forensic autopsy revealed the existence of a gastrointestinal perforation after the ingestion of a plastic teaspoon, which the postmortem CT scan had failed to detect. Although technological advances continue to assist the forensic pathologist in his diagnosis, autopsy still has a leading role in forensic investigations and does not yet seem to be replaceable by imaging techniques alone.

Mammals form scars to quickly seal wounds and ensure survival by an incompletely understood mechanism1–5. Here we show that skin scars originate from prefabricated matrix in the subcutaneous fascia. Fate mapping and live imaging revealed that fascia fibroblasts rise to the skin surface after wounding, dragging their surrounding extracellular jelly-like matrix, including embedded blood vessels, macrophages and peripheral nerves, to form the provisional matrix. Genetic ablation of fascia fibroblasts prevented matrix from homing into wounds and resulted in defective scars, whereas placing an impermeable film beneath the skin—preventing fascia fibroblasts from migrating upwards—led to chronic open wounds. Thus, fascia contains a specialized prefabricated kit of sentry fibroblasts, embedded within a movable sealant, that preassemble together diverse cell types and matrix components needed to heal wounds. Our findings suggest that chronic and excessive skin wounds may be attributed to the mobility of the fascia matrix. Cells that populate scar tissue in mammalian skin migrate to wounds as prefabricated matrix from the subcutaneous fascia, including embedded blood vessels, macrophages and peripheral nerves.

OBJECTIVE To examine associations among objectively measured physical activity (PA), body mass index (BMI), waist circumference (WC), and cardiorespiratory fitness (CRF) in firefighters. METHODS Career firefighters (n = 29; male = 100%) wore accelerometers to assess PA. BMI and WC classified obesity. Each participant completed a stage-graded exercise test to determine maximal oxygen uptake ((Equation is included in full-text article.)). RESULTS Two linear regression models were used to investigate whether PA intensities, step count, BMI, or WC were predictive of "true" (Equation is included in full-text article.). Vigorous physical activity (VPA) was predictive of "true" (Equation is included in full-text article.)(F[1,27] = 7.89, R = 0.23, P

Results of anatomic shoulder arthroplasty for glenohumeral osteoarthritis with severe glenoid retroversion are unpredictable with a high rate of glenoid loosening. Reverse shoulder arthroplasty (RSA) has been suggested as an alternative, with good early results. We sought to confirm this at longer follow-up (minimum 5 years). The study hypothesis was that early results would endure over time.We retrospectively reviewed all RSAs performed in 7 centers from 1998 to 2010. The inclusion criteria were primary glenohumeral osteoarthritis with B1, B2, B3, or C glenoid. Forty-nine shoulders in 45 patients fulfilled the criteria. Bone grafting was performed in 16 cases. Clinical outcomes were evaluated with the Constant score (CS) and shoulder range of motion.The mean total CS increased from 30 preoperatively to 68 points (P.001) with significant improvements in all the subsections of the CS and range of motion. Scapular notching was observed in 20 shoulders (43%), grade 1 in 5 (11%), grade 2 in 7 (15%), grade 3 in 5 (11%), and grade 4 in 3 (6%). The glenoid bone graft healed in all the shoulders. Partial inferior lysis of the bone graft was present in 8 cases (50%). Scapular notching and glenoid bone graft resorption had no influence on the CS (P = .147 and P = .798).RSA for the treatment of primary glenohumeral osteoarthritis in patients with posterior glenoid deficiency and humeral subluxation without rotator cuff insufficiency resulted in excellent clinical outcomes at a minimum of 5 years of follow-up.

Purpose Outcomes of open or arthroscopic rotator cuff repairs are well reported in the literature. The purpose of the study was to evaluate the prevalence and clinical impact of osteoarthritis 20 years following rotator cuff repair. The hypothesis was that, at long follow-up, most shoulders would have developed gleno-humeral osteoarthritis. Methods The authors retrospectively recalled all 322 patients, operated for rotator cuff tears in 1994 at 6 different centres, for clinical and radiographic assessment. At 20 years of follow-up, 24 were re-operated (5 arthroplasty) and 53.4% were lost to follow-up. This left 126 patients, had been clinically assessed, had Magnetic Resonance Images (MRI) that allowed anatomic assessment of tendon healing (Sugaya), fatty infiltration (Goutallier), and X rays in order to analyse arthritis without head migration (Samilson) and with head migration (Hamada and Fukuda). Only patients with complete data were selected. Results Mean aged was 52.3 years (25.3–68.6) at index operation. The Constant score was 45.3 ± 19.6 preoperatively to 67.4 ± 18.7 points at 20 years. The SSV was 73.5 ± 21 postoperatively. The rate of osteoarthritis was 29%. Osteoarthritis was associated with a significant inferior Constant score compared to the non-arthritic group (61 versus 71 points, p = 0.02), mainly due to a significant lower strength (5.4 versus 8.7 points, p = 0.007). Massive rotator cuff tears were significantly associated with a higher rate of osteoarthritis. Only 4,8% patients after cuff repear needed a reverse shoulder arthroplasty. Significantly less osteoarthritis was observed when the rotator cuff repair remained intact. Suprasupinatus retear had a significant influence on fatty infiltration of the infrasupinatus muscle and on the progression towards osteoarthritis. Conclusion Twenty years after open rotator cuff repair, the rate of osteoarthritis was 29%. Massive rotator cuff tears were significantly associated with a higher rate of osteoarthritis. Less osteoarthritis was observed when suprasupinatus healed. Level of evidence IV.

The main complication of volar locking plates for distal radius fractures is flexor tendon rupture. The flexor pollicis longus (FPL) is the most commonly ruptured. Repair of the pronator quadratus (PQ) is one of the ways to prevent tendon rupture. The main purpose of this series was to evaluate the role of PQ repair after volar plating to prevent flexor tendon rupture using ultrasound (US). This work was a mono-operator prospective series of 20 consecutive patients with volar locking plates for distal radius fracture between September 2014 and May 2015. The PQ was repaired in all patients. A clinical, ultrasound, and perioperative evaluation of the flexor tendon was performed by this same surgeon. There was no flexor tendon rupture or tenosynovitis. There were no type A cases, which are characterized by contact between the plate and the FPL, and mostly type C cases, which are characterized by no contact between the plate and the FPL on US imaging. The suture of the PQ was sustainable over time when we removed the plate. Pronator quadratus repair is one of the ways to prevent flexor tendon rupture after volar plating. The outward-running suture is an effective technique for repairing the PQ. Ultrasound may be helpful during follow-up to detect asymptomatic flexor tendon irritation.

Purpose To investigate a possible influence of repetitive micro-traumata on the ovaries in the course of oocyte retrieval during IVF/ICSI treatment on serum anti-Müllerian hormone (AMH) levels. Methods The study included retrospectively collected data from women who underwent three or more consecutive IVF/ICSI treatments between 2007 and 2017. The primary endpoint of the study was to evaluate changes in serum AMH levels on cycle days 1–3 during the course of repetitive IVF/ICSI treatments. Results A total of 125 patients were included in this study. Median AMH levels before the first, second and third IVF/ICSI cycles were 3.8 ng/mL (IQR 1.8–7.1), 3.3 ng/mL (IQR 1.8–6.1) and 3.0 ng/mL (IQR 1.6–5.3), respectively (p = n.s.). In patients who underwent IVF/ICSI due to polycystic ovary syndrome (PCOS), we found a significant decrease in AMH serum levels between the first [AMH 9.7 ng/mL (IQR 7.4–14.4)] and the third [AMH 5.3 ng/mL (IQR 3.3–10.4)] IVF/ICSI cycles (p = 0.026). When performing a generalized linear model, we found PCOS to be an independent predictor for serum AMH decrease during the course of three oocyte retrievals (p

Background Scapular fractures after reverse shoulder arthroplasty (RSA) are an increasingly reported complication. Information is missing regarding midterm to long-term follow-up consequences. The aim of this study was to determine the rate of scapular fracture (acromial base and spine) after Grammont-style RSA and to report functional and radiographic results of patients with a minimum 5-year follow-up. Materials and methods We retrospectively reviewed 1953 Grammont-style RSAs in 1745 patients in a multicenter study. Of these, 953 patients (1035 RSAs) had minimum 5-year follow-up for functional and radiographic assessment (anteroposterior and scapular Y views. Results Twenty-six patients (1.3%) had sustained a scapular fracture; of these, 19 (10 acromial base and 9 spine fractures) had minimum 5-year follow-up and were reviewed at a mean follow-up of 97 months. Three patients (15.8%) were diagnosed at the last follow-up after an undiagnosed fracture. There were 3 traumatic cases (15.8%) and 13 (68.4%) without antecedent trauma. These 16 patients underwent nonoperative treatment. The fracture was healed in 8 (4 acromion and 4 spine). The average active forward elevation was 109° (range, 50°-170°), and the Constant score was 47.0 points (range, 8-81 points). Conclusions Scapular fractures after Grammont-style RSAs are rare (1.3%) but remain a concern. These fractures occur mainly in the early postoperative 6 months. Immobilization with an abduction splint frequently resulted in nonunion or malunion. Final functional outcomes are poor regardless of acromial or spine fracture compared with primary RSA without fracture.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by lung epithelial cell injury, increased (myo) fibroblast activation, and extracellular matrix deposition. Extracellular vesicles (EVs) regulate intercellular communication by carrying a variety of signaling mediators, including WNT (wingless/integrated) proteins. The relevance of EVs in pulmonary fibrosis and their potential contribution to disease pathogenesis, however, remain unexplored.Objectives: To characterize EVs and study the role of EV-bound WNT signaling in IPF.Methods: We isolated EVs from BAL fluid (BALF) from experimental lung fibrosis as well as samples from IPF, non-IPF interstitial lung disease (ILD), non-ILD, and healthy volunteers from two independent cohorts. EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. Primary human lung fibroblasts (phLFs) were used for EV isolation and analyzed by metabolic activity assays, cell counting, quantitative PCR, and Western blotting upon WNT gain- and loss-of-function studies.Measurements and Main Results: We found increased EVs, particularly exosomes, in BALF from experimental lung fibrosis as well as from patients with IPF. WNT5A was secreted on EVs in lung fibrosis and induced by transforming growth factor-beta in primary human lung fibroblasts. The phLF-derived EVs induced phLF proliferation, which was attenuated by WNT5A silencing and antibody-mediated inhibition and required intact EV structure. Similarly, EVs from IPF BALF induced phLF proliferation, which was mediated by WNT5A.Conclusions: Increased EVs function as carriers for signaling mediators, such as WNT5A, in IPF and thus contribute to disease pathogenesis. Characterization of EV secretion and composition may lead to novel approaches to diagnose and develop treatments for pulmonary fibrosis.

Scapular stress fractures after reverse shoulder arthroplasty (RSA) are a potentially serious complication with modern lateralized and onlay implants. The aim of this study was to report the scapular spine stress fracture rate after RSA with an onlay, 145° humeral stem, analyzing potential fracture risk factors and clinical outcomes in a large cohort of patients.A consecutive series of 485 RSAs were implanted with the Aequalis Ascend Flex stem. Data collection included preoperative and postoperative clinical and radiographic assessment findings (rotator cuff Goutallier grade; Hamada, Walch, and Favard classifications; range of motion; Constant score) and perioperative data. Patients with a scapular spine fracture following RSA were matched with nonfracture control patients, and preoperative variables were tested to determine whether they were predictive of a scapular spine fracture.A scapular spine fracture following RSA occurred in 21 patients (4.3%), with a mean time to diagnosis of 8.6 months (range, 1-34 months). No preoperative factor was found to be a significant predictor of scapular spine fracture. Both groups showed significant improvements in active mobility measurements and Constant scores from preoperatively to final follow-up (P .001). The control group scored significantly better than the scapular spine fracture group regarding the Constant score and forward flexion.Scapular spine fractures have shown an increased prevalence after onlay-design RSA. This series was not able to link any clear risk factors. Functional results are limited, regardless of the fracture management.

Background MOG-IgG-associated disease (MOGAD) in adults typically presents as a monophasic or relapsing optic, spinal, or opticospinal neuroinflammatory syndrome. Current recommendations discourage testing for MOG-IgG in patients with clinical or paraclinical findings more typical of MS, or in patients with a progressive clinical course. However, this approach may impede identification of the full phenotypic spectrum of this recently described disorder. Methods We retrospectively reviewed charts of 39 MOG-IgG-seropositive patients from two Ohio-based neuroimmunology centers to identify unusual disease patterns. Those with a progressive course were included in this case series. Results We describe five cases of progressive myelopathy associated with MOG-IgG. Most patients had features suggestive of MS, including typical MRI and cerebrospinal fluid findings. However, MOG-IgG positive patients with progressive myelopathy showed poor response to MS disease modifying therapy and better response to intravenous immunoglobulins similar to previous reports on MOGAD patients. Conclusion MOG-IgG-seropositive patients may present with progressive myelopathy and may have a clinical and radiologic phenotype suggestive of primary progressive or secondary progressive MS, or progressive solitary sclerosis. MOG-IgG testing should be considered in patients with progressive myelopathy, especially if clinically worsening on MS therapy.

BACKGROUND AND AIM: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. APPROACH AND RESULTS: This bi-institutional study of patients with confirmed iCCA (n = 412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain–containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1–associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08–3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95–5.94; P < 0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P < 0.001]; regional lymph node metastases [P < 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97–2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high-risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8–73.5) or high-risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. CONCLUSIONS: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.

Glioblastomas are highly malignant tumors of the central nervous system. Evidence suggests that these tumors display large intra- and inter-patient heterogeneity hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. However, the source for dynamic reorganization of cellular states within their spatial context remains elusive. Here, we in-depth characterized glioblastomas by spatially resolved transcriptomics, metabolomics and proteomics. By deciphering exclusive and shared transcriptional programs across patients, we inferred that glioblastomas develop along defined neural lineages and adapt to inflammatory or metabolic stimuli reminiscent of reactive transformation in mature astrocytes. Metabolic profiling and imaging mass cytometry supported the assumption that tumor heterogeneity is dictated by microenvironmental alterations. Analysis of copy number variation (CNV) revealed a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. Deconvolution of age-dependent transcriptional programs in malignant and non-malignant specimens identified the aging environment as the major driver of inflammatory transformation in GBM, suggesting that tumor cells adopt transcriptional programs similar to inflammatory transformation in astrocytes. Glioblastoma stem cells implanted into human neocortical slices of varying age levels, independently confirmed that the ageing environment dynamically shapes the intratumoral heterogeneity towards reactive transcriptional programs. Our findings provide insights into the spatial architecture of glioblastoma, suggesting that both locally inherent tumor as well as global alterations of the tumor microenvironment shape its transcriptional heterogeneity. Global age-related inflammation in the human brain is driving distinct transcriptional transformation in glioblastomas, which requires an adjustment of the currently prevailing glioma models.

Background: The Walch type B pattern of glenohumeral osteoarthritis is characterized by posterior humeral head subluxation (PHHS). At present, it is unknown whether the percentage of subluxation measured on axillary radiographs is consistent with measurements on 2-dimensional (2D) axial or 3-dimensional (3D) volumetric computed tomography (CT). The purpose of this study was to evaluate PHHS across imaging modalities (radiographs, 2D CT, and 3D CT). Methods: A cohort of 30 patients with Walch type B shoulders underwent radiography and standardized CT scans. The cohort comprised 10 type B1, 10 type B2, and 10 type B3 glenoids. PHHS was measured using the scapulohumeral subluxation method on axillary radiographs and 2D CT. On 3D CT, PHHS was measured volumetrically. PHHS was statistically compared between imaging modalities, with P ≤ .05 considered significant. Results: The mean PHHS value for the entire group was 69% ± 24% on radiographs, 65% ± 23% with 2D CT, and 74% ± 24% with 3D volumetric CT. PHHS as measured on complete axillary radiographs was not significantly different than that measured on 2D CT (P = .941). Additionally, PHHS on 3D volumetric CT was 9.5% greater than that on 2D CT (P < .001). There were no significant differences in PHHS between the type B1, B2, and B3 groups with 2D or 3D CT measurement techniques (P > .102). Conclusion: Significant differences in PHHS were found between measurement techniques (P < .035). A 9.5% difference in PHHS between 2D and 3D CT can be mostly accounted for by the linear (2D) vs. volumetric (3D) measurement techniques (a linear 80% PHHS value is mathematically equivalent to a volumetric PHHS value of 89.6%). Surgeons should be aware that subluxation values and therefore thresholds vary across different imaging modalities and measurement techniques.

Hair analysis is very useful for toxicological investigations since, by providing a wider detection window, it gives the possibility to perform a retrospective study on the historical consumption of a substance. Unfortunately, there are no data available for hair concentrations in metformin-related deaths. In this study, the authors present 2 cases of fatal metformin intoxication in which, for the first time, hair analysis was performed using a specific GC–MS/MS method. Metformin was tested positive in femoral blood (112.3 mg/L and 64.7 mg/L respectively) and cardiac blood (226.9 and 203.2 mg/L) of the two subjects. For case 1, other samples were also tested positive, including vitreous humor (31.1 mg/L) and gastric contents (773.5 mg/L). In case 2, metformin was measured at 844.9 mg/L in urine. Metformin hair concentrations were 28.3–44.8 and 22.5 ng/mg for both cases, respectively. The concentrations found in the 2 fatal cases are clearly higher than those obtained in a previous study with subjects under treatment (0.3–3.8 ng/mg) or those found in 3 post-mortem cases where metformin death was excluded (0.6–1.4 ng/mg). Excessive sweating during the agonal phase due to fatal hypoglycemia could explain these elevated concentrations as sweat can have contaminated the hair.

Freezing of gait (FOG) in Parkinson’s disease (PD) occurs frequently in situations with high environmental complexity. The supplementary motor cortex (SMC) is regarded as a major network node that exerts cortical input for motor control in these situations. We aimed at assessing the impact of single-session (excitatory) intermittent theta burst stimulation (iTBS) of the SMC on established walking during FOG provoking situations such as passing through narrow spaces and turning for directional changes. Twelve PD patients with FOG underwent two visits in the off-medication state with either iTBS or sham stimulation. At each visit, spatiotemporal gait parameters were measured during walking without obstacles and in FOG-provoking situations before and after stimulation. When patients passed through narrow spaces, decreased stride time along with increased stride length and walking speed (i.e., improved gait) was observed after both sham stimulation and iTBS. These effects, particularly on stride time, were attenuated by real iTBS. During turning, iTBS resulted in decreased stride time along with unchanged stride length, a constellation compatible with increased stepping frequency. The observed iTBS effects are regarded as relative gait deterioration. We conclude that iTBS over the SMC increases stepping frequency in PD patients with FOG, particularly in FOG provoking situations.

BackgroundIn contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity.Methods and resultsCLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009–2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure.Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest.ConclusionIn patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes.ClinicalTrials identifierISRCTN43070564

BackgroundOutpatient COVID-19 has been insufficiently characterized.ObjectiveTo determine the progression of disease and subsequent determinants of hospitalization.DesignA prospective outpatient cohort.SettingOutpatients were recruited by phone between April 21 to June 23, 2020 after receiving outpatient or emergency department testing within a large health network in Maryland, USA.ParticipantsOutpatient adults with positive RT-PCR results for SARS-CoV-2.MeasurementsSymptoms, portable pulse oximeter oxygen saturation (SaO2), heart rate, and temperature were collected by participants on days 0, 3, 7, 14, 21, and 28 after enrollment. Baseline demographics, comorbid conditions were evaluated for risk of subsequent hospitalization using negative binomial, logistic, and random effects logistic regression.ResultsAmong 118 SARS-CoV-2 infected outpatients, the median age was 56.0 years (IQR, 50.0 to 63.0) and 50 (42.4%) were male. Among those reporting active symptoms, the most common symptoms during the first week since symptom onset included weakness/fatigue (67.3%), cough (58.0%), headache (43.8%), and sore throat (34.8%). Participants returned to their usual health a median of 20 days (IQR, 13 to 38) from the symptom onset, and only 65.5% of respondents were at their usual health during the fourth week of illness. Over 28 days, 10.9% presented to the emergency department and 7.6% required hospitalization. Individuals at the same duration of illness had a 6.1 times increased adjusted odds of subsequent hospitalization per every percent decrease in home SaO2(95% confidence interval [CI]: 1.41 to 31.23, p=0.02).LimitationsSeverity and duration of illness may differ in a younger population.ConclusionSymptoms often persisted but uncommonly progressed to hospitalization. Home SaO2might be an important adjunctive tool to identify progression of COVID-19.RegistrationClinicaltrials.gov NCT number:NCT04496466Funding SourceThe Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases Discovery Program and the Johns Hopkins University School of Medicine

Three-dimensional (3D) geometry of the normal glenohumeral bone anatomy and relations is poorly documented. Our aims were (1) to determine the 3D geometry of the normal glenohumeral joint (GHJ) with reference to the scapular body plane and (2) to identify spatial correlations between the orientation and direction of the humeral head and the glenoid.Computed tomographies (CTs) of the normal, noninjured GHJ were collected from patients who had undergone CTs in the setting of (1) polytrauma, (2) traumatic head injury, (3) chronic acromioclavicular joint dislocations, and (4) unilateral trauma with a contralateral normal shoulder. We performed 3D segmentation and measurements with a fully automatic software (Glenosys; Imascap). Measurements were made in reference to the scapular body plane and its transverse axis. Geometric measurements included version, inclination, direction, orientation, best-fit sphere radius (BFSR), humeral subluxation, critical shoulder angle, reverse shoulder angle, glenoid area, and glenohumeral distance. Statistical correlations were sought between glenoid and humeral 3D measurements (Pearson correlation).A total of 122 normal GHJs (64 men, 58 women, age: 52 ± 17 years) were studied. The glenoid BFSR was always larger than the humerus BFSR (constant factor of 1.5, standard deviation = 0.2). The mean glenoid version and inclination were -6° ± 4° and 7° ± 5°, respectively. Men and women were found to have significantly different values for inclination (6° vs. 9°, P = .02), but not for version. Humeral subluxation was 59% ± 7%, with a linear correlation with glenoid retroversion (r = -0.70, P.001) regardless of age. There was a significant and linear correlation between glenoid and humeral orientation and direction (r = 0.72 and r = 0.70, P.001).The 3D geometry of the glenoid and humeral head present distinct limits in normal shoulders that can be set as references in daily practice: version and inclination are -6° and 7°, respectively, and humeral posterior subluxation is 59%; interindividual variations, regardless of the size, are relative to the scapular plane. There exists a strong correlation between the position of the humeral head and the glenoid orientation and direction.

Objective Within the past decade, important genetic drivers of pheochromocytoma and paraganglioma (PPGLs) development have been identified. The pathophysiological mechanism that translates these alterations into functional autonomy and potentially malignant behavior has not been elucidated in detail. Here we used MALDI-mass spectrometry imaging (MALDI-MSI) of formalin-fixed paraffin-embedded tissue specimens to comprehensively characterize the metabolic profiles of PPGLs. Design and methods MALDI-MSI was conducted in 344 PPGLs and results correlated with genetic and phenotypic information. We experimentally silenced genetic drivers by siRNA in PC12 cells to confirm their metabolic impact in vitro. Results Tissue abundance of kynurenine pathway metabolites such as xanthurenic acid was significantly lower (P = 2.35E−09) in the pseudohypoxia pathway cluster 1 compared to PPGLs of the kinase-driven PPGLs cluster 2. Lower abundance of xanthurenic acid was associated with shorter metastasis-free survival (log-rank tests P = 7.96E−06) and identified as a risk factor for metastasis independent of the genetic status (hazard ratio, 32.6, P = 0.002). Knockdown of Sdhb and Vhl in an in vitro model demonstrated that inositol metabolism and sialic acids were similarly modulated as in tumors of the respective cluster. Conclusions The present study has identified distinct tissue metabolomic profiles of PPGLs in relation to tumor genotypes. In addition, we revealed significantly altered metabolites in the kynurenine pathway in metastatic PPGLs, which can aid in the prediction of its malignant potential. However, further validation studies will be required to confirm our findings.

Purpose: To delineate recurrent oncogenic driver alterations and dysregulated pathways in esophageal adenocarcinoma and to assess their prognostic value. Experimental Design: We analyzed a large cohort of patients with lower esophageal and junctional adenocarcinoma, prospectively sequenced by MSK-IMPACT with high-quality clinical annotation. Patients were subdivided according to treatment intent, curative versus palliative, which closely mirrored clinical staging. Genomic features, alterations, and pathways were examined for association with overall survival using Cox proportional hazard models, adjusted for relevant clinicopathologic factors knowable at the time of diagnosis. Results: Analysis of 487 patients revealed 16 oncogenic driver alterations, mostly amplifications, present in ≥5% of patients. Patients in the palliative-intent cohort, compared with those in the curative-intent cohort, were more likely to have metastatic disease, ERBB2 amplifications, Cell-cycle and RTK–RAS pathway alterations, as well as a higher fraction of genome altered and rate of whole-genome doubling. In multivariable analyses, CDKN2A alterations, SMAD4 alterations, KRAS amplifications, Cell-cycle and TGFβ pathways, and overall number of oncogenic drivers were independently associated with worse overall survival. ERBB2 amplification was associated with improved survival, presumably due to trastuzumab therapy. Conclusions: Our study suggests that higher levels of genomic instability are associated with more advanced disease in esophageal adenocarcinoma. Furthermore, CDKN2A, KRAS, and SMAD4 represent prognostic biomarkers, given their strong association with poor survival.

Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr–Igf1r–Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications., A combination of single-cell approaches, lineage tracing and metabolomics is used to characterize the changes to intestinal stem cell function in the small intestine that underlie intestinal maladaptation in mice fed an obesogenic diet.

ImportanceThe effects of SARS-CoV-2 infection on immune responses during pregnancy have not been systematically evaluated.ObjectiveTo assess the impact of SARS-CoV-2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to SARS-CoV-2 among pregnant and non-pregnant women.DesignImmune responses to SARS-CoV-2 were analyzed using samples from pregnant and non-pregnant women who had either tested positive or negative for SARS-CoV-2. We measured, proinflammatory and placental cytokine mRNAs, neonatal Fc receptor (FcRn) receptor expression, and tetanus antibody transfer in maternal and cord blood samples. Additionally, we measured anti-spike (S) IgG, anti-S-receptor binding domain (RBD) IgG, and neutralizing antibody (nAb) responses to SARS-CoV-2 in serum or plasma collected from non-pregnant women, pregnant women, and cord blood.SettingJohns Hopkins Hospital (JHH)ParticipantsPregnant women were recruited through JHH outpatient obstetric clinics and the JHH Labor & Delivery unit. Non-pregnant women were recruited after receiving outpatient SARS-CoV-2 testing within Johns Hopkins Health System, USA. Adult non-pregnant women with positive RT-PCR results for SARS-CoV-2, within the age range of 18-48 years, were included in the study.ExposuresSARS-CoV-2Main Outcomes and MeasuresParticipant demographic characteristics, antibody titers, cytokine mRNA expression, and FcRn receptor expression.ResultsSARS-COV-2 positive pregnant women expressed more IL1β, but not IL6, in blood samples collected within 14 days versus > 14 days after a confirmed SARS-CoV-2 test, with similar patterns observed in the fetal side of placentas, particularly among asymptomatic pregnant women. Pregnant women with confirmed SARS-CoV-2 infection also had reduced anti-S-RBD IgG titers and were less likely to have detectable nAb as compared with non-pregnant women. Although SARS-CoV-2 infection did not disrupt FcRn expression in the placenta, maternal transfer of nAb was inhibited by SARS-CoV-2 infection during pregnancy.Conclusions and RelevanceSARS-CoV-2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of COVID-19 therapeutics in pregnancy. The long-term implications of placental inflammation for neonatal health also requires greater consideration.

Background: Cuff tear arthropathy (CTA) is characterized by superior migration of the humeral head with superior erosion of the glenoid. Rarely, humeral head migration can be anteroinferior with associated anterior erosion of the glenoid, a pattern described by Favard as the type E4 glenoid. The purpose of this retrospective imaging study was to analyze the 2D and 3D characteristics of the E4 glenoid. Methods: A shoulder arthroplasty database of 258 cuff tear arthropathies was examined to identify patients with an E4 type deformity. This resulted in a study cohort of 15 females and 2 males with an average age of 75 years. All patients had radiographs and CT scans available for analysis. CT-scan DICOM (Digital Imaging and Communications in Medicine) data were uploaded to a validated three-dimensional (3D) imaging software. Muscle fatty infiltration, glenoid measurements (anteversion, inclination), and humeral head subluxation according to the scapular plane were determined. Results: The mean anteversion and inclination of the E4 cohort were 32&deg, &plusmn, 14&deg, and &minus, 5&deg, 2, respectively. The mean anterior subluxation was 19% &plusmn, 16%. All cases had severe grade 3 or 4 fatty infiltration of the infraspinatus, whereas only 65% had grade 3 or 4 subscapularis fatty infiltration. A significant correlation existed between glenoid anteversion and humeral head subluxation (p &lt, 0.001), but no correlation was found with muscle fatty infiltration. The CT analysis demonstrated an acquired erosive biconcave morphology in 11 patients (65%) and monoconcavity in 6 patients (35%). Conclusion: The E4 type glenoid deformity in cuff tear arthropathy is characterized by an anterior erosion and anteversion associated with anterior subluxation of the humeral head.

Highlights • Clusters of decreased grey matter were associated with lateral flexion of the trunk. • Robust clusters were found in the posterior parietal cortex and the thalamus. • A tilt of the SVV correlated with the degree of trunk deviation. • Grey matter values from the thalamic cluster correlated with the SVV estimates., Background Disruption of central networks, particularly of those responsible for integrating multimodal afferents in a spatial reference frame, were proposed in the pathophysiology of lateral trunk flexion in Parkinson’s disease (PD). Knowledge about the underlying neuroanatomical structures is limited. Objective To investigate if decreased focal grey matter (GM) is associated with trunk flexion to the side and if the revealed GM clusters correlate with a disturbed perception of verticality in PD. Methods 37 PD patients with and without lateral trunk flexion were recruited. Standardized photos were taken from each patient and trunk orientation was measured by a blinded rater. Voxel-based morphometry (VBM) was used to detect associated clusters of decreased GM. The subjective visual vertical (SVV) was assessed as a marker for perception of verticality and SVV estimates were correlated with GM clusters. Results VBM revealed clusters of decreased GM in the right posterior parietal cortex and in the right thalamus were associated with lateral trunk flexion. The SVV correlated with the extent of trunk flexion, and the side of the SVV tilt correlated with the side of trunk flexion. GM values from the thalamus correlated with the SVV estimates. Conclusions We report an association between neurodegenerative changes within the posterior parietal cortex and the thalamus and lateral trunk flexion in PD. These brain structures are part of a network proposed to be engaged in postural control and spatial self-perception. Disturbed perception of verticality points to a shifted egocentric spatial reference as an important pathophysiological feature.

Shigella spp. are the causative agents of bacillary dysentery or shigellosis, mainly in children living in developing countries. The study of Shigella entire life cycle in vivo and the evaluation of vaccine candidates’ protection efficacy have been hampered by the lack of a suitable animal model of infection (1). None of the ones evaluated so far (mouse, rabbit, guinea pig) allows to recapitulate shigellosis symptoms upon Shigella oral challenge. Historical reports suggest that dysentery and scurvy are both metabolic diseases associated with ascorbate-deficiency. Mammals which are susceptible to Shigella infection (humans, non-human primates and guinea pigs) are the lonely ones which are unable to synthesize ascorbate. We optimized a low-ascorbate diet to induce moderate ascorbate-deficiency but not scurvy in guinea pigs (Ascplasma conc.=1.6 μM vs 36 μM with optimal ascorbate supply). We demonstrated that moderate ascorbate-deficiency increases shigellosis severity during extended period of time (up to 48h) with all strains tested (Shigella flexneri 5a and 2a, Shigella sonnei). At late time-points, a massive influx of neutrophils was observed both within the disrupted colonic mucosa and in the luminal compartment, although Shigella remains able to disseminate deep into the organ to reach the sub-mucosal layer and the bloodstream. This new model of shigellosis opens new doors for the study both of Shigella infection strategy and innate and adaptive immune responses to Shigella infection. It may be also of a great interest to study the virulence of other pathogen for which no suitable animal model of infection is available (Vibrio cholerae, Yersinia pestis, Mycobacterium tuberculosis or Campylobacter jejuni, among others).SignificanceThe study of Shigella virulence cycle in vivo has been hampered by the lack of a suitable animal model, which would allow the colonic mucosa infection upon oral challenge. Based on historical reports and physiological aspects, it was suggested that ascorbate-deficiency may stand as a new dysentery risk-factor. To test this hypothesis, we set up a new ascorbate-deficient guinea pig model and demonstrated for the first time that the Shigella infectious process occurred for extended period of time (up to 48h) and demonstrated that shigellosis severity was higher in ascorbate-deficient animal. Ascorbate-deficient guinea pig model of infection may be used to assess the virulence of other pathogens for which no suitable animal model of infection is still lacking.

Objectives California is experiencing a syphilis and congenital syphilis epidemic, and many persons diagnosed with syphilis report a history of recent incarceration or sexual contact with a person who has recently been incarcerated. Fresno County’s local health department and jail collaborated to implement a routine syphilis screening policy for male adults aged 18-30 and female adults aged 18-35 booked into the facility. We evaluated syphilis screening, case finding, and treatment rates after implementation of the new policy. Methods We linked jail census and laboratory data to syphilis surveillance data to assess screening coverage, positivity, and treatment rates for age-eligible persons who were booked into Fresno County Jail from April 1, 2016, through December 31, 2017. Results Of 24 045 age-eligible persons who were booked into the jail during the study period, 5897 (24.5%) were female and 18 148 (75.5%) were male. Of 7144 (29.7%) persons who were screened for syphilis, 611 (8.6%) had a reactive rapid plasma reagin blood test result (16.4% [253 of 1546] of female adults; 6.4% [358 of 5598] of male adults) and 238 (3.3%) were newly diagnosed with syphilis, as confirmed by matching to the surveillance system (6.9% [106 of 1546] of female adults; 2.4% [132 of 5598] of male adults). Of persons identified with syphilis, 51.7% (n = 123 of 238) received adequate recommended treatment (59.4% [63 of 106] of female adults; 45.5% [60 of 132] of male adults). Conclusions The age-based syphilis screening policy adopted in this jail yielded high positivity, including newly identified syphilis infections among female adults of childbearing age. The targeted screening policy was formalized in the county-negotiated contract with the jail’s private correctional health care company in 2018—a strategy that can be replicated.