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Bariatric surgery has expanded tremendously internationally over the past decade. In recent years, bariatric surgery has experienced a significant growth in Germany. However, the question arises as to whether this development is in line with international developments or whether there is still room for improvement that could be challenged. 63,990 primary bariatric procedures recorded in the German Bariatric Surgery Registry (GBSR) were analyzed from 2005 to April 2021. The distribution of procedures according to different variants was analyzed and presented. In the last 16 years, 17 different procedures have been performed. The most common surgical procedure was sleeve gastrectomy (SG), followed by Roux-Y gastric bypass (RYGB) (42%). Adjustable gastric banding (AGB) has declined over time, from 23.5% in the first 5 years to 0.2% in recent years. In comparison, omega-loop gastric bypass has increased over the past 5 years (from 0.4% in the first 5 years to 5.9% in the last 5 years). Laparoscopic procedures have accounted for 96.4% of all bariatric surgeries in recent years. The frequency of some procedures has decreased and some bariatric procedures have lost significance. Overall, bariatric surgery in Germany has developed positively compared to the international trend. Nevertheless, there is one area that needs to be optimized: the development of robotic bariatric surgery, which crawls behind in Germany compared to other countries. To establish the technology in bariatric surgery in a timely manner, a balance must be found between cost neutrality and patient-oriented applications.

This study investigates the outcome of one-stage and two-stage Roux-Y gastric bypass (RYGB) as a revision procedure after failed adjustable gastric banding (AGB).Data of patients who underwent a one-stage RYGB (OS-RYGB) or a two-stage RYGB (TS-RYGB) revision procedure after failing AGB between 2005 and 2019 were analyzed. Outcome criteria were perioperative complications, operating time, change in weight and BMI, and remission of comorbidities at 1-year follow-up.Data from 230 patients after OS-RYGB and 197 after TS-RYGB were analyzed. The total perioperative complication rates were not significantly different between the two groups (overall p 5%). In the category of other complications, there was a significant difference between the two groups, with a lower rate in TS-RYGB than in OS-RYGB (p = 0.020). Wound infections occurred more frequently after TS-RYGB than after OS-RYGB (p = 0.015). Mean operating time differed significantly between the two groups (OS-RYGB (149.9 min) and TS-RYGB 191 min; p 0.001). The change in hypertension was significantly higher in OS-RYGB (37.9 vs. 21.1%; p = 0.007). Other comorbidities showed no significant change within 1 year after surgery. Regarding the change in BMI, %TWL, and %EWL, there were no significant benefits for either group (p = 0.574, 0.762, and 0.378, respectively).Removing a failed AGB using the OS- or TS-RYGB is safe and feasible. The decision between OS- and TS-RYGB is still individual and depends on the patient's general condition, the desired goal of the procedure, and the personal competence of the surgeon. Further studies are needed to clarify long-term outcome and effect of both procedures.

Since the start of the SARS‐CoV‐2 pandemic, it has been difficult to differentiate between SARS‐CoV‐2 re‐infection and prolonged RNA shedding. In this report, we identified patients with positive RT‐PCR results for SARS‐CoV‐2 ≥70 days apart. Clinical and laboratory data were collected and criteria were applied to discern whether the presentation was consistent with SARS‐CoV‐2 re‐infection or prolonged viral RNA shedding. Eleven individuals met the initial testing criteria, of which, seven met at least one criteria for re‐infection and four were consistent with prolonged RNA shedding. These data demonstrate the need for criteria to differentiate SARS‐CoV‐2 re‐infection from prolonged RNA shedding.

Central nervous system-penetrant therapies with intracranial efficacy against non-small cell lung cancer (NSCLC) brain metastases are urgently needed. We report preclinical studies investigating brain penetration and intracranial activity of the MET inhibitor tepotinib. After intravenous infusion of tepotinib in Wistar rats (n = 3), mean (±standard deviation) total tepotinib concentration was 2.87-fold higher in brain (505 ± 22 ng/g) than plasma (177 ± 20 ng/mL). In equilibrium dialysis experiments performed in triplicate, mean tepotinib unbound fraction was 0.35% at 0.3 and 3.0 µM tepotinib in rat brain tissue, and 4.0% at 0.3 and 1.0 µM tepotinib in rat plasma. The calculated unbound brain-to-plasma ratio was 0.25, indicating brain penetration sufficient for intracranial target inhibition. Of 20 screened subcutaneous patient-derived xenograft (PDX) models from lung cancer brain metastases (n = 1), two NSCLC brain metastases models (LU5349 and LU5406) were sensitive to the suboptimal dose of tepotinib of 30 mg/kg/qd (tumor volume change [%TV]: -12% and -88%, respectively). Molecular profiling (nCounter®; NanoString) revealed high-level MET amplification in both tumors (mean MET gene copy number: 11.2 and 24.2, respectively). Tepotinib sensitivity was confirmed for both subcutaneous models at a clinically relevant dose (125 mg/kg/qd; n = 5). LU5349 and LU5406 were orthotopically implanted into brains of mice and monitored by magnetic resonance imaging (MRI). Tepotinib 125 mg/kg/qd induced pronounced tumor regression, including complete or near-complete regressions, compared with vehicle in both orthotopic models (n = 10; median %TV: LU5349, -84%; LU5406, -63%). Intracranial antitumor activity of tepotinib did not appear to correlate with blood-brain barrier leakiness assessed in T1-weighted gadolinium contrast-enhanced MRI.

Cardiovascular deaths: What do the genes say?

The death of a young person is most often a tragic occurrence, more so when this death was unexpected. Forensic pathologists are mandated to investigate such deaths, and there has been a strong move internationally towards genetic testing as an additional investigative tool. The aim of our article is to bring the advantage of implementing the so-called molecular autopsy in a local setting to the attention of medical practitioners. When a multidisciplinary approach is taken in cases of sudden unexpected death, the benefits to family members, and society as a whole, are irrefutable.

Beginning January 1, 2005, bariatric surgery cases were examined with the help of the quality assurance study for operative medicine. All data were registered and analyzed prospectively in cooperation with the Institute of Quality Assurance in Surgery at the Otto-von-Guericke University Magdeburg, Germany. The comparative study focuses on perioperative morbidity, complications, and remission of obesity-associated diseases after gastric bypass (RYGB) and sleeve gastrectomy (SG) at 5-year follow-up. Data collection includes patients of full age who underwent SG or RYGB surgery between 2005 and 2017. The bougie is limited to 33–40 French for SG. The Roux-en-Y length for RYGB is set to 120–180 cm, and the biliodigestive length is set to 40–60 cm. Outcome criteria are perioperative morbidity, postoperative and intraoperative complications, and remission on comorbidities. Between 2005 and 2017, 64,349 patients were enrolled in German Bariatric Surgery Registry (GBSR). Primary operations that were performed were 56.328. Out of 24,146 RYGB and 24,085 SG procedures, 922 patients had a complete 5-year follow-up. These are 342 SG patients and 580 patients with RYGB. A matching was realized for n = 285 (83.3%) patient pairs based on age, BMI, gender, ASA, and comorbidities. A significant disadvantage was identified for the SG procedure regarding reflux disease compared with RYGB (36.3% vs. 8.10%; p

The emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all individuals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of individuals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of individuals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of individuals (18.8 – 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly individuals may require a fourth dose to provide protection against SARS-CoV-2.

Genomic sequencing is essential to track the evolution and spread of SARS-CoV-2, optimize molecular tests, treatments, vaccines, and guide public health responses. To investigate the global SARS-CoV-2 genomic surveillance, we used sequences shared via GISAID to estimate the impact of sequencing intensity and turnaround times on variant detection in 189 countries. In the first two years of the pandemic, 78% of high-income countries sequenced >0.5% of their COVID-19 cases, while 42% of low- and middle-income countries reached that mark. Around 25% of the genomes from high income countries were submitted within 21 days, a pattern observed in 5% of the genomes from low- and middle-income countries. We found that sequencing around 0.5% of the cases, with a turnaround time

Urban green spaces (UGS) can have a positive impact on health and thereby potentially ease the strain on the health care system. However, the availability and benefits seem to vary between different sociodemographic groups. The aim of this study was to investigate associations between sociodemographic factors and availability to UGS among people aged 65 years or older. Data on sociodemographic variables and residential coordinates were obtained for three cross-sectional cohorts in two cities (Malmö and Kristianstad) and three years (2010, 2015, and 2019). Three measures of urban green spaces; total (UGS), public (PGS) and quiet (QGS), within 300 m were used to determine availability. The results indicated higher availability to both total and publicly available urban green spaces for groups with lower socioeconomic status (SES) is positive from a health perspective. However, availability to high qualitative publicly available urban green spaces, from a noise perspective, was lower, indicating the opposite.

Next-generation sequencing technology has afforded the discovery of many novel variants that are of significance to inheritable pharmacogenomics (PGx) traits but a large proportion of them have unknown consequences. These include missense variants resulting in single amino acid substitutions in cytochrome P450 (CYP) proteins that can impair enzyme function, leading to altered drug efficacy and toxicity. While most unknown variants are rare, an overlooked minority are variants that are collectively rare but enriched in specific populations. Here, we analyzed sequence variation data in 141,456 individuals from across eight study populations in gnomAD for 38 CYP genes to identify such variants in addition to common variants. By further comparison with data from two PGx-specific databases (PharmVar and PharmGKB) and ClinVar, we identified 234 missense variants in 35 CYP genes, of which 107 were unknown to these databases. Most unknown variants (n = 83) were population-specific common variants and several (n = 7) were found in important CYP pharmacogenes (CYP2D6, CYP4F2, and CYP2C19). Overall, 29% (n = 31) of 107 unknown variants were predicted to affect CYP enzyme function although further biochemical characterization is necessary. These variants may elucidate part of the unexplained interpopulation differences observed in drug response.

Cytochrome P450 1A1 (CYP1A1) metabolizes estrogens, melatonin, and other key endogenous signaling molecules critical for embryonic/fetal development. The enzyme has increasing expression during pregnancy, and its inhibition or knockout increases embryonic/fetal lethality and/or developmental problems. Here, we present a virtual screening model for CYP1A1 inhibitors based on the orthosteric and predicted allosteric sites of the enzyme. Using 1001 reference compounds with CYP1A1 activity data, we optimized the decision thresholds of our model and classified the training compounds with 68.3% balanced accuracy (91.0% sensitivity and 45.7% specificity). We applied our final model to 11 known CYP1A1 orthosteric binders and related compounds, and found that our ranking of the known orthosteric binders generally agrees with the relative activity of CYP1A1 in metabolizing these compounds. We also applied the model to 22 new test compounds with unknown/unclear CYP1A1 inhibitory activity, and predicted 16 of them are CYP1A1 inhibitors. The CYP1A1 potency and modes of inhibition of these 22 compounds were experimentally determined. We confirmed that most predicted inhibitors, including drugs contraindicated during pregnancy (amiodarone, bicalutamide, cyproterone acetate, ketoconazole, and tamoxifen) and environmental agents suspected to be endocrine disruptors (bisphenol A, diethyl and dibutyl phthalates, and zearalenone), are indeed potent inhibitors of CYP1A1. Our results suggest that virtual screening may be used as a rapid tier-one method to screen for potential CYP1A1 inhibitors, and flag them out for further experimental evaluations. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03111-2.

Purpose: PROCLAIM-CX-2029 is a phase I first-in-human study of CX-2029, a Probody–drug conjugate targeting CD71 (transferrin receptor 1) in adults with advanced solid tumors. Although the transferrin receptor is highly expressed across multiple tumor types, it has not been considered a target for antibody–drug conjugates (ADCs) due to its broad expression on normal cells. CX-2029 is a masked form of a proprietary anti-CD71 antibody conjugated to monomethyl auristatin E, designed to be unmasked in the tumor microenvironment by tumor-associated proteases, therefore limiting off-tumor toxicity and creating a therapeutic window for this previously undruggable target. Patients and Methods: This was a dose-escalation, multicenter trial to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of CX-2029. The primary endpoint was to determine the maximum tolerated dose (MTD) and cycle 1 dose-limiting toxicity (DLT). CX-2029 was administered i.v. every 3 weeks. Results: Forty-five patients were enrolled in eight dose levels. No DLTs were reported in the dose escalation through 4 mg/kg. At 5 mg/kg, there were two DLTs (febrile neutropenia and pancytopenia). Following expansion of the 4 mg/kg dose to six patients, two additional DLTs were observed (infusion-related reaction and neutropenia/anemia). Both the 4 and 5 mg/kg doses were declared above the maximum tolerated dose. The recommended phase II dose is 3 mg/kg. The most common dose-dependent hematologic toxicities were anemia and neutropenia. Confirmed partial responses were observed in three patients, all with squamous histologies. Conclusions: The Probody therapeutic platform enables targeting CD71, a previously undruggable ADC target, at tolerable doses associated with clinical activity. See related commentary by Oberoi and Garralda, p. 4459

Tepotinib is a highly selective and potent MET inhibitor in development for the treatment of patients with solid tumors. Given the favorable tolerability and safety profiles up to the maximum tested dose in the first‐in‐human (FIH) trial, an efficacy‐driven translational modeling approach was proposed to establish the recommended phase II dose (RP2D). To study the in vivo pharmacokinetics (PKs)/target inhibition/tumor growth inhibition relationship, a subcutaneous KP‐4 pancreatic cell‐line xenograft model in mice with sensitivity to MET pathway inhibition was selected as a surrogate tumor model. Further clinical PK and target inhibition data (derived from predose and postdose paired tumor biopsies) from a FIH study were integrated with the longitudinal PKs and target inhibition profiles from the mouse xenograft study to establish a translational PK/pharmacodynamic (PD) model. Preclinical data showed that tumor regression with tepotinib treatment in KP‐4 xenograft tumors corresponded to 95% target inhibition. We therefore concluded that a PD criterion of sustained, near‐to‐complete (>95%) phospho‐MET inhibition in tumors should be targeted for tepotinib to be effective. Simulations of dose‐dependent target inhibition profiles in human tumors that exceeded the PD threshold in more than 90% of patients established an RP2D of tepotinib 500 mg once daily. This translational mathematical modeling approach supports an efficacy‐driven rationale for tepotinib phase II dose selection of 500 mg once daily. Tepotinib at this dose has obtained regulatory approval for the treatment of patients with non‐small cell lung cancer harboring MET exon 14 skipping.

BACKGROUND: Immune checkpoint inhibitors (ICI) blocking inhibitory immune pathways (e.g., programmed cell death protein-1/-ligand1 [PD-1/PD-L1]) have revolutionized cancer therapy for numerous malignancies. There have been an increasing number of cases of active tuberculosis (TB) reported in association with ICI use, and recent data suggest alterations in immune responses in TB by ICI. The aim of this study was to characterize the frequency of latent tuberculosis infection (LTBI) and active TB in a large cohort of ICI treated patients in a low TB incidence area. METHODS: We conducted a retrospective review of all ICI treated patients tested for TB between January, 1997 and August, 2018. Data extracted included patient demographics, TB risk factors, latent/active TB diagnosis and treatment, tumor type, ICI used, immunosuppressive medications, and mortality related to TB. RESULTS: We identified 1844 ICI treated patients, including 30 abnormal TB test results. Two patients were diagnosed with active TB, both prior to starting ICI therapy. One patient was treated for TB prior to starting ICI and the other patient was successfully treated concurrently. Seven patients were diagnosed with LTBI and none developed active TB. Twenty patients had indeterminate interferon gamma release assays (IGRA). CONCLUSIONS: Despite recent reports of TB in patients taking ICI, we found no patients developing TB during ICI therapy in our large retrospective cohort of ICI treated cancer patients in a non-endemic TB area. The high rate of indeterminate IGRA results suggests the need for prospective research with better diagnostics to quantify the actual risk of TB in this patient population.

The World Health Summit 2011 confirmed the epidemic-like occurrence of diabetes mellitus and obesity. In Germany, 62.7 % and 21.9 % of the population have a BMI of more than 25 kg/m² and more than 30 kg/m2, respectively. Currently, 10.5 obese people per 100 000 German inhabitants undergo bariatric surgery, while 86 and 114.8 per 100 000 in France and in Sweden, respectively, favor bariatric surgical interventions. Aim By means of a scientific case report, the instructive case of a young patient with morbid obesity is illustrated based on 1) selective references from the medical literature and 2) insights from the daily clinical practice in the case-specific medical and perioperative management after successful surgery for malformation in his childhood and, thus, the limited therapeutic options of metabolic surgery. Case report (case-, diagnostic-, and treatment-specific aspects) 35-year-old patient with morbid obesity. Medical history: Status after surgical intervention for gastroschisis as a newborn (surgery report not available). Clinical findings: Super obesity characterized by 234 kg and 174 cm (→ BMI: 77.3 kg/m²), hypogonadotrophic hypogonadism. Approach & course: Outcome (early postoperative and mid- to long-term): The patient tolerated the intervention well. Postoperative course was uneventful with regard to mobilization, beginning of oral nutrition, and wound healing; there was a subsequent weight reduction due to a “common channel” of 250 cm. Conclusion While the increase of obesity prevalence in adults has currently stopped, incidence in children and teenagers is rapidly rising. The consequence might be that children and young adults who have undergone bariatric surgery in childhood and adolescence can develop complications from these former interventions as adults. Therefore, it is reasonable to recommend follow-up investigations within specialized centers according to well-established standards. On the other hand, the increasing prevalence of obesity in childhood leads to the possibility that adults who underwent pediatric surgery because of embryonal malformations may require an appointment with a bariatric surgeon at some point. For these patients (as a representative example of the transition of care phenomenon), the risk of metabolic surgical intervention is increased; such operations require the appropriate knowledge and expertise of the bariatric surgeon on embryonal malformations and their approach by pediatric surgery.

In Sweden, societal support for older people is the responsibility of the municipalities. However, due to Sweden's current aging-in-place policy for older people, there is a need to assess how the use of such services varies based on sociodemographic factors. The aim of this study was to describe the use of different forms of social services and institutional long-term care (ILTC) in an older population and to evaluate the impact of sociodemographic factors.This was a cross-sectional register-based study, including all individuals aged 65 years and older in two Swedish municipalities in 2010, 2015, and 2019. The study analyzed the use of social services and ILTC in relation to sex, place of birth, cohabitation status, and type of housing.Women, those born in Sweden, and those living in an apartment were more likely to receive assistance than men, those born abroad, or living in single family houses, respectively. People living alone were consistently more likely to have assistance, as well as ILTC.There may be a discrepancy between the individual's need and the assistance provided from the municipality in certain sociodemographic groups in the older population in Sweden.

Purpose EAU guidelines recommend multiparametric MRI of the prostate (mpMRI) prior to biopsy to increase accuracy and reduce biopsies. Whether biopsy can be avoided in case of negative mpMRI remains unclear. Aim of this study is to evaluate predictors of overall prostate cancer (PCa) in negative mpMRI. Methods A total of 216 patients from 2018 to 2020 with suspicion of PCa and negative mpMRI (PI-RADS ≤ 2) were interviewed by telephone about outcome and further follow-up. Clinically significant PCa (csPCa) was defined as ISUP ≥ 2. Patients with vs. without biopsy and with vs. without PCa were compared. Univariate and multivariate analyses were performed to evaluate predictors of PCa occurrence in patients with negative mpMRI. Results 15.7% and 5.1% of patients with PI-RADS ≤ 2 on mpMRI showed PCa and csPCa, respectively. PCa patients had higher PSAD (0.14 vs. 0.09 ng/ml2; p = 0.001) and lower prostate volume (50.5 vs. 74.0 ml; p = 0.003). Patients without biopsy (25%) after MRI were older (69 vs. 65.5 years; p = 0.027), showed lower PSA (5.7 vs. 6.73 ng/ml; p = 0.033) and lower PSA density (0.09 vs. 0.1 ng/ml2; p = 0.027). Multivariate analysis revealed age (OR 1.09 [1.02–1.16]; p = 0.011), prostate volume (OR 0.982 [0.065; 0.997]; p = 0.027), total PSA level (OR 1.22 [1.01–1.47], p = 0.033), free PSA (OR 0.431 [0.177; 0.927]; p = 0.049) and no PI-RADS lesion vs PI-RADS 1–2 lesion (OR 0.38 [0.15–0.91], p = 0.032.) as predictive factors for the endpoint presence of PCa. Conclusions Biopsy for selected patient groups (higher age, prostate volume and free PSA as well as lower PSA-Density) with negative mpMRI can be avoided, if sufficient follow-up care is guaranteed. Detailed counseling regarding residual risk for undetected prostate cancer should be mandatory.

Oseltamivir-resistant influenza viruses arise due to amino acid mutations in key residues of the viral neuraminidase (NA). These changes often come at a fitness cost; however, it is known that permissive mutations in the viral NA can overcome this cost. This result was observed in former seasonal A(H1N1) viruses in 2007 which expressed the H275Y substitution (N1 numbering) with no apparent fitness cost and lead to widespread oseltamivir resistance. Therefore, this study aims to predict permissive mutations that may similarly enable fit H275Y variants to arise in currently circulating A(H1N1)pdm09 viruses. The first approach in this study utilized

CX-072 is an anti-PD-L1 (programmed death ligand 1) Probody therapeutic (Pb-Tx) designed to be preferentially activated by proteases in the tumor microenvironment and not in healthy tissue. Here, we report the model-informed drug development of CX-072. A quantitative systems pharmacology (QSP) model that captured known mechanisms of Pb-Tx activation, biodistribution, elimination, and target engagement was used to inform clinical translation. The QSP model predicted that a trough level of masked CX-072 (intact CX-072) of 13-99 nM would correspond to a targeted, 95% receptor occupancy in the tumor. The QSP model predictions appeared consistent with preliminary human single-dose pharmacokinetic (PK) data following CX-072 0.03-30.0 mg/kg as monotherapy: CX-072 circulated predominantly as intact CX-072 with minimal evidence of target-mediated drug disposition. A preliminary population PK (POPPK) analysis based upon 130 subjects receiving 0.03-30.0 mg/kg as monotherapy included a provision for a putative time-dependent and dose-dependent antidrug antibody (ADA) effect on clearance (CL) with a mixture model. Preliminary POPPK estimates for intact CX-072 time-invariant CL and volume of distribution were 0.306 L/day and 4.84 L, respectively. Exposure-response analyses did not identify statistically significant relationships with best change from baseline sum of measurements and either adverse events of grade ≥ 3 or of special interest. Simulations suggested that > 95% of patients receiving CX-072 10 mg/kg every two weeks would exceed the targeted trough level regardless of ADA, and that dose adjustment by body weight was not necessary, supporting a fixed 800 mg dose for evaluation in phase II.

Cytokine storm syndromes (CSS) are severe hyperinflammatory conditions characterized by excessive immune system activation leading to organ damage and death. Hemophagocytic lymphohistiocytosis (HLH), a disease often associated with inherited defects in cell-mediated cytotoxicity, serves as a prototypical CSS for which the 5-year survival is only 60%. Frontline therapy for HLH consists of the glucocorticoid dexamethasone (DEX) and the chemotherapeutic agent etoposide. Many patients, however, are refractory to this treatment or relapse after an initial response. Notably, many cytokines that are elevated in HLH activate the JAK/STAT pathway, and the JAK1/2 inhibitor ruxolitinib (RUX) has shown efficacy in murine HLH models and humans with refractory disease. We recently reported that cytokine-induced JAK/STAT signaling mediates DEX resistance in T cell acute lymphoblastic leukemia (T-ALL) cells, and that this could be effectively reversed by RUX. On the basis of these findings, we hypothesized that cytokine-mediated JAK/STAT signaling might similarly contribute to DEX resistance in HLH, and that RUX treatment would overcome this phenomenon. Using ex vivo assays, a murine model of HLH, and primary patient samples, we demonstrate that the hypercytokinemia of HLH reduces the apoptotic potential of CD8 T cells leading to relative DEX resistance. Upon exposure to RUX, this apoptotic potential is restored, thereby sensitizing CD8 T cells to DEX-induced apoptosis in vitro and significantly reducing tissue immunopathology and HLH disease manifestations in vivo. Our findings provide rationale for combining DEX and RUX to enhance the lymphotoxic effects of DEX and thus improve the outcomes for patients with HLH and related CSS.

Summary Background Three clusters of coronavirus disease 2019 (COVID-19) linked to a tour group from China, a company conference, and a church were identified in Singapore in February, 2020. Methods We gathered epidemiological and clinical data from individuals with confirmed COVID-19, via interviews and inpatient medical records, and we did field investigations to assess interactions and possible modes of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Open source reports were obtained for overseas cases. We reported the median (IQR) incubation period of SARS-CoV-2. Findings As of Feb 15, 2020, 36 cases of COVID-19 were linked epidemiologically to the first three clusters of circumscribed local transmission in Singapore. 425 close contacts were quarantined. Direct or prolonged close contact was reported among affected individuals, although indirect transmission (eg, via fomites and shared food) could not be excluded. The median incubation period of SARS-CoV-2 was 4 days (IQR 3–6). The serial interval between transmission pairs ranged between 3 days and 8 days. Interpretation SARS-CoV-2 is transmissible in community settings, and local clusters of COVID-19 are expected in countries with high travel volume from China before the lockdown of Wuhan and institution of travel restrictions. Enhanced surveillance and contact tracing is essential to minimise the risk of widespread transmission in the community. Funding None.

Genodermatoses are genetically inherited dermatologic conditions. The management of cutaneous findings in genodermatoses is challenging, and first-line therapies, such as steroids and/or retinoids, are often inadequate. In recent years, research on the molecular basis of genodermatoses has led to the use of biologic therapies for intractable disease. Here, we review the evidence regarding the use of available biologic therapies for the management of dermatologic findings in genodermatoses. Biologic therapies appear to be promising therapeutic options for several recalcitrant genodermatoses, especially those with underlying immune dysregulation. However, not all genodermatoses are amenable to biologic therapies, and some have been shown to paradoxically worsen under treatment. Biologic therapies offer a novel avenue to target refractory genodermatoses. However, evidence supporting the use of biologic therapies in the management of genodermatoses is mostly limited to case reports and case series. Further studies are warranted to determine the safety and efficacy of biologic therapies for the management of cutaneous findings in genodermatoses.

Context Dietary carotenoid intake is associated with vitamin A status and healthy visual and cognitive function in early life. To date, however, only limited population-level data on the concentrations of carotenoids in human milk or infant blood have been available to assess the dietary exposure of infants to carotenoids. Objective This systematic review seeks to define worldwide carotenoid concentrations in human milk and infant blood. Data Sources The PubMed, Embase, and Web of Science databases were searched for original research articles published before February 2021. Data Extraction Dietary carotenoid concentrations in human milk and in blood plasma or serum from healthy infants (≤1 year of age), along with study location, infant age, and lactation stage, were extracted. Means and 95%CIs were analyzed within and across variables. Data Analysis Publications on carotenoid concentrations in infant blood (47 publications, n = 4553 unique individuals) and human milk (65 publications, n = 2871 unique individuals) described populations from 22 and 31 countries, respectively. Carotenoid species concentrations ranged from 0.3 to 20 µg/dL in blood and from 0.1 to 30 µg/dL in human milk, with carotenoid concentrations generally decreasing in milk across lactation stages and increasing in blood with infant age. Conclusion Concentrations of the major dietary carotenoids—β-carotene, lycopene, lutein, β-cryptoxanthin, zeaxanthin, and α-carotene—have been reported in both infant blood and human milk across infant ages and lactation stages, with β-carotene, lutein, and lycopene tending to be more abundant than other carotenoids. Despite heterogeneous amounts of data available for each outcome, infants worldwide are exposed to a variety of dietary carotenoids. The estimates of dietary carotenoids in human milk and infant blood can facilitate the interpretation of future studies and the design of nutritionally relevant experiments on dietary carotenoids and infant health.

OBJECTIVES Congenital tricuspid valve dysplasia (TVD) is a rare cardiac disease, often discussed in the same way as Ebstein’s anomaly. Though the morphology of TVD is different, the clinical appearance is similar. The indication for surgical treatment depends on the morphology of the tricuspid valve (TV) and the clinical presentation. METHODS We reviewed all patients below 18 years of age who underwent TV repair between 2005 and 2019 and identified 9 with a TVD. The diagnosis was verified with the operative notes and patients were excluded if the septal leaflet was displaced as in Ebstein’s anomaly. The aim of the study was to describe the morphology of the TV and analyse the surgical possibilities and their results. RESULTS The median age at surgery was 2.3 years (5 days to 14 years), 3 patients were neonates with a duct-dependent pulmonary circulation. Morphology of the TV showed a tethering of at least 1 leaflet in all patients, a restrictive septal leaflet in 8, a large anterior leaflet in 7 and a small posterior leaflet in 4. Surgical techniques included an annuloplasty in 7 patients, a leaflet procedure in 6 patients, an edge-to-edge stitch in 5 patients and a primary Starnes procedure in 1 neonate. During a median follow-up time of 2.8 years (5 months to 15 years), 1 valve replacement and 1 conversion to univentricular palliation were necessary. CONCLUSIONS Unequal leaflet size and tethering are the most common features of TVD. A variety of surgical techniques is available to achieve good results beyond the neonatal period.

In recent decades, an extensive collection of research has shown various benefits of bariatric surgery in the remission of obesity-related diseases and in weight loss in patients with obesity. This study investigated whether sleeve gastrectomy (SG) or adjustable gastric banding (AGB) has the best benefit in terms of perioperative risk, weight loss, and remission of comorbidities.The German Bariatric Surgery Registry included 32,051 patients after SG and AGB. Outcome criteria were perioperative morbidity, perioperative complications, and remission of comorbidities after a one-year follow-up.Out of them 16,441 patients had completed one-year follow-up (2042 patients after AGB and 14,399 after SG). The %EWL was 40.8±23.4 for AGB and 62.4±22.6 for SG (P0.001). BMI reduction was a significant difference in favor of SG (8.0±4.7 after AGB vs. 15.5±5.9 after SG; P0.001). Significant differences in favor of SG were also found for remission of IDDM (P0.001), NIDDM (P0.001), hypertension (P0.001), sleep apnea (P0.001), and reflux disease (P0.001). However, no significant difference was found between the two groups in terms of general intraoperative and general postoperative complications (P=0.809 and P=0.883, respectively). Specific postoperative complications were documented significantly more often after SG (3.4% in SG vs. 1% in AGB; P0.001).Based on the results of our study, we can conclude that both SG and AGB can be safe surgical procedures. However, SG achieved more significant results in terms of remission of comorbidities. AGB is effective in patients without severe comorbidities and high BMI.

A group convened and led by the Virus Evolution Working Group of the World Health Organization reports on its deliberations and announces a naming scheme that will enable clear communication about SARS-CoV-2 variants of interest and concern.

To date, the extent to which early experience shapes the functional characteristics of neural circuits is still a matter of debate. In the present study, we tested whether congenital deafness and/or the acquisition of a sign language alter the temporal processing characteristics of the visual system. Moreover, we investigated whether, assuming cross-modal plasticity in deaf individuals, the temporal processing characteristics of possibly reorganised auditory areas resemble those of the visual cortex. Steady-state visual evoked potentials (SSVEPs) were recorded in congenitally deaf native signers, hearing native signers, and hearing nonsigners. The luminance of the visual stimuli was periodically modulated at 12, 21, and 40 Hz. For hearing nonsigners, the optimal driving rate was 12 Hz. By contrast, for the group of hearing signers, the optimal driving rate was 12 and 21 Hz, whereas for the group of deaf signers, the optimal driving rate was 21 Hz. We did not observe evidence for cross-modal recruitment of auditory cortex in the group of deaf signers. These results suggest a higher preferred neural processing rate as a consequence of the acquisition of a sign language.

The slow wave state is a general state of quiescence interrupted by sudden bursts of activity or so-called slow wave events (SWEs). Recently, the relationship between SWEs and blood oxygen level–dependent (BOLD) functional magnetic resonance imaging (fMRI) signals was assessed in rodent models which revealed cortex-wide BOLD activation. However, it remains unclear which macroscopic signature corresponds to these specific neurophysiological events in the human brain. Therefore, we analyzed simultaneous electroencephalographic (EEG)-fMRI data during human non-REM sleep. SWEs individually detected in the EEG data were used as predictors in event-related fMRI analyses to examine the relationship between SWEs and fMRI signals. For all 10 subjects we identified significant changes in BOLD activity associated with SWEs covering substantial parts of the gray matter. As demonstrated in rodents, we observed a direct relation of a neurophysiological event to specific BOLD activation patterns. We found a correlation between the number of SWEs and the spatial extent of these BOLD activation patterns and discovered that the amplitude of the BOLD response strongly depends on the SWE amplitude. As altered SWE propagation has recently been found in neuropsychiatric diseases, it is critical to reveal the brain’s physiological slow wave state networks to potentially establish early imaging biomarkers for various diseases long before disease onset.

Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9451062/ We propose a novel, non-discriminatory classification of monkeypox virus diversity. Together with the World Health Organization, we named three clades (I, IIa and IIb) in order of detection. Within IIb, the cause of the current global outbreak, we identified multiple lineages (A.1, A.2, A.1.1 and B.1) to support real-time genomic surveillance. info:eu-repo/semantics/publishedVersion

Genomic sequencing is essential to track the evolution and spread of SARS-CoV-2, optimize molecular tests, treatments, vaccines, and guide public health responses. To investigate the global SARS-CoV-2 genomic surveillance, we used sequences shared via GISAID to estimate the impact of sequencing intensity and turnaround times on variant detection in 189 countries. In the first two years of the pandemic, 78% of high-income countries sequenced >0.5% of their COVID-19 cases, while 42% of low- and middle-income countries reached that mark. Around 25% of the genomes from high income countries were submitted within 21 days, a pattern observed in 5% of the genomes from low- and middle-income countries. We found that sequencing around 0.5% of the cases, with a turnaround time

Mitochondrial-derived vesicles (MDVs) are implicated in diverse physiological processes-for example, mitochondrial quality control-and are linked to various neurodegenerative diseases. However, their specific cargo composition and complex molecular biogenesis are still unknown. Here we report the proteome and lipidome of steady-state TOMM20(+) MDVs. We identified 107 high-confidence MDV cargoes, which include all beta-barrel proteins and the TOM import complex. MDV cargoes are delivered as fully assembled complexes to lysosomes, thus representing a selective mitochondrial quality control mechanism for multi-subunit complexes, including the TOM machinery. Moreover, we define key biogenesis steps of phosphatidic acid-enriched MDVs starting with the MIRO1/2-dependent formation of thin membrane protrusions pulled along microtubule filaments, followed by MID49/MID51/MFF-dependent recruitment of the dynamin family GTPase DRP1 and finally DRP1-dependent scission. In summary, we define the function of MDVs in mitochondrial quality control and present a mechanistic model for global GTPase-driven MDV biogenesis.

PURPOSE MET exon 14 skipping alterations ( METex14) comprise a diverse set of actionable oncogene drivers in non–small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in METex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described. MATERIALS AND METHODS METex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and METex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to METex14 were evaluated. RESULTS Of 40,824 NSCLCs, 692 METex14 cases (1.7%) were identified, including 332 in Guardant360, 188 in VISION, and 172 in GenePlus. The demographics and mutation type and/or sites were similar in the Asian versus Western cohorts. MET amplification, which were found to be associated with sensitivity to MET kinase inhibitors, co-occurs in 7.6%-13.8% of cases, whereas kinase domain secondary mutation of MET co-occurs in 5%-6%. When co-occurring with METex14, EGFR mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, METex14 (39%, 7 of 18) and KRAS (44%, 8 of 18) had similar rates of clonal dominance. PIK3CA and PTEN mutations were almost always subclones (89%, 16 of 18) to METex14. Moreover, RET-CCDC6 fusion and EGFR mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance. CONCLUSION METex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether METex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.

With increasing BMI, the complexity of treating patients with obesity rises. The focus of this study is to investigate the effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on perioperative morbidity and remission of comorbidities at 3 years in patients with a BMI 50 kg/mA retrospective multicenter analysis of a prospectively maintained database was performed to enroll patients with a 3-year follow-up after SG or RYGB between 2005 and 2019 and a BMI of 50 kg/mWe analyzed data from 2939 patients who had at least a preoperative BMI 50 kg/mBoth procedures positively affected comorbidities, BMI, and %EWL in patients with super obesity 3 years after surgery. In some categories, RYGB was better than SG. Nevertheless, the decision between the two methods remains a matter of the surgeon's experience and the patient's general condition.

The mechanistic target of rapamycin (mTOR) promotes pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective; however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased heart is unknown. We performed cardiomyocyte genome‐wide sequencing to define mTOR‐dependent gene expression control at the level of mRNA translation. We identify the muscle‐specific protein Cullin‐associated NEDD8‐dissociated protein 2 (Cand2) as a translationally upregulated gene, dependent on the activity of mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. Mechanistically, we show that Cand2 links mTOR signaling to pathological cell growth by increasing Grk5 protein expression. Our data suggest that cell‐type‐specific targeting of mTOR might have therapeutic value against pathological cardiac remodeling., Genome‐wide translational profiling identifies mTORC1‐dependent genes in cardiomyocytes in response to neurohumoral stimulation. Expression of the muscle‐specific gene Cand2 is controlled by mTORC1 and Cand2 regulates cardiac function and pathological hypertrophy.

Objectives To describe characteristics, treatment and outcomes of non-small cell lung cancer (NSCLC) patients with MET alterations (MET exon 14 [METex14] skipping or MET amplification [METamp]) in real-world clinical care. Methods This non-interventional cohort study used real-world data extracted from electronic medical records from academic oncology sites in Israel, The Netherlands, Taiwan, and the USA. Patients had confirmed diagnosis of advanced (Stage IIIB–IV) NSCLC harboring MET alterations (date of diagnosis = index date) between 1 Jan 2010 and 30 Sept 2018. Medical history was assessed prior to and at the index date (baseline period), and outcomes from first date of treatment to death, loss to follow-up, or end of study period. Results A total of 117 patients were included (METex14 n = 70; METamp n = 47); testing methods were heterogeneous. Concomitant oncogenic mutations were more common in the METamp cohort than METex14. Patients in the METex14 cohort were older than those in METamp, and a larger proportion were never smokers. Anticancer first-line therapies received by patients (METex14; METamp) included chemotherapy only (44%; 41%), MET inhibitors (33%; 29%), immune checkpoint inhibitor (ICI) mono-(12%; 15%) and combination-therapy (8%; 3%). Second-line therapies included chemotherapy (35%; 30%) and MET inhibitors (30%; 39%). In the METex14 cohort, objective response rate (ORR) was generally low (first-line 28%; second-line 30%); no patients who received ICIs had a response. In the METamp cohort, ORR was 36% in first-line and 22% in second-line. Median (95% confidence interval) overall survival from start of first-line therapy was 12.0 months (6.8, 19.2) in the METex14 cohort and 22.0 months (9.8, 31.2) in METamp. Conclusions Heterogeneous treatments reflect the changing landscape and availability of new treatments, as well as the high unmet medical need in older, METex14 patients who had more advanced disease at diagnosis. MET-targeted therapies could be beneficial in patients with these rare MET alterations.

PROBODY therapeutics (Pb‐Tx) are protease‐activatable prodrugs of monoclonal antibodies (mAbs) designed to target tumors where protease activity is elevated while avoiding normal tissue. They are composed of a parental mAb, a mask that inhibits antibody binding to target, and a protease‐cleavable substrate between the mask and the mAb. We report a quantitative systems pharmacology model for the rational design and clinical translation of Pb‐Tx. The model adequately described monkey pharmacokinetic data following the administration of six anti‐CD166 Pb‐Tx of varying mask strength and substrate cleavability and captured the trend of decreasing Pb‐Tx systemic clearance with increasing mask strength. Projections to humans suggested both higher levels of Pb‐Tx in tumor relative to parental mAb and an optimal mask strength for maximizing tumor receptor–mediated uptake. Simulations further suggested the majority of circulating species in humans would be intact/masked Pb‐Tx, with no significant flux of cleaved/activated species from tumor to the systemic compartment.

Attitudes of the general public may be an influencing factor for low surgery rates: When skepticism is high, support for individuals wanting or needing to undergo surgery may diminish. This study assesses the relevance of barriers to metabolic surgery. The study was conducted using a representative sample of the German population (n = 1007). Participants were asked to imagine that they would have to decide for or against metabolic surgery and rate how this decision would be influenced by a number of reasons given to them (Likert scale). Results are presented by weight status. The barrier found most irrelevant is that surgery could be considered cheating across all weight groups. About a fourth of the sample state that not knowing enough about surgery (28.5%), being afraid of surgery (28.3%), and potential negative consequences after surgery (24.5%) are reasons against metabolic surgery that were rated extremely relevant. Having obesity was a significant predictor of endorsement in two variables: feeling like cheating (lower probability for relevance, OR = 0.58, p = 0.025) and a lack of knowledge (lower probability for relevance, OR = 0.59, p = 0.031). In summary, the public’s view of weight loss surgery lacks information about post-surgical consequences. It is important to address these points in the public and in social networks of patients as they may be pre- or antecedent of surgery stigma.

Occupational exposure assessment is almost exclusively accomplished with personal sampling. However, personal sampling can be burdensome and suffers from low sample sizes, resulting in inadequately characterized workplace exposures. Sensor networks offer the opportunity to measure occupational hazards with a high degree of spatiotemporal resolution. Here, we demonstrate an approach to estimate personal exposure to respirable particulate matter (PM), carbon monoxide (CO), ozone (O3), and noise using hazard data from a sensor network. We simulated stationary and mobile employees that work at the study site, a heavy-vehicle manufacturing facility. Network-derived exposure estimates compared favorably to measurements taken with a suite of personal direct-reading instruments (DRIs) deployed to mimic personal sampling but varied by hazard and type of employee. The root mean square error (RMSE) between network-derived exposure estimates and personal DRI measurements for mobile employees was 0.15 mg/m3, 1 ppm, 82 ppb, and 3 dBA for PM, CO, O3, and noise, respectively. Pearson correlation between network-derived exposure estimates and DRI measurements ranged from 0.39 (noise for mobile employees) to 0.75 (noise for stationary employees). Despite the error observed estimating personal exposure to occupational hazards it holds promise as an additional tool to be used with traditional personal sampling due to the ability to frequently and easily collect exposure information on many employees.

Use of botanicals and natural substances in consumer products has increased in recent years. Such extracts can contain protein that may theoretically represent a potential risk of IgE-mediated allergy. No method has yet been generally accepted or validated for assessment of the allergenic potential of proteins. For development of suitable methods datasets of allergenic and nonallergenic (or low allergenic) proteins are required that can serve, respectively, as positive and negative controls. However, data are unavailable on proteins that lack or have low allergenic potential. Here, low allergenic potential proteins are identified based on the assumption that proteins with established human exposure, but with a lack of an association with allergy, possess low allergenic potential. Proteins were extracted from sources considered to have less allergenic potential (corn, potato, spinach, rice, and tomato) as well as higher allergenic potential (wheat) regarding common allergenic foods. Proteins were identified and semi-quantified by label-free proteomic analysis conducted using mass spectrometry. Predicted allergenicity was determined using AllerCatPro (https://allercatpro.bii.a-star.edu.sg/). In summary, 9077 proteins were identified and semi-quantified from 6 protein sources. Within the top 10% of the most abundant proteins identified, 178 characterized proteins were found to have no evidence for allergenicity predicted by AllerCatPro and were considered to have low allergenic potential. This panel of low allergenic potential proteins provides a pragmatic approach to aid the development of alternative methods for robust testing strategies to distinguish between proteins of high and low allergenic potential to assess the risk of proteins from natural or botanical sources.