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The new Peer Review Organizations (PSRO) will review the quality, necessity, and appropriateness of medical care for which payment is made under the terms of the Social Security Act. The many differences between teaching and nonteaching hospitals suggest that it may be inappropriate to evaluate institutional services using a single set of norms of care, diagnosis, and treatment. (Author)

Extracorporeal photopheresis (ECP), a personalized cellular immunotherapy, constitutes a promising treatment for steroid-refractory/-resistant graft-versus-host disease (SR-GvHD), with encouraging clinical response rates. To further investigate its mechanism of action, ECP's effects on T helper (Th) cells as well as on expression of immune checkpoint (PD-1 and Tim-3) and apoptotic (Fas receptor [FasR]) molecules were investigated in 27 patients with SR-GvHD. Our data show that GvHD patients had significantly higher levels of Th2, Th17, Th22 and granulocyte-macrophage colony-stimulating factor (GM-CSF)-positive Th (ThG) cells and clearly lower levels of T follicular helper (Tfh) cells, including Th1- and Th2-like cells, compared with healthy donors. ECP therapy for GvHD was effective through the modulation of different Th subsets: increases of Th22 (1.52-fold) and Tfh cells (1.48-fold) in acute GvHD (aGvHD) and increases of Th2-like Tfh cells (1.74-fold) in chronic GvHD (cGvHD) patients were associated with clinical response. Expression of FasR was further upregulated in CD4+CD8+ T cells. Additionally, Tim-3-expressing effector T cells associated with the severity of GvHD were reduced. Taken together, these data show that ECP therapy exerts immunomodulatory effects by promoting a balanced immune reconstitution and inducing immune tolerance. Therefore it represents an attractive option for the treatment of GvHD.

Purpose To analyze precision and safety of femtosecond laser-assisted descemetorhexis as well as postoperative corneal wound healing in human ex vivo specimens. Setting Department of Ophthalmology, University Hospital, LMU Munich, Munich, Germany. Design Experimental ex vivo study. Methods Four donor corneas underwent femtosecond laser-assisted descemetorhexis. The descemetorhexis was performed using the LDV Z8 femtosecond laser followed by live/dead staining, phase contrast microscopy and scanning electron microscopy. The descemetorhexis parameters were set using a modified optical coherence tomography image capturing of 8 segments within a focus of 100 μm at the posterior corneal stroma (reversed capsulotomy program). Results Live/dead sample staining analysis demonstrated that the femtosecond laser had minimal impact on the vitality of surrounding endothelial cells. Phase contrast microscopy and scanning electron microscopy evaluation showed that the laser produced precise, clear-cut edges leaving no stromal tissue bridges. Conclusions Femtosecond laser-assisted descemetorhexis could serve as a safe and precise technique with only minimal endothelial cell damage. To minimize stromal damage, further laser energy profile adjustments are necessary to optimize corneal treatment within different stages of corneal tissue swelling.

Supplemental material, sj-docx-1-eso-10.1177_23969873231174942 for Ischaemic stroke despite antiplatelet therapy: Causes and outcomes by Norbert Silimon, Boudewijn Drop, Leander Clénin, Krassen Nedeltchev, Timo Kahles, Alexander A Tarnutzer, Mira Katan, Leo Bonati, Stephan Salmen, Sylvan Albert, Alexander Salerno, Emmanuel Carrera, Christian Berger, Nils Peters, Friedrich Medlin, Carlo Cereda, Manuel Bolognese, Georg Kägi, Susanne Renaud, Julien Niederhauser, Christophe Bonvin, Michael Schärer, Marie-Luise Mono, Andreas Luft, Biljana Rodic-Tatic, Urs Fischer, Simon Jung, Marcel Arnold, Thomas Meinel and David Seiffge in European Stroke Journal

Supplemental material, sj-pdf-2-eso-10.1177_23969873231174942 for Ischaemic stroke despite antiplatelet therapy: Causes and outcomes by Norbert Silimon, Boudewijn Drop, Leander Clénin, Krassen Nedeltchev, Timo Kahles, Alexander A Tarnutzer, Mira Katan, Leo Bonati, Stephan Salmen, Sylvan Albert, Alexander Salerno, Emmanuel Carrera, Christian Berger, Nils Peters, Friedrich Medlin, Carlo Cereda, Manuel Bolognese, Georg Kägi, Susanne Renaud, Julien Niederhauser, Christophe Bonvin, Michael Schärer, Marie-Luise Mono, Andreas Luft, Biljana Rodic-Tatic, Urs Fischer, Simon Jung, Marcel Arnold, Thomas Meinel and David Seiffge in European Stroke Journal

Supplemental material, sj-docx-1-eso-10.1177_23969873231185895 for Safety and effectiveness of IV Thrombolysis in retinal artery occlusion: A multicenter retrospective cohort study by Philipp Baumgartner, Lucas Kook, Valerian L Altersberger, Henrik Gensicke, Elena Ardila-Jurado, Georg Kägi, Alexander Salerno, Patrik Michel, Kiran M Gopisingh, Paul J Nederkoorn, Jan F Scheitz, Christian H Nolte, Mirjam R Heldner, Marcel Arnold, Charlotte Cordonnier, Lucie Della Schiava, Christian Hametner, Peter A. Ringleb, Ronen R Leker, Hamza Jubran, Andreas R Luft, Stefan T Engelter and Susanne Wegener in European Stroke Journal

Allogeneic haematopoietic-cell transplantation (allo-HCT) is a potentially curative therapy for high-risk myelodysplastic syndrome (MDS). Reduced-intensity conditioning (RIC) is usually associated with lower non-relapse mortality (NRM), higher relapse rate and similar overall-survival (OS) as myeloablative-conditioning (MAC). Fludarabine/treosulfan (FT) is a reduced-toxicity regimen with intense anti-leukaemia activity and a favourable toxicity profile. We investigated post-transplant outcomes in 1722 MDS patients following allo-HCT with FT (n=367), RIC (n=687) or MAC (n=668). FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51years, respectively (P&nbsp

Background The World Trade Center (WTC) general responder cohort (GRC) was exposed to environmental toxins possibly associated with increased risk of developing autoimmune conditions. Objectives Two study designs were used to assess incidence and risks of autoimmune conditions in the GRC. Methods Three clinically trained professionals established the status of possible GRC cases of autoimmune disorders adhering to diagnostic criteria, supplemented, as needed, by specialists' review of consenting responders' medical records. Nested case-control analyses using conditional logistic regression estimated the risk associated with high WTC exposure (being in the 9/11/2001 dust cloud or ≥median days' response worked) compared with low WTC exposure (all other GRC members'). Four controls were matched to each case on age at case diagnosis (±2 years), sex, race/ethnicity, and year of program enrollment. Sex-specific and sensitivity analyses were performed. GRC age- and sex-adjusted standardized incidence ratios (SIRs) were compared with the Rochester Epidemiology Project (REP). Complete REP inpatient and outpatient medical records were reviewed by specialists. Conditions meeting standardized criteria on ≥2 visits were classified as REP confirmed cases. Results Six hundred and twenty-eight responders were diagnosed with autoimmune conditions between 2002 and 2017. In the nested case-control analyses, high WTC exposure was not associated with autoimmune domains and conditions (rheumatologic domain odds ratio [OR] = 1.03, 95% confidence interval [CI] = 0.77, 1.37; rheumatoid arthritis OR = 1.12, 95% CI = 0.70, 1.77). GRC members had lower SIR than REP. Women's risks were generally greater than men's. Conclusions The study found no statistically significant increased risk of autoimmune conditions with WTC exposures.

Background Sepsis and inflammation can cause intensive care unit‐acquired weakness (ICUAW). Increased interleukin‐6 (IL‐6) plasma levels are a risk factor for ICUAW. IL‐6 signalling involves the glycoprotein 130 (gp130) receptor and the JAK/STAT‐pathway, but its role in sepsis‐induced muscle wasting is uncertain. In a clinical observational study, we found that the IL‐6 target gene, SOCS3, was increased in skeletal muscle of ICUAW patients indicative for JAK/STAT‐pathway activation. We tested the hypothesis that the IL‐6/gp130‐pathway mediates ICUAW muscle atrophy. Methods We sequenced RNA (RNAseq) from tibialis anterior (TA) muscle of cecal ligation and puncture‐operated (CLP) and sham‐operated wildtype (WT) mice. The effects of the IL‐6/gp130/JAK2/STAT3‐pathway were investigated by analysing the atrophy phenotype, gene expression, and protein contents of C2C12 myotubes. Mice lacking Il6st, encoding gp130, in myocytes (cKO) and WT controls, as well as mice treated with the JAK2 inhibitor AG490 or vehicle were exposed to CLP or sham surgery for 24 or 96 h. Results Analyses of differentially expressed genes in RNAseq (≥2‐log2‐fold change, P

On 11 September 2001 the World Trade Center (WTC) in New York was attacked by terrorists, causing the collapse of multiple buildings including the iconic 110-story ‘Twin Towers’. Thousands of people died that day from the collapse of the buildings, fires, falling from the buildings, falling debris, or other related accidents. Survivors of the attacks, those who worked in search and rescue during and after the buildings collapsed, and those working in recovery and clean-up operations were exposed to severe psychological stressors. Concurrently, these ‘WTC-affected’ individuals breathed and ingested a mixture of organic and particulate neurotoxins and pro-inflammogens generated as a result of the attack and building collapse. Twenty years later, researchers have documented neurocognitive and motor dysfunctions that resemble the typical features of neurodegenerative disease in some WTC responders at midlife. Cortical atrophy, which usually manifests later in life, has also been observed in this population. Evidence indicates that neurocognitive symptoms and corresponding brain atrophy are associated with both physical exposures at the WTC and chronic post-traumatic stress disorder, including regularly re-experiencing traumatic memories of the events while awake or during sleep. Despite these findings, little is understood about the long-term effects of these physical and mental exposures on the brain health of WTC-affected individuals, and the potential for neurocognitive disorders. Here, we review the existing evidence concerning neurological outcomes in WTC-affected individuals, with the aim of contextualizing this research for policymakers, researchers and clinicians and educating WTC-affected individuals and their friends and families. We conclude by providing a rationale and recommendations for monitoring the neurological health of WTC-affected individuals. Here, the authors summarize the evidence concerning the neurological health of individuals affected by the 11 September 2001 terrorist attacks and present the outcome of a meeting convened by the US National Institute for Occupational Safety and Health that aimed to generate recommendations for future research in this population.

Inflammatory markers represent important candidates responsible for the altered behavior and physiology observed after stressful experiences. In the maternal brain, the olfactory bulb (OB) is a key constituent of the neural circuit that mediates the reciprocal interaction between mother and infant. This study aimed to investigate the effects of stress during pregnancy on maternal behavior and inflammatory changes in the olfactory bulb of lactating mice. Female Balb/c mice were divided into two groups: control (CT) and restraint stress (RS). Maternal behavior was performed during the first 8 days of life of the offspring. On the 10th day after parturition, corticosterone, gene, and protein expression were assessed. Stress during pregnancy decreased the maternal index at postnatal day 4 and the nuclear factor-κB 1 (NFκB1) gene expression in the OB. Moreover, females from the RS group showed increased interleukin (IL-1β) protein expression. In contrast, stressed females exhibited a decreased tumor necrosis factor (TNF-α) protein expression in the OB. In conclusion, exposure to stress during pregnancy was able to induce specific postnatal effects on maternal behavior and balance of inflammatory mediators in the OB.

BACKGROUND Inflammation is a complex mechanism with an objective to destroy and eliminate the invading microorganisms. During acute inflammation, the neutrophils are the major cells involved in this process and, although they defend the organism, must die to not generate damage. The two major mechanisms that drive neutrophils to death are: apoptosis and a novel mechanism recently discovered denominated NETosis. This process is a "suicidal mechanism", in which the cells release "neutrophil extracellular traps" (NETs) during the inflammatory response. Octyl gallate (OG) is one of the gallic acid derivates, with several protective effects, such as antioxidant and anti-inflammatory in cancer models. Thus, this study aimed to investigate the action of OG on the proliferation of lymphocytes, neutrophils activation, and its effectiveness in an experimental sepsis model. METHODS Lymphocytes and neutrophils were obtained from healthy donors. Cell viability, apoptosis, NETs release and antioxidant capacity of OG were observed. In addition, survival was evaluated in an experimental model of sepsis in C57BL/6 mice. RESULTS Our study demonstrated, for the first time, that the OG can act as an inhibitor of reactive oxygen species (ROS) release, NETs formation in primary human neutrophils and, modulates the lipopolysaccharide (LPS) effect in neutrophil apoptosis. The OG also inhibited peripheral blood mononuclear cells (PBMCs) proliferation in vitro. Despite the positive results, we did not observe an increase in the survival of septic animals. CONCLUSIONS The pharmacological potential of OG, modulating activation of neutrophils and lymphocytes, suggests the use as an adjuvant therapeutic strategy in inflammatory diseases.

To evaluate the reliability of spectral-domain optical coherence tomography (SD-OCT; RTVue XR; Optovue, Inc., Fremont, CA, USA) for thickness mapping of the entire cornea (CT), corneal epithelium (ET). and corneal stroma (ST) over a 9-mm zone in healthy eyes. We sought to develop reference values for different age groups and elucidate potential sex- and age-dependent characteristics of corneal sublayer pachymetry maps.Three consecutive SD-OCT scans were obtained in 166 healthy right eyes (mean age = 50 ± 20 years). The thickness maps contain 25 sectors over a 9-mm diameter zone. To test measurement reliability, intraclass correlation coefficients (ICC), coefficients of variation (CoV), and within-subject standard deviations (WSSD) were calculated.CT, ET, and ST ICCs ranged from 0.961 to 0.998, 0.896 to 0.945, and 0.955 to 0.998, respectively. CoV values for CT, ET, and ST ranged between 0.3 and 1.5%, 1.6 and 4.2%, and 0.4 and 1.7%, respectively. WSSD ranged from 6 to 41, 4 to 8, and 7 to 46 µm, respectively. A negative correlation was found between age and ET (p 0.05) but not between age and ST or CT. No gender-related differences in CT, ET, or ST were detected. CoV of CT, ET, and ST measurements showed a positive correlation with age in 28, 64, and 28% of the sectors, respectively.SD-OCT is a rapid and noninvasive technique that provides excellent reliability for corneal sublayer thickness measurements over a 9-mm zone. The reliability of the ET measurement seems to be negatively affected by age. Peripheral CT and global ET thin with age.Die Spectral-Domain optische Kohärenztomografie (SD-OCT) hat in den letzten Jahren zunehmend auch im vorderen Augenabschnitt an Bedeutung gewonnen. Moderne SD-OCT-Geräte (RTVue XR; Optovue, Inc., Fremont, CA, USA) sind in der Lage, Pachymetriekarten der gesamten Kornea (CT), des Korneaepithels (ET) und des Korneastromas (ST) über eine 9-mm-Zone zu bestimmen. Ziele dieser Studie waren, neben einer Überprüfung der Reliabilität des Geräts, sowohl die Bestimmung von Referenzwerten für verschiedene Altersgruppen als auch die Untersuchung möglicher alters- oder geschlechtsabhängiger Merkmale der einzelnen Korneaschichten an gesunden Augen.Es wurden 3 aufeinanderfolgende SD-OCT-Aufnahmen an 166 gesunden rechten Augen (Durchschnittsalter = 50 ± 20 Jahre) angefertigt. Die Pachymetriekarten gliedern sich in 25 Sektoren über eine Fläche mit einem Durchmesser von 9 mm. Um die Reliabilität zu messen, wurden „Intraclass Correlation Coefficients“ (ICC), „Coefficients of Variation“ (CoV) und „Within-subject Standard Deviations“ (WSSD) berechnet.Die ICCs von CT, ET und ST lagen jeweils zwischen 0,961 und 0,998, 0,896 und 0,945 sowie 0,955 und 0,998. Der CoV für CT, ET und ST lag jeweils zwischen 0,3 und 1,5%, 1,6 und 4,2% sowie 0,4 und 1,7%. Die WSSD betrug 6 – 41 µm für die CT, 4 – 8 µm für die ET und 7 – 46 µm für die ST. Die Untersuchungen ergaben eine negative Korrelation zwischen Alter und ET (p 0,05). Für CT und ST konnte keine signifikante Korrelation gezeigt werden. Es wurden keine geschlechtsspezifischen Unterschiede für CT, ET oder ST festgestellt. Der CoV zeigte eine positive Korrelation mit dem Alter der Probanden in bis zu 64% der Sektoren.Die SD-OCT ist eine schnelle, nicht invasive Technik, welche für Messungen der Dicke einzelner Korneaschichten bis zu einer 9-mm-Zone eine exzellente Reliabilität bietet. Allerdings muss beachtet werden, dass die Wiederholbarkeit von Messungen des Epithels mit steigendem Alter sinkt. Ebenfalls altersabhängig wird die periphere Kornea sowie das gesamte Korneaepithel mit der Zeit dünner.

The reproductive traits of the mymarid wasp Cosmocomoidea annulicornis (Ogloblin) (Hymenoptera: Mymaridae) attacking eggs of the sharpshooter Tapajosa rubromarginata (Signoret) (Hemiptera: Cicadellidae) were evaluated under laboratory conditions. Bioassays were carried out to estimate the realized fecundity and egg load of females. The ovigeny index was calculated and different biological traits, such as body size, oöcyte length, gaster length and wing length, were analysed to assess significant associations between these traits and the species fitness. In addition, the effect of host availability and feeding on longevity and potential fecundity throughout life and the effect of female age on egg maturation dynamics were assessed. The results showed that C. annulicornis is a strongly synovigenic species. A positive correlation was found between fecundity and longevity of the females and between body size and oöcyte length. Contrary to expected, body size was not related to fecundity and longevity. Females lived significantly longer in the presence of hosts and honey than when they were host-deprived and honey-fed or both host and honey deprived. Host availability had a significant effect on the amount of eggs laid by C. annulicornis females. Female age was negatively associated with oöcyte length. Furthermore, females were able to mature additional eggs as they aged, nevertheless, when host-deprived, senescent females presented significantly less mature eggs than younger ones, suggesting a possible egg oosorption. These results might contribute to a better understanding of the reproductive potential of this species as a biocontrol agent.

Introduction Chronic kidney disease (CKD) engenders salt-sensitive hypertension. Whether or not tissue Na+ accumulation is increased in CKD patients remains uncertain. How tissue Na+ is affected after renal transplantation has not been assessed. Methods We measured tissue Na+ amount in 31 CKD patients (stage 5) and prospectively evaluated tissue Na+ content at 3 and 6 months, following living-donor kidney transplantation. Additionally, pre- and post-transplantation data were compared to 31 age- and sex-matched control subjects. 23Na–magnetic resonance imaging (23Na-MRI) was used to quantify muscle and skin Na+ of the lower leg and water distribution was assessed by bioimpedance spectroscopy. Results Compared to control subjects, CKD patients showed increased muscle (20.7 ± 5.0 vs. 15.5 ± 1.8 arbitrary units [a.u.], P < 0.001) and skin Na+ content (21.4 ± 7.7 vs. 15.0 ± 2.3 a.u., P < 0.001), whereas plasma Na+ concentration did not differ between groups. Restoration of kidney function by successful renal transplantation was accompanied by mobilization of tissue Na+ from muscle (20.7 ± 5.0 vs. 16.8 ± 2.8 a.u., P < 0.001) and skin tissue (21.4 ± 7.7 vs. 16.8 ± 5.2 a.u., P < 0.001). The reduction of tissue Na+ after transplantation was associated with improved renal function, normalization of blood pressure as well as an increase in lymphatic growth-factor concentration (vascular endothelial growth factor C [VEGF-C] 4.5 ± 1.8 vs. 6.7 ± 2.7 ng/ml, P < 0.01). Conclusions Tissue Na+ accumulation in predialysis patients with CKD was almost completely reversed to the level of healthy controls after successful kidney transplantation., Graphical abstract

Background Septic cardiomyopathy worsens the prognosis of critically ill patients. Clinical data suggest that interleukin‐1β (IL‐1β), activated by the NLRP3 inflammasome, compromises cardiac function. Whether or not deleting Nlrp3 would prevent cardiac atrophy and improve diastolic cardiac function in sepsis was unclear. Here, we investigated the role of NLRP3/IL‐1β in sepsis‐induced cardiomyopathy and cardiac atrophy. Methods Male Nlrp3 knockout (KO) and wild‐type (WT) mice were exposed to polymicrobial sepsis by caecal ligation and puncture (CLP) surgery (KO, n = 27; WT, n = 33) to induce septic cardiomyopathy. Sham‐treated mice served as controls (KO, n = 11; WT, n = 16). Heart weights and morphology, echocardiography and analyses of gene and protein expression were used to evaluate septic cardiomyopathy and cardiac atrophy. IL‐1β effects on primary and immortalized cardiomyocytes were investigated by morphological and molecular analyses. IonOptix and real‐time deformability cytometry (RT‐DC) analysis were used to investigate functional and mechanical effects of IL‐1β on cardiomyocytes. Results Heart morphology and echocardiography revealed preserved systolic (stroke volume: WT sham vs. WT CLP: 33.1 ± 7.2 μL vs. 24.6 ± 8.7 μL, P

Civilians who survive wartime attacks commonly experience substantial psychological distress, including acute stress reactions (ASRs) and posttraumatic stress disorder (PTSD). The authors sought to determine the level of Israeli civilian exposure to wartime attacks, prevalence of posttraumatic stress disorder (PTSD) and physical injuries, and associated medical costs over a 7-year period.Data from the National Insurance Institute of Israel on civilian survivors of wartime attacks in the 2009-2015 period were retrospectively examined.Overall, 11,476 civilians were affected by 243 wartime attacks during the study period. Of these individuals, 7,561 (65.9%) received early intervention (EI) psychological treatment for ASRs, 1,332 (11.6%) were subsequently adjudicated as having a disability (all causes), and 519 (4.5%) were adjudicated as disabled by PTSD through the end of 2016. Individuals who received immediate ASR treatment were less likely to be disabled by PTSD (p=0.001). Among those without physical injuries, the EI was associated with decreased PTSD disability (2.6% of those receiving the EI developed PTSD, whereas 7.2% of those who did not receive the EI developed PTSD); however, for those with physical injuries, the PTSD rate was higher among those who received the EI (30.4%) than among those who did not receive the EI (5.2%). Individuals having a disability other than PTSD incurred higher medical costs ($7,153 in 2016 U.S. dollars) than individuals with PTSD ($1,960).An approach of providing case management, medical care, behavioral health screening, and EI for ASRs in the wake of wartime attacks on civilians minimized long-term PTSD-related disability.

Objective: The objective of this study was to estimate treatment costs of Hematopoietic stem cell transplantation (HSCT) at a reference center in Brazil. Methods: The study population consisted of patients from the Unified Health System HSCT who underwent HSCT in southern Brazil between 2016 and 2019. Costs were measured using a micro-costing approach, based on Time-Driven Activity-based Costing (TDABC) adapted for economic studies in health and included the following steps: definition of the research question, structured data collection, and statistical analysis of results. Results: The total cost of HSCT was $155,110 ($92,794 – $249,146 USD). Matched unrelated donor HSCT was more expensive than matched related donor HSCT. The major cost factors involve post-ransplant complications, mainly the occurrence of infections. Concerning cost composition, exams and procedures represent the largest expense in HSCT (45%). Conclusion: These estimates could be applicable to further evaluations for HSCT cost-effectiveness and help healthcare decision-makers in middle-income countries

Allogeneic hematopoietic stem cell transplantation (alloSCT) carries the promise of cure for many malignant and non-malignant diseases of the lympho-hematopoietic system. Although outcome has improved considerably since the pioneering Seattle achievements more than 5 decades ago, non-relapse mortality (NRM) remains a major burden of alloSCT. There is increasing evidence that endothelial dysfunction is involved in many of the life-threatening complications of alloSCT, such as sinusoidal obstruction syndrome/venoocclusive disease, transplant-associated thrombotic microangiopathy, and refractory acute graft-versus host disease. This review delineates the role of the endothelium in severe complications after alloSCT and describes the current status of search for biomarkers predicting endothelial complications, including markers of endothelial vulnerability and markers of endothelial injury. Finally, implications of our current understanding of transplant-associated endothelial pathology for prevention and management of complications after alloSCT are discussed.

ObjectiveHigh levels of psychological distress increase the risk of a wide range of medical diseases. In this study, we investigated the association between posttraumatic stress disorder (PTSD) and kidney disease.MethodsWorld Trade Center (WTC) responders were included if they had two or more measures of estimated glomerular filtration rate (eGFR). The PTSD Checklist (PCL) was used to define no PTSD (PCL < 40), "mild" PTSD (40 ≤ PCL

Introduction World Trade Center (WTC) responders have a high risk of early-onset cognitive impairment (CI), but little is known about the etiology including the extent to which CI in WTC responders is accompanied by cortical atrophy as is common in progressive diseases causing age-related CI such as Alzheimer’s disease and related dementias. In the current study, we entrained an artificial neural network (ANN) to determine the accuracy of cortical thickness (CTX) on magnetic resonance imaging to identify World Trade Center responders at midlife (aged 44–65 years) with possible dementia. Methods A total of 119 WTC responders (57 with CI and 62 with intact cognition) underwent a structural MRI scanning protocol including T1-weighted MPRAGE as part of two imaging studies. The discovery study was divided into training and validation samples, while a second replication sample was used. An ANN was trained using regional CTX measured across 34 unilateral regions of interest (ROIs) using Freesurfer software and ‘Desikan-Killiany’ brain atlas. The discovery sample was used for model development, and the replication sample was used to evaluate predictive accuracy. Results In the WTC responder cohort, the ANN algorithm showed high discrimination performance for CI. The ANN model using regional CTX data from both hemispheres achieved an area under the receiver operating characteristic curve (AUC) of 0.96 95% C.I. ​= ​[0.91–1.00] (Accuracy ​= ​96.0%, Precision ​= ​97.8%, Recall ​= ​95.8%, Sensitivity ​= ​95.8%, Specificity ​= ​98.0%, F1 ​= ​96.8%) for the discovery sample and AUC ​= ​0.90 [0.70–1.00] (Accuracy ​= ​90.0%, Precision ​= ​90.0%, Sensitivity ​= ​90.0%, Specificity ​= ​90.0%, F1 ​= ​90.0%) in the replication sample. Conclusion Analysis of bilateral regional CTX data derived from T1-weighted MPRAGE images by ANN analysis demonstrated excellent accuracy in distinguishing WTC responders with early-onset CI.

Purpose There is an ongoing controversial debate about the effectiveness of laser treatments in chronic central serous chorioretinopathy (cCSC). We performed a prospective non-randomized interventional study to learn about the effects of a subthreshold laser treatment (Topcon Endpoint Management™, Topcon Healthcare Inc., Tokyo, Japan) in patients with cCSC. Methods Patients with cCSC and a minimum symptom duration of 4 months were included and treated with a standardized laser pattern covering the macular area. Retreatment was performed every 3 months if persistent subretinal fluid was observed. The primary endpoint was resolution of subretinal fluid at 6 months. Further outcome parameters included best corrected visual acuity, microperimetry, central macular and subfoveal choroidal thickness. Results A total of 42 eyes of 39 patients were included. Mean patient age was 48 ± 10.6 years (range 25–67). Mean symptomatic time before inclusion into the study was 134 ± 133.4 weeks (16–518). Before inclusion, 78.6% of the patients had failed to resolve subretinal fluid under mineralocorticoid receptor antagonists and 14.3% had a recurrence after half-dose photodynamic therapy. Complete resolution of subretinal fluid was observed in 42.9% at 6 months and in 53.8% at 12 months after baseline. Central retinal thickness decreased from 398 ± 135 µm to 291 ± 68 µm (p Conclusion The results show that the investigated laser treatment is effective in reducing subretinal fluid and leads to an improvement of functional parameters.

Background Posttraumatic stress disorder (PTSD) symptoms are common in the immediate aftermath of a trauma, but it is their persistence over time that leads to a diagnosis. This pattern highlights the critical role of symptom maintenance to understanding and treating the disorder. Relatively few studies have explored whether PTSD symptoms may be interacting or triggering one another to worsen and maintain the disorder, a dynamic we refer to as “symptom cascades.” Additionally, little work has tested in real-time how other maintenance factors, such as stress, contribute to such events in daily life. Methods The present study in a group (N = 202) of World Trade Center (WTC) responders oversampled for PTSD tested day-to-day temporal associations among PTSD symptom dimensions (i.e., intrusions, avoidance, numbing, and hyperarousal) and stress across one week. Results Longitudinal models found hyperarousal on a given day predicted increased PTSD symptoms the next day, with the effect sizes almost double compared to other symptom dimensions or daily stress. Intrusions, in contrast, showed little prospective predictive effects, but instead were most susceptible to the effects from other symptoms the day before. Avoidance and numbing showed weaker bidirectional effects. Limitations Findings are from a unique population and based on naturalistic observation. Conclusions Results are consistent with the idea of symptom cascades, they underscore hyperarousal's strong role in forecasting short-term increases in PTSD (even more than stress per se) and they raise the prospect of highly specific ecological momentary interventions to potentially disrupt PTSD maintenance in daily life.

Lamellar macular holes (LMHs) are an entity of a progressive disease in which the efficacy of the therapy of choice, vitrectomy, seems to be reduced. It is unknown whether highly concentrated autologous platelet-rich plasma (PRP) is of value in the therapy of LMHs. The purpose of this study was to gauge the potential of highly concentrated PRP to restore foveal anatomy in LMH surgery.In this interventional case series, eight eyes of eight patients with progressive LMH were included. All patients underwent a 23-gauge pars plana vitrectomy with induction of a posterior vitreous detachment and peeling of tractive epiretinal membranes whenever present. Under air tamponade, 0.1 mL of highly concentrated autologous PRP was applied. Subsequently, a gas or air tamponade was performed. All patients were instructed to rest in the supine position for the first 1 to 2 postoperative hours. Best-corrected visual acuity (BCVA) testing, microperimetry, spectral-domain optical coherence tomography (SD-OCT) and fundus photography were performed prior to and 3 months after surgery.SD-OCT showed closure of the macular defect with restoration of a normal foveal configuration in all (8 of 8) patients 3 months postoperatively. BCVA improved significantly, from 0.28 ± 0.08 to 0.12 ± 0.14 logMAR (Wilcoxon: p = 0.03). Microperimetry remained unchanged (24.13 ± 1.96 vs. 23.7 ± 1.54 dB; p = 0.46). No clinically significant intra- or postoperative complications were observed.The use of highly concentrated PRP enables excellent anatomical and functional outcomes in the surgical therapy of LMH. Further prospective comparative trials are warranted to compare this promising technique with existing surgical strategies.Makulaschichtforamina sind eine progrediente Erkrankung, bei der die Wirksamkeit der Therapie der Wahl, der Vitrektomie, reduziert zu sein scheint. Das Potenzial von hochkonzentriertem autologem Thrombozytenkonzentrat (Platelet-rich Plasma, PRP) in der Therapie von Makulaschichtforamina ist unbekannt. Ziel dieser Studie ist die Beurteilung des Potenzials von hochkonzentriertem autologem Thrombozytenkonzentrat in der chirurgischen Therapie von Makulaschichtforamina.In diese interventionelle Fallserie wurden 8 Augen von 8 Patienten mit progressivem LMH eingeschlossen. Alle Patienten erhielten eine 23-Gauge-Pars-plana-Vitrektomie mit Induktion einer hinteren Glaskörperabhebung und Peeling traktiver epiretinaler Membranen, sofern vorhanden. Unter Lufttamponade wurde 0,1 ml hochkonzentriertes autologes Thrombozytenkonzentrat appliziert. Anschließend wurde eine Gas- oder Lufttamponade eingegeben. Alle Patienten wurden angewiesen, in den ersten 1 – 2 postoperativen Stunden in Rückenlage zu ruhen. Der bestkorrigierte Visus (BCVA), Mikroperimetrie, optische Kohärenztomografie (SD-OCT) und die Fundusfotografie erfolgten präoperativ sowie 3 Monate postoperativ.In der SD-OCT zeigte sich einen Verschluss des Makuladefekts mit Wiederherstellung der normalen fovealen Konfiguration bei allen (8 von 8) Patienten 3 Monate postoperativ. Die bestkorrigierte Sehschärfe verbesserte sich signifikant von 0,28 ± 0,08 auf 0,12 ± 0,14 logMAR (Wilcoxon: p = 0,03). Die Mikroperimetrie blieb stabil (24,13 ± 1,96 vs. 23,7 ± 1,54 dB; p = 0,46). Es wurden keine klinisch signifikanten intra- oder postoperativen Komplikationen beobachtet.Die Verwendung von hochkonzentriertem autologem Thrombozytenkonzentrat ermöglicht hervorragende anatomische und funktionelle Ergebnisse in der chirurgischen Therapie der Makulaschichtforamina. Weitere prospektive Vergleichsstudien sind notwendig, um diese vielversprechende Technik mit bestehenden chirurgischen Strategien zu vergleichen.

Background Whether patients with stroke and cancer exhibit specific characteristics has remained controversial. Methods Medical records of patients with ischemic stroke in 2014 or 2015 registered in the Swiss Stroke Registry of Zurich were retrospectively analyzed and integrated with regional cancer registry data. Associations of clinical and outcome parameters with cancer diagnosed up to 5 years prior to stroke were tested. Results Of 753 patients with ischemic stroke, 59 patients with cancer were identified. History of venous thromboembolism (p p = 0.001), erythrocyte sedimentation rate (p = 0.003), C-reactive protein (CRP) (p p = 0.003) were associated with cancer. For platelets, pathologically low (p = 0.034) or high levels (p p = 0.038 and p = 0.001). Poor post-stroke survival was associated with cancer (HR 2.2, p Conclusions Considering cancer as a cofactor for post-stroke outcome may impact clinical decision making.

Gene expression has provided promising insights into the pathophysiology of post-traumatic stress disorder (PTSD); however, specific regulatory transcriptomic mechanisms remain unknown. The present study addressed this limitation by performing transcriptome-wide RNA-Seq of whole-blood samples from 226 World Trade Center responders. The investigation focused on differential expression (DE) at the gene, isoform, and for the first time, alternative splicing (AS) levels associated with the symptoms of PTSD: total burden, re-experiencing, avoidance, numbing, and hyperarousal subdimensions. These symptoms were associated with 76, 1, 48, 15, and 49 DE genes, respectively (FDR

Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

Background Despite the prevalence of antidepressant-related sexual side effects, comparisons of treatments for these problematic side effects are lacking. Methods To address this, we performed a systematic review and Bayesian network meta-analysis to compare interventions for antidepressant-induced sexual dysfunction in adults. Using PubMed and clinicaltrials.gov, we identified published and unpublished prospective treatment trials from 1985 to September 2020 (primary outcome: the Arizona sexual experience scale [ASEX] score). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework. Results We identified 57 citations (27 randomized controlled trials, 66 treatment arms, 27 open-label trials, and 3 crossover trials) that evaluated 33 interventions (3108 patients). In the systematic review, 44% (25/57) of trials reported successful interventions; this was more common in open-label (70%, 19/27) compared to placebo-controlled studies (22%, 6/27). In the meta-analysis of placebo-controlled studies that used the ASEX (N = 8), pycnogenol was superior to placebo (standardized mean difference: −1.8, 95% credible interval [CrI]: [−3.7 to 0.0]) and there was evidence that, at a 6% threshold, sildenafil improved sexual dysfunction (standardized mean difference: −1.2, 95% CrI [−2.5 to 0.1]). In the meta-analysis including single-arm studies (15 studies), treatment response was more common with sildenafil, tianeptine, maca, tiagabine, and mirtazapine compared to placebo, but these differences failed to reach statistical significance. Conclusions While heterogeneity across randomized controlled trials complicates identifying the single best intervention, multiple trials suggest that sildenafil ameliorates antidepressant-induced sexual dysfunction. More randomized controlled trials are needed to examine the putative efficacy of other interventions.

Although genetic risk scores have been used to predict hypertension, their utility in the clinical setting remains uncertain. Our study comprised N=218 792 FinnGen participants (mean age 58 years, 56% women) and N=22 624 well phenotyped FINRISK participants (mean age 50 years, 53% women). We used public genome-wide association data to compute polygenic risk scores (PRSs) for systolic and diastolic blood pressure (BP). Using time-to-event analysis, we then assessed (1) the association of BP PRSs with hypertension and cardiovascular disease (CVD) in FinnGen and (2) the improvement in model discrimination when combining BP PRSs with the validated 4- and 10-year clinical risk scores for hypertension and CVD in FINRISK. In FinnGen, compared with having a 20 to 80 percentile range PRS, a PRS in the highest 2.5% conferred 2.3-fold (95% CI, 2.2–2.4) risk of hypertension and 10.6 years (95% CI, 9.9–11.4) earlier hypertension onset. In subgroup analyses, this risk was only 1.6-fold (95% CI, 1.5–1.7) for late-onset hypertension (age ≥55 years) but 2.8-fold (95% CI, 2.6–2.9) for early-onset hypertension (age

Background: Individuals who participated in response efforts at the World Trade Center (WTC) following 9/11/2001 are experiencing elevated incidence of mild cognitive impairment (MCI) at midlife. Objective: We hypothesized that white matter connectivity measured using diffusion spectrum imaging (DSI) would be restructured in WTC responders with MCI versus cognitively unimpaired responders. Methods: Twenty responders (mean age 56; 10 MCI/10 unimpaired) recruited from an epidemiological study were characterized using NIA-AA criteria alongside controls matched on demographics (age/sex/occupation/race/education). Axial DSI was acquired on a 3T Siemen’s Biograph mMR scanner (12-channel head coil) using a multi-band diffusion sequence. Connectometry examined whole-brain tract-level differences in white matter integrity. Fractional anisotropy (FA), mean diffusivity (MD), and quantified anisotropy were extracted for region of interest (ROI) analyses using the Desikan-Killiany atlas. Results: Connectometry identified both increased and decreased connectivity within regions of the brains of responders with MCI identified in the corticothalamic pathway and cortico-striatal pathway that survived adjustment for multiple comparisons. MCI was also associated with higher FA values in five ROIs including in the rostral anterior cingulate; lower MD values in four ROIs including the left rostral anterior cingulate; and higher MD values in the right inferior circular insula. Analyses by cognitive domain revealed nominal associations in domains of response speed, verbal learning, verbal retention, and visuospatial learning. Conclusions: WTC responders with MCI at midlife showed early signs of neurodegeneration characterized by both increased and decreased white matter diffusivity in regions commonly affected by early-onset Alzheimer’s disease.

Objective: to characterize hospitalizations for female breast cancer in the public network of the Metropolitan Region of Porto Alegre from 2016 to 2018. Method: population-based epidemiological study, observational, cross-sectional and retrospective study with analysis of secondary health data accessed in the Hospital Information System of the Unified Health System of hospitalizations with a diagnosis of breast cancer. The extracted variables were hospitalizations by age group, race/color, length of stay, deaths, mortality rate and hospital expenditure. Results: In this period, 7,049 hospitalizations occurred, 3,807 (54%) between 50 and 69 years of age. The average stay in hospital was 4 days and the average total cost/year by SUS was 375,374.604 reais. In the triennium there were 504 (7.15%) due to the disease. Conclusion: Hospitalizations for breast cancer in women in the RMPA have a direct impact on thein crease in expenses and on the longer use of hospital beds, making assistance to this type of disease increasingly costly.

Vor uber 100 Jahren wurde ein genetischer Einfluss auf den Blutdruck nachgewiesen und ein einfacher Erbgang gemas den Mendel-Regeln vermutet. Platt und Pickering fuhrten eine lebhafte Debatte uber dieses Thema. Platt favorisierte die Idee, dass ein einzelnes Gen oder nur wenige Gene fur den Bluthochdruck verantwortlich seien. Pickering legte Forschungsergebnisse vor, die vermuten liesen, dass viele Gene Einfluss auf den Blutdruck ausuben. Dies alles in einer Zeit, in der man noch nicht wusste, was Gene uberhaupt sind. Genomweite Assoziationsstudien (GWAS) nach dem Pickering-Modell weisen auf > 500 blutdruckrelevante Genloci hin, die uber das gesamte Genom verteilt sind. Jedes einzelne Gen ubt nur einen kleinen Einfluss auf den Blutdruck aus. Als Ausenseiter der Hochdruckforschung gelten sekundare Ursachen. Bei Phaochromozytom, Aldosteronismus, Cushing-Syndrom und sogar bei der fibromuskularen Dysplasie (renovaskulare Hypertonie) lassen die Ergebnisse darauf schliesen, dass der sekundaren Hypertonie regelmasig eine genetische Ursache zugrunde liegt. Damit wurde auch die Theorie von Platt teilweise bestatigt. Mittlerweile wurde eine Vielzahl von Hypertonieformen mit einem genetischen Erbgang nach Mendel beschrieben. Jede dieser Genvarianten ubt einen betrachtlichen Einfluss auf den Blutdruck aus. Eine Vielzahl neuer physiologischer Mechanismen wurde dadurch aufgeklart. Diese Befunde werden therapeutische Bedeutung haben. Also obliegt es den Klinikern, uber diese Forschungsergebnisse bestens informiert zu sein.