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BACKGROUND & AIMS: This study aimed to assess the accuracy of functional luminal imaging probe (FLIP) Panometry to detect esophagogastric junction (EGJ) obstruction assigned by high-resolution manometry (HRM) and the Chicago Classification version 4.0 (CCv4.0). METHODS: 687 adult patients that completed FLIP and HRM for primary esophageal motility evaluation and 35 asymptomatic volunteers (“controls”) were included. EGJ opening was evaluated with 16-cm FLIP during sedated endoscopy via EGJ-distensibility index (DI) and maximum EGJ diameter. HRM was classified according to CCv4.0 and focused on studies with a conclusive disorder of EGJ outflow (i.e. achalasia subtypes I, II, or III; or EGJ outflow obstruction with abnormal timed barium esophagram) or normal EGJ outflow. RESULTS: All 35 controls had EGJ-DI >3.0mm(2)/mmHg and maximum EGJ diameter >16mm. Per HRM and CCv4.0, 245 patients had a conclusive disorder of EGJ outflow and 314 patients had normal EGJ outflow. Among the 241 patients with reduced EGJ opening (REO: EGJ-DI

Background: Individuals with obesity frequently contend with pain, but few studies address the clinical impact of comorbidity within this population. This study compared the early weight loss outco...

Among recent advances in diagnostics for dysphagia and esophageal motility disorders is the update to the Chicago Classification (version 4.0) for interpretation of high-resolution manometry (HRM) and diagnosis of esophageal motility disorders. The update incorporates application of complementary testing strategies during HRM, such as provocative HRM maneuvers, and recommendation for barium esophagram or functional luminal imaging probe (FLIP) panometry to help clarify inconclusive HRM findings. FLIP panometry also represents an emerging technology for evaluation of esophageal distensibility and motility at the time of endoscopy.

Within the brain, traumatic brain injury (TBI) alters synaptic plasticity and increases neuroinflammation and neuronal death. Yet, there lacks effective TBI treatments providing pleiotropic beneficial effects on these diverse cellular processes necessary for functional recovery. Here, we show the diabetes drug, metformin, significantly improves cognitive functions after controlled cortical impact (CCI) injury in mice, showing improved spatial learning and nest building. Furthermore, injured animals treated with metformin exhibit increased ramification of microglia processes, indicating reduced neuroinflammation. Finally, metformin treatment in vitro increased neuronal activation of partitioning defective 1 (Par1), a family of Ser/Thr kinases playing a key role in synaptic plasticity and neuroinflammation. These results suggest metformin is a promising therapeutic agent for targeting multiple cellular processes necessary for functional TBI recovery.

Numerous diagnostic and therapeutic innovations in the treatment of advanced prostate cancer, both in the hormone-sensitive and in the castration-resistant situation, recently led to a new orientation in the management of this tumor. However, there are potential indications beyond the ones covered by the S3 guideline on early detection, diagnosis and therapy of prostate cancer in clinical care that might be helpful for patients.Since July 2018, an interdisciplinary group of experts from nuclear medicine, radiologists, radio-oncologists and urologists developed a consensus paper on state-of-the-art innovations in imaging diagnostics and radionuclide-based therapies for advanced prostate cancer.Provided by the working group are suggestions and strategies to improve the implementation of new imaging techniques such as multiparametric magnetic resonance imaging (mpMRI), PSMA-PET/CT (prostate-specific membrane antigen-positron emission tomography/computed tomography) and innovative therapeutic options (radium-223 dichloride, lutetium-177-PSMA) in the complex treatment of metastatic castration-resistant prostate cancer (mCRPC).HINTERGRUND: Die zahlreichen diagnostischen und therapeutischen Innovationen beim fortgeschrittenen Prostatakarzinom, sowohl in der hormonsensitiven als auch in der kastrationsresistenten Situation, haben in den letzten Jahren zu einer Neuorientierung beim Management dieses Tumors geführt. Ungeachtet der bereits in Teilen in der S3-Leitlinie zu Früherkennung, Diagnose und Therapie des Prostatakarzinoms abgebildeten neuen diagnostischen und therapeutischen Methoden, gibt es in der klinischen Versorgung darüber hinaus gehende Fälle, in denen Patienten von diesen innovativen Verfahren potenziell profitieren könnten.Seit Juli 2018 trifft sich deshalb eine interdisziplinäre Expertengruppe aus Nuklearmedizinern, Radiologen, Radioonkologen und Urologen, um ein Konsensuspapier zu Innovationen der bildgebenden Diagnostik und radionuklidbasierten Therapien des fortgeschrittenen Prostatakarzinoms vor dem Hintergrund aktueller Studien und Erfahrungen im klinischen Alltag zu erarbeiten.Der Arbeitskreis gibt Anregungen, um zu einer besseren Implementierung neuer bildgebender Techniken, wie multiparametrische Magnetresonanztomographie (mpMRT), PSMA-PET/CT (prostataspezifisches Membranantigen – Positronenemissionstomographie/Computertomographie) und innovativer therapeutischer Optionen (Radium-223-dichlorid, Lutetium-177-PSMA) bei den komplexen Therapieoptionen des fortgeschrittenen Prostatakarzinoms beizutragen.

Introduction High-resolution manometry (HRM) is generally considered the primary method to evaluate esophageal motility; functional luminal imaging probe (FLIP) panometry represents a novel method to do so and is completed during sedated endoscopy. This study aimed to compare HRM and FLIP panometry in predicting esophageal retention on timed barium esophagram (TBE). Methods A total of 329 adult patients who completed FLIP, HRM, and TBE for primary esophageal motility evaluation were included. An abnormal TBE was defined by a 1-minute column height >5 cm or impaction of a 12.5-mm barium tablet. The integrated relaxation pressure (IRP) on HRM was assessed in the supine and upright patient positions. Esophagogastric junction (EGJ) opening was evaluated with 16-cm FLIP performed during sedated endoscopy through EGJ-distensibility index and maximum EGJ diameter. Results Receiver operating characteristic curves to identify an abnormal TBE demonstrated AUC (95% confidence interval) of 0.79 (0.75-0.84) for supine IRP, 0.79 (0.76-0.86) for upright IRP, 0.84 (0.79-0.88) for EGJ-distensibility index, and 0.88 (0.85-0.92) for maximum EGJ diameter. Logistic regression to predict abnormal TBE showed odds ratios (95% confidence interval) of 1.8 (0.84-3.7) for consistent IRP elevation and 39.7 (16.4-96.2) for reduced EGJ opening on FLIP panometry. Of 40 patients with HRM-FLIP panometry discordance, HRM-IRP was consistent with TBE in 23% while FLIP panometry was consistent with TBE in 78%. Discussion FLIP panometry provided superior detection of esophageal retention over IRP on HRM. However, application of a complementary evaluation involving FLIP panometry, HRM, and TBE may be necessary to accurately diagnose esophageal motility disorders.

More than 30 years have passed since endothelial nitric oxide synthesis was described using the umbilical artery and vein endothelium. That seminal report set the cornerstone for unveiling the molecular aspects of endothelial function. In parallel, the understanding of placental physiology has gained growing interest, due to its crucial role in intrauterine development, with considerable long-term health consequences. This review discusses the evidence for nitric oxide (NO) as a critical player of placental development and function, with a special focus on endothelial nitric oxide synthase (eNOS) vascular effects. Also, the regulation of eNOS-dependent vascular responses in normal pregnancy and pregnancy-related diseases and their impact on prenatal and postnatal vascular health are discussed. Recent and compelling evidence has reinforced that eNOS regulation results from a complex network of processes, with novel data concerning mechanisms such as mechano-sensing, epigenetic, posttranslational modifications, and the expression of NO- and l-arginine-related pathways. In this regard, most of these mechanisms are expressed in an arterial-venous-specific manner and reflect traits of the fetal systemic circulation. Several studies using umbilical endothelial cells are not aimed to understand placental function but general endothelial function, reinforcing the influence of the placenta on general knowledge in physiology.

The lack of interpretability of neural networks is partially why they are not adopted in a wider variety of applications. Many works focus on explaining their predictions, but few take tabular data into consideration, which led to a small adoption even though this data is of high academic and business interest. We present relevance aggregation, an algorithm that combines the relevance computed from several samples as learned by a neural network and generates scores for each input feature. We also present two methods for visualizing the learned patterns, leading to a better model comprehension. The method was tested in synthetic and real-world datasets (breast cancer gene expression, online shopping behavior, and national high school exam) for classification and regression tasks. It correctly identified which features are the most important for the network’s predictions. The selected features can be distinct for each class. The rank of features scores also matches their contribution to the model’s performance. The results selected relevant features from the data, paving the way for knowledge discovery. The top-ranked features were consistently able to improve the performance of another independent classifier. For poorly trained neural networks, relevance aggregation helped identify incorrect rules or machine bias.

Purpose The aim of this retrospective study was to evaluate the use of [68Ga]Ga-PSMA PET/CT in therapy response assessment (TRA) of mCRPC patients treated with [177Lu]Lu-PSMA-617 and its correlation with overall survival (OS). Methods Thirty-nine patients were included in the study. Patient-/lesion-based early and late response assessment (ERA/LRA) was defined as PET2 (after two therapy cycles) vs. PET1 (before the first cycle) (n = 29) and end of treatment PET vs. PET1 (n = 17), respectively. PET-based response (PET parameters; modified (m) PERCIST/EORTC), biochemical response (ΔPSA; category-based) and category-based clinical response (CRA) was tested for correlation/agreement. PET-based TRA was correlated with OS. Results A significant correlation/agreement was shown between PET parameters and CRA as well as biochemical response in LRA of all lesions and between mPERCIST-based and category-based PSA response assessment in LRA (bone lesion-based, P = 0.045, κ = 0.184). At ERA, OS was significantly higher in CR/PR/SD compared to progressive disease applying mPERCIST/EORTC criteria (P = 0.0024). Conclusion In [177Lu]Lu-PSMA-617-treated mCRPC patients OS of the group of CR/PR/SD was significantly higher compared to the progressive disease group (mPERCIST/EORTC) in ERA. Therefore, [68Ga]Ga-PSMA PET might serve as a complementary diagnostic tool for TRA offering prognostic value regarding OS.

ZusammenfassungDiese Handlungsempfehlung soll eine Grundlage für die Qualitätssicherung der Radiosynoviorthese (RSO) bei entzündlichen (nichtinfektiösen) Gelenkerkrankungen schaffen. Sie wurde interdisziplinär erarbeitet und beschreibt die allgemeine Zielsetzung, Definitionen, klinische Hintergrundinformationen und Kontraindikationen dieser Radionuklidtherapie. Aufgeführt werden die Anforderungen, die an ein Behandlungszentrum gestellt werden, prätherapeutisch notwendige Untersuchungsbefunde sowie Empfehlungen, wie die Behandlung technisch und organisatorisch durchgeführt werden sollte. Ferner finden sich Angaben zur Kontrolle und Nachsorge der therapierten Patienten. Grundsätzlich sollen Behandlung und Nachsorge in Abstimmung und Zusammenarbeit der beteiligten Fachdisziplinen erfolgen.

Objective Individuals with obesity frequently contend with chronic pain, but few studies address the clinical impact of coordinated pain services on this population. The current study addresses this topic by comparing the effectiveness of a comprehensive pain rehabilitation program for patients with and without obesity. Methods A retrospective analysis of registry data was conducted. Obesity was considered as one of three weight groups, based on the following body mass index cutoffs: normal weight (18.5 to < 25 kg/m2), overweight (25 to < 30 kg/m2), and obese (> 30 kg/m2). These groups were compared on the Pain Severity Ratings (PSR) Scale, the Pain Disability Index (PDI), and the Depression, Anxiety, Stress Scales—Short Form (DASS-SF). Results Groups differed on baseline pain disability and depression. Patients with obesity had higher scores on both the PDI (P = .028) and the DASS-SF depression subscale (P = .006). Contrary to the hypothesis, after controlling for baseline score and sex there were no significant differences between weight groups with regards to PSR, PDI, or any DASS-SF subscale at discharge. At 1-year follow-up, individuals who were overweight and obese had significantly more anxiety compared to individuals whose weight was in the normal range. Conclusions Multidisciplinary pain rehabilitation programs appear to be an effective treatment intervention for patients who have concomitant chronic pain and obesity, to a degree comparable to patients who have chronic pain but do not contend with obesity. Implications for program development, clinical interventions, and future research are discussed.

Zusammenfassung Hintergrund Mit der zunehmenden Verbreitung der Lu-177-PSMA-RLT zur Behandlung des fortgeschrittenen Prostatakarzinoms ist von Interesse, wie sich die Versorgungssituation mit Blick auf die hierfür nötigen nuklearmedizinischen Therapiebetten angesichts hoher Fallzahlen beim fortgeschrittenen PCa hypothetisch darstellen würde, und ob es hier potenziell zu einem infrastrukturbedingten Engpass für die Patientenversorgung kommen könnte. Methodik Das in deutschen Krankenhäusern verfügbare Angebot an nuklearmedizinischen Therapiebetten wurde dem bei etwaiger Zulassung eines Therapeutikums zur Lu-177-PSMA-RLT als Letztlinientherapie für mCRPC-Patienten perspektivisch insgesamt zu rechnenden nuklearmedizinischen Nachfragepotenzial an Therapiebetten in einer Basiskalkulation gegenübergestellt. Eine mögliche Ausweitung des Lu-PSMA-Indikationsspektrums wurde dabei nicht berücksichtigt. Ergebnisse Nach der Basiskalkulation ergäbe sich bei einer bundesweit aktuellen nuklearmedizinischen Bettenkapazität von ca. 234 000 Behandlungstagen eine rechnerisch geringe Reserve von bundesweit ca. 19 000 nuklearmedizinischen Bettentagen, was umgerechnet einer Reserve von 63 Betten für die interessierende Fragestellung entspricht. Dabei zeigen sich regionale Unterschiede bei der Bettenkapazität: Während sich für einige Bundesländer eine rechnerische Unterkapazität an nuklearmedizinischen Therapiebetten bei Zulassung der Lu-177-PSMA-RLT andeutet, gilt dies für andere Bundesländer weniger. Diskussion Diese Basiskalkulation zeigt, dass die Kapazität nuklearmedizinischer Therapiebetten bei einer etwaig zugelassenen Lu-177-PSMA-RLT für mCRPC sehr gut ausgelastet sein dürfte, in einigen Bundesländern sogar an ihre Grenzen stoßen könnte. Bei einer perspektivischen Ausweitung des Indikationsspektrums oder absehbar klinischen Etablierung weiterer therapeutischer Radiopharmaka könnte die Bettenzahl mittelfristig einen Engpassfaktor für das flächendeckende Behandlungsangebot darstellen.

Absence seizures are generalized nonmotor epileptic seizures with abrupt onset and termination. Transient impairment of consciousness and spike-slow wave discharges (SWDs) in EEG are their characteristic manifestations. This type of seizure is severe in two common pediatric syndromes: childhood (CAE) and juvenile (JAE) absence epilepsy. The appearance of low-cost, portable EEG devices has paved the way for long-term, remote monitoring of CAE and JAE patients. The potential benefits of this kind of monitoring include facilitating diagnosis, personalized drug titration, and determining the duration of pharmacotherapy. Herein, we present a novel absence detection algorithm based on the properties of the complex Morlet continuous wavelet transform of SWDs. We used a dataset containing EEGs from 64 patients (37 h of recordings with almost 400 seizures) and 30 age and sex-matched controls (9 h of recordings) for development and testing. For seizures lasting longer than 2 s, the detector, which analyzed two bipolar EEG channels (Fp1-T3 and Fp2-T4), achieved a sensitivity of 97.6% with 0.7/h detection rate. In the patients, all false detections were associated with epileptiform discharges, which did not yield clinical manifestations. When the duration threshold was raised to 3 s, the false detection rate fell to 0.5/h. The overlap of automatically detected seizures with the actual seizures was equal to ~96%. For EEG recordings sampled at 250 Hz, the one-channel processing speed for midrange smartphones running Android 10 (about 0.2 s per 1 min of EEG) was high enough for real-time seizure detection.

Rationale: Maternal obesity is associated with asthma in the offspring. Whether cord blood leptin is associated with risk of asthma in offspring is unclear.Objectives: To assess whether cord blood ...

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

In den letzten Jahren gewinnt die nuklearmedizinische Theranostik mit radioaktiv markierten PSMA(prostataspezifisches Membranantigen)-Liganden einen zunehmenden Stellenwert in der Behandlung des Prostatakarzinoms. In dieser Arbeit sollen theranostische Ansatze unter Verwendung radioaktiv markierter PSMA-Liganden dargestellt und deren Stellenwert fur Diagnostik und Therapie von fortgeschrittenen Prostatakarzinomen beleuchtet werden. Aktuelle Erkenntnisse der Literatur werden zusammengefasst dargestellt. Die PSMA-PET/CT zeigt eine hohe Sensitivitat und Spezifitat in der Bildgebung des Prostatakarzinoms, insbesondere bei Patienten mit biochemischem Rezidiv. Daruber hinaus zeigen sich auch vielversprechende Daten zum Primar-Staging und zum Therapiemonitoring. Die Radioligandentherapie mit α‑ und β‑Strahlern ist eine erfolgversprechende Drittlinientherapieoption bei austherapierten, metastasierten Patienten. Zunehmende Bedeutung kommt der Reduktion von Nebenwirkungen und der Optimierung der Therapiesequenz zu. Die nuklearmedizinische Theranostik hat einen zunehmenden klinischen Stellenwert fur die Diagnostik und Behandlung des Prostatakarzinoms.

Schistosomiasis represents one of the most devastating worm parasitosis in the world. Current diagnostic methods are insufficient to determine the infection grade and the disease related organ damage. We herein investigated whether discrimination of infection grade and its correlation to liver damage could be accurately performed by multimodal imaging in a mouse model of Schistosoma mansoni infection. Therefore, groups of uninfected and infected mice underwent MRI and [18F]FDG PET/CT imaging. Anatomical MRI images were used for liver volumetry and for quantification of hepatic granulomas. For PET/CT images a volume of interest based analyses were employed to calculate the [18F]FDG uptake in liver, portal vein, spleen and abdomen. Herein, we demonstrate that the combined use of [18F]FDG-PET/CT and MRI represents an appropriate diagnostic tool for Schistosoma mansoni infection, but fails to discriminate the infection grade and the linked organ damage. Only the splenic [18F]FDG uptake in the 25 cercariae group (5.68 ± 0.90%ID/cc) and 50 cercariae group (4.98 ± 1.43%ID/cc) was significantly higher compared to the control group (2.13 ± 0.69%ID/cc). Nevertheless, future multimodal imaging studies with new radiopharmaceuticals could build a highly sensitive and specific basis for the diagnosis and evaluation of organ damage of schistosomiasis.

Obstructive sleep apnea (OSA), a breathing disorder featured by chronic intermittent hypoxia (CIH) is associated with pulmonary hypertension (PH). Rodents exposed to CIH develop pulmonary vascular remodeling and PH, but the pathogenic mechanisms are not well known. Overexpression of Stim-activated Transient Receptor Potential Channels (TRPC) and Calcium Release-Activated Calcium Channel Protein (ORAI) TRPC-ORAI Ca 2+ channels (STOC) has been involved in pulmonary vascular remodeling and PH in sustained hypoxia. However, it is not known if CIH may change STOC levels. Accordingly, we studied the effects of CIH on the expression of STOC subunits in the lung and if these changes paralleled the progression of the vascular pulmonary remodeling and PH in a preclinical model of OSA. Male Sprague-Dawley rats (∼200 g) were exposed to CIH (5%O 2 , 12 times/h for 8 h) for 14, 21, and 28 days. We measured right ventricular systolic pressure (RVSP), cardiac morphometry with MRI, pulmonary vascular remodeling, and wire-myographic arterial responses to KCl and endothelin-1 (ET-1). Pulmonary RNA and protein STOC levels of TRPC1, TRPC4, TRPC6, ORAI 1, ORAI 2, and STIM1 subunits were measured by qPCR and western blot, and results were compared with age-matched controls. CIH elicited a progressive increase of RVSP and vascular contractile responses to KCl and ET-1, leading to vascular remodeling and augmented right ventricular ejection fraction, which was significant at 28 days of CIH. The levels of TRPC1, TRPC4, TRPC 6, ORAI 1, and STIM 1 channels increased following CIH, and some of them paralleled morphologic and functional changes. Our findings show that CIH increased pulmonary STOC expression, paralleling vascular remodeling and PH.

ZusammenfassungSeit Einführung der PET/CT im Jahr 2001 bzw. der PET/MRT im Jahr 2010 ist die PET als Hybridbildgebung und Instrument einer bildgesteuerten Präzisionsmedizin zunehmend zu einem Versorgungsstandard in der Onkologie geworden. Die zentrale Schnittstelle in der Kommunikation zwischen den zuweisenden onkologisch tätigen Ärzten und dem Nuklearmediziner und Radiologen stellt der schriftliche Befund dar, der das Patientenmanagement und Outcome beeinflusst, aber auch juristisch-relevante Dokumentation der erbrachten Leistung und ärztlichen Beurteilung der erhobenen Befunde ist. Eine qualitativ hochwertige, auf die klinische Frage fokussierte Hybridbildgebung sollte im weiteren Fortgang mit einem gleichermaßen qualitativ hochwertigen, strukturierten schriftlichen Befund verbunden sein, der die klinische Frage zur Zufriedenheit des zuweisenden Arztes beantwortet. Im vorliegenden Manuskript werden daher Konsensempfehlungen zur Befundstruktur, zu Befundinhalten und zur konklusiven Beurteilung einer onkologischen Hybridbildgebung gegeben. Darüber hinaus werden beispielhafte Vorlagen für ebensolche Befunde dargestellt. Die hier dargelegten Empfehlungen zur strukturierten Befunderstellung sollen eine weitere Standardisierung und Harmonisierung onkologischer Befunde im Kontext einer Hybridbildgebung fördern und so die Kommunikation mit den zuweisenden Ärzten vereinfachen und die Akzeptanz und Wertschätzung der onkologischen Hybridbildgebung weiter unterstützen.

ZusammenfassungDie limbisch prädominante altersassoziierte TDP-43(Transactivation response(TAR)-DNA-binding protein 43 kDa)-Enzephalopathie (LATE) wurde kürzlich als eigene neuropathologische Entität im Demenzspektrum charakterisiert. Neuropathologische Veränderungen im Sinne von LATE wurden zuvor bereits als Komorbidität der Alzheimer-Krankheit (AD) beschrieben und spätestens seit 2008 auch als ein von der AD unabhängiger autoptischer Befund. Die Konzeptualisierung von LATE rückt nun die pathogenetische Bedeutung von limbischem TDP-43 als alternative oder komorbide Ursache einer der klinischen AD ähnlichen amnestischen Demenz in das Bewusstsein. LATE könnte divergierende klinische und Biomarkerbefunde erklären, bei denen eine ausgeprägte mnestische Störung ohne Amyloid- und Tau-Veränderungen im Sinne einer AD-Pathologie nachweisbar ist. Ob LATE eine eigenständige neuropathologische Entität darstellt oder eine regionale Ausprägung innerhalb des Spektrums der bekannten TDP-43-assoziierten neurodegenerativen Erkrankungen ist aktuell Gegenstand kontroverser Diskussionen. Die weitere, gezielte Erforschung von TDP-43-Proteinopathien ist davon unabhängig ein vielversprechender Forschungsansatz, um Wissenslücken in der Alzheimer- und Demenzforschung zu schließen. So könnte ganz praktisch die Anreicherung eines amnestischen Phänotyps in klinischen Studien zu amyloidzentrierten Therapien durch das erhöhte Risiko limbischer TDP-43-Komorbidität den Nachweis der klinischen Wirksamkeit erschweren. Dieser Artikel stellt den aktuellen Stand der Diskussion zu LATE vor und illustriert das Konzept und daraus abgeleitete klinische Überlegungen an einem Fallbeispiel.

Background Persistent and relapsing babesiosis caused by Babesia microti often occurs in immunocompromised patients, and has been associated with resistance to antimicrobial agents such as atovaquone. Given the rising incidence of babesiosis in the United States, novel drugs are urgently needed. In the current study, we tested whether clofazimine (CFZ), an antibiotic used to treat leprosy and drug-resistant tuberculosis, is effective against B. microti. Methods Mice with severe combined immunodeficiency were infected with 107B. microti–infected erythrocytes. Parasites were detected by means of microscopic examination of Giemsa-stained blood smears or nested polymerase chain reaction. CFZ was administered orally. Results Uninterrupted monotherapy with CFZ curtailed the rise of parasitemia and achieved radical cure. B. microti parasites and B. microti DNA were cleared by days 10 and 50 of therapy, respectively. A 7-day administration of CFZ delayed the rise of parasitemia by 22 days. This rise was caused by B. microti isolates that did not carry mutations in the cytochrome b gene. Accordingly, a 14-day administration of CFZ was sufficient to resolve high-grade parasitemia caused by atovaquone-resistant B. microti parasites. Conclusions Clofazimine is effective against B. microti infection in the immunocompromised host. Additional preclinical studies are required to identify the minimal dose and dosage of CFZ for babesiosis.

Summary Background With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. Methods We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by 18F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (18F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60–74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov , NCT00697333 . Findings From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the 18F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9–54), the risk of locoregional progression in the 18F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5–21] vs 29% [17–38] at 1 year; HR 0·57 [95% CI 0·30–1·06]). The risk of locoregional progression in the 18F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9–24] vs 30% [20–39] at 1 year; HR 0·64 [95% CI 0·37–1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the 18F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13). Interpretation 18F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours. Funding German Cancer Aid (Deutsche Krebshilfe).

Molecular imaging & biology : MIB 24(3), 466-478 (2021). doi:10.1007/s11307-021-01677-y, Published by Springer Nature Switzerland, Cham

Since the beginning of the year 2020, the coronavirus-19 disease (COVID-19) pandemic has undoubtedly posed significant challenges to healthcare systems worldwide. It has also affected, in a way previously unimaginable, our lifestyle and the way we relate to each other, not only at work, but also in the community and in the family setting. Healthcare systems worldwide have been forced to make huge alterations to be able to handle the different stages of the pandemic. [...]

Healthcare professionals must be aware that babesiosis caused by reinfection might occur., Babesiosis developed in a 62-year-old immunocompetent physician, who had an uneventful recovery after receiving atovaquone and azithromycin. Three years later, babesiosis developed again, and he was again successfully given treatment. Clinical and laboratory evidence were highly supportive of Babesia reinfection. Healthcare professionals should be aware that reinfection might occur in babesiosis.

(Background) Aim of this retrospective analysis was to investigate in mCRPC patients treated with [177Lu]Lu-PSMA-617 whether the absorbed dose (AD) in organs at risk (OAR, i.e., kidneys and parotid glands) can be calculated using simplified methodologies with sufficient accuracy. For this calculation, results and kinetics of the first therapy cycle were used. (Methods) 46 patients treated with 2 to 6 cycles of [177Lu]Lu-PSMA-617 were included. As reference (current clinical standard) full dosimetry of the OAR based on quantitative imaging (whole body scintigraphy and quantitative SPECT/CT at 2, 24, 48 and 72 h p.i.) for every cycle was used. Alternatively, two dosimetry schemes, simplified in terms of image acquisition and dose calculation, were established, both assuming nearly unchanged kinetics of the radiopharmaceutical for subsequent cycles. (Results) In general, for both OAR the simplified methods provided results that were consistent with the dosimetric reference method, both per cycle and in terms of cumulative AD. Best results were obtained when imaging was performed at 48 h p.i. in each of the subsequent cycles. However, both simplified methods tended to underestimate the cumulative AD. (Conclusion) Simplified dosimetry schemes are feasible to tailor multi-cycle [177Lu]Lu-PSMA-targeted therapies.

Diagnosing asthma in preschool children remains an unsolved challenge, at a time when early identification would allow for better education and treatment to prevent morbidity and lung function deterioration. Objective To evaluate if the asthma predictive index (API) can be used as surrogate for asthma diagnosis in preschoolers. Methods Birth cohort of 339 pregnant women enrolled at delivery and their offspring, who were followed for atopy, wheezing, and other respiratory illnesses through 30 months of age. The API was determined at 30 months of age by the researchers; and examined its association with physician-diagnosed asthma during the first 30 months, made independently by the primary care physician not involved in the study. Results Among 307 offspring with complete follow-up, 44 (14.3%) were API+. Maternal body mass index, maternal education, past oral contraceptive use, birthweight, placenta weight, age of daycare at 12 m, gastroesophageal reflux disease at 12 m, acute otitis media at 18 m, bronchiolitis, croup and pneumonia, cord blood adiponectin were all associated with API+. In the multivariable analysis, API+ was associated with almost sixfold odds of asthma diagnosis (adjusted OR = 5.7, 95% CI [2.6-12.3]), after adjusting for the relevant covariates above including respiratory infections like bronchiolitis and pneumonia. The API sensitivity was 48%, specificity 92%, 61% PPV, 88% NPV, 6.4 LR+, 0.56 LR-, 0.84 diagnosis accuracy. The adjusted odds for asthma was 11.4. Conclusions This longitudinal birth cohort suggests, for first time, that API (a structured definition for asthma), could be used as a diagnostic tool, not only as a prognostic tool, in toddlers and preschoolers.

Funder: Wellcome Trust (GB), Funder: Research Trainees Coordinating Centre; doi: http://dx.doi.org/10.13039/501100000659, Funder: British Heart Foundation; doi: http://dx.doi.org/10.13039/501100000274, Funder: Karolinska Institute, Background: The vascular endothelium has important endocrine and paracrine roles, particularly in the regulation of vascular tone and immune function, and it has been implicated in the pathophysiology of a range of cardiovascular and inflammatory conditions. This study uses a series of transgenic murine models to explore for the first time the role of the hypoxia-inducible factors, HIF-1α and HIF-2α in the pulmonary and systemic circulations as potential regulators of systemic vascular function in normoxic or hypoxic conditions and in response to inflammatory stress. We developed a series of transgenic mouse models, the HIF-1α Tie2Cre, deficient in HIF1-α in the systemic and pulmonary vascular endothelium and the L1Cre, a pulmonary endothelium specific knockout of HIF-1α or HIF-2α. In vivo, arterial blood pressure and metabolic activity were monitored continuously in normal atmospheric conditions and following an acute stimulus with hypoxia (10%) or lipopolysaccharide (LPS). Ex vivo, femoral artery reactivity was assessed using wire myography. Results: Under normoxia, the HIF-1α Tie2Cre mouse had increased systolic and diastolic arterial pressure compared to litter mate controls over the day–night cycle under normal environmental conditions. VO2 and VCO2 were also increased. Femoral arteries displayed impaired endothelial relaxation in response to acetylcholine mediated by a reduction in the nitric oxide dependent portion of the response. HIF-1α L1Cre mice displayed a similar pattern of increased systemic blood pressure, metabolic rate and impaired vascular relaxation without features of pulmonary hypertension, polycythaemia or renal dysfunction under normal conditions. In response to acute hypoxia, deficiency of HIF-1α was associated with faster resolution of hypoxia-induced haemodynamic and metabolic compromise. In addition, systemic haemodynamics were less compromised by LPS treatment. Conclusions: These data show that deficiency of HIF-1α in the systemic or pulmonary endothelium is associated with increased systemic blood pressure and metabolic rate, a pattern that persists in both normoxic conditions and in response to acute stress with potential implications for our understanding of the pathophysiology of vascular dysfunction in acute and chronic disease.

Besides PSMA, prostate cancer cells also express gastrin-releasing peptide receptor (GRPr) which is therefore a promising target for theranostic approaches. The high affinity GRPr antagonist RM2 can be labeled with beta-emitting radiometals for therapeutic purposes. The aim of this study was to calculate absorbed doses for critical organs and tumor lesions for [177Lu]Lu-RM2 therapy administered in a group of metastatic castration-resistant prostate cancer (mCRPC) patients who had insufficient PSMA expression or showed lower PSMA accumulation after previous cycles of [177Lu]Lu-PSMA-617 therapy. Thirty-five patients suffering from mCRPC without further treatment options for approved therapies were examined with [68Ga]Ga-RM2-PET/CT. Out of these, 4 patients (mean age 68 years) were treated with [177Lu]Lu-RM2; two of these also received a 2nd therapy cycle. Mean activity was 4.5 ± 0.9 GBq. For dosimetry, patients underwent planar WB-scintigraphy and SPECT/CT imaging of the upper and lower abdomen at approximately 1, 24, 48, and 72 h p.i. along with blood sampling. Absorbed doses for kidneys, pancreas, liver, spleen, gallbladder wall, and tumor lesions were derived based on quantitative SPECT/CT according to RADAR dosimetry scheme; individual organ masses were extracted from CT. Absorbed dose to bone marrow was calculated based on serial whole-body images and blood sampling according to the EANM guideline. Therapy was well tolerated by all patients and no side effects were observed. An increased uptake in tumor lesions and the pancreas was seen within the first 1 h. Mean absorbed organ doses were 1.08 ± 0.44 Gy/GBq in the pancreas, 0.35 ± 0.14 Gy/GBq in the kidneys, 0.05 ± 0.02 Gy/GBq in the liver, 0.07 ± 0.02 Gy/GBq in the gallbladder wall, 0.10 ± 0.06 Gy/GBq in the spleen, and 0.02 ± 0.01 Gy/GBq for the red bone marrow. The mean dose for tumor lesions was 6.20 ± 3.00 Gy/GBq. Application of GRPr antagonist [177Lu]Lu-RM2 is suitable for targeted radiotherapy of mCRPC as it shows high tumor uptake and rapid clearance from normal organs. Absorbed doses in tumor lesions are therapeutically relevant. The critical organ receiving the highest absorbed dose was the pancreas. Results suggest that the activity administered for each cycle could be increased to maximize the absorbed dose of tumors and metastases.

Objective:To determine if constraints on agricultural production were a novel construct in the Panama Food Security Questionnaire (FSQ) and to characterize agricultural and economic determinants of food insecurity during the planting, growing and harvesting time periods in subsistence farming communities.Design:This longitudinal study followed households during land preparation, growing and harvest periods in one agricultural cycle. Agricultural production and economic variables were recorded and the Panama FSQ was administered. Exploratory factor analysis was used to verify construct validity of the FSQ. A food insecurity score (FIS), ranging from 0 to 42, was derived. Multiple regression analyses of FIS were conducted for each agricultural period.Setting:Fifteen rural villages in Panama.Participants:Subsistence farming households (n 237).Results:The FSQ contained four constructs: (i) ability to buy food; (ii) decreased amount/number of meals; (iii) feeling hungry; and (iv) lower agricultural production because of weather or lack of resources. Although most households were mildly food insecure in all time periods, determinants of food insecurity differed in each. Higher FIS was associated during land preparation with less rice and legumes planted and lower asset-based wealth; during growing months with less rice, more maize and pigeon peas planted and not selling produce; and during harvest with less rice planted, fewer chickens and lower income.Conclusions:Constraints on agriculture was a novel construct of the Panama FSQ. Different income-related variables emerged in each agricultural period. Planting staple foods and raising chickens were associated with food security, but some crop choices were associated with food insecurity.

ZusammenfassungDie S1-Leitlinie soll bei der Indikationsstellung, Durchführung, Interpretation und Befundung von SPECT-Untersuchungen des Dopamintransporters (DAT) mit DaTSCANTM unterstützen. Gegenüber der Vorgängerversion von 2007 berücksichtigt die vorliegende Aktualisierung und Überarbeitung die neuere wissenschaftliche Literatur, zwischenzeitlich veröffentlichte Guidelines der europäischen (EANM) und amerikanischen Fachgesellschaften (SNM), sowie die aktuelle Fassung der S3-Leitlinie „Idiopathisches Parkinson-Syndrom“ der Deutschen Gesellschaft für Neurologie. Zudem finden neue technische Möglichkeiten Berücksichtigung.

Intrauterine growth restriction (IUGR) is a common obstetric complication with immediate and life-long consequences for offspring health. Yet the mechanisms underlying its aetiology require elucidation. Recent work in the guinea pig shows that progressive uterine artery occlusion induced IUGR and vascular dysfunction in pups. Here we explore the extent to which uterine artery occlusion influences fetal outcomes via impacts on placental morphology. Our study demonstrates that uterine artery occlusion severely compromised both the labyrinth exchange zone (increased fibrosis and reduced vascularisation, trophoblast volume, surface area and diffusing capacity) and interlobium zone (increased apoptosis), which likely contributed to the IUGR observed., JL-T and ANS-P are supported by a Newton International and Dorothy Hodgkin Research Fellowships from the Royal Society, respectively. EAH is supported by FONDECYT 1151119 and, BJK is supported by FONDECYT 1181341 and VRI-Puente P1714/2017.

BACKGROUND Deleterious long-term effects in the offspring from women with pregravid obesity have been described; however, the evidence supporting early metabolic and inflammatory markers in the offspring at birth and gender differences are conflicting. OBJECTIVE The present study aimed to compare cord blood adipokines and cytokines concentrations and anthropometric characteristics of the offspring of women with maternal obesity (MO) and normal-weight mothers (NWM). Also, maternal and neonatal variables on the association of maternal body mass index (BMI) with cord blood adipokines were evaluated. METHODS A cross-sectional analysis of a subsample of mother-child dyads participating in a cohort study (n = 221) was assessed. Anthropometrics, cord blood adipokines (leptin and adiponectin) and cytokines (interleukin [IL]-1β, IL-4, IL-10, IL-12 p40, IL-12p70, IL-13, and tumor necrosis factor α) concentrations in the offspring of normal-weight women (BMI >18.5 and 30 kg/m2) without comorbidities was performed. RESULTS Offspring from mothers with obesity had higher birth weight, a higher proportion of large for gestational age, higher ponderal index, and heavier placentae than offspring from normal-weight mothers (P

Poor sleep is associated with hypertension, a major risk factor for cardiovascular disease1,2. However, the mechanism(s) through which sleep loss impacts blood pressure remain largely unknown, including the inter-related brain and peripheral body systems that regulate vascular function3. In a repeated-measures experimental study of 66 healthy adult participants, we demonstrate four core findings addressing this question. First, a night of sleep loss significantly increased blood pressure—both systolic and diastolic, yet this change in vascular tone was independent of any increase in heart rate. Second, sleep loss compromised functional brain connectivity within regions that regulate vascular tone. Third, sleep-loss related changes in brain connectivity and vascular tone were significantly inter-dependent, with changes in brain nodes explaining the shift towards hypertension. Fourth, sleep-loss related changes in mood, specifically reductions in positive and amplification in negative states, each demonstrated an interaction with the impairments in brain connectivity and blood pressure. Together, these findings support an embodied framework in which sleep loss confers increased risk of cardiovascular disease through interactions between brain homeostatic control, mood-state and blood pressure.

BACKGROUND Prostate cancer is the most common type of solid tumor in men and the second most common cause of cancer-related death in males in Germany. The conventional strategy for its primary detection, i.e., systematic ultrasound-guided prostate biopsy in men who have elevated PSA levels and/or positive findings on digital rectal examination, fails to reveal all cases. The same is true of the use of conventional computed tomography (CT), magnetic resonance imaging (MRI), and skeletal scintigraphy for the early detection of recurrences and distant metastases. METHODS This review is based on pertinent publications retrieved by a selective search, including the German clinical practice guideline on prostate cancer and systematic review articles. RESULTS Prospective multicenter trials have shown that the detection of clinically significant prostate cancer is markedly improved with multiparametric MRI (mpMRI) and MR/TRUS fusion biopsy (TRUS = transrectal ultrasonography), compared to conventional systematic biopsy. A recent Cochrane review showed that the rate of overdiagnosis of low-risk prostate cancer was reduced with mpMRI and MR/TRUS fusion biopsy compared with conventional systematic biopsy (95/1000 vs. 139/1000), and that clinically significant prostate cancer was more reliably detected (sensitivity 72% vs. 63%), albeit with slightly lower specificity (96% vs. 100%). Prostate-specific membrane antigen (PSMA) hybrid imaging improves the detection of lymphogenic and bony metastases in patients with high-risk prostate cancer. PSMA hybrid imaging is most commonly used to detect biochemical recurrences. A meta-analysis showed that the detection rate depends on the PSA concentration: 74.1% overall, 33.7% with PSA

Systemic inflammation and coagulopathy are characteristic hallmarks of COVID19. “COVID coagulopathy” manifests mainly as a prothrombotic state affecting both large and small blood vessels, and presenting as arterial, venous, and microangiopathic thrombotic events with von Willebrand factor (VWF) and soluble thrombomodulin increased in hospitalized patients. The causes of coagulopathy are poorly understood. Aim: To investigate the relationship between von Willebrand factor (VWF) biomarkers, intravascular hemolysis, coagulation, and organ damage in COVID19 patients and to study their association with disease severity and mortality. Methods: 181 hospitalized adult COVID19 patients were randomly selected with a balanced distribution of survivors and non-survivors during the period of March 26th 2020 to May 5th 2020. The medical records and laboratory values were reviewed. Statistical analysis was performed using R studio V.3.6.2. Results: Patients who died (n=90) had significantly lower ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity, elevated lactate dehydrogenase levels, increased schistocyte/RBC fragment counts, and elevated VWF antigen and activity levels compared to patients discharged alive (n=91). In 31 patients, we measured several of these biomarkers on two or more occasions. The trending of ADAMTS13 activity illustrated that it is not steady throughout the hospitalization course. ADAMTS13 activity levels tended to improve and/or reach normal levels in patients that survived, yet ADAMTS13 activity levels worsened in most patients that died. Likewise, the VWF antigen and activity levels tended to decrease in patients that survived whereas tended to increase well above the normal range (2-3 folds) in patients that died. D-Dimer levels trended downwards in survivors, sometimes to levels less than 1 µg/ml, yet tended to increase in patients who died. Given the relationship between ADAMTS13 activity and mortality, we wanted to determine a cut-point of initial ADAMTS13 activity (within 72 hours from admission) to predict mortality. 102 patients in our cohort had an ADAMTS13 activity measurement within this timeframe. We determined that this optimal cut-point of initial ADAMTS13 activity was 43% using Youden’s J statistic. Only 30% of patients who had an ADAMTS13 activity level of less than 43% on admission survived, yet 60% of patients survived who had an ADAMTS13 activity level of greater than 43% on admission. Conclusions: COVID-19 may present with low ADAMTS13 activity in a subset of hospitalized patients. Presence of schistocytes/RBC fragment and elevated D-dimer levels on admission may warrant a work-up for ADAMTS13 activity and VWF antigen and activity levels. These findings indicate the need for future investigation to study the relationship between endothelial and coagulation activation and the efficacy of treatments aimed at prevention and/or amelioration of microangiopathy in COVID-19.

BACKGROUND: Metastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 ((177)Lu)–PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment. METHODS: We conducted an international, open-label, phase 3 trial evaluating (177)Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor–pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 ((68)Ga)–labeled PSMA-11 positron-emission tomographic–computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either (177)Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 ((223)Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment. RESULTS: From June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. (177)Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P

Background Functional luminal imaging probe (FLIP) Panometry assesses the esophageal response to distention and may complement the assessment of primary peristalsis on high-resolution manometry (HRM). We aimed to investigate whether FLIP Panometry provides complementary information in patients with normal esophageal motility on HRM. Methods Adult patients that completed FLIP and had an HRM classification of normal motility were retrospectively identified for inclusion. 16-cm FLIP studies performed during endoscopy were evaluated to assess EGJ distensibility, secondary peristalsis, and identify an abnormal response to distention involving sustained LES contraction (sLESC). Clinical characteristics and esophagram were assessed when available. Key results Of 164 patients included (mean(SD) age 48(16) years, 75% female), 111 (68%) had normal Panometry with EGJ-distensibility index (DI) ≥2.0 mm2 /mmHg, maximum EGJ diameter ≥16mm and antegrade contractions. Abnormal EGJ distensibility was observed in 44/164 (27%), and 38/164 (23%) had an abnormal contractile response to distension. sLESC was observed in 11/164 (7%). Among 68 patients that completed esophagram, abnormal EGJ distensibility was more frequently observed with an abnormal esophagram than normal EGJ opening: 14/23 (61%) vs 10/45 (22%); P=0.003. Epiphrenic diverticula were present in 3/164 patients: 2/3 had sLESC. Conclusions & inferences Symptomatic patients with normal esophageal motility on HRM predominantly have normal FLIP Panometry; however, abnormal FLIP findings can be observed. While abnormal Panometry findings appear clinically relevant via an association with abnormal bolus retention, complementary tests, such as provocative maneuvers with HRM and timed barium esophagram, are useful to determine clinical context.

Background: To date, there are no effective treatments for Alzheimer’s disease (AD). Thus, a significant need for research of therapies remains. Objective: One promising pharmacological target is the hormone fibroblast growth factor 21 (FGF21), which is thought to be neuroprotective. A clinical candidate for medical use could be the FGF21 analogue LY2405319 (LY), which has a specificity and potency comparable to FGF21. Methods: The present study investigated the potential neuroprotective effect of LY via PPARγ/apoE/abca1 pathway, which is known to degrade amyloid-β (Aβ) plaques by using primary glial cells and hippocampal organotypic brain slice cultures (OBSCs) from 30- and 50-week-old transgenic APPswe/PS1dE9 (tg) mice. By LY treatment of 52-week-old tg mice with advanced Aβ deposition, we further aimed to elaborate the effect of LY on AD pathology in vivo. Results: LY application to primary glial cells caused an upregulation of pparγ, apoE, and abca1 mRNA expression and significantly decreased number and area of Aβ plaques in OBSCs. LY treatment in tg mice increased cerebral [18F] FDG uptake and N-acetylaspartate/creatine ratio indicating enhanced neuronal activity and integrity. Although LY did not reduce the number of Aβ plaques in tg mice, the number of iba1-positive cells was significantly decreased indicating reduced microgliosis. Conclusion: These data identified LY in vitro as an activator of Aβ degrading genes leading to cerebral Aβ load amelioration in early and late AD pathology. Although Aβ plaque reduction by LY failed in vivo, LY may be used as therapeutic agent to treat AD-related neuroinflammation and impaired neuronal integrity.

Convalescent plasma with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) antibodies (CCP) may hold promise as treatment for Coronavirus Disease 2019 (COVID-19). We compared the mortality and clinical outcome of patients with COVID-19 who received 200mL of CCP with a Spike protein IgG titer ≥1:2,430 (median 1:47,385) within 72 hours of admission to propensity score-matched controls cared for at a medical center in the Bronx, between April 13 to May 4, 2020. Matching criteria for controls were age, sex, body mass index, race, ethnicity, comorbidities, week of admission, oxygen requirement, D-dimer, lymphocyte counts, corticosteroids, and anticoagulation use. There was no difference in mortality or oxygenation between CCP recipients and controls at day 28. When stratified by age, compared to matched controls, CCP recipients

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LBA4 Background: Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains invariably fatal. Prostate-specific membrane antigen (PSMA) is highly expressed in mCRPC lesions. 177Lu-PSMA-617 is a targeted radioligand therapy that delivers ß-particle radiation to PSMA-expressing cells and surrounding microenvironment. Method: VISION was an international, randomized, open-label phase III study evaluating 177Lu-PSMA-617 in men with PSMA-positive mCRPC previously treated with next-generation androgen receptor signaling inhibition and 1–2 taxane regimens. PSMA positivity (threshold greater than liver) was determined by central review of 68Ga-PSMA-11 scans. Patients were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq every 6 weeks x 6 cycles) plus standard of care (SOC) versus SOC alone. SOC was investigator determined but excluded cytotoxic chemotherapy and radium-223. The alternate primary endpoints were radiographic progression-free survival (rPFS) using PCWG3 criteria by independent central review (ICR) and overall survival (OS). Under the null hypothesis, median rPFS was assumed to be 4 months and OS 10 months for 177Lu-PSMA-617 + SOC for a hazard ratio (HR) of 1.00. Under the alternative hypothesis, median rPFS was assumed to be 6 months for a HR of 0.67 and median OS was assumed to be 13.7 months for a HR of 0.7306. Key secondary endpoints were objective response rate (ORR; RECIST v1.1), disease control rate (DCR), and time to first symptomatic skeletal event (SSE). Results: Between 4 June 2018 and 23 October 2019, 831 of 1179 screened patients were randomized 2:1 to receive 177Lu-PSMA-617 + SOC (n = 551) or SOC only (n = 280). Median study follow-up was 20.9 months at the data cut-off (27 January 2021). Treatment groups were balanced in terms of demographics and baseline characteristics. 177Lu-PSMA-617 + SOC significantly improved rPFS versus SOC alone (median rPFS, 8.7 vs 3.4 months; HR, 0.40 [99.2% CI: 0.29, 0.57]; p < 0.001, one-sided). The alternate primary endpoint of OS was also significantly improved versus SOC alone (median OS, 15.3 vs 11.3 months; HR, 0.62 [95% CI: 0.52, 0.74]; p < 0.001, one-sided). All key secondary endpoints were statistically significant between the treatment arms in favor of 177Lu-PSMA-617 + SOC, including ICR-determined ORR (29.8% vs 1.7%), ICR-determined DCR (89.0% vs 66.7%) and time to first SSE (median time, 11.5 vs 6.8 months; HR, 0.50). While a higher rate of high-grade treatment-emergent adverse events was observed with 177Lu-PSMA-617 (52.7% vs 38.0%), therapy was well tolerated. Conclusions: 177Lu-PSMA-617 plus SOC treatment is a well-tolerated regimen that improves rPFS and prolongs OS compared with SOC alone in men with advanced-stage PSMA-positive mCRPC, supporting its adoption as a standard of care. Clinical trial information: NCT03511664.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

The causes of coagulopathy associated with COVID-19 disease are poorly understood. We aimed to investigate the relationship between markers of endothelial activation, intravascular hemolysis, coagulation, and organ damage in COVID-19 patients and study their association with disease severity and mortality. We conducted a retrospective study of 181 hospitalized COVID-19 patients randomly selected with equal distribution of survivors and non-survivors. Patients who died had significantly lower ADAMTS13 activity, significantly higher LDH, schistocytes and von Willebrand Factor levels compared to patients discharged alive. Only 30% of patients with an initial ADAMTS13 activity

Background Esophagogastric junction outflow obstruction (EGJOO) as defined by Chicago Classification of esophageal motility disorders (CCv3.0) encompasses a broad range of diagnoses, thus posing clinical challenges. Our aims were to evaluate multiple rapid swallow (MRS) and rapid drink challenge (RDC) during high-resolution manometry (HRM) to aid identifying clinically relevant EGJOO. Methods Patients with a HRM diagnosis of EGJOO based on CCv3.0 that also completed MRS and RDC during HRM and barium esophagram were retrospectively identified. Radiographic EGJOO (RAD-EGJOO) was defined by either liquid barium retention or delayed passage of a barium tablet on barium esophagram. Thirty healthy asymptomatic controls that completed HRM were also included. MRS involved drinking 2 mL for 5 successive swallows. RDC involved rapid drinking of 200 mL liquid. Integrated relaxation pressure (IRP) and presence of panesophageal pressurization (PEP) during MRS and RDC were assessed. Key results One hundred one patients, mean (SD) age 56 (16) years, were included; 32% had RAD-EGJOO, 68% did not. RAD-EGJOO patients more frequently had elevated (>12 mmHg) upright IRP (100%), MRS-IRP (56%), RDC-IRP (53%), and PEP during RDC (66%) than both controls [17%; 0%; 7%; 3%] and patients without RAD-EGJOO [83%; 35%; 39%; 41%] Having IRP >12 mmHg during both MRS and RDC was twice as likely to be associated with RAD-EGJOO (19%) than those without RAD-EGJOO (9%) among patients with upright IRP >12 mmHg. Conclusions and inferences Adjunctive HRM maneuvers MRS and RDC appear to help identify clinically significant EGJOO. While future outcome studies are needed, comprehensive multimodal evaluation helps clarify relevance of EGJOO on HRM.