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Limited data are available about the potential health effects of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnant women and their developing offspring. We established the International Registry of Coronavirus Exposure in Pregnancy (IRCEP) to provide data on the risk of major adverse obstetric and neonatal outcomes among women with varying degrees of severity and timing of coronavirus disease 2019 (COVID-19) during pregnancy. We describe here the cohort and share the lessons learned. The IRCEP enrolls women tested for SARS-CoV-2 or with a clinical diagnosis of COVID-19 during pregnancy and obtains information using an online data collection system. By March 2021, 17,532 participants from 77 countries had enrolled; 54% enrolled during pregnancy and 46% afterward. Among women with symptomatic COVID-19 with a positive SARS-CoV-2 test (n = 4,934), symptoms were mild in 41%, moderate in 52%, and severe in 7%; 7.7% were hospitalized for COVID-19 and 1.7% were admitted to an intensive care unit. The biggest challenges were retention of participants enrolled during pregnancy and the potential bias introduced when participants enroll after pregnancy outcomes are known. Multiple biases need to be considered and addressed when estimating and interpreting the effects of COVID-19 in pregnancy in these types of cohorts.

Background: Mobile medical devices for self-patient use are a rapidly evolving section of telehealth. We examined the INSTINCT® ultrasound system, a portable, self-operated ultrasound device attach...

(1) Background: To determine the importance of diffusion-weighted whole-body MRI with background body signal suppression (DWIBS) in the staging process of patients with suspected head and neck carcinomas. (2) Methods: A total of 30 patients (24 male, 6 female) with a median age of 67 years with clinically suspected head and neck carcinoma with pathologic cervical nodal swelling in ultrasound underwent the staging procedure with computed tomography (CT) and whole-body MRI including DWIBS. (3) Results: In a total of 9 patients, abnormalities in the routine work-up of pretherapeutic staging were found. Five cases of either secondary cancer or distant metastases were only visible in DWIBS, while being missed on CT. One diagnosis was only detectable in CT and not in DWIBS, whereas three diagnoses were recognizable in both modalities. (4) Conclusions: DWIBS in addition to a standard neck MRI in cervical lymphadenopathy suspicious for head and neck cancer yielded additional clinically relevant diagnoses in 17% of cases that would have been missed by current staging routine procedures. DWIBS offered a negative predictive value of 98.78% for ruling out distant metastases or secondary malignancies.

Purpose of the study: To discuss selected aspects of our local and national experience in treating and vaccinating pregnant women with SARS-CoV-2 infection and COVID-19 disease.Materials and methods: A comprehensive, retrospective review of COVID-19 parturients in our center as well as a detailed literature review of several aspects from the groundbreaking research done in Israel to investigate the direct obstetrical impact of COVID-19, indirect effect of the lockdown measures and the vaccination effort among pregnant women.Results: The study shows our local and national experience in treating COVID-19 in pregnancy and the maternal and neonatal impact of vaccination in nationwide scale. We treated our first COVID-19 pregnant patient on April 4th, 2020 reaching a total of 193 pregnant women, with PCR-positive SARS-CoV-2 by 8th March 2021. Several studies from Israel have evaluated pregnancy-related outcomes of COVID-19, be it maternal, obstetrical or neonatal complications. We suggest that only in a small subset of severely ill mothers, intubated and otherwise respiratory or hemodynamically unstable, an emergency cesarean delivery should be considered, factoring gestational age, in order to assist maternal ventilation and circulation, as well as to avoid possible secondary fetal compromise due the maternal deterioration.In addition, there is conflicting evidence as to the price of lockdown on obstetrical outcomes, i.e., not the direct medical impact of the virus, but rather the impact of the measures to contain its spread - mainly lockdowns, which has been a major tool in Israel to combat COVID-19.Finally, we demonstrate to overall safety and efficacy of vaccination pregnant women and the beneficial impact on pregnancy outcome and neonatal gain of protecting antibodies.Conclusion: The data emerging from Israel is overall reassuring, as for the association of COVID-19 with adverse pregnancy outcome and the possible protective effect of the vaccinations. Further, long term studies, should be conducted to answer the long-term maternal outcomes, as well and neonatal prognosis.

ObjectivesTo determine the profile of cytokines in patients with severe COVID-19 who were enrolled in a trial of COVID-19 convalescent plasma (CCP).MethodsPatients were randomized to receive standard treatment and 3 CCP units or standard treatment alone (CAPSID trial, ClinicalTrials.gov NCT04433910). The primary outcome was a dichotomous composite outcome (survival and no longer severe COVID-19 on day 21). Time to clinical improvement was a key secondary endpoint. The concentrations of 27 cytokines were measured (baseline, day 7). We analyzed the change and the correlation between serum cytokine levels over time in different subgroups and the prediction of outcome in receiver operating characteristics (ROC) analyses and in multivariate models.ResultsThe majority of cytokines showed significant changes from baseline to day 7. Some were strongly correlated amongst each other (at baseline the cluster IL-1ß, IL-2, IL-6, IL-8, G-CSF, MIP-1α, the cluster PDGF-BB, RANTES or the cluster IL-4, IL-17, Eotaxin, bFGF, TNF-α). The correlation matrix substantially changed from baseline to day 7. The heatmaps of the absolute values of the correlation matrix indicated an association of CCP treatment and clinical outcome with the cytokine pattern. Low levels of IP-10, IFN-γ, MCP-1 and IL-1ß on day 0 were predictive of treatment success in a ROC analysis. In multivariate models, low levels of IL-1ß, IFN-γ and MCP-1 on day 0 were significantly associated with both treatment success and shorter time to clinical improvement. Low levels of IP-10, IL-1RA, IL-6, MCP-1 and IFN-γ on day 7 and high levels of IL-9, PDGF and RANTES on day 7 were predictive of treatment success in ROC analyses. Low levels of IP-10, MCP-1 and high levels of RANTES, on day 7 were associated with both treatment success and shorter time to clinical improvement in multivariate models.ConclusionThis analysis demonstrates a considerable dynamic of cytokines over time, which is influenced by both treatment and clinical course of COVID-19. Levels of IL-1ß and MCP-1 at baseline and MCP-1, IP-10 and RANTES on day 7 were associated with a favorable outcome across several endpoints. These cytokines should be included in future trials for further evaluation as predictive factors.

BACKGROUNDResults of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported, but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP.METHODSOf 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP donors (n = 113) with asymptomatic to moderate COVID-19 were included as a reference group.RESULTSThe median follow-up of patients was 396 days, and the estimated 1-year survival was 78.7% in the CCP group and 60.2% in the control (P = 0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared with the control group (91.5% versus 60.2%, P = 0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase in neutralizing antibodies after vaccination between the CCP and control groups.CONCLUSIONThe trial demonstrated a trend toward better outcome in the CCP group without reaching statistical significance. A predefined subgroup analysis showed a significantly better outcome (long-term survival, time to discharge from ICU, and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared with the control group. A substantial long-term disease burden remains after severe COVID-19.Trial registrationEudraCT 2020-001310-38 and ClinicalTrials.gov NCT04433910.FundingBundesministerium für Gesundheit (German Federal Ministry of Health).

The effects of adjuvants for increasing the immunogenicity of influenza vaccines are well known. However, the effect of adjuvants on increasing the breadth of cross-reactivity is less well understood. In this study we have performed a systematic screen of different toll-like receptor (TLR) agonists, with and without a squalene-in-water emulsion on the immunogenicity of a recombinant trimerized hemagglutinin (HA) vaccine in mice after single-dose administration. Antibody (Ab) cross-reactivity for other variants within and outside the immunizing subtype (homosubtypic and heterosubtypic cross-reactivity, respectively) was assessed using a protein microarray approach. Most adjuvants induced broad IgG profiles, although the response to a combination of CpG, MPLA and AddaVax (termed ‘IVAX-1’) appeared more quickly and reached a greater magnitude than the other formulations tested. Antigen-specific plasma cell labeling experiments show the components of IVAX-1 are synergistic. This adjuvant preferentially stimulates CD4 T cells to produce Th1>Th2 type (IgG2c>IgG1) antibodies and cytokine responses. Moreover, IVAX-1 induces identical homo- and heterosubtypic IgG and IgA cross-reactivity profiles when administered intranasally. Consistent with these observations, a single-cell transcriptomics analysis demonstrated significant increases in expression of IgG1, IgG2b and IgG2c genes of B cells in H5/IVAX-1 immunized mice relative to naïve mice, as well as significant increases in expression of the IFNγ gene of both CD4 and CD8 T cells. These data support the use of adjuvants for enhancing the breath and durability of antibody responses of influenza virus vaccines.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8–0.9 per week increase; p Conclusions Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.

WOS:000613461600006 PubMed ID: 32926494 Objectives To evaluate the maternal and perinatal outcomes of pregnancies affected by SARS-CoV-2 infection. Methods This was a multinational retrospective cohort study including women with a singleton pregnancy and laboratory-confirmed SARS-CoV-2 infection, conducted in 72 centers in 22 different countries in Europe, the USA, South America, Asia and Australia, between 1 February 2020 and 30 April 2020. Confirmed SARS-CoV-2 infection was defined as a positive result on real-time reverse-transcription polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab specimens. The primary outcome was a composite measure of maternal mortality and morbidity, including admission to the intensive care unit (ICU), use of mechanical ventilation and death. Results In total, 388 women with a singleton pregnancy tested positive for SARS-CoV-2 on RT-PCR of a nasopharyngeal swab and were included in the study. Composite adverse maternal outcome was observed in 47/388 (12.1%) women; 43 (11.1%) women were admitted to the ICU, 36 (9.3%) required mechanical ventilation and three (0.8%) died. Of the 388 women included in the study, 122 (31.4%) were still pregnant at the time of data analysis. Among the other 266 women, six (19.4% of the 31 women with first-trimester infection) had miscarriage, three (1.1%) had termination of pregnancy, six (2.3%) had stillbirth and 251 (94.4%) delivered a liveborn infant. The rate of preterm birth before 37 weeks' gestation was 26.3% (70/266). Of the 251 liveborn infants, 69/251(27.5%) were admitted to the neonatal ICU, and there were five (2.0%) neonatal deaths. The overall rate of perinatal death was 4.1% (11/266). Only one (1/251, 0.4%) infant, born to a mother who tested positive during the third trimester, was found to be positive for SARS-CoV-2 on RT-PCR. Conclusions SARS-CoV-2 infection in pregnant women is associated with a 0.8% rate of maternal mortality, but an 11.1% rate of admission to the ICU. The risk of vertical transmission seems to be negligible. (C) 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Background: Early detection of liver cirrhosis is crucial for secondary prevention of complications. However, noninvasive blood-based patient monitoring tools are lacking. In this explorative study, we conducted a targeted metabolomic analysis in order to identify possible serum markers indicating alcoholic liver cirrhosis (aLiC) with or without hepatocellular carcinoma (HCC). Methods: Venous blood of 30 individuals was collected: healthy controls (“Con”, n = 12), patients with aLiC without and with HCC (“aLiC”: n = 6 and “aLiC + HCC”: n = 6), and patients with other liver diseases (“oLiD”: n = 6). A targeted metabolomic analysis was conducted using the AbsoluteIDQ® p180 Kit (Biocrates Life Sciences®, Innsbruck, Austria). Statistical analysis was performed by applying a one-way ANOVA on all subgroups followed by a t test for pairwise comparison of subgroups and logistic regression analysis. Results: ANOVA revealed 29 metabolites that significantly discriminate between the different cohorts. Among these analytes, 25 were significantly altered in Con versus aLiC, as indicated by t test, most importantly SM C18:1 (p < 0.001), SM C20:2 (p = 0.001), SM (OH) C22:2 (p < 0.001), lysoPC a C20:4 (p < 0.001), and PC aa C36:5 (p < 0.001). To a similar extent, the metabolites discriminated also between the oLiD and aLiC but less between the Con or oLiD and aLiC + HCC cohorts. Most of these analytes were either lyso- and phosphatidylcholines or sphingomyelins. Results were not significant for comparison of Con versus oLiD and aLiC versus aLiC + HCC. Conclusion: Decreased lyso- and phosphatidylcholine as well as sphingomyelin species in venous blood could help to detect liver cirrhosis in patients with non-cirrhotic liver disease.

The purpose of this paper was to assess the impact and the post-traumatic potential of late termination of pregnancy (TOP) and stillbirth on medical staff and characterise personal attributes that modulate these possible outcomes. Fifty-one participants involved in the treatment of women undergoing late TOPs and stillbirths answered questionnaires including demographics, Neuroticism subscale of the Big Five Inventory (BFI), Life Orientation Test-Revised (LOT-R), Posttraumatic Diagnostic Scale (PDS), Brief Symptom Inventory (BSI-18) and questions regarding exposure to stillbirths and late TOPs. None of the participants met the full post-traumatic stress disorder (PTSD) criteria. A correlation with a marginal significance was found between the number of TOP's/stillbirths attended during the past year and traumatic symptoms. Neuroticism moderated the association between presence in TOP's/stillbirths and post-traumatic symptoms among those who attended this event over the past month. According to our results, medical personnel do not appear to develop long-term and lingering posttraumatic symptoms following attending TOP's/stillbirths. Impact Statement

Background Studies of preterm delivery after COVID-19 are often subject to selection bias and do not distinguish between early vs. late infection in pregnancy, nor between spontaneous vs. medically indicated preterm delivery. This study aimed to estimate the risk of preterm birth (overall, spontaneous, and indicated) after COVID-19 during pregnancy, while considering different levels of disease severity and timing. Methods Pregnant and recently pregnant people who were tested for or clinically diagnosed with COVID-19 during pregnancy enrolled in an international internet-based cohort study between June 2020 and July 2021. We used several analytic approaches to minimize confounding and immortal time bias, including multivariable regression, time-to-delivery models, and a case-time-control design. Results Among 14,264 eligible participants from 70 countries who did not report a pregnancy loss before 20 gestational weeks, 5893 had completed their pregnancies and reported delivery information; others were censored at time of their last follow-up. Participants with symptomatic COVID-19 before 20 weeks’ gestation had no increased risk of preterm delivery compared to those testing negative, with adjusted risks of 10.0% (95% CI 7.8, 12.0) vs. 9.8% (9.1, 10.5). Mild COVID-19 later in pregnancy was not clearly associated with preterm delivery. In contrast, severe COVID-19 after 20 weeks’ gestation led to an increase in preterm delivery compared to milder disease. For example, the risk ratio for preterm delivery comparing severe to mild/moderate COVID-19 at 35 weeks was 2.8 (2.0, 4.0); corresponding risk ratios for indicated and spontaneous preterm delivery were 3.7 (2.0, 7.0) and 2.3 (1.2, 3.9), respectively. Conclusions Severe COVID-19 late in pregnancy sharply increased the risk of preterm delivery compared to no COVID-19. This elevated risk was primarily due to an increase in medically indicated preterm deliveries, included preterm cesarean sections, although an increase in spontaneous preterm delivery was also observed. In contrast, mild or moderate COVID-19 conferred minimal risk, as did severe disease early in pregnancy.

To assess challenges to optimal rheumatology care from the perspective of patients served by our institution's rheumatology division.Focus group study of adult rheumatic disease patients who attend clinics at a university teaching hospital in Montreal, Canada.Individuals participated in 1-h focus group discussions concerning their experiences and beliefs regarding rheumatology care. Sessions were recorded and transcripts generated. A thematic analysis approach was used by two individual analyzers.Eighteen patients participated in three focus groups (group one = 8 patients; group two = 5; group three = 5). Eleven patients had systemic lupus erythematosus, 6 had rheumatoid arthritis, and 1 patient had psoriatic arthritis. The average age (standard deviation) was 51.2 (14.0) years, disease duration 23.5 (14.5) years, and in the majority had at least a high school education. All participants were female and 72.2% were Caucasian. Three main themes emerged: theme 1 identified patients' needs for information and support, at diagnosis and throughout the disease trajectory; theme 2 identified barriers to accessing health care: theme 3 identified patients' beliefs regarding improvements needed to optimize their experiences throughout the disease course.Our focus group study not only clarified the needs of rheumatology patients with chronic inflammatory disease, and identified barriers to optimal rheumatology care, but also was a source of recommendations that might improve patient experiences in seeking health care in a rheumatology setting. Limitations include the fact that our participants were all female, and mostly were middle aged, Caucasian and well educated. Regardless, the findings can help inform efforts to improve rheumatology care. Key Points • Our focus group study clarified the needs of chronic inflammatory rheumatic disease, and identified barriers to optimal rheumatology care. • Despite some potential limitations, our work provides recommendations that could improve patient experiences when seeking health care in a rheumatology setting.

It has still to be ascertained whether severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with worse maternal and fetal outcomes compared to low risk gestations.This study aimed to evaluate maternal and perinatal outcomes in high- and low-risk pregnancies complicated by severe acute respiratory syndrome coronavirus 2 infection.This was a multinational retrospective cohort study involving women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection from 76 centers from 25 countries in Europe, the United States, South America, Asia, and Australia from April 4, 2020, to October 28, 2020. The primary outcome was a composite measure of maternal mortality and morbidity, including admission to the intensive care unit, use of mechanical ventilation, or death. The secondary outcome was a composite measure of adverse perinatal outcome, including miscarriage, fetal loss, neonatal and perinatal death, and admission to the neonatal intensive care unit. All outcomes were assessed in high- and low-risk pregnancies. Pregnancies were considered high risk in case of either preexisting chronic medical conditions in pregnancy or obstetrical disorders occurring in pregnancy. The Fisher exact test and logistic regression analysis were used to analyze the data.A total of 887 singleton pregnancies who tested positive for severe acute respiratory syndrome coronavirus 2 infection using reverse transcription-polymerase chain reaction of nasal and pharyngeal swab specimens were included in the study. The risk of composite adverse maternal outcomes was higher in high-risk pregnancies than in low-risk pregnancies (odds ratio, 1.52; 95% confidence interval, 1.03-2.24; P=.035). In addition, women carrying high-risk pregnancies were at higher risk of hospital admission (odds ratio, 1.48; 95% confidence interval, 1.07-2.04; P=.002), presence of severe respiratory symptoms (odds ratio, 2.13; 95% confidence interval, 0.41-3.21; P=.001), admission to the intensive care unit (odds ratio, 2.63; 95% confidence interval, 1.42-4.88), and invasive mechanical ventilation (odds ratio, 2.65; 95% confidence interval, 1.19-5.94; P=.002). When exploring perinatal outcomes, high-risk pregnancies were at high risk of adverse perinatal outcomes (odds ratio, 1.78; 95% confidence interval, 0.15-2.72; P=.009). However, such association was mainly because of the higher incidence of miscarriage in high-risk pregnancies compared with that in low-risk pregnancies (5.3% vs 1.6%, P=.008); furthermore, there was no difference in other explored outcomes between the 2 study groups. At logistic regression analysis, maternal age (odds ratio, 1.12; 95% confidence interval, 1.02-1.22; P=.023) and high-risk pregnancy (odds ratio, 4.21; 95% confidence interval, 3.90-5.11; P.001) were independently associated with adverse maternal outcomes.High-risk pregnancies complicated by severe acute respiratory syndrome coronavirus 2 infection were at higher risk of adverse maternal outcomes than low-risk pregnancies complicated by severe acute respiratory syndrome coronavirus 2 infection.

Antibody drug conjugates (ADCs) can undergo in vivo biotransformation (e.g., payload metabolism, deconjugation) leading to reduced or complete loss of activity. The location/site of conjugation of payload-linker can have an effect on ADC stability and hence needs to be carefully optimized. Affinity capture LC-MS of intact ADCs or ADC subfragments has been extensively used to evaluate ADC biotransformation. However, the current methods have certain limitations such as the requirement of specific capture reagents, limited mass resolution of low mass change metabolites, low sensitivity, and use of capillary or nanoflow LC-MS. To address these challenges, we developed a generic affinity capture LC-MS assay that can be utilized to evaluate the biotransformation of any site-specific ADC independent of antibody type and site of conjugation (Fab and Fc) in preclinical studies. The method involves a combination of some or all of these steps: (1) "mono capture" or "dual capture" of ADCs from serum with streptavidin magnetic beads coated with a generic biotinylated antihuman capture reagent, (2) "on-bead" digestion with IdeS and/or PNGase F, and (3) reduction of interchain disulfide bonds to generate ∼25 kDa ADC subfragments, which are finally analyzed by LC-HRMS on a TOF mass spectrometer. The advantages of this method are that it can be performed using commercially available generic reagents and requires sample preparation time of less than 7 h. Furthermore, by reducing the size of intact ADC (∼150 kDa) to subfragments (∼25 kDa), the identification of conjugated payload and its metabolites can be achieved with excellent sensitivity and resolution (hydrolysis and other small mass change metabolites). This method was successfully applied to evaluate the in vitro and in vivo biotransformation of ADCs conjugated at different sites (LC, HC-Fab, and HC-Fc) with various classes of payload-linkers.

We investigated the diagnostic utility of combined nerve and vascular ultrasound in thoracic outlet syndrome (TOS) in a retrospective cohort study on two sites, involving 167 consecutive patients with the clinical symptoms suggestive of neurogenic and/or vascular TOS, and an age- and sex-matched control group. All patients and control subjects underwent nerve ultrasound of the supraclavicular brachial plexus to look for fibromuscular anomalies / compression of the brachial plexus in the scalenic region, and vascular ultrasound of the infraclavicular subclavian artery with the arm in neutral and abducted position, serving as an indicator for costoclavicular compression of the neurovascular bundle. Based on clinical symptoms, neurogenic TOS (81%) was the most frequent type of TOS, followed by combined neurogenic and arterial TOS (8%). The frequency of abnormal nerve and/or vascular ultrasound findings differed significantly from the control group (Pst rib. As implied by the higher sensitivity of vascular ultrasound, the most common site of compression was the costoclavicular space, but multilevel compression was also frequently observed. In summary, combined nerve and vascular ultrasound is a sensitive and reliable method to support the diagnosis of TOS. It can also identify the site(s) of compression, with obvious therapeutic consequences.

BACKGROUND: It has still to be ascertained whether severe acute respiratory syndrome coronavirus 2 infection in pregnancy is associated with worse maternal and fetal outcomes compared to low risk gestations. OBJECTIVE: This study aimed to evaluate maternal and perinatal outcomes in high- and low-risk pregnancies complicated by severe acute respiratory syndrome coronavirus 2 infection. STUDY DESIGN: This was a multinational retrospective cohort study involving women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection from 76 centers from 25 countries in Europe, the United States, South America, Asia, and Australia from April 4, 2020, to October 28, 2020. The primary outcome was a composite measure of maternal mortality and morbidity, including admission to the intensive care unit, use of mechanical ventilation, or death. The secondary outcome was a composite measure of adverse perinatal outcome, including miscarriage, fetal loss, neonatal and perinatal death, and admission to the neonatal intensive care unit. All outcomes were assessed in high- and low-risk pregnancies. Pregnancies were considered high risk in case of either preexisting chronic medical conditions in pregnancy or obstetrical disorders occurring in pregnancy. The Fisher exact test and logistic regression analysis were used to analyze the data. RESULTS: A total of 887 singleton pregnancies who tested positive for severe acute respiratory syndrome coronavirus 2 infection using reverse transcription-polymerase chain reaction of nasal and pharyngeal swab specimens were included in the study. The risk of composite adverse maternal outcomes was higher in high-risk pregnancies than in low-risk pregnancies (odds ratio, 1.52; 95% confidence interval, 1.03-2.24; P=.035). In addition, women carrying high-risk pregnancies were at higher risk of hospital admission (odds ratio, 1.48; 95% confidence interval, 1.07-2.04; P=.002), presence of severe respiratory symptoms (odds ratio, 2.13; 95% confidence interval, 0.41-3.21; P=.001), admission to the intensive care unit (odds ratio, 2.63; 95% confidence interval, 1.42-4.88), and invasive mechanical ventilation (odds ratio, 2.65; 95% confidence interval, 1.19-5.94; P=.002). When exploring perinatal outcomes, high-risk pregnancies were at high risk of adverse perinatal outcomes (odds ratio, 1.78; 95% confidence interval, 0.15-2.72; P=.009). However, such association was mainly because of the higher incidence of miscarriage in high-risk pregnancies compared with that in low-risk pregnancies (5.3% vs 1.6%, P=.008); furthermore, there was no difference in other explored outcomes between the 2 study groups. At logistic regression analysis, maternal age (odds ratio, 1.12; 95% confidence interval, 1.02-1.22; P=.023) and high-risk pregnancy (odds ratio, 4.21; 95% confidence interval, 3.90-5.11; P

We aimed to analyze the technical success rate of manual percutaneous aspiration thrombectomy (PAT) in patients with peripheral arterial thromboembolism as a complication of infrainguinal percutaneous transluminal angioplasty (PTA) and we sought to evaluate the 30-day postintervention clinical outcome.We retrospectively identified 29 patients (men/women, 18/11; mean age, 74 years) who underwent infrainguinal PAT to treat thromboembolic complications of infrainguinal PTA. Primary and secondary technical successes were defined as residual stenosis of 50 % of the vessel diameter after PAT alone and PAT with additional PTA, respectively. Clinical outcome parameters (e. g., amputation, need for further intervention) were evaluated during the first 30 days after intervention.The primary and secondary technical success rates were 58.6 % (17/29) and 79.3 % (23/29), respectively. Clinical outcome data were available for 93.1 % (27/29) of patients. No further intervention was required within 30 days in 81.5 % (22/27) of patients. Four patients underwent minor amputations owing to preexisting ulcerations (Rutherford Category 5), and no patients underwent major amputations (Rutherford Category 6). Revascularization of the previously treated vessel segment with PTA was necessary on the first postintervention day in one patient.Manual PAT, with PTA if needed, has a good technical success rate and satisfactory early clinical outcome in patients with iatrogenic thromboembolic complications after infrainguinal PTA.· Manual PAT is a possible first-choice treatment of infrainguinal PTA-induced acute thromboembolism.. · Performing additional PTA increases the success rate of manual PAT.. · Unlike catheter-directed intraarterial lysis, manual PAT carries no risk of bleeding..· Schicho A, Bäumler W, Verloh N et al. Percutaneous Aspiration Thrombectomy for Arterial Thromboembolic Occlusion Following Percutaneous Transluminal Angioplasty: Technical Success Rates and Clinical Outcomes. Fortschr Röntgenstr 2022; 194: 291 - 295.ZIEL: Bestimmung der technischen Erfolgsrate einer manuell durchgeführten, perkutanen Aspirationsthrombektomie (PAT) in Patienten mit peripherer arterieller Thrombembolie als Komplikation einer infrainguinalen perkutanen transluminalen Angioplastie (PTA) sowie Erhebung des klinischen Outcomes innerhalb der ersten 30 Tage nach der Intervention.Es wurden retrospektiv 29 Patienten (männlich/weiblich, 18/11; mittleres Alter, 74 Jahre) identifiziert, bei denen eine infrainguinale PAT zur Behandlung einer thrombembolischen Komplikation im Rahmen einer infrainguinalen PTA durchgeführt wurde. Primärer bzw. sekundärer technischer Erfolg wurden definiert als residuelle Gefäßstenose 50 % des Gefäßdurchmessers nach alleiniger PAT bzw. nach PAT mit additiver PTA. Parameter des klinischen Outcomes (bspw. Amputation, Notwendigkeit eines Folgeeingriffs) wurden für die ersten 30 postinterventionellen Tage erhoben.Die primäre bzw. sekundäre technische Erfolgsrate lag bei 58,6 % (17/29) bzw. 79,3 % (23/29). Daten über das klinische Outcome waren von 93,1 % (27/29) der Patienten verfügbar. Innerhalb der ersten 30 Tage nach der Intervention war in 81,5 % (22/27) der Patienten kein Folgeeingriff nötig. Bei 4 Patienten wurden Minor-Amputationen aufgrund vorbestehender Ulcera (Rutherford-Kategorie 5) durchgeführt; es erfolgten keine Major-Amputationen (Rutherford-Kategory 6). Bei einer Patientin war am ersten postinterventionellen Tag eine neuerliche Revaskularisation des am Vortag mittels PTA behandelten Gefäßabschnitts notwendig.Bei Patienten mit thrombembolischer Komplikation i.R.e. infrainguinalen PTA weist eine manuelle PAT, falls notwendig in Kombination mit PTA, gute technische sowie klinische Erfolgsraten auf.· Eine manuelle PAT ist eine mögliche primäre Behandlungsmethode akuter thrombembolischer Komplikationen nach infrainguinaler PTA.. · Deutliche Steigerung des PAT-Erfolgs durch additive PTA möglich.. · PAT hat gegenüber der intraarteriellen Katheterlyse keine Blutungsrisiken..

BACKGROUND: COVID-19 convalescent plasma (CCP) has been considered a treatment option for COVID-19. This trial assessed the efficacy of a neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment. METHODS: Patients (n = 105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21. RESULTS: The primary outcome occurred in 43.4% of patients in the CCP group and 32.7% in the control group (P = 0.32). The median time to clinical improvement was 26 days in the CCP group and 66 days in the control group (P = 0.27). The median time to discharge from the hospital was 31 days in the CCP group and 51 days in the control group (P = 0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies, the primary outcome occurred in 56.0% of the patients (vs. 32.1%), with significantly shorter intervals to clinical improvement (20 vs. 66 days, P < 0.05) and to hospital discharge (21 vs. 51 days, P = 0.03) and better survival (day-60 probability of survival 91.6% vs. 68.1%, P = 0.02) in comparison with the control group. CONCLUSION: CCP added to standard treatment was not associated with a significant improvement in the primary and secondary outcomes. A predefined subgroup analysis showed a significant benefit of CCP among patients who received a larger amount of neutralizing antibodies. TRIAL REGISTRATION: ClinicalTrials.gov NCT04433910. FUNDING: Bundesministerium für Gesundheit (German Federal Ministry of Health): ZMVI1-2520COR802.

Background The COVID-19 pandemic is an ongoing global healthcare crisis that negatively affects pregnant women. Although patients with an acute infection during pregnancy have been widely studied, information regarding labor and delivery while infected is sparse. The aim of the study was to ascertain maternal, obstetrical, and perinatal outcomes of women who gave birth while infected with SARS-CoV-2. Methods Patients diagnosed with COVID-19 during pregnancy at a tertiary medical center in 4/20–2/21 were identified by a retrospective database search. Those with an active intrapartum SARS-CoV-2 infection were compared with those who recovered at least 10 days before labor and delivery. Results Of the 176 women included in the study, 84 had a SARS-CoV-2 infection at the time of delivery and 92 had recovered from the infection. There was no statistically significant between-group difference in mean gestational age at delivery (39 weeks for both, p = 0.71) and overall rate of cesarean delivery (26.2% vs 17.4%, respectively, p = 0.35) or non-elective cesarean delivery (10.71% vs 4.34%, respectively, p = 0.48). In the active-infection group, the rate of severe disease was 2.4%, and of critical disease (with intensive care unit admission, mechanical ventilation, and ECMO), 3.6%, compared to zero for both in the recovered group. No differences were found between the groups in adverse perinatal outcomes. Conclusion Delivery is safe and feasible in women with active SARS-CoV-2 infection. Nevertheless, we found a non-significant trend for more severe disease and for cesarean delivery and urgent cesarean delivery (for COVID-19-related indications) in women with an intrapartum SARS-CoV-2 infection.

T-cell engagers (TCEs) are a growing class of biotherapeutics being investigated in the clinic for treatment of a variety of hematological and solid tumor indications. However, preclinical evaluation of TCEs in vivo has been mostly limited to xenograft tumor models in human T-cell reconstituted immunodeficient mice, which have a number of limitations. To explore the efficacy of human TCEs in fully immunocompetent hosts, we developed a knock-in mouse model (hCD3E-epi) in which a 5-residue N-terminal fragment of murine CD3-epsilon was replaced with an 11-residue stretch from the human sequence that encodes for a common epitope recognized by anti-human CD3E antibodies in the clinic. T cells from hCD3E-epi mice underwent normal thymic development and could be efficiently activated upon crosslinking of the T-cell receptor with anti-human CD3E antibodies in vitro. Furthermore, a TCE targeting human CD3E and murine CD20 induced robust T-cell redirected killing of murine CD20-positive B cells in ex vivo hCD3E-epi splenocyte cultures, and also depleted nearly 100% of peripheral B cells for up to 7 days following in vivo administration. These results highlight the utility of this novel mouse model for exploring the efficacy of human TCEs in vivo, and suggest a useful tool for evaluating TCEs in combination with immuno-oncology/non-immuno-oncology agents against heme and solid tumor targets in hosts with a fully intact immune system.

Background In adults, intussusception has been considered traditionally to have an underlying aetiology. The aim of this study was to determine CT and clinical features of small-bowel intussusceptions that required surgical intervention. Methods Adult patients were identified in whom small-bowel intussusceptions were noted on CT images. The appearance, number, type (enteroenteric versus enterocolic), length and maximum short-axis diameter of intussusceptions, and presence of bowel obstruction (short-axis diameter of proximal small bowel greater than 3 cm) were analysed. The outcome was defined as surgical (complicated) or self-limiting (uncomplicated). Associations between complicated and uncomplicated intussusceptions and patient characteristics were investigated. Results Among 75 patients (56 male) with a mean age of 45 years, 103 intussusceptions were identified, of which 98 (95 per cent) were enteroenteric and 5 (5 per cent) enterocolic. Only 12 of 103 intussusceptions (12 per cent) in 12 of 75 (16 per cent) patients required surgical therapy and were considered to be complicated, with half of these having a neoplastic lead point. Length (P < 0.001), diameter (P < 0.001) and type (P = 0.002) of intussusception as well as presence of vessels (P = 0.023) within an intussusception on a CT scan, clinical symptoms (P = 0.007) and signs of bowel obstruction (P < 0.001) were associated with a surgical outcome. Conclusion Clinical symptoms, signs of bowel obstruction, type and length of intussusception, and a visible tumour within an intussusception on CT scan were critical signs of complicated intussusception, requiring surgical intervention., Small bowel intussusceptions in adults are usually considered to have an underlying disease in nearly all cases. The authors evaluated retrospectively the clinical significance of 103 small bowel intussusceptions in 75 adult patients detected by CT by analysing the characteristics of patients, CT morphology of intussusceptions and correlation of surgical results in nearly one-third of patients. Only 12 of 103 intussusceptions (12 per cent) in 12 of 75 (16 per cent) patients required surgical therapy. Clinical symptoms, signs of bowel obstruction, type and length of intussusception, and a visible tumour within an intussusception on a CT scan were critical signs of complicated intussusception, that is one requiring surgical treatment.

The course of COVID-19 has been shown to be worse in pregnant women compared with their non-pregnant counterparts. The aim of this study is to share our experience treating pregnant women with COVID-19 and to establish a cohort for future studies of the long-term effects of the disease. We reviewed medical records of all SARS-CoV-2-positive pregnant women who were treated at our hospital for any reason, be it COVID-19 related or not, between April 2020 and February 2021. We extracted data regarding medical history, course of pregnancy, delivery, and neonatal outcomes. A total of 193 SARS-CoV-2-positive pregnant women were treated at our establishment during the study period, half of which were asymptomatic. Sixteen were hospitalized for COVID-19 symptoms, the most common being fatigue/malaise (58%) and cough (48%). Three women required mechanical ventilation and extracorporeal membrane oxygenation treatment. One hundred forty-four SARS-CoV-2-positive women were delivered during the study period. Of them, 24 (17%) underwent induction of labor, and four (17%) were due to symptomatic COVID-19. One hundred fifteen (80%) experienced vaginal delivery, and 29 (20%) underwent cesarean delivery. Neonatal outcomes were favorable; only 2% of 5-min Apgar scores were 7, and all umbilical cord pH levels were 7.1. Six infants tested positive for SARS-CoV-2; they were all asymptomatic, and none required treatment for viral infection. COVID-19 during pregnancy is a disease with potential substantial adverse maternal and neonatal outcomes. There is still much unknown regarding the long-term effects of the disease on parturients and their offspring.

Ligand-binding assay (LBA) and LC–MS have been the preferred bioanalytical techniques for the quantitation and biotransformation assessment of various therapeutic modalities. This review provides an overview of the applications of LBA, LC–MS/MS and LC–HRMS for the bioanalysis of complex protein therapeutics including antibody–drug conjugates, fusion proteins and PEGylated proteins as well as oligonucleotide therapeutics. The strengths and limitations of LBA and LC–MS, along with some guidelines on the choice of appropriate bioanalytical technique(s) for the bioanalysis of these therapeutic modalities are presented. With the discovery of novel and more complex therapeutic modalities, there is an increased need for the biopharmaceutical industry to develop a comprehensive bioanalytical strategy integrating both LBA and LC–MS.

Background To compare the frequency of adverse events of thermal microwave (MWA) and radiofrequency ablation (RFA) with non-thermal irreversible electroporation (IRE) in percutaneous ablation of hepatocellular carcinoma (HCC). Patients and methods We retrospectively analyzed 117 MWA/RFA and 47 IRE procedures (one tumor treated per procedure; 144 men and 20 women; median age, 66 years) regarding adverse events, duration of hospital and intensive care unit (ICU) stays and occurrence of a post-ablation syndrome. Complications were classified according to the Clavien & Dindo classification system. Results 70.1% of the RFA/MWA and 63.8% of the IRE procedures were performed without complications. Grade I and II complications (any deviation from the normal postinterventional course, e.g., analgesics) occurred in 26.5% (31/117) of MWA/RFA and 34.0% (16/47) of IRE procedures. Grade III and IV (major) complications occurred in 2.6% (3/117) of MWA/RFA and 2.1% (1/47) of IRE procedures. There was no significant difference in the frequency of complications (p = 0.864), duration of hospital and ICU stay and the occurrence of a post-ablation syndrome between the two groups. Conclusions Our results suggest that thermal (MWA and RFA) and non-thermal IRE ablation of malignant liver tumors have comparable complication rates despite the higher number of punctures and the lack of track cauterization in IRE.

Heat shock protein Hsp70 (Hsp70) is found on the cell surface of a large variety of human and mouse tumor cell types including U87, GL261 glioblastoma, and 4T1 mammary carcinoma cells. We studied the role of membrane-bound Hsp70 (mHsp70) in the formation of cell-to-cell connections via tunneling nanotubes (TNTs) using live-cell STED nanoscopy. This technique allows the visualization of microstructures in the 100-nm range in the living cells. We could show that the presence of tumor-derived mHsp70 in TNTs with a diameter ranging from 120 to 140 nm predominantly originates from cholesterol-rich-microdomains containing the lipid compound globoyltriaosylceramide (Gb3). Under non-stress conditions, Hsp70 and Gb3 are structurally clustered in the membrane of TNTs of tumor cells that showed tumor type specific variations in the amount of cell-to-cell connection networks. Furthermore depletion of cholesterol and ionizing radiation as a stress factor results in a complete loss of Hsp70-containing TNTs. Electronic supplementary material The online version of this article (10.1007/s12192-018-00958-w) contains supplementary material, which is available to authorized users.

Background Fistulas are serious complications of splenic and perisplenic fluid accumulations, which are often difficult to detect by routine imaging methods. Purpose To evaluate the occurrence of spontaneous fistulas detectable during computed tomography-guided percutaneous drainage placement (CTGDP) with contrast filling of splenic or perisplenic fluid collections and to assess characteristics in comparison with perihepatic or peripancreatic fluid accumulations, also being treated with CTGDP. Material and Methods In 127 CTGDP-procedures, pre-interventional CTs conducted with intravenous contrast agent were compared to post-interventional CTs including contrast filling of the drain to identify spontaneous fistulas. Patient and case characteristics were evaluated, and therapeutic consequences of fistula identification were analyzed. Results A total of 43 perisplenic, 40 peripancreatic, and 44 perihepatic drains were evaluated; 13 (30.2%) perisplenic, 7 (17.5%) peripancreatic, and 10 (22.7%) perihepatic fistulas were observed. Concerning the frequency of fistulas, no significant difference was found between the patient groups ( P = 0.39). All fistulas were solely proven in CT scans including contrast filling of the drain. Seven fistulas (23.3%) required additional interventions. Perihepatic drains were significantly more often associated with recent surgery ( P Conclusion Spontaneous fistulas detected during CTGDP of splenic or perisplenic fluid collections are common. Post-interventional contrast filling of the drain drastically improves the detection rate of perisplenic, peripancreatic and perihepatic fistulas simultaneously initiating appropriate follow-up interventions.

Traditionally the biotransformation of antibody drug conjugates (ADCs) has been evaluated by affinity capture on streptavidin magnetic beads coated with a biotinylated capture reagent. To reduce the complexity of the analyte, the affinity captured ADCs are digested with enzymes ("on-bead" or after elution), and/or interchain disulfides are reduced to generate LC and HC fragments prior to mass spectrometry analysis. The "on-bead" enzymatic digestion with IdeS and PNGase F is not efficient and requires longer incubation times to achieve complete Fc and N-glycan removal. This results in a prolonged sample preparation time (7-18 h) and is not suitable for labile ADCs due to the possibility of assay-induced artifacts. To address these challenges, we developed an affinity capture method, where the ADCs are first captured onto streptavidin cartridges coated with a biotinylated generic capture reagent, followed by a 15 min "on-cartridge" digestion with IdeS or PNGase F. The ADCs are then eluted and directly analyzed by LC-HRMS. This method was successfully applied for the biotransformation assessment of site-specific ADCs with payload conjugated on the Fab or Fc. The reduced complexity of the analyte (Fc and N-glycan removal) combined with HRMS enabled sensitive and accurate identification of minor mass change catabolites and changes in the DAR distribution. This automated cartridge-based affinity capture method is fast with a total sample preparation time of less than 4 h (hands-on time of less than 1 h) and can be utilized for any human mAb/ADC independent of isotype (IgG1, IgG2, and IgG4).

Regulation of transcription is a tightly choreographed process. The establishment of RNA polymerase II promoter proximal pausing soon after transcription initiation and the release of Pol II into productive elongation are key regulatory processes that occur in early elongation. We describe the techniques and tools that have become available for the study of promoter proximal pausing and their utility for future experiments. We then provide an overview of the factors and interactions that govern a multipartite pausing process and address emerging questions surrounding the mechanism of RNA polymerase II's subsequent advancement into the gene body. Finally, we address remaining controversies and future areas of study.

Proton minibeam radiotherapy (pMBRT) is a spatial fractionation method using sub-millimeter beams at center-to-center (ctc) distances of a few millimeters to widen the therapeutic index by reduction of side effects in normal tissues. Interlaced minibeams from two opposing or four orthogonal directions are calculated to minimize side effects. In particular, heterogeneous dose distributions applied to the tumor are investigated to evaluate optimized sparing capabilities of normal tissues at the close tumor surrounding. A 5 cm thick tumor is considered at 10 cm depth within a 25 cm thick water phantom. Pencil and planar minibeams are interlaced from two (opposing) directions as well as planar beams from four directions. An initial beam size of σ0 = 0.2 mm (standard deviation) is assumed in all cases. Tissue sparing potential is evaluated by calculating mean clonogenic cell survival using a linear-quadratic model on the calculated dose distributions. Interlacing proton minibeams for homogeneous irradiation of the tumor has only minor benefits for the mean clonogenic cell survival compared to unidirectional minibeam irradiation modes. Enhanced mean cell survival, however, is obtained when a heterogeneous dose distribution within the tumor is permitted. The benefits hold true even for an elevated mean tumor dose, which is necessary to avoid cold spots within the tumor in concerns of a prescribed dose. The heterogeneous irradiation of the tumor allows for larger ctc distances. Thus, a high mean cell survival of up to 47% is maintained even close to the tumor edges for single fraction doses in the tumor of at least 10 Gy. Similar benefits would result for heavy ion minibeams with the advantage of smaller minibeams in deep tissue potentially offering even increased tissue sparing. The enhanced mean clonogenic cell survival through large ctc distances for interlaced pMBRT with heterogeneous tumor dose distribution results in optimum tissue sparing potential. The calculations show the largest enhancement of the mean cell survival in normal tissue for high-dose fractions. Thus, hypo-fractionation or even single dose fractions become possible for tumor irradiation. A widened therapeutic index at big cost reductions is offered by interlaced proton or heavy ion minibeam therapy.

Background: Retrospective evaluation of the safety and efficacy of the retrieval of misplaced central venous catheters (CVCs) in subclavian arteries using the femoral closure device Angio-Seal™. Methods: The clinical data of five patients (female, n = 2; mean age, 55.0 years ± 11.9) in whom a misplaced CVC within a subclavian artery was removed followed by closure of the vessel entry site with 8-French (F) Angio-Seal™ was analyzed. Results: In 4/5 patients (80%; CVC diameter, 7-8F) the procedure was technically successful without complications. In 1/5 patients (20%; CVC diameter, 11.5F) the procedure failed and an additional covered stent was placed for successful closure of the vessel entry site. There were no complications associated with the Angio-Seal™ or stent implantation during follow-up. Conclusion: Retrieval of a misplaced CVC within a subclavian artery using the percutaneous closure device Angio-Seal™ is quite safe and effective; however, caution is required if there is a mismatch in the diameter of the Angio-Seal™ and CVC. In the case of procedure failure, successful closure of the vessel entry site can be achieved by covered stent placement.

Accurate knowledge of the exact stopping location of ions inside the patient would allow full exploitation of their ballistic properties for patient treatment. The localized energy deposition of a pulsed particle beam induces a rapid temperature increase of the irradiated volume and leads to the emission of ionoacoustic (IA) waves. Detecting the time-of-flight (ToF) of the IA wave allows inferring information on the Bragg peak location and can henceforth be used for in-vivo range verification. A challenge for IA is the poor signal-to-noise ratio at clinically relevant doses and viable machines. We present a frequency-based measurement technique, labeled as ionoacoustic tandem phase detection (iTPD) utilizing lock-in amplifiers. The phase shift of the IA signal to a reference signal is measured to derive the ToF. Experimental IA measurements with a 3.5 MHz lead zirconate titanate (PZT) transducer and lock-in amplifiers were performed in water using 22 MeV proton bursts. A digital iTPD was performed in-silico at clinical dose levels on experimental data obtained from a clinical facility and secondly, on simulations emulating a heterogeneous geometry. For the experimental setup using 22 MeV protons, a localization accuracy and precision obtained through iTPD deviates from a time-based reference analysis by less than 15 μm. Several methodological aspects were investigated experimentally in systematic manner. Lastly, iTPD was evaluated in-silico for clinical beam energies indicating that iTPD is in reach of sub-mm accuracy for fractionated doses < 5 Gy. iTPD can be used to accurately measure the ToF of IA signals online via its phase shift in frequency domain. An application of iTPD to the clinical scenario using a single pulsed beam is feasible but requires further development to reach

Background/aim Endothelin causes vasoconstriction via the endothelin-A receptor (ET-A) in the intrahepatic circulation in cirrhosis and its increase leads to portal hypertension. The aim of the study was to investigate the acute effect of a selective ET-A antagonist in patients with portal hypertension and cirrhosis. Methods Proof-of-concept study with two different substudies: (a) local intrahepatic administration of the ET-A antagonist BQ 123 and (b) systemic oral administration of the ET-A antagonist Ambrisentan. Portal pressure was determined by hepatic venous pressure gradient (HVPG, both substudies) and hepatic arterial blood flow (HABF) by intra-arterial Doppler measurements (substudy 1) before and under the ET-A antagonist. Systemic haemodynamic parameters were measured in substudy 2. Results Twelve patients (Child-Pugh [CP] B/C n = 7/5) were included in substudy 1 and 14 patients (CP A/B/C n = 4/6/4) in substudy 2. The relative decrease in HVPG was -12.5% (IQR: -40% to 0%; P = .05) in substudy 1 and -5.0% (IQR: -11.5% to 0%; P = .01) in substudy 2. Substudy 1 revealed higher decrease in HVPG in CP B patients. HABF increased significantly and patients without portal pressure decrease showed a higher increase of HABF. Substudy 2 showed a slight decrease in the mean arterial pressure without changes of other systemic haemodynamic parameters. Conclusion Administration of a selective ET-A antagonist decreases the portal pressure in cirrhotic patients. This decrease was higher in CP B patients and the non-responders showed a higher increase in hepatic arterial flow. Selective ET-A antagonists might be a future treatment option in patients with portal hypertension.

[London] : Macmillan Publishers Limited, part of Springer Nature (2020). doi:10.1038/s41598-020-76568-3, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

ObjectiveTo develop a tool to assess current (past 30 days) and lifetime marijuana use in older Veterans.SettingUS Veteran’s Affairs Healthcare System.Participants704 older Veterans were screened, 339 completed the initial survey, 100 completed the follow-up.Primary outcome measurePearson’s correlation coefficient to assess strength of association between initial and follow-up survey on measures of current and lifetime marijuana use.ResultsBoth a ‘gram-month’ measure of marijuana smoked in the past 30 days (r=0.83) and a frequency-based measure assessing total number of times smoked in the past 30 days were reliable (r=0.89). Both a simple categorical measure of lifetime use (agreement=85%) and a continuous measure of lifetime use (r=0.82) were reliable.ConclusionsThe Cannabis Assessment Tool offers a reliable assessment of past 30 days and lifetime assessments of smoking cannabis in older adults.

The incidence and evolution of venous thrombosis adjacent to the ablation zone after percutaneous irreversible electroporation (IRE) were evaluated to identify potential risk factors in patients with hepatic malignancies. 205 venous structures (in 87 patients) within a ≤1.0 cm radius of the ablation zone were assessed after IRE of 112 hepatic lesions (74 primary, 38 secondary hepatic malignancies) by pre-interventional and post-interventional (1–3 days, 6 weeks and 3 months after IRE) contrast-enhanced magnetic resonance imaging. The relationships between venous thrombosis and clinical features were analysed using a binary logistic regression model. In 27 of 87 patients (31%), a total of 67 venous complications were noted during the 3 months follow-up. Thrombosis represented the most frequently observed complication (n = 47; 70.1%), followed by vessel narrowing (n = 20; 29.9%). 5 (10.6%) of 47 thromboses showed spontaneous regression 3 months after IRE. A small vessel diameter (p = 0.011) and post-interventional vessel narrowing (p = 0.006) were independently associated with delayed post-ablative thrombosis. Delayed venous thrombosis frequently occurs after IRE of hepatic malignancies. Pre-existing vessel narrowing and a small vessel diameter represent significant risk factors that require further surveillance and potentially therapeutic intervention.

Background. Cardiovascular disease (CVD) annually claims more lives and costs more dollars than any other disease globally amid widening health disparities, despite the known significant reductions in this burden by low cost dietary changes. The world’s first medical school-based teaching kitchen therefore launched CHOP-Medical Students as the largest known multisite cohort study of hands-on cooking and nutrition education versus traditional curriculum for medical students. Methods. This analysis provides a novel integration of artificial intelligence-based machine learning (ML) with causal inference statistics. 43 ML automated algorithms were tested, with the top performer compared to triply robust propensity score-adjusted multilevel mixed effects regression panel analysis of longitudinal data. Inverse-variance weighted fixed effects meta-analysis pooled the individual estimates for competencies. Results. 3,248 unique medical trainees met study criteria from 20 medical schools nationally from August 1, 2012, to June 26, 2017, generating 4,026 completed validated surveys. ML analysis produced similar results to the causal inference statistics based on root mean squared error and accuracy. Hands-on cooking and nutrition education compared to traditional medical school curriculum significantly improved student competencies (OR 2.14, 95% CI 2.00–2.28, p<0.001) and MedDiet adherence (OR 1.40, 95% CI 1.07–1.84, p=0.015), while reducing trainees’ soft drink consumption (OR 0.56, 95% CI 0.37–0.85, p=0.007). Overall improved competencies were demonstrated from the initial study site through the scale-up of the intervention to 10 sites nationally (p<0.001). Discussion. This study provides the first machine learning-augmented causal inference analysis of a multisite cohort showing hands-on cooking and nutrition education for medical trainees improves their competencies counseling patients on nutrition, while improving students’ own diets. This study suggests that the public health and medical sectors can unite population health management and precision medicine for a sustainable model of next-generation health systems providing effective, equitable, accessible care beginning with reversing the CVD epidemic.

Cell therapies suffer from poor survival post-transplant due to placement into hostile implant sites characterized by host immune response and innate production of high levels of reactive oxygen species (ROS). We hypothesized that cellular encapsulation within an injectable, antioxidant hydrogel would improve viability of cells exposed to high oxidative stress. To test this hypothesis, we applied a dual thermo- and ROS-responsive hydrogel comprising the ABC triblock polymer poly[(propylene sulfide)-block-(N,N-dimethyl acrylamide)-block-(N-isopropylacrylamide)] (PPS135-b-PDMA152-b-PNIPAAM225, PDN). The PPS chemistry reacts irreversibly with ROS such as hydrogen peroxide (H2O2), imparting inherent antioxidant properties to the system. Here, PDN hydrogels were successfully integrated with type 1 collagen to form ROS-protective, composite hydrogels amenable to spreading and growth of adherent cell types such as mesenchymal stem cells (MSCs). It was also shown that, using a control hydrogel substituting nonreactive polycaprolactone in place of PPS, the ROS-reactive PPS chemistry is directly responsible for PDN hydrogel cytoprotection of both MSCs and insulin-producing β-cell pseudo-islets against H2O2 toxicity. In sum, these results establish the potential of cytoprotective, thermogelling PDN biomaterials for injectable delivery of cell therapies.

The relative biological effectiveness (RBE) based on the induction of dicentrics in any cell type is principally an important information for the increasing application of high-LET radiation in cancer therapy. Since the standard system of human lymphocytes for measuring dicentrics are not compatible with our microbeam irradiation setup where attaching cells are essential, we used human–hamster hybrid AL cells which do attach on foils and fulfil the special experimental requirement for microbeam irradiations. In this work, the dose–response of AL cells to photons of different energy, 70 and 200 kV X-rays and 60Co γ-rays, is characterized and compared to human lymphocytes. The total number of induced dicentrics in AL cells is approximately one order of magnitude smaller. Despite the smaller α and β parameters of the measured linear–quadratic dose–response relationship, the α/β-ratio versus photon energy dependence is identical within the accuracy of measurement for AL cells and human lymphocytes. Thus, the influence of the reference radiation used for RBE determination is the same. For therapy relevant doses of 2 Gy (60Co equivalent), the difference in RBE is around 20% only. These findings indicate that the biological effectiveness in AL cells can give important information for human cells, especially for studies where attaching cells are essential.

This guideline provides evidence-based key recommendations for diagnosis and therapy of complications of liver cirrhosis and upgrades the 2011 version. An interdisciplinary team of medical experts and patient support groups developed the guideline following the AWMF recommendations for evidence based consensus guidelines. New chapters concerning diagnosis and therapy of hepatic encephalopathy were added.Die Leitlinie Komplikationen der Leberzirrhose der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) ersetzt die Leitlinie aus dem Jahr 2011. Sie basiert auf den Empfehlungen der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) für eine evidenzbasierte Konsensus-Leitlinie der Entwicklungsstufe S2k und wurde interdisziplinär unter Beteiligung aller relevanten Fachgesellschaften und der Patientenvertretung erstellt. Neben den in der Vorgängerversion behandelten Kapiteln Aszites, spontan bakterielle Peritonitis, hepatorenales Syndrom, hepatischer Hydrothorax und hepatopulmonales Syndrom wurden die Kapitel Diagnostik und Therapie der Hepatischen Enzephalopathie neu aufgenommen.

The accumulation and spatial distribution of 53BP1, BRCA1 and Rad51, key proteins in DNA double-strand break (DSB) repair, was investigated with high temporal resolution over a time span of 24 h, using STED nanoscopy. DNA lesions were induced by irradiation with high-LET (linear energy transfer) α-particles. We show that 53BP1 IRIF formation occurs quickly in almost all cells and after about 6 h the fraction of 53BP1 IRIF positive cells slowly declines. Against the expectations BRCA1 and Rad51 IRIF formation is only shortly delayed but with the maximum of cells showing foci after 6 and 8 h after irradiation. At this stage, almost all IRIF in a given Rad51-positive cell show Rad51 accumulation, suggesting that repair via homologous recombination is attempted at almost all residual DSB sites. The frequency of BRCA1 IRIF positive cells increases much earlier and remains high after Rad51 positive cells start to decline, supporting models claiming that functional roles of BRCA1 change over time. Correlation analysis showed a high degree of correlation of Rad51 with BRCA1, while the exclusion of 53BP1 from the actual resection-zone is demonstrated by anti-correlation of Rad51 and 53BP1. Interestingly, these correlation and anti-correlation patterns exhibit complementary temporal variation.

Evaluation of the prevalence and significance of unsuspected extravascular findings on computed tomography angiography (CTA) of the body before endovascular or surgical treatment in vascular patients. This study was approved by the local institutional review board. Radiology reports of 806 patients who underwent CTA of the body during January 2004 until December 2014 before endovascular or surgical treatment of vascular diseases were retrospectively reviewed. All unexpected extravascular abnormalities were classified as clinically non-significant (requiring no follow-up) or clinically significant (requiring further follow-up/immediate treatment). The course of patients with significant extravascular findings was retrospectively evaluated. Overall 806 patients were included in this study (592 men; mean age: 67 years). In 778 (96.5 %) of 806 patients 3293 incidental extravascular findings were diagnosed. There were 259 suspicious findings in 205 patients (25.4 %) that required further follow-up or immediate treatment. A previously unknown malignant tumor was diagnosed in 23 (2.9 %) patients. 10 patients (1.2 %) were diagnosed with lung cancer. Malignant tumors were detected more often in men than in women (3.5 % versus 0.9 %). Patients with an incidental tumor were significantly older than patients without a tumor (mean age: 72.3 vs. 67.5 years). Clinically significant unexpected extravascular findings are common in vascular patients. Especially noteworthy are malignant tumors of the lung. · Clinically relevant extravascular findings were detected in 25.4 % of the patients.. · The incidence of malignant tumors was 2.9 %.. · Lung cancer had the highest incidence among all malignancies (1.2 %)..· Turowski LS, Dollinger M, Wohlgemuth WA et al. Preoperative computed tomography angiography (CTA) of the body in vascular patients: prevalence and significance of unsuspected extravascular findings. Fortschr Röntgenstr 2019; 191: 716 - 724.ZIEL: Evaluation der Prävalenz und Signifikanz von unerwarteten extravaskulären Befunden in Ganzkörper-computertomografischen Angiografie-Scans (CTA) vor endovaskulärer oder chirurgischer Behandlung von Gefäßpatienten. Diese Studie wurde von der örtlichen Ethikkommission genehmigt. Es wurden radiologische Befunde von Patienten, die eine Ganzkörper-CTA im Zeitraum zwischen Januar 2004 und Dezember 2014 vor endovaskulärer oder chirurgischer Therapie von Erkrankungen der Gefäße erhielten, retrospektiv aufgearbeitet. Alle unerwarteten extravaskulären Befunde wurden als klinisch nicht relevant (Verlaufskontrollen nicht indiziert) oder klinisch relevant (Verlaufskontrollen/sofortige Behandlung indiziert) klassifiziert. Der weitere Verlsauf von Patienten mit klinisch relevanten extravaskulären Befunden wurde retrospektiv evaluiert. Es wurden 806 Patienten in diese Studie eingeschlossen (592 Männer; Durchschnittsalter 67 Jahre). Bei 778 (96,5 %) von 806 Patienten wurden insgesamt 3293 extravaskuläre Zufallsbefunde festgestellt. Darunter befanden sich 259 suspekte Befunde bei 205 Patienten (25,4 %), die Verlaufskontrollen oder eine sofortige Behandlung erforderten. Ein bis dahin unbekanntes Malignom wurde bei 23 Patienten (2,9 %) diagnostiziert, darunter waren 10 Patienten (1,2 %) mit einem Lungenkarzinom. Bei Männern wurden mehr maligne Tumoren nachgewiesen als bei Frauen (3,5 % versus 0,9 %; p = 0,055; Fisher-Test). Patienten mit einem zufällig entdeckten malignen Tumor waren signifikant älter als Patienten ohne Tumorbefund (Durchschnittsalter 72,3 vs. 67,5 Jahre; p = 0,0432; t-test). Klinisch relevante extravaskuläre Zufallsbefunde treten häufig auf bei Gefäßpatienten. Besonders beachtenswert sind maligne Tumoren der Lunge. · Bei 25,4 % der Patienten wurden klinisch relevante extravaskuläre Zufallsbefunde diagnostiziert.. · Die Inzidenz maligner Tumoren lag bei 2,9 %.. · Das Bronchialkarzinom hat unter den Malignomen die höchste Inzidenz (1,2 %)..

The biophysical simulation tool PARTRAC contains modules for DNA damage response representing non-homologous end joining of DNA double-strand breaks (DSB) and the formation of chromosomal aberrations. Individual DNA ends from the induced DSB are followed regarding both their enzymatic processing and spatial mobility, as is needed for chromosome aberrations to arise via ligating broken ends from different chromosomes. In particular, by tracking the genomic locations of the ligated fragments and the positions of centromeres, the induction of dicentrics can be modeled. In recent experiments, the impact of spatial clustering of DNA damage on dicentric yields has been assessed in AL human-hamster hybrid cells: Defined numbers of 20 MeV protons (linear energy transfer, LET 2.6 keV/μm), 45 MeV Li ions (60 keV/μm) and 55 MeV C ions (310 keV/μm) focused to sub-μm spot sizes were applied with the ion microbeam SNAKE in diverse grid modes, keeping the absorbed dose constant. The impact of the μm-scaled spatial distribution of DSB (focusing effect) has thus been separated from nm-scaled DSB complexity (LET effect). The data provide a unique benchmark for the model calculations. Model and parameter refinements are described that enabled the simulations to largely reproduce both the LET-dependence and the focusing effect as well as the usual biphasic rejoining kinetics. The predictive power of the refined model has been benchmarked against dicentric yields for photon irradiation.

Nucleoli have attracted interest for their role as cellular stress sensors and as potential targets for cancer treatment. The effect of DNA double-strand breaks (DSBs) in nucleoli on rRNA transcription and nucleolar organisation appears to depend on the agent used to introduce DSBs, DSB frequency and the presence (or not) of DSBs outside the nucleoli. To address the controversy, we targeted nucleoli with carbon ions at the ion microbeam SNAKE. Localized ion irradiation with 1–100 carbon ions per point (about 0.3–30 Gy per nucleus) did not lead to overall reduced ribonucleotide incorporation in the targeted nucleolus or other nucleoli of the same cell. However, both 5-ethynyluridine incorporation and Parp1 protein levels were locally decreased at the damaged nucleolar chromatin regions marked by γH2AX, suggesting localized inhibition of rRNA transcription. This locally restricted transcriptional inhibition was not accompanied by nucleolar segregation, a structural reorganisation observed after inhibition of rRNA transcription by treatment with actinomycin D or UV irradiation. The presented data indicate that even multiple complex DSBs do not lead to a pan-nucleolar response if they affect only a subnucleolar region., Summary: Highly localized damage induced in nucleoli by carbon ion irradiation at the microbeam SNAKE only locally inhibits rRNA transcription, but does not cause nucleolar segregation.