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OBJECTIVES To characterize, using magnetic resonance imaging (MRI), the distribution of blood flow and oxygen transport in human fetuses with subtypes of congenital heart disease (CHD) that present with neonatal cyanosis. METHODS Blood flow was measured in the major vessels of 152 late-gestation human fetuses with CHD and 40 gestational-age-matched normal fetuses, using cine phase-contrast MRI. Oxygen saturation (SaO2 ) was measured in the major vessels of 57 fetuses with CHD and 40 controls. RESULTS Compared with controls, we found lower combined ventricular output in fetuses with single-ventricle physiology, with the lowest being observed in fetuses with severe forms of Ebstein's anomaly. Obstructive lesions of the left or right heart were associated with increased flow across the contralateral side. Pulmonary blood flow was reduced in fetuses with Ebstein's anomaly, while those with Ebstein's anomaly and tricuspid atresia had reduced umbilical flow. Flow in the superior vena cava was elevated in fetuses with transposition of the great arteries, normal in fetuses with hypoplastic left heart, tetralogy of Fallot or tricuspid atresia and reduced in fetuses with Ebstein's anomaly. Umbilical vein SaO2 was reduced in fetuses with hypoplastic left heart or tetralogy of Fallot. Ascending aorta and superior vena cava SaO2 were reduced in nearly all CHD subtypes. CONCLUSIONS Fetuses with cyanotic CHD exhibit profound changes in the distribution of blood flow and oxygen transport, which result in changes in cerebral, pulmonary and placental blood flow and oxygenation. These alterations of fetal circulatory physiology may influence the neonatal course and help account for abnormalities of prenatal growth and development that have been described in newborns with cyanotic CHD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Peritoneal-mediastinal communication is a rare complication of peritoneal dialysis (PD). We report the first case of peritoneal-mediastinal communication complication in a 36-year-old Caucasian man on continuous cycler peritoneal dialysis (CCPD) after undergoing cardiac surgery. He developed end-stage kidney disease (ESKD) due to calcineurin inhibitor nephrotoxicity and BK virus nephropathy in the setting of prior heart transplantation. He was initially started on intermittent hemodialysis (iHD) and was switched to CCPD 1 year later. He presented with increased drainage from his sternal incision site and reduced ultrafiltration. A contrast-enhanced chest computed tomography scan revealed an anterior chest wall subcutaneous fluid collection. He was found to have a peritoneal-mediastinal communication intraoperatively. He was successfully managed with "low-volume" PD by using reduced fill volumes for all his exchanges and did not require transition to iHD. He also had no vascular access options because of multiple prior thromboses, which would have made transitioning to iHD not feasible. This case further highlights the complex management of an ESKD patient who cannot do iHD and only do low-volume PD because of a surgical complication and the need for a multidisciplinary approach to ensure appropriate patient care.

Jonathan Corren,1 Sarbjit S Saini,2 Remi Gagnon,3 Mark H Moss,4 Gordon Sussman,5 Joshua Jacobs,6 Elizabeth Laws,7 Elinore S Chung,8 Tatiana Constant,8 Yiping Sun,8 Jennifer Maloney,8 Jennifer D Hamilton,8 Marcella Ruddy,8 Claire Q Wang,8 Meagan P O’Brien8 1Departments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 2Department of Internal Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA; 3Clinique Spécialisée en Allergie de la Capitale, Québec, QC, Canada; 4Departments of Medicine and Pediatrics, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 5Department of Medicine, University of Toronto, Toronto, ON, Canada; 6Allergy and Asthma Clinical Research, Inc, Walnut Creek, CA, USA; 7Sanofi, Bridgewater, NJ, USA; 8Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USACorrespondence: Meagan P O’BrienRegeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USATel +1 914 826-5271Email meagan.obrien@regeneron.comJonathan CorrenDepartments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave, Los Angeles, CA, 90095, USATel +1 310 312-5050, ext 250Email jcorren@ucla.eduBackground: Subcutaneous immunotherapy (SCIT) has been proven as an effective therapy against some allergens for seasonal allergic rhinitis (SAR) patients unresponsive to intranasal corticosteroids and/or antihistamines but carries risk of systemic allergic reactions. Dupilumab blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation in multiple diseases.Objective: To evaluate the efficacy and safety of SCIT+dupilumab vs SCIT alone.Methods: This phase 2a, multicenter, double-blind, placebo-controlled parallel-group study conducted in 103 adults with grass pollen-induced SAR (NCT03558997) randomized patients 1:1:1:1 to SCIT, dupilumab (300 mg every 2 weeks), SCIT+dupilumab, or placebo. SCIT was administered using an 8-week cluster protocol followed by 8 weeks of maintenance injections. Primary endpoint was change from pre-treatment baseline in area under the curve (AUC) in total nasal symptom score (TNSS) 0– 1 h following nasal allergen challenge (NAC) with timothy grass extract at Week 17.Results: Although 16 weeks of treatment with SCIT+dupilumab did not significantly improve TNSS AUC (0– 1 h) following NAC at Week 17 vs SCIT (least squares mean − 56.76% vs − 52.03%), a higher proportion of SCIT+dupilumab-treated patients (61.5%) achieved SCIT maintenance dose vs SCIT (46.2%). A lower proportion of SCIT+dupilumab-treated patients (7.7%) required epinephrine rescue treatment vs SCIT (19.2%). There were significantly fewer withdrawals in the SCIT+dupilumab group than in the SCIT group (n = 2 [7.7%] vs n = 8 [30.8%]; P = 0.0216); the majority of SCIT group withdrawals were due to SCIT-related intolerability, compared with no discontinuations from the SCIT+dupilumab group.Conclusion: In SAR patients, 16 weeks of SCIT+dupilumab may improve SCIT tolerability but did not incrementally reduce post-allergen challenge nasal symptoms compared with SCIT alone.Clinical Study Number: NCT03558997.Keywords: dupilumab, seasonal allergic rhinitis, subcutaneous immunotherapy, nasal allergen responses

Introduction Advanced breast cancer (aBC) remains incurable and the quest for more effective systemic anticancer agents continues. Promising results have led to the FDA approval of three antibody-drug conjugates (ADCs) and two immune checkpoint inhibitors (ICIs) to date for patients with aBC. Areas covered With the anticipated emergence of newer ADCs and ICIs for patients with several subtypes of breast cancer, and given their potential synergy, their use in combination is of clinical interest. In this article, we review the use of ADCs and ICIs in patients with breast cancer, assess the scientific rationale for their combination, and provide an overview of ongoing trials and some early efficacy and safety results of such dual therapy. Expert opinion Improvement in the medicinal chemistry of next-generation ADCs, their rational combination with ICIs and other agents, and the development of multiparametric immune biomarkers could help to significantly improve the outlook for patients with refractory aBC.

It was 11 March 2020 when the World Health Organization (WHO) declared the name COVID-19 for coronavirus disease and also described it as a pandemic. Till that day 118,000 cases were confirmed of pneumonia with breathing problem throughout the world. At the start of New Year when COVID-19 came into knowledge a few days later, the gene sequencing of the virus was revealed. Today the number of confirmed cases is scary, i.e. 9,472,473 in the whole world and 484,236 deaths have been recorded by WHO till 26 June 2020. WHO's global risk assessment is very high [1]. The report is enlightening the lessons learned by India from the highly affected countries.

The complexity of neoplasia and its treatment are a challenge to the formulation of general criteria that are applicable across solid cancers. Determining the number of prior lines of therapy (LoT) is critically important for optimising future treatment, conducting medication audits, and assessing eligibility for clinical trial enrolment. Currently, however, no accepted set of criteria or definitions exists to enumerate LoT. In this article, we seek to open a dialogue to address this challenge by proposing a systematic and comprehensive framework to determine LoT uniformly across solid malignancies. First, key terms, including LoT and ‘clinical progression of disease’ are defined. Next, we clarify which therapies should be assigned a LoT, and why. Finally, we propose reporting LoT in a novel and standardised format as LoT N (CLoT + PLoT), where CLoT is the number of systemic anti-cancer therapies (SACT) administered with curative intent and/or in the early setting, PLoT is the number of SACT given with palliative intent and/or in the advanced setting, and N is the sum of CLoT and PLoT. As a next step, the cancer research community should develop and adopt standardised guidelines for enumerating LoT in a uniform manner.

The Halcyon™ platform is self‐contained, combining a treatment planning (Eclipse) system TPS) with information management and radiation delivery components. The standard TPS beam model is configured and locked down by the vendor. A portal dosimetry‐based system for patient‐specific QA (PSQA) is also included. While ensuring consistency across the user base, this closed model may not be optimal for every department. We set out to commission independent TPS (RayStation 9B, RaySearch Laboratories) and PSQA (PerFraction, Sun Nuclear Corp.) systems for use with the Halcyon linac. The output factors and PDDs for very small fields (0.5 × 0.5 cm2) were collected to augment the standard Varian dataset. The MLC leaf‐end parameters were estimated based on the various static and dynamic tests with simple model fields and honed by minimizing the mean and standard deviation of dose difference between the ion chamber measurements and RayStation Monte Carlo calculations for 15 VMAT and IMRT test plans. Two chamber measurements were taken per plan, in the high (isocenter) and lower dose regions. The ratio of low to high doses ranged from 0.4 to 0.8. All percent dose differences were expressed relative to the local dose. The mean error was 0.0 ± 1.1% (TG119‐style confidence limit ± 2%). Gamma analysis with the helical diode array using the standard 3%Global/2mm criteria resulted in the average passing rate of 99.3 ± 0.5% (confidence limit 98.3%–100%). The average local dose error for all detectors across all plans was 0.2% ± 5.3%. The ion chamber results compared favorably with our recalculation with Eclipse and PerFraction, as well as with several published Eclipse reports. Dose distribution gamma analysis comparisons between RayStation and PerFraction with 2%Local/2mm criteria yielded an average passing rate of 98.5% ± 0.8% (confidence limit 96.9%–100%). It is feasible to use the Halcyon accelerator with independent planning and verification systems without sacrificing dosimetric accuracy.

Background Patients with coronavirus disease 2019 (COVID-19) who have underlying malignancy have a higher mortality rate compared with those without cancer, although the magnitude of such excess risk is not clearly defined. We performed a systematic review and pooled analysis to provide precise estimates of the mortality rate among patients with both cancer and COVID-19. Methods A systematic literature search involving peer-reviewed publications, preprints and conference proceedings up to July 16, 2020, was performed. The primary end-point was the case fatality rate (CFR), defined as the rate of death among patients with cancer and COVID-19. The CFR was assessed with a random effects model, which was used to derive a pooled CFR and its 95% confidence interval (CI). Results Fifty-two studies, involving a total of 18,650 patients with both COVID-19 and cancer, were selected for the pooled analysis. A total of 4243 deaths were recorded in this population. The probability of death was 25.6% (95% CI: 22.0%–29.5%; I2 = 48.9%) in this patient population. Conclusions Patients with cancer who develop COVID-19 have high probability of mortality. Appropriate and aggressive preventive measures must be taken to reduce the risk of COVID-19 in patients with cancer and to optimally manage those who do contract the infection., Highlights • Patients with both cancer and coronavirus disease 2019 (COVID-19) have a higher mortality than reported in the overall COVID-19-positive population. • We aim to provide precise mortality estimates among patients with cancer and COVID-19. • Pooled case mortality rate was 25.6% (95% CI: 22.0%–29.5%; I2 = 48.9%). • Aggressive measures must be taken to reduce risk of infection in patients with cancer.

Objective To review the published literature on current and new treatments for chronic spontaneous urticaria (CSU) and to provide guidance on the potential use of these therapeutics. Data Sources A PubMed search was performed to include English-language articles with the keywords chronic spontaneous urticaria, pathophysiology, quality of life, and treatments, with a preference to those articles written in the last 5 years. ClinicalTrials.gov was reviewed for recent relevant clinical trials related to potential CSU therapeutics. Study Selections Literature was included if it provided information related to the current understanding of the pathophysiology and management of CSU as well as potential novel therapeutics currently in development. Results CSU has a significant effect on patients' quality of life. Current therapies include antihistamines, leukotriene receptor antagonists, omalizumab, and immunosuppressants; however, additional treatments are needed. New therapeutics under investigation include IgG1 anti-IgE monoclonal antibodies (ligelizumab), chemoattractant rector–homologous molecule expressed on TH2 cells antagonists (AZD1981), Bruton tyrosine kinase inhibitors (fenebrutinib), anti–siglec-8 monoclonal antibody (AK002), and topical spleen tyrosine kinase inhibitors (GSK2646264). We review the mechanisms of action as well as recently published data from clinical trials regarding the efficacy and safety of these treatments. Conclusion The development of new treatments for CSU will lead to improved options for patients and may assist with improving our understanding of disease pathophysiology.

PURPOSE OF REVIEW: This article aims to provide a comprehensive understanding of the evaluation, diagnosis, and management of scapular dyskinesis and its impact on the kinetic chain in tennis athletes. RECENT FINDINGS: Optimal glenohumeral biomechanics are intimately associated with proper scapular motion and function. The tennis serve requires the scapula to act as a force transducer in the kinetic chain to convert potential energy generated in the lower extremities to kinetic energy in the upper extremity. Any aberration within this complex kinetic chain will result in force uncoupling and increases the potential for injury through compensatory mechanisms. Specifically, scapular dyskinesis has been associated with an increased risk of shoulder pain of up to 43% in overhead athletes. These pathologies include rotator cuff disease, subacromial and posterior impingement, labral injuries, and SLAP tears. Although the direct causality of these injuries remains controversial, multiple kinematic studies have demonstrated altered scapular positioning increasing the predilection for soft tissue pathology. SUMMARY: The diagnosis of scapular dyskinesis is predicated upon a thorough history, physical examination, and observational analysis of key nodes in the kinetic chain during tennis activity. Conservative management remains the mainstay of treatment and consists of a graduated physical therapy regimen. Although shoulder pain in the overhead athletes is often multifactorial, early recognition and treatment of scapular dyskinesis generally carry a favorable prognosis and result in improved patient outcomes.

Pathophysiological mechanisms and cascades take place after a mild traumatic brain injury (mTBI) that can cause long-term sequelae, including chronic traumatic encephalopathy in patients with multiple concurrent TBIs. As diagnostic imaging has become more advanced, microanatomical changes present after mTBI may now be more readily visible. In this narrative review, the authors discuss emerging diagnostics and findings in mTBI through advanced imaging, electroencephalograms, neurophysiologic processes, Q2 biochemical markers, and clinical tissue tests in an effort to help osteopathic physicians to understand, diagnose, and manage the pathophysiology behind mTBI, which is increasingly prevalent in the United States.

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Càncer; Immuno-oncologia Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Cáncer; Inmuno-oncología Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Cancer; Immuno-oncology The coronavirus disease-2019 (COVID-19) pandemic has had a significant impact on patients with underlying malignancy. In this article, we summarize emerging data related to patients with cancer and COVID-19. Among patients with COVID-19, a higher proportion have an underlying diagnosis of cancer than seen in the general population. Also, patients with malignancy are likely to be more vulnerable than the general population to contracting COVID-19. Mortality is significantly higher in patients with both cancer and COVID-19 compared with the overall COVID-19-positive population. The early months of the pandemic saw a decrease in cancer screening and diagnosis, as well as postponement of standard treatments, which could lead to excess deaths from cancer in the future. No funding was received from any source. No Rapid Service Fee was received by the journal for the publication of this article.

KEY POINTS The application of fetal cardiovascular magnetic resonance imaging (CMR) to assess fetal cardiovascular physiology and cardiac function through the quantification of ventricular volumes has previously been investigated, but the approach has not yet been fully validated. Ventricular output measurements calculated from heart rate and stroke volumes (SV) of the right and left ventricles measured by ventricular volumetry (VV) exhibited a high level of agreement with phase-contrast (PC) blood flow measurements in the main pulmonary artery and ascending aorta, respectively. Ejection fraction of the right ventricle, which is lower than that of the left ventricle in postnatal subjects, was similar to the left ventricular ejection fraction in the fetus; probably due to the different loading conditions present in the fetal circulation. This study provides evidence to support the reliability of VV in the sheep fetus, providing evidence for its use in animal models of human diseases affecting the fetal circulation. ABSTRACT The application of ventricular volumetry (VV) by cardiovascular magnetic resonance imaging (CMR) in the fetus remains challenging due to the small size of the fetal heart and high heart rate. The reliability of this technique in utero has not yet been established. The aim of this study was to assess the feasibility and reliability of VV in a fetal sheep model of human pregnancy. Right and left ventricular outputs by stroke volume (SV) measured using VV were compared with 2D phase-contrast (PC) CMR measurements of blood flow in the main pulmonary artery (MPA) and ascending aorta (AAo). At 124-140 days (d) gestation, singleton bearing Merino ewes underwent CMR under general anaesthesia using fetal femoral artery catheters, implanted at 109-117d, to trigger cine steady state free precession acquisitions of ventricular short-axis stacks. The short-axis cine stacks were segmented at end-systole and end-diastole, yielding right and left ventricular SV, ejection fraction, and cardiac outputs (SV × heart rate). PC cine acquisitions of MPA and AAo were analysed to measure blood flow, which served as comparators for the right and left cardiac outputs by VV. There was good correlation and agreement between VV and PC measures of ventricular outputs with no significant bias (r2 = 0.926; P

Chronic urticaria (CU) and angioedema can occur at any age. Although most CU with or without angioedema occurs in adults, it can also present in children or the elderly and can complicate pregnancy and breast-feeding. The presentations of CU and angioedema are different in children, middle-aged adults, and older patients as are the differential diagnoses. Therefore, the management of CU and angioedema in these different age groups and special populations needs to take into account the age-specific features of urticaria and angioedema. Here, we describe the evaluation, diagnosis, and treatment of CU and angioedema in children, middle-aged adults, and older patients. This review focuses on CU with or without angioedema and does not discuss acute urticaria or bradykinin-mediated angioedema.

A broadband circularly polarized slotted square patch antenna with horizontal meandered strip (HMS) is presented and studied. The HMS feeding technique provides the good impedance matching and broadside symmetrical radiation patterns. A set of cross asymmetrical slots are etched on the radiating patch to realize the circular polarization. An electrically small stub is added on the edge of the antenna for further improvement in performance. Measured 10-dB impedance bandwidth (IBW) and 3-dB axial ratio bandwidth (ARBW) of the proposed antenna are 32.31 % (3.14–4.35 GHz) and 20.91 % (3.34–4.12 GHz), respectively. The gain of the antenna is varied from 3.5 to 4.86dBi within 3-dB ARBW. Measured results matched well with the simulated results.

A self-referencing plasmonic platform is proposed and analyzed. By introducing a thin gold layer below a periodic two-dimensional nano-grating, the structure supports multiple modes including localized surface plasmon resonance (LSPR), surface plasmon resonance (SPR), and Fabry-Perot resonances. These modes get coupled to each other creating multiple Fano resonances. A coupled mode between the LSPR and SPR responses is spatially separated from the sensor surface and is not sensitive to refractive index changes in the surrounding materials or surface attachments. This mode can be used for self-referencing the measurements. In contrast, the LSPR dominant mode shifts in wavelength when the refractive index of the surrounding medium is changed. The proposed structure is easy to fabricate using conventional lithography and electron beam deposition methods. A bulk sensitivity of 429 nm/RIU is achieved. The sensor also has the ability to detect nanometer thick surface attachments on the top of the grating.

Background and Objectives The emergence of resistant strains of Cutibacterium acnes can limit the efficacy of currently approved antibiotics for acne. VB-1953 is a next-generation antibiotic that exerts a bactericidal effect on resistant C. acnes. In this study, we investigated the safety, tolerability, and efficacy of VB-1953 topical gel in patients with moderate to severe acne having clindamycin-resistant C. acnes. Methods An investigator-initiated, open label, single-arm clinical study was conducted in patients with moderate to severe facial acne vulgaris showing poor or no response to previous clindamycin treatment. Nineteen subjects were enrolled in the study based on laboratory screening for the presence of clindamycin-resistant C. acnes in acne swab samples collected from patients. VB-1953 2% gel was applied on the entire face twice daily over 12 weeks. The primary efficacy endpoints were absolute changes in inflammatory and noninflammatory lesion counts from baseline at week 12, while the secondary efficacy endpoint was the proportion of subjects achieving Investigator Global Assessment success (score of 0 or 1) or a grade 2 or higher improvement from baseline at week 12. The presence and severity of local skin reactions (erythema, edema, scaling/dryness, burning/stinging, pruritus) were evaluated for safety. Additionally, the detection and quantification of drug-resistant C. acnes strains were performed in the laboratory using acne swab samples collected from patients. Results The occurrence of treatment-emergent adverse events or changes in vital signs, physical examinations, and urinalysis for any of the patients during the course of the entire study were clinically insignificant. Topical application of 2% VB-1953 topical gel resulted in a significant reduction of mean absolute inflammatory and noninflammatory lesion counts by 53.1% and 52.2%, respectively (p

This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GALEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast-cell-driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic urticaria, i.e. chronic spontaneous urticaria and chronic inducible urticaria, is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This article is protected by copyright. All rights reserved.

Introduction/Background* India experienced a deadly second wave of COVID-19 pandemic starting mid-February 2021 with test positivity rate of 25-45 % suggesting high community transmission. Indian COVID-19 vaccination program for 60 years + and above 45 years with co-morbidities began on 1st March 2021. As per COVIDsurg collaborative data, between 0.6% and 1.6% of patients develop COVID-19 infection after elective surgery. Even after use of mitigation measures like pre-surgery RT/PCR and COVID free surgical pathways, COVID-19 is a significant nosocomial infection with 4- and 8-fold increased risk of death in the 30 days following surgery. Our aim was to study vaccine compliance in patients counselled to be vaccinated before surgery, pre-surgery RT/PCR positivity rate, 30-day post-operative SARS Cov-2 rate and peri-operative outcomes. Methodology In this prospective observational study, patients waitlisted for major gynaecological cancer surgeries who were also eligible for COVID-19 vaccination were enrolled. Patients were counselled to get atleast one dose vaccinated 2 weeks before elective surgery. In cases of neo-adjuvant chemotherapy, vaccination was advised atleast 2 weeks after the last dose of chemotherapy. Patients vaccinated with atleast 1 dose - 2 weeks prior to surgery or those with both doses vaccinated atleast a week prior to surgery were eligible for study. Mitigation measures of negative pre-surgery RT/PCR (within 24 hours prior to surgery) and COVID free surgical pathway were used. Result(s)* In the overall cohort of 53 patients, 34 got vaccinated suggesting compliance of 64%. In the unvaccinated cohort, 52.6% were pře-surgery RT/PCR +ve against 5.8% vaccinated patients (p = 0.0001). Thirty- day post-operative SARS Cov-2 rate was 44.4% and 0% in the unvaccinated and vaccinated cohort respectively (p = 0.0001). No cases of severe COVID-19 requiring hospitalisation were seen in the vaccinated cohort. There was no 30-day post-operative mortality in either cohorts. Conclusion* Counselling regarding COVID-19 vaccination prior to surgery should be an essential part of pre-operative work up. COVID-19 vaccination prior to surgery has two-fold advantage. It prevents the postponement of elective cancer surgeries which are time bound. There is a significant decreased risk of severe COVID-19 infection and related morbidity post-operatively in the vaccinated population.

The ductus arteriosus (DA) functionally closes during the transition from fetal to postnatal life because of lung aeration and corresponding cardiovascular changes. The thorough and explicit measurement and visualization of the right and left heart output during this transition has not been previously accomplished. We combined 4D flow MRI (dynamic volumetric blood flow measurements) and T2 relaxometry (oxygen delivery quantification) in surgically instrumented newborn piglets to assess the DA. This was performed in Large White‐Landrace‐Duroc piglets (n = 34) spanning four age groups: term‐9 days, term‐3, term+1, and term+5. Subject's DA status was classified using 4D flow: closed DA, forward DA flow, reversed DA flow, and bidirectional DA flow. Over all states, vessel diameters and flows normalized to body weight increased with age (for example in the ascending aorta flow—term‐9: 126.6 ± 45.4; term+5: 260.2 ± 80.0 ml/min per kg; p = 0.0005; ascending aorta diameter—term‐9: 5.2 ± 0.8; term+5: 7.7 ± 0.4 mm; p = 0.0004). In subjects with reversed DA blood flow there was lower common carotid artery blood flow (forward: 37.5 ± 9.0; reversed: 20.0 ± 7.4 ml/min per kg; p = 0.032). Linear regression revealed that as net DA flow decreases, common carotid artery flow decreases (R2 = 0.32, p = 0.004), and left (R2 = 0.33, p = 0.003) and right (R2 = 0.34, p = 0.003) pulmonary artery flow increases. Bidirectional DA blood flow changed oxygen saturation as determined by MRI between the ascending and descending aorta (ascending aorta: 90.1% ± 8.4%; descending aorta: 75.6% ± 14.2%; p, At birth, the lungs and surrounding vasculature work to functionally close the ductus arteriosus (DA). This process is delayed in preterm newborns. MRI techniques, namely 4D flow and T2 relaxometry, can be used to comprehensively assess cardiac blood flow and oxygen delivery in newborns. These approaches are demonstrated across preterm and term‐born piglets, and whole heart blood flow visualization is paired alongside flow and oxygenation quantification.

In this work, an algorithm was developed to record and suppress the physiological tremor present in the hands of surgeon doing robotic surgical procedure due to fatigue or otherwise. A prototype setup of master handle having six degree of freedom with a vibration motor was designed and fabricated to record the hand tremor. The work involved recording the composite simulated motion consisting of both voluntary motion of surgeon’s hand and associated involuntary motion of tremor in real time, determination of peak frequencies of both the motions and providing necessary information on the graphical user interface. The adaptive algorithm is capable to cancel out the involuntary motion from the recorded raw signal in real time. After filtration, only voluntary motion remains for further processing. The developed algorithm promises potential to make robotic surgery more precise and error free.

Eye movements during electroencephalogram (EEG) recordings are the major sources of artifacts. These artifacts tend to mask the EEG signals. So, to obtain good quality EEG signals, these artifacts must be removed without deteriorating the underlying EEG activity. In this paper, a new algorithm is proposed that combines canonical correlation analysis (CCA) and noise adjusted principal component transform (NAPCT) to efficiently remove the electrooculogram (EOG) and blink artifacts in a considerably fast manner. CCA-NAPCT is implemented after the preliminary outlier thresholding of EEG data. CCA is used to estimate the noise covariance matrix while NAPCT is implemented for noise removal. The results of this algorithm on EOG affected BCI competition III dataset IVb and blink contaminated EEG data of four subjects showed the efficacy of the proposed algorithm in effective removal of noise. The algorithm provides an average signal to noise ratio and root mean square error values of 3.616 & 42.456 with artifactual EEG data respectively. Moreover, the average correlation coefficients (0.8839) and mutual information (1.1546) values also verify the efficacy of algorithm more firmly as supported by comparison with the state-of-the-art technique. The proposed algorithm successfully removed the artifactual components with no manual intervention.

Key points Substrate restriction during critical developmental windows of gestation programmes offspring for a predisposition towards cardiovascular disease in adult life. This study aimed to determine the effect of maternal resveratrol (RSV) treatment in an animal model in which chronic fetal catheterisation is possible and the timing of organ maturation reflects that of the human. Maternal RSV treatment increased uterine artery blood flow, fetal oxygenation and fetal weight. RSV was not detectable in the fetal circulation, indicating that it may not cross the sheep placenta. This study highlights RSV as a possible intervention to restore fetal substrate supply in pregnancies affected by placental insufficiency. Abstract Suboptimal in utero environments with reduced substrate supply during critical developmental windows of gestation predispose offspring to non-communicable diseases such as cardiovascular disease (CVD). Improving fetal substrate supply in these pregnancies may ameliorate the predisposition these offspring have toward adult-onset CVD. This study aimed to determine the effect of maternal resveratrol (RSV) supplementation on uterine artery blood flow and the direct effects of RSV on the fetal heart in a chronically catheterised sheep model of human pregnancy. Maternal RSV treatment significantly increased uterine artery blood flow as measured by phase contrast magnetic resonance imaging, mean gestational fetal P a O 2 and S a O 2 as well as fetal weight. RSV was not detectable in the fetal circulation, and mRNA and protein expression of the histone/protein deacetylase SIRT1 did not differ between treatment groups. No effect of maternal RSV supplementation on AKT/mTOR or CAMKII signalling in the fetal left ventricle was observed. Maternal RSV supplementation is capable of increasing fetal oxygenation and growth in an animal model in which cardiac development parallels that of the human.

Purpose The purpose of this paper is to examine the effect of choice of accounting standards on the value relevance and accrual quality of reported earnings and book values under International Financial Reporting Standards (IFRS) versus US Generally Accepted Accounting Principles (GAAP). Design/methodology/approach The authors examine the effect of choice of accounting standards on the value relevance and accrual quality of reported earnings and book values under IFRS versus US GAAP using 404 firms from 37 countries listed in the USA. They use the modified Jones (1991) model to measure accruals. Findings The authors find that value relevance of the book value of equity is increasing (significantly) when the sample firms use IFRS to prepare their financial statements. They also find some evidence in support of the mediating effect of the choice of accounting standards on the accrual quality of the sample firms. The results of this paper indicate that sample firms with lower accrual quality (larger discretionary accruals) experience higher returns during the fiscal year. However, the authors also find that the positive association between size of discretionary accruals and returns is decreasing in the use of IFRS by the sample firms. Originality/value This paper adds to prior literature on the harmonization of accounting standards and emphasizes the role of accounting standards in the quality of financial reporting. By using the financial data of all foreign registrants listed in the USA, the authors are able to provide deeper and more representative evidence.

Non-randomized open-label clinical trial of oral alendronate after teriparatide therapy in people with spinal cord injury (SCI) and low bone mineral density (BMD). To determine if alendronate would prevent bone loss after discontinuation of teriparatide. Outpatient research clinic at Northwestern University Feinberg School of Medicine. Seventeen participants with chronic SCI who recently completed 12–24 months of teriparatide treatment received oral alendronate 70 mg once weekly for 12 months. Participants were evaluated at baseline, 6 months and 12 months. Bone was assessed by: DXA at the spine and hip, CT at the distal femur/proximal tibia, serum collected for bone markers, and bone strength determined by finite element (FE) analysis of the proximal tibia. Areal BMD showed no significant change from baseline at the total hip or femoral neck, where mean change (SD) was 1.3% (4.7) and 0.54% (5.0), respectively. However, areal BMD increased significantly at the spine by 2.5% (4.6). CT demonstrated significant increases in bone mineral content at the femoral epiphysis, metaphysis, and diaphysis, 15% (18), 7.7% (12), and 3.0% (3.5), respectively. Measurements at the tibia illustrated improvements and reductions, but no changes to FE-predicted strength were observed. Biomarkers illustrated inhibition of bone formation and resorption, with P1NP and CTX decreasing by 52% (82) and 62% (74), respectively. Twelve months of alendronate after discontinuation of teriparatide in people with SCI can prevent bone loss and may increase bone mass and preserve bone strength at the spine, hip, and some sites of the knee.

BACKGROUND Delayed cerebral vasospasm is a feared complication of aneurysmal subarachnoid hemorrhage (SAH). OBJECTIVE To investigate the relationship of systemic inflammation, measured using the systemic immune-inflammation (SII) index, with delayed angiographic or sonographic vasospasm. We hypothesize that early elevations in SII index serve as an independent predictor of vasospasm. METHODS We retrospectively reviewed the medical records of 289 SAH patients for angiographic or sonographic evidence of delayed cerebral vasospasm. SII index [(neutrophils × platelets/lymphocytes)/1000] was calculated from laboratory data at admission and dichotomized based on whether or not the patient developed vasospasm. Multivariable logistic regression and receiver operating characteristic (ROC) analysis were performed to determine the ability of SII index to predict the development of vasospasm. RESULTS A total of 246 patients were included in our study, of which 166 (67.5%) developed angiographic or sonographic evidence of cerebral vasospasm. Admission SII index was elevated for SAH in patients with vasospasm compared to those without (P

Recalcitrant dermatophytic infections of the glabrous skin (tinea corporis/cruris/faciei) pose a huge challenge to health care systems. Combinations of oral and topical drugs may potentially improve cure rates, but the same has never been objectively assessed for this condition in laboratory or clinical studies. The present study was undertaken with the aim of identifying synergistic combinations of oral and topical antifungals by testing clinical isolates obtained from patients with recalcitrant tinea corporis/cruris. Forty-two patients with tinea corporis/cruris who had failed oral antifungals or had relapsed within 4 weeks of apparent clinical cure were recruited. Twenty-one isolates were identified by sequencing (all belonging to the Trichophyton mentagrophytes/T. interdigitale species complex) and subjected to antifungal susceptibility testing (AFST) and squalene epoxidase (SQLE) gene mutation analysis. Finally, five isolates, four with underlying SQLE gene mutations and one wild-type strain, were chosen for checkerboard studies using various combinations of antifungal agents. Most isolates (n = 16) showed high MICs of terbinafine (TRB) (0.5 to >16 μg/ml), with SQLE gene mutations being present in all isolates with MICs of ≥0.5 μg/ml. Synergistic interactions were noted with combinations of itraconazole with luliconazole, TRB, and ketoconazole and propylene glycol monocaprylate (PGMC) with luliconazole and with the triple combination of PGMC with luliconazole and ketoconazole. In vitro synergistic interactions provide a sound scientific basis for the possible clinical use of antifungal combinations. Hence, these synergistic combinations may be tested for clinical utility in the wake of rising resistance among dermatophytic infections of the glabrous skin.

Background Fractures of the distal radius are a common injury. The British Orthopaedic Association (BOA) and The British Society for Surgery of the Hand (BSSH) have released new guidelines outlining the management of these fractures, specifically identifying “thresholds for intervention,” based on radiological parameters for management with open reduction and internal fixation (ORIF). Questions/Purposes Have our distal radius fractures (DRFs), previously managed with ORIF, met the new guidelines' thresholds for intervention, based on radiological parameters? Patients and Methods A retrospective assessment of DRFs treated with ORIF was performed between January 2017 and August 2018. Patients were categorized into three cohorts based on their age. The five radiological parameters of ulnar variance, dorsal tilt, radial inclination, radial height, and intra-articular step were measured on the initial plain radiograph, “pre-manipulation film,” postplaster application radiograph, and “post-manipulation film.”These were compared with the “thresholds for intervention” outlined in the BOA/BSSH guidelines. Results A total of 94 patients underwent an ORIF with a mean age of 56 years (range 17–86 years). As many as 75.74% of patients on the ”pre-manipulation film” met the “threshold for intervention” on at least one radiological parameter, while 53.57% of patients on the “post-manipulation” met at least one “threshold for intervention.” Dorsal tilt was the parameter that most often met the threshold in both films at 53.37% and 40.11%, respectively. Conclusion Within our trust, there is a tendency to over manage the distal radius fracture with ORIF, potentially resulting in unnecessary operations. Education surrounding the new guidelines will better serve our decision-making. Level of Evidence This is a level III study.

Coronavirus disease 2019 (COVID-19) has resulted in millions of deaths globally. The pandemic has had a severe impact on oncology care and research. Patients with underlying cancer are more vulnerable to contracting COVID-19, and also have a more severe clinical course following the infection. The rollout of COVID-19 vaccines in many parts of the world has raised hopes of controlling the pandemic. In this editorial, the authors outline key characteristics of the currently approved COVID-19 vaccines, provide a brief overview of key emerging issues such as vaccine-induced immune thrombotic thrombocytopenia and SARS-CoV-2 variants of concern, and review the available data related to the efficacy and side effects of vaccinating patients with cancer. ispartof: ONCOLOGY AND THERAPY vol:9 issue:2 pages:255-265 ispartof: location:New Zealand status: published

An important point-of-care diagnostic technology for COVID-19 is X-ray imaging of the lungs Here we present a novel deep learning training method which combines both supervised and reinforcement learning methodologies which allows transfer learning in a convolutional neural network (CNN) The method integrated hill-climbing techniques and stochastic gradient descent with momentum to train the CNN architectures without overfitting on small datasets The model was trained using the Kaggle COVID-19 Chest Radiography dataset The dataset consists of 219 COVID-19 positive images, 1341 normal images, and 1345 viral pneumonia images Since training of a CNN can be affected by bias and depends on the limitations of available computing power, the data set was reduced to 219 images for each class From each of the classes, 150 random images were used for training the CNN algorithm and the model was tested with 69 independent images Transfer training was done on three models, namely, VGG-19, DenseNet-201, and NASNet The DenseNet-201 architecture performed the best in terms of accuracy achieving an accuracy of 96 1% The VGG-19 and DenseNet-201 had sensitivity of 91 3 % while NASnet had a slightly higher sensitivity of 92 8% This shows that we can have high confidence of the classification results achieved by these models These results show that deep learning methodologies can be used for identifying COVID-19 patients quickly and accurately © 2021 SPIE

Introduction: Up to 50% of subarachnoid hemorrhage (SAH) patients develop cardiac injury. The relationship between early systemic inflammation and cardiac injury after SAH is unknown. Here we examined changes in blood leukocyte counts and their relationship to cardiac dysfunction. Methods: We reviewed the medical records of 288 SAH patients admitted to our Comprehensive Stroke Center. Patients were dichotomized based on elevated (≥0.04ng/mL) or normal (70%) from echocardiogram data. We performed univariate and multivariate logistic regression to establish the relationship between blood leukocyte counts and cardiac injury. Results: Of 288 SAH patients, 241 had TnI levels performed at the time of admission and 119 (49.4%) of these had elevated TnI on admission. Patients with elevated TnI were significantly older, had higher grade SAH, abnormal EF, and were more likely to have hypertension and dyslipidemia. 10 (4.1%) had low EF while 58 (24.1%) had high EF on admission echocardiogram. In univariate analysis, total leukocyte count (p Conclusions: Blood total leukocyte count is an independent predictor of cardiac injury in SAH patients. This highlights the role of inflammation in mediating cardiac dysfunction after brain hemorrhage, and raises questions regarding the potential of anti-inflammatory therapy for cardioprotection in SAH.

With the increasing use of deep learning methodologies in various biomedical applications, there is a need for a large number of labeled medical image datasets for training and validation purposes. However, the accumulation of labeled datasets is expensive and time consuming. Recently, generative adversarial networks (GAN) have been utilized to generate synthetic datasets. Currently, the accuracy of generative adversarial networks is calculated using a structural similarity index measure (SSIM). SSIM is not adequate for comparison of images as it underestimates the distortions near hard edges. In this paper, we compare the real DRIVE dataset to the synthetic FunSyn-Net using Fourier transform techniques and show that Fourier behavior is quite different in the two datasets, especially at high frequencies. It is observed that for real images, the amplitude of the Fourier components exponentially decreased with increasing frequency. For the synthesized images, the rate of decrease of the amplitude is much slower. If a linear function is fit to the high frequency components, the slope distributions for the two datasets are completely different with no offset. The average slope in the log scale for DRIVE dataset and FunSyn-Net were 0.0195, and 0.009 respectively. We also looked at auto correlations for the horizontal cut of the Fourier transform and again saw a statistically significant difference between the means for the two datasets. Finally, we also observed that Fourier transforms with real images have higher magnitude squared coherence as compared to the synthesized images. Fourier transform has shown great success for finding differences between real and synthesized images and can be used to improve the synthesized GAN models.

We propose a new method for training convolutional neural networks which integrates reinforcement learning along with supervised learning and use ti for transfer learning for classification of glaucoma from colored fundus images. The training method uses hill climbing techniques via two different climber types, viz "random movment" and "random detection" integrated with supervised learning model though stochastic gradient descent with momentum (SGDM) model. The model was trained and tested using the Drishti GS and RIM-ONE-r2 datasets having glaucomatous and normal fundus images. The performance metrics for prediction was tested by transfer learning on five CNN architectures, namely GoogLenet, DesnseNet-201, NASNet, VGG-19 and Inception-resnet-v2. A fivefold classification was used for evaluating the perfroamnace and high sensitivities while high maintaining high accuracies were achieved. Of the models tested, the denseNet-201 architecture performed the best in terms of sensitivity and area under the curve (AUC). This method of training allows transfer learning on small datasets and can be applied for tele-ophthalmology applications including training with local datasets., Submitted for publication in JOSA A: Optics and Image Science, currently under revision

Key points Maternal undernutrition during gestation alters fetal lung development by impacting surfactant maturation. However, the direction of change remains controversial. We examined the effects of maternal late gestation maternal undernutrition (LGUN) on maternal and fetal outcomes, signaling pathways involved in fetal lung development, pulmonary hemodynamics and oxygen delivery in sheep using a combination of molecular and MRI techniques. LGUN decreased fetal plasma glucose concentration without affecting arterial. Surfactant maturation was not affected; however, main pulmonary artery blood flow was significantly increased in the LGUN fetuses. This is the first study to explore the relationship between in utero MRI measures of pulmonary hemodynamics and lung development. Across all treatment groups, left pulmonary artery blood flow and oxygen delivery were negatively correlated with SFTP-B mRNA and protein expression in late gestation. Abstract Restriction of fetal substrate supply has an adverse effect on surfactant maturation in the lung and thus affects the transition from in utero placental oxygenation to pulmonary ventilation ex utero. The effects on surfactant maturation are mediated by alteration in mechanisms regulating surfactant protein and phospholipid synthesis. This study aimed to determine the effects of late gestation maternal undernutrition (LGUN) and LGUN plus fetal glucose infusion (LGUN+G) compared to Control on surfactant maturation and lung development, and the relationship with pulmonary blood flow and oxygen delivery (DO2 ) measured by magnetic resonance imaging (MRI) with molecules that regulate lung development. LGUN from 115 d to 140 d gestation significantly decreased fetal body weight, which was normalized by glucose infusion. LGUN and LGUN+G resulted in decreased fetal plasma glucose concentration, with no change in fetal arterial compared to Control. There was no effect of LGUN and LGUN+G on the mRNA expression of surfactant proteins (SFTP) and genes regulating surfactant maturation in the fetal lung. However, blood flow in the main pulmonary artery (MPA) was significantly increased in LGUN, despite no change in blood flow in the left or right pulmonary artery (LPA or RPA) and DO2 to the fetal lung. There was a negative relationship between LPA flow and DO2 to the left lung with SFTP-B and GLUT1 mRNA expression, while their relationship with VEGFR2 was positive. These results suggest that increased pulmonary blood flow measured by MRI may have an adverse effect on surfactant maturation during fetal lung development. This article is protected by copyright. All rights reserved.

Superior capsule reconstruction (SCR) creates a humeral head depressor in the setting of a massive, irreparable rotator cuff tear. Recently, a 6-mm-thick acellular dermal allograft (ACD) has been shown to be noninferior to the standard fascia lata autograft in recreating native shoulder biomechanics. This paper outlines a reproducible means by which to perform an arthroscopic SCR using a 6-mm ACD. A standard diagnostic arthroscopy first assesses the integrity of the subscapularis and infraspinatus tendons. The glenoid anchors are then placed. Accessory anterior and posterolateral portals are made as well as a lateral portal by which to shuttle the graft. Suture management is paramount. Ideally allograft preparation occurs on the back table simultaneously to maintain efficiency. Suture passage through premade holes in the graft, and when the sutures have passed through and been tensioned, the graft is shuttled into place and tied down with medial and lateral row anchors in SpeedBridge fashion. The thickness of ACD has been shown to influence the ability of the reconstructed superior capsule to perform its role as a humeral head depressor. This technique describes the use of a 6-mm-thick ACD to perform an arthroscopic SCR that minimizes both donor-site morbidity and operative time., Technique Video Video 1 The patient is prepped and draped in the beach chair position in usual sterile fashion with the operative shoulder exposed. A diagnostic arthroscopy is begun and the remaining rotator cuff is debrided as appropriate, including the footprint on the tuberosity. Accessory portals are made anteriorly and posterolaterally for suture management. Three sutures are placed through the remaining subscapularis tendon anteriorly and brought out of the accessory anterior portal. Similarly, 3 sutures are placed through the remaining infraspinatus tendon posteriorly and placed through the accessory posterolateral portal. While the diagnostic arthroscopy is taking place, the graft preparation begins on the back table while the shoulder is prepared for insertion of the acellular dermal allograft (ACD). The graft is folded in half, with the crease facing posteriorly. Four corner sutures are placed with #2 FiberWire (Arthrex, Naples, FL). Holes are then created at the medial border for the glenoid side, through which knotless SutureTak sutures are passed in mattress fashion. Holes on the anterior and posterior sides are created for side-to-side repair to the remaining subscapularis and infraspinatus, respectively. Medial sided holes are created one centimeter from the graft’s lateral edge and will incorporate SutureTapes from the humeral-sided medial row SwiveLock anchors (Arthrex). These holes are created with a fresh 11-blade scalpel to ensure a single pass through the 6-mm thick ACD. Passing sutures may be employed, or a Hewson suture passer may alternatively be used. While the graft preparation takes place, the shoulder is debrided as appropriate, a bony bed is created on the humerus, and anchor placement begins on the glenoid with three knotless Bio-SutureTak anchors (Arthrex). In addition, side-to-side sutures are passed through the remaining subscapularis anteriorly and infraspinatus posteriorly. Medial row anchors are placed on the humerus just lateral to the articular margin with tape-loaded SwiveLock anchors. The graft is then brought to the shoulder and the appropriate sutures are placed through each respective hole with either shuttle sutures or a Hewson suture passer. The graft is shown outside the PassPort cannula with all sutures passed through. For demonstration purposes, only 2 anterior and posterior sutures have been placed. The technique recommended includes three sutures. The graft is then cigar-rolled around a KingFisher clamp and placed into the joint. Subsequently it is shuttled to its final location using the medial glenoid anchor pull-sutures. The anterior and posterior side-to-side sutures are tied. Finally, the medial row humeral tapes are brought further laterally to lateral row SwiveLock anchors. The final images demonstrate the final resting position of the graft.

X-ray diffraction (XRD) is one of the most developed and widely used material characterization techniques. This technique requires relatively simple equipment and offers the advantages of being nondestructive, fast, and applicable to a vast range of sample sizes. The samples for XRD analysis usually require minimal or no preparation. XRD generally refers to a set of techniques, meant primarily for characterization of crystalline materials, while some information can also be obtained for amorphous substances. The applicability of this technique to polycrystalline materials has made it an indispensable tool in characterization of coatings and for studying their effect on the structure of underlying substrates. XRD patterns can provide vital information, such as crystal geometry, identification of compounds, and arrangement of atoms. Modern precision equipment has made it possible to measure minute shifts in diffraction lines, which can provide a nondestructive estimate of residual stresses in a component. Similarly broadening of diffraction lines can provide information regarding microstrains. Availability of standard random samples of various materials has made it possible to carry out texture analysis. The technique can also be used for providing quantitative information, such as for estimating the amount of different phases present within the sample. The limitation of this technique is generally linked to the depth of penetration of X-rays in the material being analyzed. Although the shallow depth of penetration in metals essentially restricts this characterization method to surface layers, the weak diffraction pattern obtained for thin films sometimes deprives the analysis of its speed and accuracy.

Purpose: Ten percent of pregnancies are affected by intrauterine growth restriction (IUGR), and evidence suggests that affected neonates have reduced activity of hepatic cytochrome P450 (CYP) drug metabolising enzymes. Given that almost all pregnant individuals take medications and additional medications are often required during an IUGR pregnancy, we aimed to determine the impact of IUGR on hepatic CYP activity in sheep fetuses and pregnant ewes. Methods: Specific probes were used to determine the impact of IUGR on the activity of several CYP isoenzymes (CYP1A2, CYP2C19, CYP2D6 and CYP3A) in sheep fetuses and pregnant ewes. Probes were administered intravenously to the ewe at 132 days (d) gestation (term 150 d), followed by blood sampling from the maternal and fetal circulation over 24 h. Maternal and fetal liver tissue was collected at 139–140 d gestation, from which microsomes were isolated and incubated with probes. Metabolite and maternal plasma cortisol concentrations were measured using Liquid Chromatography – tandem mass spectrometry (LC-MS/MS). Results: Maternal plasma cortisol concentration and maternal hepatic CYP1A2 and CYP3A activity was significantly higher in IUGR pregnancies. Maternal hepatic CYP activity was higher than fetal hepatic CYP activity for all CYPs tested, and there was minimal CYP1A2 or CYP3A activity in the late gestation fetus when assessed using in vitro methods. Conclusions: The physiological changes to the maternal-placental-fetal unit in an IUGR pregnancy have significant effects on maternal drug metabolism, suggesting changes in medications and/or doses may be required to optimise maternal and fetal health. Refereed/Peer-reviewed

Intrauterine growth restriction (IUGR) is a result of limited substrate supply to the developing fetus in utero, and can be caused by either placental, genetic or environmental factors. Babies born IUGR can have poor long-term health outcomes, including being at higher risk of developing cardiovascular disease. Limited substrate supply in the IUGR fetus not only changes the structure of the heart but may also affect metabolism and function of the developing heart. We have utilised two imaging modalities, two-photon microscopy and phase-contrast MRI (PC-MRI), to assess alterations in cardiac metabolism and function using a sheep model of IUGR. Two-photon imaging revealed that the left ventricle of IUGR fetuses (at 140-141 d GA) had a reduced optical redox ratio, suggesting a reliance on glycolysis for ATP production. Concurrently, the use of PC-MRI to measure foetal left ventricular cardiac output (LVCO) revealed a positive correlation between LVCO and redox ratio in IUGR, but not control fetuses. These data suggest that altered heart metabolism in IUGR fetuses is indicative of reduced cardiac output, which may contribute to poor cardiac outcomes in adulthood. Refereed/Peer-reviewed

As part of the National Antimicrobial Resistance Monitoring System (NARMS) activities, the United States Department of Agriculture (USDA) Food Safety Inspection Service (FSIS) collected cecal samples from food animal slaughter facilities throughout the country between 2014 and 2018. Of the 26,780 cecal samples from cattle, swine, chicken and turkey , 6,350 (23.71%) tested positive for Salmonella . NARMS tested Salmonella for susceptibility to aminoglycosides, folate pathway inhibitors, macrolides, phenicols, quinolones, beta lactams, and tetracyclines. Using the regional subdivisions defined in the USDA Office of Investigation, we used chi-square test to assess potential association between the region from which the samples were collected and both Salmonella prevalence and susceptibility. The results show a significant association between region and Salmonella prevalence, when accounting for source and establishment size, with the southeast region having the highest probability of finding Salmonella . However, the western region had the highest resistance probability across all antimicrobial classes except for macrolides, which showed no regional association. This association between region and resistance was strongest among isolates from cattle. Analysis of whole-genome sequencing data indicated that a significantly higher prevalence of Salmonella Newport in cattle in the western region (accounting for 9.52% of cattle isolates, compared to 3.44% in other regions) may account for the greater resistance to multiple drug classes. Approximately 90% of Salmonella Newport in the west exhibited the MDR-AmpC phenotype encoded by aph(3'')-Ib/aph(6)-Id , bla CMY-2 , floR , sul2 , and tetA. . Thus, differences in resistance across regions may be due to geographical differences in the prevalence of specific Salmonella serotypes and their accompanying resistance genes.

Introduction: Insufficient maternal cardiac output (CO) has been implicated in poor pregnancy outcomes in mothers with heart disease (HD). Simultaneous delineation of vascular flows in the mother and her fetus have not been reported but could contribute to our understanding of the mechanisms of adverse events in this susceptible population. Methods: Pregnant women with moderate or severe HD (n=22; age 32±5 years) were studied using magnetic resonance imaging (MRI) and were compared with healthy controls (n=21; 34±3 years). Each MRI study included maternal and fetal components during the third trimester of pregnancy (corresponding to peak CO) and six months postpartum (surrogate for baseline hemodynamics). Phase contrast (PC) imaging was used to quantify maternal and fetal vascular flows. Fetal vessel T1 and T2 oximetry was used for derivation of fetal oxygen delivery and consumption. Maternal cardiac index (CI) was calculated using CO and pre-pregnancy body surface area. In the HD group, an “adapter” to pregnancy was defined as a woman with peak pregnancy CI measurement which met or exceeded the mean CI in the control population. Maternal and fetal outcomes were recorded. Results: There was no antepartum differences in absolute CO or CI in HD versus controls (CO 7.2±1.5 versus 7.3±1.6 L/min, p=0.79; CI 4.0±0.7 versus 4.3±0.7 L/min/m 2 , p=0.28). The percent increase in CO and CI (antepartum minus postpartum) was greater in women with HD versus controls (CO 46±24% versus 27±16%, p=0.02; CI 51±28% versus 28±17%, p Conclusions: Maternal and fetal vascular flows can be characterized in pregnancy using MRI. Impaired adaptation to pregnancy in women with HD, as determined by magnitude of change in CO/CI, appears to be associated with adverse outcomes of pregnancy in the mother.

New Findings: What is the central question of this study? Uterine artery blood flow helps to maintain fetal oxygen and nutrient delivery. We investigated the effects of increased uterine artery blood flow mediated by resveratrol on fetal growth, haemodynamics, blood pressure regulation and oxygenation in pregnant sheep. What is the main finding and its importance? Fetuses from resveratrol-treated ewes were significantly larger and exhibited a haemodynamic profile that might promote peripheral growth. Absolute uterine artery blood flow was positively correlated with umbilical vein oxygen saturation, absolute fetal oxygen delivery and fetal growth. Increasing uterine artery blood flow with compounds such as resveratrol might have clinical significance for pregnancy conditions in which fetal growth and oxygenation are compromised. Abstract: High placental vascular resistance hinders uterine artery (UtA) blood flow and fetal substrate delivery. In the same group of animals as the present study, we have previously shown that resveratrol (RSV) increases UtA blood flow, fetal weight and oxygenation in an ovine model of human pregnancy. However, the mechanisms behind changes in growth and the effects of increases in UtA blood flow on fetal circulatory physiology have yet to be investigated. Twin-bearing ewes received s.c. vehicle (VEH, n = 5) or RSV (n = 6) delivery systems at 113 days of gestation (term = 150 days). Magnetic resonance imaging was performed at 123−124 days to quantify fetal volume, blood flow and oxygen saturation of major fetal vessels. At 128 days, i.v. infusions of sodium nitroprusside and phenylephrine were administered to study the vascular tone of the fetal descending aorta. Maternal RSV increased fetal body volume (P = 0.0075) and weight (P = 0.0358), with no change in brain volume or brain weight. There was a positive relationship between absolute UtA blood flow and umbilical vein oxygen saturation, absolute fetal oxygen delivery and combined fetal twin volume (all P ≤ 0.05). There were no differences between groups in fetal haemodynamics or blood pressure regulation except for higher blood flow to the lower body in RSV fetuses (P = 0.0170). The observed increase in fetal weight might be helpful in pregnancy conditions in which fetal growth and oxygen delivery are compromised. Further preclinical investigations on the mechanism(s) accounting for these changes and the potential to improve growth in complicated pregnancies are warranted. © 2021 The Authors. Experimental Physiology Refereed/Peer-reviewed

Aim To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial. Patients and methods 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac). Results At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74–1.00) for L+T versus T and 0.93 (95% CI, 0.81–1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70–1.06) for L+T versus T and 0.88 (95% CI, 0.71–1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64–1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69–1.00; 6-yr DFS% = 83% versus79%)] subgroups. Conclusion T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer. Trial Registration clinicaltrials.gov Identifier NCT00490139 .

Key points Human placental function is evaluated using non-invasive Doppler ultrasound of umbilical and uterine artery pulsatility indices as measures of resistance in placental vascular beds, while measurement of placental oxygen consumption ( V O 2 ) is only possible during Caesarean delivery. This study shows the feasibility of using magnetic resonance imaging (MRI) in utero to measure blood flow and oxygen content in uterine and umbilical vessels to calculate oxygen delivery to and V O 2 by the gravid uterus, uteroplacenta and fetus. Normal late gestational human uteroplacental V O 2 by MRI was ∼4 ml min-1 kg-1 fetal weight, which was similar to our MRI measurements in sheep and to those previously measured using invasive techniques. Our MRI approach can quantify uteroplacental V O 2 , which involves the quantification of maternal- and fetal-placental blood flows, fetal oxygen delivery and V O 2 , and the oxygen gradient between uterine- and umbilical-venous blood, providing a comprehensive assessment of placental function with clinical potential. Abstract It has not been feasible to perform routine clinical measurement of human placental oxygen consumption ( V O 2 ) and in vitro studies do not reflect true metabolism in utero. Here we propose an MRI method to non-invasively quantify in utero placental and fetal oxygen delivery ( D O 2 ) and V O 2 in healthy humans and sheep. Women (n = 20) and Merino sheep (n = 10; 23 sets of measurements) with singleton pregnancies underwent an MRI in late gestation (36 ± 2 weeks and 128 ± 9 days, respectively; mean ± SD). Blood flow (phase-contrast) and oxygen content (T1 and T2 relaxometry) were measured in the major uterine- and umbilical-placental vessels, allowing calculation of uteroplacental and fetal D O 2 and V O 2 . Maternal D O 2 (ml min-1 kg-1 fetus) to the gravid uterus was similar in humans and sheep (human = 54 ± 15, sheep = 53 ± 21, P = 0.854), while fetal D O 2 (human = 25 ± 4, sheep = 22 ± 5, P = 0.049) was slightly lower in sheep. Uteroplacental and fetal V O 2 (ml min-1 kg-1 fetus; uteroplacental: human = 4.1 ± 1.5, sheep = 3.5 ± 1.9, P = 0.281; fetus: human = 6.8 ± 1.3, sheep = 7.2 ± 1.7, P = 0.426) were similar between species. Late gestational uteroplacental:fetal V O 2 ratio did not change with age (human, P = 0.256; sheep, P = 0.121). Human umbilical blood flow (ml min-1 kg-1 fetus) decreased with advancing age (P = 0.008), while fetal V O 2 was preserved through an increase in oxygen extraction (P = 0.046). By contrast, sheep fetal V O 2 was preserved through stable umbilical flow (ml min-1 kg-1 ; P = 0.443) and oxygen extraction (P = 0.582). MRI derived measurements of uteroplacental and fetal V O 2 between humans and sheep were similar and in keeping with prior data obtained using invasive techniques. Taken together, these data confirm the reliability of our approach, which offers a novel clinical 'placental function test'.

Background Treatment of patients with asthma or food allergy with omalizumab results in several consistent changes in circulating basophils. The multiple basophil phenotypes observed in patients with chronic spontaneous urticaria (CSU) present some unique attributes that may not respond in a similar fashion to patients with asthma or food allergy. As part of a clinical study on the therapeutic outcomes of omalizumab treatment in CSU, the basophil compartment was examined for changes in characteristics predicted by prior studies. Objective This study sought to examine the changes in basophil function and its relationship to auto-antibodies in serum during treatment with omalizumab. Methods At multiple time points before and during omalizumab treatment of patients with CSU, basophil surface IgE and FceRI expression, cellular spleen tyrosine kinase (SYK) expression, IgE-mediated histamine release (HR), and the presence of auto-antibodies in serum were determined. Results Three basophil phenotypes were enumerated in the clinical study and used to group results in this basophil study: subjects with (1) basopenia, (2) normal basophil numbers with normal IgE-mediated HR, and (3) normal basophil numbers with poor HR. Basopenia was highly associated with the presence of auto-antibodies to unoccupied FceRI and basophil numbers did not change during treatment. Likewise, subjects who are basopenic showed no changes in SYK expression or HR during treatment. In basophils of subjects who are nonbasopenic, increases in SYK expression and HR showed the expected inverse relationship to starting SYK and HR levels. Treatment with omalizumab resulted in similar kinetics for decreases in surface FceRI and IgE in all 3 groups. Conclusions A unifying interpretation of the results revolves around the presence of auto-antibodies to FceRI in CSU. If present, basopenia and an absence of changes in basophils during omalizumab treatment are observed. If auto-antibodies are absent, the changes in the basophil compartment are consistent with prior studies of asthma and food allergy. These group differences also are related to efficacy of the treatment for clinical outcomes, as found in the parent clinical study.

We present heightened skin reactivity in vivo to two MRGPRX2 drug ligands in patients with chronic spontaneous urticaria. Selectivity for the MRGPRX2 pathway by drug ligands was demonstrated by the loss of drug activation in MRGPRX2-KO LAD2 cells.

Three cardinal manifestations of neoplasia, namely inflammation, immune dysfunction, and coagulopathy are also seen in patients with severe SARS-CoV-2 infection, providing a biological rationale for testing selected anticancer drugs for their ability to control the symptoms and/or modify the course of COVID-19., SCOPUS: no.j, info:eu-repo/semantics/published