Oxaliplatin-Based Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 12 Trials.

PURPOSE: A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS: We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS: A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION: In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

Dynamic Luminescence of Lead-Doped Calcium Zinc Germanate Clinopyroxene for Multimode Anticounterfeiting.

Anticounterfeiting plays an essential role in authenticating genuine documents and combating forged products. To further advance the anticounterfeiting technology, there is a strong demand to design new functional materials with unique properties that will be appropriate for making multimode complex security labels. Recently, dynamic security labels have emerged as a new type of advanced anticounterfeiting method as they can hold a much higher security level than the traditional static ones. In this work, we report that calcium zinc germanate (CZGO) clinopyroxenes doped with lead ions have several interesting optical properties, such as dynamic fluorescence, long persistent luminescence, and photochromism. We find that the concentration of lead dopants can significantly impact the reaction kinetics as well as the crystallinity and luminescence properties of CZGO phosphors. By fully utilizing these unique properties, we have successfully fabricated several security labels with multilevel information encoding and dynamic optical performance. The combination of multimode and dynamic luminescence makes these labels extremely challenging to illegally duplicate. With further optimization, this lead-doped CZGO clinopyroxene can be well-integrated into modern anticounterfeiting techniques that will generate highly secure anticounterfeiting labels to combat fake products.

Complementary Approaches to Interrogate Mitophagy Flux in Pancreatic ß-Cells.

Mitophagy is a quality control mechanism necessary to maintain optimal mitochondrial function. Dysfunctional ß-cell mitophagy results in insufficient insulin release. Advanced quantitative assessments of mitophagy often require the use of genetic reporters. The mt-Keima mouse model, which expresses a mitochondria-targeted pH-sensitive dual-excitation ratiometric probe for quantifying mitophagy via flow cytometry, has been optimized in ß-cells. The ratio of acidic-to-neutral mt-Keima wavelength emissions can be used to robustly quantify mitophagy. However, using genetic mitophagy reporters can be challenging when working with complex genetic mouse models or difficult-to-transfect cells, such as primary human islets. This protocol describes a novel complementary dye-based method to quantify ß-cell mitophagy in primary islets using MtPhagy. MtPhagy is a pH-sensitive, cell-permeable dye that accumulates in the mitochondria and increases its fluorescence intensity when mitochondria are in low pH environments, such as lysosomes during mitophagy. By combining the MtPhagy dye with Fluozin-3-AM, a Zn2+ indicator that selects for ß-cells, and Tetramethylrhodamine, ethyl ester (TMRE) to assess mitochondrial membrane potential, mitophagy flux can be quantified specifically in ß-cells via flow cytometry. These two approaches are highly complementary, allowing for flexibility and precision in assessing mitochondrial quality control in numerous ß-cell models.

Using electron energy-loss spectroscopy to measure nanoscale electronic and vibrational dynamics in a TEM.

Electron energy-loss spectroscopy (EELS) can measure similar information to x-ray, UV-Vis, and IR spectroscopies but with atomic resolution and increased scattering cross-sections. Recent advances in electron monochromators have expanded EELS capabilities from chemical identification to the realms of synchrotron-level core-loss measurements and to low-loss, 10-100 meV excitations, such as phonons, excitons, and valence structures. EELS measurements are easily correlated with electron diffraction and atomic-scale real-space imaging in a transmission electron microscope (TEM) to provide detailed local pictures of quasiparticle and bonding states. This perspective provides an overview of existing high-resolution EELS (HR-EELS) capabilities while also motivating the powerful next step in the field-ultrafast EELS in a TEM. Ultrafast EELS aims to combine atomic-level, element-specific, and correlated temporal measurements to better understand spatially specific excited-state phenomena. Ultrafast EELS measurements also add to the abilities of steady-state HR-EELS by being able to image the electromagnetic field and use electrons to excite photon-forbidden and momentum-specific transitions. We discuss the technical challenges ultrafast HR-EELS currently faces, as well as how integration with in situ and cryo measurements could expand the technique to new systems of interest, especially molecular and biological samples.

Process and Methodological Considerations for Observational Analyses of Vector Control Interventions in Sub-Saharan Africa Using Routine Malaria Data.

Progress in malaria control has stalled in recent years. With growing resistance to existing malaria vector control insecticides and the introduction of new vector control products, national malaria control programs (NMCPs) increasingly need to make data-driven, subnational decisions to inform vector control deployment. As NMCPs are increasingly conducting subnational stratification of malaria control interventions, including malaria vector control, country-specific frameworks and platforms are increasingly needed to guide data use for vector control deployment. Integration of routine health systems data, entomological data, and vector control program data in observational longitudinal analyses offers an opportunity for NMCPs and research institutions to conduct evaluations of existing and novel vector control interventions. Drawing on the experience of implementing 22 vector control evaluations across 14 countries in sub-Saharan Africa, as well as published and gray literature on vector control impact evaluations using routine health information system data, this article provides practical guidance on the design of these evaluations, makes recommendations for key variables and data sources, and proposes methods to address challenges in data quality. Key recommendations include appropriate parameterization of impact and coverage indicators, incorporating explanatory covariates and contextual factors from multiple sources (including rapid diagnostic testing stockouts; insecticide susceptibility; vector density measures; vector control coverage, use, and durability; climate and other malaria and non-malaria health programs), and assessing data quality before the evaluation through either on-the-ground or remote data quality assessments. These recommendations may increase the frequency, rigor, and utilization of routine data sources to inform national program decision-making for vector control.

Periprostatic adipose tissue (PPAT) supernatant from obese mice releases anticontractile substances and increases human prostate epithelial cell proliferation: the role of nitric oxide and adenosine.

Background: The prostate gland is surrounded by periprostatic adipose tissue (PPAT) that can release mediators that interfere in prostate function. In this study, we examined the effect of periprostatic adipose tissue supernatant obtained from obese mice on prostate reactivity in vitro and on the viability of human prostatic epithelial cell lines. Methods: Male C57BL/6 mice were fed a standard or high-fat diet after which PPAT was isolated, incubated in Krebs-Henseleit solution for 30 min (without prostate) or 60 min (with prostate), and the supernatant was then collected and screened for biological activity. Total nitrate and nitrite (NOx-) and adenosine were quantified, and the supernatant was then collected and screened for biological activity. NOx- and adenosine were quantified. Concentration-response curves to phenylephrine (PE) were obtained in prostatic tissue from lean and obese mice incubated with or without periprostatic adipose tissue. In some experiments, periprostatic adipose tissue was co-incubated with inhibitors of the nitric oxide (NO)-cyclic guanosine monophosphate pathway (L-NAME, 1400W, ODQ), adenylate cyclase (SQ22536) or with adenosine A2A (ZM241385), and A2B (MRS1754) receptor antagonists. PNT1-A (normal) and BPH-1 (hyperplasic) human epithelial cells were cultured and incubated with supernatant from periprostatic adipose tissue for 24, 48, or 72 h in the absence or presence of these inhibitors/antagonists, after which cell viability and proliferation were assessed. Results: The levels of NOx- and adenosine were significantly higher in the periprostatic adipose tissue supernatant (30 min, without prostate) when compared to the vehicle. A trend toward an increase in the levels of NOX was observed after 60 min. PPAT supernatant from obese mice significantly reduced the PE-induced contractions only in prostate from obese mice. The co-incubation of periprostatic adipose tissue with L-NAME, 1400W, ODQ, or ZM241385 attenuated the anticontractile activity of the periprostatic adipose tissue supernatant. Incubation with the supernatant of periprostatic adipose tissue from obese mice significantly increased the viability of PNT1-A cells and attenuated expression of the apoptosis marker protein caspase-3 when compared to cells incubated with periprostatic adipose tissue from lean mice. Hyperplastic cells (BPH-1) incubated with periprostatic adipose tissue from obese mice showed greater proliferation after 24 h, 48 h, and 72 h compared to cells incubated with culture medium alone. BPH-1 cell proliferation in the presence of PPAT supernatant was attenuated by NO-signaling pathway inhibitors and by adenosine receptor antagonists after 72 h. Conclusion: NO and adenosine are involved in the anticontractile and pro-proliferative activities of periprostatic adipose tissue supernatant from obese mice. More studies are needed to determine whether the blockade of NO and/or adenosine derived from periprostatic adipose tissue can improve prostate function.

Telehealth Utilization in High-Risk Pregnancies During COVID-19.

Purpose: To determine how telehealth has influenced outcomes in high-risk obstetrics patients during the Coronavirus disease 2019 (COVID-19) pandemic. Methods: A retrospective chart review was conducted to identify patterns in both telehealth and in-person clinic visits among patients of a Maternal Fetal Medicine (MFM) department from the onset of the COVID-19 pandemic from March 2020 until October 2021. For the descriptive analysis, p-values were calculated using Wilcoxon rank sum for continuous variables and chi-square or Fisher exact (where cell n < 5) for categorical variables. Variables of interest were then tested for their univariate association with telehealth utilization using logistic regression. Variables found to meet the criterion of p < 0.2 in the univariate case were introduced into a multivariable logistic model with a backward elimination for determining variable retention. We aimed to analyze whether telehealth visits significantly impacted pregnancy outcomes. Results: Four hundred nineteen high-risk patients visited the clinic via in-person and/or telehealth appointments during the study period: 320 patients without telehealth visits and 99 patients with telehealth visits. Care provided by telehealth visits was not found to be related to self-reported race (p = 0.81), maternal body mass index (p = 1.0), or maternal age (p = 0.53). Patients with private insurance were more likely to have telehealth visits than patients with public insurance (79.9% vs. 65.5%, p < 0.01). In univariate logistic analyses, patients with diagnoses of anxiety (p < 0.01), asthma (p = 0.03), and depression (p < 0.01), at the time care was established, were more likely to have telehealth visits. Those patients with telehealth visits did not have any statistical differences in mode of delivery (p = 0.2) or pregnancy outcomes (p = 0.12), including fetal demise, preterm delivery, or delivery at term as compared with patients with all in-office visits. In multivariable analysis, patient conditions of anxiety (p < 0.01), maternal obesity (p < 0.01), and twin pregnancy (p = 0.04) were associated with higher rates of telehealth visits. Conclusion: Patients with certain pregnancy complications elected to have more telehealth visits. Patients with private insurance were more likely to have telehealth visits than patients with public insurance. There are benefits for patients with certain pregnancy complications to incorporate telehealth visits in addition to regularly scheduled in-person clinic visits and may be suitable in a post-pandemic setting as well. Further research in this field is needed to better understand the impact of implementing telehealth in high-risk obstetrics patients.

Prediction of postnatal circulation in pulmonary atresia/critical stenosis with intact ventricular septum: systematic review and external validation of models.

OBJECTIVE: A favorable postnatal prognosis in cases of pulmonary atresia/critical stenosis with intact ventricular septum (PA/CS-IVS) is generally equated with the possibility of achieving biventricular (BV) repair. Identification of fetuses that will have postnatal univentricular (UV) circulation is key for prenatal counseling, optimization of perinatal care and decision-making regarding fetal therapy. We aimed to evaluate the accuracy of published models for predicting postnatal circulation in PA/CS-IVS using a large internationally derived validation cohort. METHODS: This was a systematic review of published uni- and multiparametric models for the prediction of postnatal circulation based on echocardiographic findings at between 20 and 28 weeks of gestation. Models were externally validated using data from the International Fetal Cardiac Intervention Registry. Sensitivity, specificity, predictive values, area under the receiver-operating-characteristics curves (AUCs) and proportion of cases with true vs predicted outcome were calculated. RESULTS: Eleven published studies that reported prognostic parameters of postnatal circulation were identified. Models varied widely in terms of the main outcome (UV (n = 3), non-BV (n = 3), BV (n = 3), right-ventricle-dependent coronary circulation (n = 1) or tricuspid valve size at birth (n = 1)) and in terms of the included predictors (single parameters only (n = 6), multiparametric score (n = 4) or both (n = 1)), and were developed on small sample sizes (range, 15-38). Nine models were validated externally given the availability of the required parameters in the validation cohort. Tricuspid valve diameter Z-score, tricuspid regurgitation, ratios between right and left cardiac structures and the presence of ventriculocoronary connections (VCC) were the most commonly evaluated parameters. Multiparametric models including up to four variables (ratios between right and left structures, right ventricular inflow duration, presence of VCC and tricuspid regurgitation) had the best performance (AUC, 0.80-0.89). Overall, the risk of UV outcome was underestimated and that of BV outcome was overestimated by most models. CONCLUSIONS: Current prenatal models for the prediction of postnatal outcome in PA/CS-IVS are heterogeneous. Multiparametric models for predicting UV and non-BV circulation perform well in identifying BV patients but have low sensitivity, underestimating the rate of fetuses that will ultimately have UV circulation. Until better discrimination can be achieved, fetal interventions may need to be limited to only those cases in which non-BV postnatal circulation is certain. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Is local review of positron emission tomography scans sufficient in diffuse large B-cell lymphoma clinical trials? A CALGB 50303 analysis.

BACKGROUND: Quantitative methods of Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) interpretation, including the percent change in FDG uptake from baseline (ΔSUV), are under investigation in lymphoma to overcome challenges associated with visual scoring systems (VSS) such as the Deauville 5-point scale (5-PS). METHODS: In CALGB 50303, patients with DLBCL received frontline R-CHOP or DA-EPOCH-R, and although there were no significant associations between interim PET responses assessed centrally after cycle 2 (iPET) using 5-PS with progression-free survival (PFS) or overall survival (OS), there were significant associations between central determinations of iPET ∆SUV with PFS/OS. In this patient cohort, we retrospectively compared local vs central iPET readings and evaluated associations between local imaging data and survival outcomes. RESULTS: Agreement between local and central review was moderate (kappa = 0.53) for VSS and high (kappa = 0.81) for ∆SUV categories (<66% vs. ≥66%). ∆SUV ≥66% at iPET was significantly associated with PFS (p = 0.03) and OS (p = 0.002), but VSS was not. Associations with PFS/OS when applying local review vs central review were comparable. CONCLUSIONS: These data suggest that local PET interpretation for response determination may be acceptable in clinical trials. Our findings also highlight limitations of VSS and call for incorporation of more objective measures of response assessment in clinical trials.

ß-Cell Cre Expression and Reduced Ins1 Gene Dosage Protect Mice From Type 1 Diabetes.

A central goal of physiological research is the understanding of cell-specific roles of disease-associated genes. Cre-mediated recombineering is the tool of choice for cell type-specific analysis of gene function in preclinical models. In the type 1 diabetes (T1D) research field, multiple lines of nonobese diabetic (NOD) mice have been engineered to express Cre recombinase in pancreatic ß cells using insulin promoter fragments, but tissue promiscuity remains a concern. Constitutive Ins1tm1.1(cre)Thor (Ins1Cre) mice on the C57/bl6-J background have high ß-cell specificity with no reported off-target effects. We explored whether NOD:Ins1Cre mice could be used to investigate ß-cell gene deletion in T1D disease modeling. We studied wild-type (Ins1WT/WT), Ins1 heterozygous (Ins1Cre/WT or Ins1Neo/WT), and Ins1 null (Ins1Cre/Neo) littermates on a NOD background. Female Ins1Neo/WT mice exhibited significant protection from diabetes, with further near-complete protection in Ins1Cre/WT mice. The effects of combined neomycin and Cre knockin in Ins1Neo/Cre mice were not additive to the Cre knockin alone. In Ins1Neo/Cre mice, protection from diabetes was associated with reduced insulitis at age 12 weeks. Collectively, these data confirm previous reports that loss of Ins1 alleles protects NOD mice from diabetes development and demonstrates, for the first time, that Cre itself may have additional protective effects. This has important implications for the experimental design and interpretation of preclinical T1D studies using ß-cell-selective Cre in NOD mice.

Upward propagation of gigantic jets revealed by 3D radio and optical mapping.

Occasionally, lightning will exit the top of a thunderstorm and connect to the lower edge of space, forming a gigantic jet. Here, we report on observations of a negative gigantic jet that transferred an extraordinary amount of charge between the troposphere and ionosphere (∼300 C). It occurred in unusual circumstances, emerging from an area of weak convection. As the discharge ascended from the cloud top, tens of very high frequency (VHF) radio sources were detected from 22 to 45 km altitude, while simultaneous optical emissions (777.4 nm OI emitted from lightning leaders) remained near cloud top (15 to 20 km altitude). This implies that the high-altitude VHF sources were produced by streamers and the streamer discharge activity can extend all the way from near cloud top to the ionosphere. The simultaneous three-dimensional radio and optical data indicate that VHF lightning networks detect emissions from streamer corona rather than the leader channel, which has broad implications to lightning physics beyond that of gigantic jets.

Alignment of the Cervix with the Vagina in Uterine Retroversion: A Possible Risk Factor in Uterine Prolapse.

Multiple observational studies have found an association of uterine prolapse with uterine retroversion. Mechanisms proposed to explain this apparent association assume that the cervix of a retroverted uterus will usually insert at the apex of the vagina, with resultant alignment of the cervix with the vagina. The angle of the axis of the cervix with the axis of the vagina was measured by two readers on 323 sagittal pelvic MRI scans and sagittal reconstructions of pelvic CT scans performed for clinical purposes. One reader observed and recorded the anatomic relations of the uterus that differed by insertion site and version: 44 of 49 retroverted uteri (89.8%) inserted at the vaginal apex, and 13 of 274 anteverted uteri (4.7%) inserted at the vaginal apex. This difference was found to be statistically significant (p < 0.05) by the Chi square test. The urinary bladder, vaginal walls, and rectum were inferiorly related to anteriorly inserted anteverted uteri. Only the vaginal lumen and the rectum at a shallow oblique angle were inferiorly related to apically inserted retroverted uteri. Most retroverted uteri insert at the apex of the vagina. Apically inserted retroverted uteri appear to receive less support from adjacent structures than anteriorly inserted anteverted uteri.

Nivolumab in patients with relapsed or refractory peripheral T-cell lymphoma: modest activity and cases of hyperprogression.

Peripheral T-cell lymphomas (PTCL), a heterogeneous group of mature aggressive non-Hodgkin's lymphomas, carry a worse prognosis for most subtypes when compared with their B-cell counterparts. Despite recent approval of newer therapies, the outlook for patients with relapsed/refractory (RR) PTCL remains poor and new treatment strategies are clearly needed. Targeting the profoundly immunosuppressive tumor microenvironment in PTCL is one such approach. To determine whether immune checkpoint blockade targeting program death receptor 1 would be effective in PTCL, we conducted an investigator-initiated phase 2 prospective study of single-agent nivolumab for RR PTCL. We report here results of the pre-specified interim analysis. METHODS: The primary objective was to assess the overall response rate (ORR). Secondary objectives were to assess safety and tolerability of nivolumab in PTCL and to assess progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Hyperprogressive disease (HPD) was defined as time-to-treatment failure of less than or equal to one month from initiation of therapy. RESULTS: Twelve patients who received at least one cycle of nivolumab were included in this interim analysis. Half (6/12) of the patients had angioimmunoblastic T-cell lymphoma (AITL), 3/12 had PTCL, not otherwise specified. Most (11/12) were advanced stage, had extranodal disease (97.1%) and had received a prior autologous stem cell transplant (50%). The ORR was 33% (95% CI: 12.3 to 63.7%) with two complete response and two partial response. The median PFS was however short at 2.7 months (95% CI: 1.5 to NE); and the median OS was 6.7 months (95% CI: 3.4 to NE). The median DOR was also short at 3.6 months (95% CI: 1.9 to NE). HPD occurred in four patients, three of whom had AITL. Observed grade 3 and higher adverse events (AEs) were non-hematologic in 5/12 (42%), while hematologic AEs were seen in 3/12 (25%). CONCLUSIONS: Nivolumab had modest clinical activity in R/R PTCL. Due to a high number of hyperprogression and short DOR, a decision was made to halt the study. These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases. TRIAL REGISTRATION NUMBER: NCT03075553.

Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis.

The dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are essential for mitochondrial function, which has been principally attributed to their regulation of fission/fusion dynamics. Here, we report that Mfn1 and 2 are critical for glucose-stimulated insulin secretion (GSIS) primarily through control of mitochondrial DNA (mtDNA) content. Whereas Mfn1 and Mfn2 individually were dispensable for glucose homeostasis, combined Mfn1/2 deletion in ß-cells reduced mtDNA content, impaired mitochondrial morphology and networking, and decreased respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies unexpectedly revealed that Mfn1/2 control of glucose homeostasis was dependent on maintenance of mtDNA content, rather than mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient ß-cells. Thus, the primary physiologic role of Mfn1 and 2 in ß-cells is coupled to the preservation of mtDNA content rather than mitochondrial architecture, and Mfn1 and 2 may be promising targets to overcome mitochondrial dysfunction and restore glucose control in diabetes.

Asystole Following Concomitant Intravenous Administration of Neostigmine and Dexmedetomidine in a Patient With Acute Colonic Pseudo-Obstruction.

Acute colonic pseudo-obstruction (ACPO) is a condition characterized by acute dilation of the large bowel without evidence of mechanical obstruction that occurs in a variety of hospitalized patients with many predisposing factors. Management includes supportive care and limitation of offending medications with mainstays of treatment of neostigmine administration and colonic decompression. We report the case of a critically ill patient with ACPO who experienced bradycardia and a brief episode of asystole when receiving concomitant dexmedetomidine and neostigmine infusions but who later remained hemodynamically stable when receiving propofol and neostigmine infusions. The bradycardia and associated hemodynamic instability experienced while on dexmedetomidine and neostigmine infusions were rapidly corrected with atropine and cessation of offending agents. Because ACPO is encountered frequently and the use of dexmedetomidine as a sedative agent in the ICU is increasing, practitioners should be aware of the additive risk of bradycardia and potential for asystole with the combination of neostigmine and dexmedetomidine. Electronic drug interaction databases should be updated and drug information sources should include a drug-drug interaction between dexmedetomidine and neostigmine to reduce the likelihood of concomitant administration.

A comparison of four systems for uterine septum diagnosis and indication for surgical correction.

INTRODUCTION: Existing guidelines do not settle on a specific length to indicate surgical incision of subseptations because of differences in the four published diagnostic methods: AFS-10 mm classification, 1988/2003, ESHRE-ESGE classification, 2013, ASRM criteria, 2016- and 5.9-mm length cut-off, 2017. With this review and data analysis we sought to identify the classification method with the most accurate association with early pregnancy loss, as to identify a subseptation length cut-off to indicate surgical correction. EVIDENCE ACQUISITION: We performed an exhaustive literature search of PubMed (MEDLINE), Embase, and Cochrane Library databases until April 20, 2020 (limited to articles published in English) of the terms "uterine septum," "arcuate uterus," "subseptation," "Müllerian anomalies," from 1980-2020. After identifying all the available classifications for uterine subseptations, we performed a secondary data analysis of our departmental database on uterine subseptations and compared the identified classification criteria. Measurement of the subseptation's length was obtained on 2-D and 3-D ultrasound in accordance with the different methods. The incidence of uterine subseptations according to each method's specifications was compared among the groups and the association with pregnancy loss was evaluated. EVIDENCE SYNTHESIS: The database comprised 125 women with uterine subseptations and all four diagnostic systems identified septate uteri within it. The 5.9-mm cut-off diagnosed 89 septate, and 36 normal uteri and was the most inclusive while the ASRM cut-off was the most restrictive one, diagnosing 92/125 as arcuate uteri, only 8/125 as septate, and 25 in the gray zone. The AFS-10 mm criteria diagnosed 92/125 as arcuate, and 33 (26.4%) as septate uteri. Subseptations were inconsistently diagnosed by the ESHRE-ESGE classification, as some subseptations longer than 10 mm would be classified as normal uteri. Five/24 women had had one previous early loss and 19/24 had recurrent pregnancy loss. The 5.9-mm system was the most sensitive, while the ASRM was the least sensitive in predicting pregnancy loss (71.2% vs. 9.5% of septate uteri). CONCLUSIONS: The proposed 5.9-mm cut-off was the most sensitive in diagnosing a septate uterus and in predicting an associated early pregnancy loss. Conversely, the AFS-10 mm and the ASRM were the most restrictive, potentially missing treatment for hazardous subseptations. This update highlights the major weaknesses in the current diagnosis of uterine subseptations and indication for surgical treatment. Standardization of clinical practice is essential for reproductive clinicians and efforts should be made to prevent even one further early pregnancy loss to uterine subseptations.

Augmenting prehospital care.

INTRODUCTION: The challenging environment of prehospital casualty care demands providers to make prompt decisions and to engage in lifesaving interventions, occasionally without them being adequately experienced. Telementoring based on augmented reality (AR) devices has the potential to decrease the decision time and minimise the distance gap between an experienced consultant and the first responder. The purpose of this study was to determine whether telementoring with AR glasses would affect chest thoracotomy performance and self-confidence of inexperienced trainees. METHODS: Two groups of inexperienced medical students performed a chest thoracotomy in an ex vivo pig model. While one group was mentored remotely using HoloLens AR glasses, the second performed the procedure independently. An observer assessed the trainees' performance. In addition, trainees and mentors evaluated their own performance. RESULTS: Quality of performance was found to be superior with remote guidance, without significant prolongation of the procedure (492 s vs 496 s, p=0.943). Moreover, sense of self-confidence among participant was substantially improved in the telementoring group in which 100% of the participants believed the procedure was successful compared with 40% in the control group (p=0.035). CONCLUSION: AR devices may have a role in future prehospital telementoring systems, to provide accessible consultation for first responders, and could thus positively affect the provider's confidence in decision-making, enhance procedure performance and ultimately improve patient prognosis. That being said, future studies are required to estimate full potential of this technology and additional adjustments are necessary for maximal optimisation and implementation in the field of prehospital care.

Impact of COVID-19 on maternal and neonatal outcomes: a systematic review and meta-analysis.

BACKGROUND: Previous outbreaks of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV) have been associated with unfavourable pregnancy outcomes. SARS-CoV-2 belongs to the human coronavirus family, and since this infection shows a pandemic trend it will involve many pregnant women. AIMS: This systematic review and meta-analysis aimed to assess the impact of coronavirus disease 19 (COVID-19) on maternal and neonatal outcomes. SOURCES: PubMed, EMBASE, MedRxiv, Scholar, Scopus, and Web of Science databases were searched up to 8th May 2020. Articles focusing on pregnancy and perinatal outcomes of COVID-19 were eligible. Participants were pregnant women with COVID-19. CONTENT: The meta-analysis was conducted following the PRISMA and MOOSE reporting guidelines. Bias risk was assessed using the Joanna Briggs Institute (JBI) manual. The protocol was registered with PROSPERO (CRD42042020184752). Twenty-four articles, including 1100 pregnancies, were selected. The pooled prevalence of pneumonia was 89% (95%CI 70-100), while the prevalence of women admitted to the intensive care unit was 8% (95%CI 1-20). Three stillbirths and five maternal deaths were reported. A pooled prevalence of 85% (95%CI 72-94) was observed for caesarean deliveries. There were three neonatal deaths. The prevalence of COVID-19-related admission to the neonatal intensive care unit was 2% (95%CI 0-6). Nineteen out of 444 neonates were positive for SARS-CoV-2 RNA at birth. Elevated levels of IgM and IgG Serum antibodies were reported in one case, but negative swab. IMPLICATIONS: Although adverse outcomes such as ICU admission or patient death can occur, the clinical course of COVID-19 in most women is not severe, and the infection does not significantly influence the pregnancy. A high caesarean delivery rate is reported, but there is no clinical evidence supporting this mode of delivery. Indeed, in most cases the disease does not threaten the mother, and vertical transmission has not been clearly demonstrated. Therefore, COVID-19 should not be considered as an indication for elective caesarean section.

NFATc3 regulation of collagen V expression contributes to cellular immunity to collagen type V and hypoxic pulmonary hypertension.

Chronic hypoxia (CH)-induced pulmonary hypertension (PH) results, in part, from T helper-17 (TH17) cell-mediated perivascular inflammation. However, the antigen(s) involved is unknown. Cellular immunity to collagen type V (col V) develops after ischemia-reperfusion injury during lung transplant and is mediated by naturally occurring (n)TH17 cells. Col5a1 gene codifies for the α1-helix of col V, which is normally hidden from the immune system within type I collagen in the extracellular matrix. COL5A1 promoter analysis revealed nuclear factor of activated T cells, cytoplasmic 3 (NFATc3) binding sites. Therefore, we hypothesized that smooth muscle NFATc3 upregulates col V expression, leading to nTH17 cell-mediated autoimmunity to col V in response to CH, representing an upstream mechanism in PH development. To test our hypothesis, we measured indexes of PH in inducible smooth muscle cell (SMC)-specific NFATc3 knockout (KO) mice exposed to either CH (380 mmHg) or normoxia and compared them with wild-type (WT) mice. KO mice did not develop PH. In addition, COL5A1 was one of the 1,792 genes differentially affected by both CH and SMC NFATc3 in isolated intrapulmonary arteries, which was confirmed by RT-PCR and immunostaining. Cellular immunity to col V was determined using a trans vivo delayed-type hypersensitivity assay (Tv-DTH). Tv-DTH response was evident only when splenocytes were used from control mice exposed to CH but not from KO mice, and mediated by nTH17 cells. Our results suggest that SMC NFATc3 is important for CH-induced PH in adult mice, in part, by regulating the expression of the lung self-antigen COL5A1 protein contributing to col V-reactive nTH17-mediated inflammation and hypertension.