As the impacts of the anthropocene intensifies in rivers, there is an increasing need to understand how these changes affect both daily and sub-daily stream flow variability, timing and flow quantities, as these are some of the most influential drivers of spatial and temporal dynamics of stream biota. In this paper, long-term changes in flow patterns of a strategic water source area in an arid region of southern Africa were quantified, focusing on the relation between daily and sub-daily and its potential impact on fish biota of the catchment. Long-term temporal trends in stream flow were modelled using Generalized Least Squares (GLS), while sub-daily and daily mean flow of the same stations were compared using a suite of metrics. Periods of similar stream flow patterns were identified using K-means cluster analysis. A spreadsheet rule-based model was developed linking fish communities to streamflow patterns providing a predictive framework for fish assemblage responses to stream flow classes. Long term reduction in flow has a strong seasonal component, with significant decreases during the wet season, not linked to long-term rainfall patterns. Flow variability has increased over time, while 78% of sub-daily flow metrics were related to daily flow metrics. Oscillating flow conditions and the loss of intermediate flow states may permanently exclude certain fish flow guilds. However, temporal partitioning is only evident when sub-daily metrics are considered, highlighting their importance for assessing ecological resilience.

Background: Comprehensive genomic profiling (CGP) was widely adopted in Japan after its coverage by national healthcare insurance began in June 2019. We investigated the clinical utility of CGP in pediatric and adolescent young adults (AYA) solid tumor patients. Procedure: Between November 2017 and December 2019, 13 patients who progressed with or who were likely to progress with standard therapies were recruited to the PROFILE-F study to undergo CGP using either FoundationOne® CDx or FoundationOne® Heme. Results: The median age was 28 years old. Tumor types were as follows: neuroblastoma (n=1), Wilms’ tumor (n=1), rhabdomyosarcoma (n=2), Ewing sarcoma (n=1), gastric cancer (n=1), rectal cancer (n=1), osteosarcoma (n=1), neuroendocrine tumor (n=2), salivary gland carcinoma (n=1), tracheal adenoid cystic carcinoma (n=1), and thymic cancer (n=1). In 92% of cases, at least one genomic alteration was identified, including CDKN2A (four cases), TP53 (three cases), and MYC (two cases). Actionable aberrations were found in 10 cases (77%), and a clinical trial candidate was found in seven cases (54%). However, no patients were able to receive biomarker-matched therapy according to their genomic alterations. Conclusions: Further efforts to increase basket trials and collection of clinical genomic data to predict response are necessary to advance precision cancer medicine in pediatric and AYA populations.

Juvenile open angle glaucoma (JOAG) is a severe type of glaucoma with childhood onset and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with rare EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cysteine ) co-segregating with disease. Affected variant carriers (N= 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early-onset form of macular degeneration, Malattia Leventinese/Doyne’s Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.

ACE 2 is the functional receptor that SARS-Cov-2 virus requires to enter cells and cause dysregulated inflammatory conditions that contribute towards acute lung injuries. The RAAS with its physiological surveillance and regulation system can be implicated in both harm and therapeutic benefit. The initial observational studies suggesting the discontinuation of ACE-I and ARBs have been firmly rebutted by international societies. On the contrary, these therapeutics may confer a survival benefit in Covid 19 infections. Understanding the biological plausibility of this pathway alongside the emerging therapeutic evidence may yield new modes of treatment. Such developments appear fundamentally important in the battle against the inevitable emergence of new variants and their potential to drive future waves of Covid 19 pandemics.

Abstract Immune checkpoint inhibitors (ICIs) have become new research hotspots in the treatment of non-small cell lung cancer, but the efficacy and safety of immunotherapy for patients with chronic viral infection are still unclear, because existing clinical trials often exclude those patients. Materials and Methods We identified 78 locally advanced or advanced NSCLC patients with chronic viral infection treated with PD-1/PD-L1 inhibitors alone or combined with the chemotherapy/bevacizumab therapy, of whom 60 with hepatitis B, 2 with hepatitis C, and 16 with syphilis. Objective response rates were assessed using the RECIST v1.1. Adverse events were graded following the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Results Objective responses were observed in 19 out of 78(24.36%) patients, and the disease control rate (DCR) was 69.23% (54/78). No patient achieved a complete response. The median progression-free survival (PFS) was 6.49 months (95% CI:3.71-9.27). PFS was 1.44 months (95%CI:0.00-4.34) for monotherapy versus 7.34 months (95%CI:4.50-10.18) for combination therapy (P=0.053). Patients in the first-line treatment group revealed relatively higher ORR and longer PFS (ORR: 48.00% vs. 13.20%, P = 0.001; PFS: 7.67 months vs. 5.57 months, P = 0.129). Patients with combined radiotherapy showed longer PFS than those without combined radiotherapy (14.07 vs.4.62, P=0.027). The incidence of adverse events of any grade was 73.07% (57/78), among which there were 7 cases of grade 4 adverse events. The incidence of leukopenia in any grade of adverse reactions was the highest (57.69%), followed by anemia (25.64%), elevated alanine aminotransferase or aspartate aminotransferase (24.36%) and fatigue (21.79%). Hepatic transaminase increased in 26.7% (16/60) of HBV-infected patients, and remained unchanged in 63.3% (38/60) patients. Conclusions The PD-1 inhibitor showed an acceptable toxicity profile and moderate efficacy on NSCLC patients with chronic viral infection, but still has the potential to increase the incidence of hepatitis.

Objective: To describe experience with using intraoperative Transesophageal Echocardiography to reliably predict the size of the rapid deployment prosthetic valve by measuring the native aortic annulus Methods: Retrospective review of single institution series of patients undergoing Aortic Valve Replacement with Rapid Deployement Bioprosthetic Valves. Included were patients that had their native aortic valve replaced either isolated or as part of any additional procedure. Aortic annulus was measured prior to initiation of the operation using transesophageal echocardiography (TEE). Correlation analysis was conducted between Echocardiographic annular measurements and actual implanted valve sizes. Results: Twenty five patients underwent rapid deployment valve implantation in the aortic position. Of these, 36% of patients had the same size valve as the measured aortic annulus, 48% of patients had a valve implanted that was 1 mm different, and 16% of patients had 2 mm difference. The mean annular size based was 22.4 mm (range: 21-28 mm). The mean valve size implanted was 23.3 mm (range: 21-27 mm). There was no statistically significant difference between the mean annular measurement and the valve size selected (0.9 mm , p = 0.8). Conclusion: TEE can further enhance valve sizing and guidance through a proper and safe deployment. Although evident in our experience, larger scale studies are needed to further elucidate conclusions on the importance of avoiding under-sizing valves.

BACKGROUND: Coagulopathy and thrombosis are well-described complications of asparaginase therapy; however, treatment practices in pediatric hematology oncology patients vary widely as evidence-based guidelines for clinical management of these complications in this population are lacking. OBJECTIVE: To assess management practices of asparaginase-related coagulopathy by pediatric hematology oncology (PHO) providers. DESIGN/METHOD: Email survey sent to 2,327 PHO providers primarily practicing in the United States. RESULTS: Two hundred and eighty-five (12.2%) attending physicians completed the survey. Only 4.6% (n=13/285) routinely prescribe prophylactic anticoagulation during induction chemotherapy for leukemia. Slightly more than half (n=145/250, 50.9%) of all providers perform baseline coagulation studies. Most providers that were surveyed (n= 185/285, 64.9%) only replete coagulant factors if the patient experiences bleeding or bruising. One hundred and thirty (n = 130/285, 45.6%) physicians replace low fibrinogen, and the median replacement was 100 mg/dL (range: 40-200 mg/dL) with the median target of at least 100 mg/dL (range: 50-200 mg/dL). A minority of physicians (n=39/250, 13.7%) replace low antithrombin at a median cutoff activity level of 60% (range 40-100 %) with a median target of 75% (range: 40-125 %). CONCLUSION: There is a significant variation in PHO provider practices for monitoring and management of asparaginase-associated hemostatic derangements. Evidence-based guidelines have the potential to standardize practices.

LETTER TO THE EDITORNo apparent impact of incremental dosing on eliciting dose at double-blind, placebo-controlled peanut challengeOlaya Álvarez García,1,2 Joan Bartra,1,3 Monica Ruiz-Garcia,1Isabel J. Skypala,1,4 Stephen R. Durham,1,4 Robert J. Boyle,1 E.N. Clare Mills,5 Paul J. Turner1

Calcification beyond basal ganglia is rare in postoperative permanent hypoparathyroidism. We report extensive bilateral intracranial calcifications involving basal ganglia, thalamus, cerebellum, and cerebral cortex in a 56-year-old lady who presented with carpopedal spasm, seizure, and severe hypocalcemia after 20 years of near-total thyroidectomy.

We present four cases of intravascular large B-cell lymphoma (IVLBCL), a rare malignancy with poor outcomes. The exclusive presence of lymphoma cells in blood vessels leads to a heterogenous presentation and poor diagnostic yield with traditional initial diagnostic tools. Timely diagnosis and treatment can lead to improved outcomes.

A document by Jose V. Pardo, written on Authorea.

A document by Yuan Ban, written on Authorea.

Emerging pathogens have been increasing exponentially over the last century. The knowledge on whether these organisms are native to ecosystems or have been recently introduced is often of great importance. Understanding the ecological and evolutionary processes promoting emergence can help to control their spread and forecast epidemics. Using restriction site-associated DNA sequencing data, we studied genetic relationships, pathways of spread, and evolutionary history of Phellinus noxius, an emerging root-rotting fungus of unknown origin, in eastern Asia, Australia, and the Pacific Islands. We analyzed patterns of genetic variation using Bayesian inference, maximum likelihood phylogeny, populations splits and mixtures measuring correlations in allele frequencies and genetic drift, and finally applied coalescent based theory using approximate Bayesian computation (ABC) with supervised machine learning. Population structure analyses revealed five genetic groups with signatures of complex recent and ancient migration histories. The most probable scenario of ancient pathogen spread is movement from west to east: from Malaysia to the Pacific Islands, with subsequent spread to Taiwan and Australia. Furthermore, ABC analyses indicate that P. noxius spread occurred thousands of generations ago, contradicting previous assumptions that it was recently introduced in multiple areas. Our results suggest that recent emergence of P. noxius in east Asia, Australia, and the Pacific Islands is likely driven by anthropogenic and natural disturbances, including deforestation, land-use change, severe weather events, and introduction of exotic plants. This study provides a novel example of utilization of genome wide allele frequency data to unravel dynamics of pathogen emergence under conditions of changing ecosystems.

Acoustic communication allows animals to coordinate and optimize resource utilization in space. Cardioderma cor, the heart-nosed bat, is one of the few species of bats known to sing during nighttime foraging. Previous research found that heart-nosed bats react aggressively to song playback, supporting the territorial defense hypothesis of singing in this species. By tracking 14 individuals nightly during the dry seasons in Tanzania we further investigated the territorial defense hypothesis from an ecological standpoint, which predicts singing should be associated with exclusive areas containing a resource. We quantified the singing behavior of individuals at all perches used throughout the night. Using home range analysis tools, we quantified overall use night ranges and singing ranges, as well as areas used in early and later time periods at night. Males engaged in antiphonal singing from small (x̄ = 3.48 ± 2.71 ha), largely exclusive areas that overlapped with overall night ranges used for gleaning prey. Individuals varied in singing effort; however, all sang significantly more as night progressed. Subsequently, areas used earlier at night and overall use areas were both larger than singing areas. Individuals varied in singing strategies. Some males sang for long periods in particular trees and had smaller core areas, while others moved frequently among singing trees. The most prolific singers used more perches overall. The results support the hypothesis that acoustic communication repertoires evolved in support of stable foraging territory advertisement and defense in some bats.

Intravenous central line catheters are often at risk of line-related thrombosis. We report on how the cardiopulmonary bypass strategy was tailored to the particular anatomical challenges with the use of an unconventional venous cannulation site to optimise intraoperative venous drainage, improve surgical exposure and avoid circulatory arrest in a case with a complex intracardiac thrombosis. This report also highlights the importance of assiduously monitoring the efficacy of anticoagulation therapy, especially in the context of small bowel syndrome.

Aluminum (Al) toxicity is the major limiting factor for plant production and crop yield on acid soils. Previous works revealed that ZFP36 played a key role in plant adaptation to water stress and rice blast. Here, we report another function of ZFP36, which is associated with detoxification of Al toxicity through abscisic acid (ABA)- dependent mechanism, in rice. Al exposure significantly increased ZFP36 expression level in an ABA-dependent manner. Knocking down ZFP36 triggered Al sensitivity, while overexpressing ZFP36 resulted in an increased Al tolerance. Chromatin immunoprecipitation-sequencing (ChIP-seq), yeast one-hybrid assay, and dual luciferase test revealed that a tonoplast-localized Al transporter, OsALS1, and antioxidant defense enzymes were targeted by ZFP36. Moreover, by combining yeast two-hybrid assay, bimolecular fluorescence complement (BiFC), GST pull-down and in vitro phosphorylation assay, we showed that ZFP36 could interact with and be phosphorylated by the pyruvate dehydrogenase kinase OsPDK1. A strong association was found between the expression, protein content and kinase activity of OsPDK1 with the responses to ABA and Al. Using transgenic plants, we have showed that OsPDK1 could inhibit OsALS1 expression via regulating ZFP36. Overall, our data demonstrates a new ZFP36-controlled mechanism of Al defense in rice plants, which is mediated by OsPDK1.

Documenting patterns of spatio-temporal change in hyper-diverse communities remains a challenge for tropical ecology, yet is increasingly urgent as some long-term studies have shown major declines in bird communities even in relatively undisturbed sites. In 1982, Terborgh et al. quantified the structure and organization of the bird community in a 97-ha. plot in southeastern Peru. We revisited the same plot in 2018 and repeated the same intense combination of methodologies as the original study in order to evaluate community-wide changes. Contrary to the results from studies elsewhere, we found little change in bird distribution and abundance within the plot, although there were some declines related to loss of mixed-species flocks with a high level of species interdependence. This apparent stability suggests that large-scale forest reserves such as Manu National Park may provide the conditions necessary for establishing refugia from at least some of the effects of global change on birds.

Introduction. During left bundle branch area pacing (LBBAP) lead implantation, intermittent monitoring of unipolar pacing characteristics validates LBB capture and can detect septal perforation. We aimed to demonstrate that continuous uninterrupted unipolar pacing from an inserted lead stylet (LS) is feasible and facilitates LBBAP implantation. Methods. Thirty patients (mean age 76 ± 14 years) were implanted with stylet-driven pacing lead (Biotronik Solia S60). In 10 patients (validation-group) conventional, interrupted implantation was performed, with comparison of unipolar pacing characteristics between LS and connector-pin (CP)-pacing after each rotation step. In 20 patients (feasibility-group) performance and safety of uninterrupted implantation during continuous pacing from the LS were analyzed. Results. In the validation-group, LS and CP-pacing impedances were highly correlated (R2=0.95, p<0.0001, bias 12±37Ω). Pacing characteristics from LS and CP showed comparable sensed electrograms and paced QRS morphologies. In the feasibility-group, continuous LS-pacing allowed beat-to-beat monitoring of impedance and QRS morphology to guide implantation. This resulted in successful LBBAP in all patients, after a mean of 1±0 attempts, with mean threshold 0.81 ± 0.4V, median sensing 6.5mV [IQR 4.4-9.5] and mean impedance 624 ± 101Ω, and positive LBBAP-criteria with median paced QRS duration 120ms [IQR 112-152ms] and median pLVAT 73ms [IQR 68-80.5ms]. No septal perforation occurred. Conclusion. Unipolar pacing from the LS allows accurate determination of pacing impedance and generates similar paced QRS morphologies and equal sensed electrograms, compared to CP pacing. Continuous LS pacing allows real-time monitoring of impedance and paced QRS morphology, which facilitates a safe and successful LBBAP lead implantation.

Cavernous transformation of the portal vein (CTPV) is a rare condition characterized by the formation of multiple tortuous tiny blood vessels within and around a portal vein which has been occluded by thrombus. Early diagnosis of CTPV is relevant for timely intervention which could save the liver from non-reversible damage

Abstract Objectives: Treatment for olfactory dysfunction is challenging due to limited therapeutic options. Olfactory training has shown improvement in smell identification, discrimination, and threshold for odor detection. The primary objective is to assess the effect of olfactory training in patients with olfactory dysfunction after pituitary surgery, using functional Magnetic Resonance Imaging (fMRI). Design: This study was designed as a two-arm pilot clinical trial. Setting: Chilean tertiary hospital providing endoscopic pituitary surgery and olfactory evaluation and treatment. Participants: We included two cohorts of subjects: healthy subjects, and patients with post-surgical olfactory dysfunction. Healthy patients were recruited voluntarily at the ENT clinic to assess fMRI testing paradigms and as a control group for the olfactory dysfunction group. Main outcome measures: The main outcome measures were functional activation analysis obtained by fMRI. Olfactory test assessment scores were also obtained during each testing session. Results: 119 patients that underwent an endoscopic transsphenoidal approach were contacted and surveyed for olfactory dysfunction. Twelve patients met inclusion criteria, but six of them declined to participate. Six patients were randomized using computer-generated random numbers. The patients in the trained group showed a significant improvement in the olfactory test results after olfactory training compared to the no-training group (P < 0.05). The group that underwent olfactory training showed more areas of activation after training than in baseline analysis (P < 0.05). Conclusion: Patients that underwent olfactory training showed significant improvement in olfactory testing. fMRI results showed more activated areas in the olfactory training group, which could be compatible with neuroplasticity.

Objective: To review the effect of the COVID-19 pandemic on the presentation of Cervical cancer. Design/ Setting: Retrospective study involving the Regional Cancer Centres in the M62 Group. Methods: Data was collected for two equal time periods. All cervical cancers were included and FIGO 2018 staging was used for the data collection. P values were calculated using binomial hypothesis test for the difference in staging. Time from symptoms to diagnosis was assessed using a normal distribution test. All other calculations were performed using chi-squared test. Statistical significance was considered if p values were <0.05. Main outcome measures: Histology, stage at diagnosis, date of onset of symptoms, investigation and type of treatment. Results: A total of 406 cases of cervical cancer were reviewed; 233 from May – October 2019 (pre-COVID) and 173 between May – October 2020 (post COVID); representing a significant reduction in new cervical cancer diagnoses of 25% post COVID (p<0.001) There was a 42% increase in the delay from start of symptoms to diagnosis Post COVID. Pre COVID, 27% of patients presented with Stage 3 or 4 disease, whilst during COVID this was 38%; statistically significant (p <0.001). When we evaluated the treatments received between the two time periods, this was also statistically significant (chi-squared, p=0.0005). Conclusions: This study has demonstrated a statistically significant increase in the stage of cervical cancer at diagnosis and a change in treatment for cervical cancer following the onset of COVID-19. The implications of this are discussed.

A document by Belen Nigro, written on Authorea.

Paraparetic Guillian-Barre Syndrome is an uncommon variant of GBS. We describe a case of a teenage boy, who developed progressive, symmetric weakness of the lower limbs following an upper respiratory tract infection. Post-infectious, monophasic, acute, symmetric course were suggestive of paraparetic GBS which were further confirmed by CSF, electrophysiologic fndings.

Rationale, aims and objectives: There is a large body of literature from all over the world that describes, analyzes, or evaluates home care models and interventions. The present article aims to identify the practical lessons that can be gained from a systematic examination of that literature. Method: We conducted a three-step sequential search process from which 113 documents were selected. That corpus was then narratively analyzed according to a realist review approach. Results: A first level of observation is that there are multiple blind spots in the existing literature on home care. The definition and delimitation of what constitutes home care services is generally under-discussed. In the same way, the composition of the basket of care provided and its fit with the need of recipients is under-addressed. Finally, the literature relies heavily on RCTs whose practical contribution to decisions or policy is disputable.At a second level, our analysis suggests that three mechanisms (system integration, case management and relational continuity) are core characteristics of home care models effectiveness. Conclusion: We conclude by providing advice for creating effective home care system change through rational and participatory design and evaluation alongside public dialogue about the purpose and future of home care.