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Study Design Feasibility study. Purpose A phantom model was used to evaluate the accuracy of a novel augmented reality (AR) system for cervical screw placement. Overview of Literature The use of navigation systems is becoming increasingly common in spine procedures. However, numerous factors limit the feasibility of regular and widespread use of navigation tools during spine surgery. AR is a new technology that has already demonstrated utility as a navigation tool during spine surgery. However, advancements in AR technology are needed to increase its adoption by the medical community. Methods AR technology that uses a fiducial-less registration system was tested in a preclinical cervical spine phantom model study for accuracy during spinal screw placement. A three-dimensional reconstruction of the spine along with trajectory lines was superimposed onto the phantom model using an AR headset. Participants used the AR system to guide screw placement, and post-instrumentation scans were compared for accuracy assessment. Results Twelve cervical screws were placed under AR guidance. All screws were placed in an acceptable anatomic position. The average distance error for the insertion point was 2.73±0.55 mm, whereas that for the endpoint was 2.71±0.69 mm. The average trajectory angle error for all insertions was 2.69°±0.59°. Conclusions This feasibility study describes a novel registration approach that superimposes spinal anatomy and trajectories onto the surgeon’s real-world view of the spine. These results demonstrate reasonable accuracy in the preclinical model. The results of this study demonstrate that this technology can assist with accurate screw placement. Further investigation using cadaveric and clinical models is warranted.

Abstract Hepatic venous pressure gradient (HVPG) is an accurate measure of portal hypertension in cirrhosis. However, the effect of catheter tip distance from hepatic vein ostium (HVO) on HVPG is unknown. We performed a retrospective study on 228 patients with 307 HVPGs in our institution. The objectives of this study were to assess the effect of catheter position on the validity of HVPG and its prognostication in cirrhosis. In this study, free hepatic vein pressure (FHVP) was considered optimal when difference between FHVP and inferior vena cava pressure was ≤ 2 mmHg. HVPG progressively decreased (p 5 to ≤ 8 cm [odds ratio {OR} 0.16 (95% CI 0.05–0.47), p = 0.001] and > 8 cm [OR 0.14 (95% CI 0.04–0.47), p = 0.002] compared to ≤ 3 cm from HVO were independent predictors of not achieving optimal FHVP. Baseline HVPG ≥ 16 mmHg was strongly associated with deaths due to cirrhosis and liver transplantation for end-stage liver disease compared to HVPG 5 cm from HVO, resulting in inaccurately low HVPG.

IntroductionA strong epidemiologic link exists between cigarette smoke (CS) exposure and susceptibility to tuberculosis (TB). Macrophage and murine studies showed that CS and nicotine impair host-protective immune cells against Mycobacterium tuberculosis (MTB) infection. While CS and nicotine may activate T regulatory cells (Tregs), little is known about how CS may affect these immunosuppressive cells with MTB infection.MethodsWe investigated whether CS-exposed Tregs could exacerbate MTB infection in co-culture with human macrophages and in recipient mice that underwent adoptive transfer of Tregs from donor CS-exposed mice.ResultsWe found that exposure of primary human Tregs to CS extract impaired the ability of unexposed human macrophages to control an MTB infection by inhibiting phagosome-lysosome fusion and autophagosome formation. Neutralizing CTLA-4 on the CS extract-exposed Tregs abrogated the impaired control of MTB infection in the macrophage and Treg co-cultures. In Foxp3+GFP+DTR+ (Thy1.2) mice depleted of endogenous Tregs, adoptive transfer of Tregs from donor CS-exposed B6.PL(Thy1.1) mice with subsequent MTB infection of the Thy1.2 mice resulted in a greater burden of MTB in the lungs and spleens than those that received Tregs from air-exposed mice. Mice that received Tregs from donor CS-exposed mice and infected with MTB had modest but significantly reduced numbers of interleukin-12-positive dendritic cells and interferon-gamma-positive CD4+ T cells in the lungs, and an increased number of total programmed cell death protein-1 (PD-1) positive CD4+ T cells in both the lungs and spleens.DiscussionPrevious studies demonstrated that CS impairs macrophages and host-protective T effector cells in controlling MTB infection. We now show that CS-exposed Tregs can also impair control of MTB in co-culture with macrophages and in a murine model.

Abstract Background The torrent of research during the coronavirus (COVID-19) pandemic has exposed the persistent challenges with reporting trials, open science practices, and scholarship in academia. These real-world examples provide unique learning opportunities for research methodologists and clinical epidemiologists-in-training. Dr. David Moher, a recognized expert on the science of research reporting and one of the founders of the Consolidated Standards of Reporting Trials (CONSORT) statement, was a guest speaker for the 2021 Hooker Distinguished Visiting Professor Lecture series at McMaster University and shared his insights about these issues. Main text This paper covers a discussion on the influence of reporting guidelines on trials and issues with the use of CONSORT as a measure of quality. Dr. Moher also addresses how the overwhelming body of COVID-19 research reflects the “publish or perish” paradigm in academia and why improvement in the reporting of trials requires policy initiatives from research institutions and funding agencies. We also discuss the rise of publication bias and other questionable reporting practices. To combat this, Dr. Moher believes open science and training initiatives led by institutions can foster research integrity, including the trustworthiness of researchers, institutions, and journals, as well as counter threats posed by predatory journals. He highlights how metrics like journal impact factor and quantity of publications also harm research integrity. Dr. Moher also discussed the importance of meta-science, the study of how research is carried out, which can help to evaluate audit and feedback systems and their effect on open science practices. Conclusion Dr. Moher advocates for policy to further improve the reporting of trials and health research. The COVID-19 pandemic has exposed how a lack of open science practices and flawed systems incentivizing researchers to publish can harm research integrity. There is a need for a culture shift in assessing careers and “productivity” in academia, and this requires collaborative top-down and bottom-up approaches.

Abstract Background Racial/ethnic minorities are at higher risk for severe COVID-19. This may be related to social determinants that lead to chronic inflammatory states. The aims of the study were to determine if there are racial/ethnic disparities with inflammatory markers and association of methylprednisolone to in hospital survival. Methods This was a secondary analysis of a retrospective cohort study of patients ≥ 18 years of age and admitted for severe COVID-19 pneumonia between March and June 2020 in 13 Hospitals in New Jersey, United States. Patients who received other formulation of corticosteroids were not included. Area under the receiver operating characteristics curves were performed to test for discriminatory ability of each inflammatory makers. Univariate and multivariate Cox regression assessed the association of variables to in hospital survival. Results Propensity matched sample (n = 759) between no methylprednisolone (n = 380) and methylprednisolone (n = 379) had 338 Whites, 102 Blacks, 61 Asian/Indians, and 251 non-Black non-White Hispanics. Compared to CRP, area under receiving operating characteristic curve for d-dimer in Hispanics (0.742) was statistically different (DeLong Test P = 0.0041). Multivariate cox regression showed that different variables in Blacks [age ≥ 60 years (HR = 3.71, P = 0.0281), mechanical ventilation (HR = 5.07, P = 0.0281) and creatinine ≥ 1.5 mg/dL (HR = 3.61, P = 0.0007)], Whites [cancer (HR = 1.68, P = 0.0213), qSOFA score of 1 (HR = 1.81, P = 0.0213), qSOFA score of 2 (HR = 5.16, P 20 mg/L (HR = 5.02, P = 0.0032)] were statistically significant for mortality. Low dose and high dose methylprednisolone were significantly associated with prolonged survival in Whites [low dose (HR = 0.37, P

Abstract Background Mortality in severe COVID-19 pneumonia is associated with thrombo-inflammation. Corticosteroids are given to attenuate the inflammation, but they are associated with thrombosis. The aims of this study were to determine the risk of venous thromboembolism between no methylprednisolone and methylprednisolone (dose versus duration) and to evaluate any synergistic dose-dependent association of heparin and methylprednisolone to 30 days in hospital survival. Methods This was a secondary analysis of a retrospective cohort. Patients included in this study were ≥ 18 years of age and admitted for severe COVID-19 pneumonia between March and June 2020 in 13 hospitals in New Jersey, United States. A propensity score analysis between administration of methylprednisolone and no methylprednisolone was fitted for 11 variables and Youden Index Method was used to determine cut-off between low dose and high dose methylprednisolone. Multivariate cox regression was to assess risk. Results In 759 patients, the incidence of venous thromboembolism was 9% of patients who received methylprednisolone and 3% of patients who did not receive methylprednisolone with a [RR 2.92 (95% CI 1.54, 5.55 P 7 days and ≤ 7 days was statistically significant (RR 5.46 95% CI 2.87, 10.34 P 7 days had a higher association of venous thromboembolism. There was no added benefit of therapeutic heparin to methylprednisolone on mechanically ventilated patients.

Abstract Replacement of lost cranial bone (partly mesodermal and partly neural crest‐derived) is challenging and includes the use of nonviable allografts. To revitalize allografts, bone marrow‐derived mesenchymal stromal cells (mesoderm‐derived BM‐MSCs) have been used with limited success. We hypothesize that coating of allografts with induced neural crest cell‐mesenchymal progenitor cells (iNCC‐MPCs) improves implant‐to‐bone integration in mouse cranial defects. Human induced pluripotent stem cells were reprogramed from dermal fibroblasts, differentiated to iNCCs and then to iNCC‐MPCs. BM‐MSCs were used as reference. Cells were labeled with luciferase (Luc2) and characterized for MSC consensus markers expression, differentiation, and risk of cellular transformation. A calvarial defect was created in non‐obese diabetic/severe combined immunodeficiency (NOD/SCID) mice and allografts were implanted, with or without cell coating. Bioluminescence imaging (BLI), microcomputed tomography (μCT), histology, immunofluorescence, and biomechanical tests were performed. Characterization of iNCC‐MPC‐Luc2 vs BM‐MSC‐Luc2 showed no difference in MSC markers expression and differentiation in vitro. In vivo, BLI indicated survival of both cell types for at least 8 weeks. At week 8, μCT analysis showed enhanced structural parameters in the iNCC‐MPC‐Luc2 group and increased bone volume in the BM‐MSC‐Luc2 group compared to controls. Histology demonstrated improved integration of iNCC‐MPC‐Luc2 allografts compared to BM‐MSC‐Luc2 group and controls. Human osteocalcin and collagen type 1 were detected at the allograft‐host interphase in cell‐seeded groups. The iNCC‐MPC‐Luc2 group also demonstrated improved biomechanical properties compared to BM‐MSC‐Luc2 implants and cell‐free controls. Our results show an improved integration of iNCC‐MPC‐Luc2‐coated allografts compared to BM‐MSC‐Luc2 and controls, suggesting the use of iNCC‐MPCs as potential cell source for cranial bone repair.

Background: Burns are one of the most prevalent forms of wound in children and adults, although timing of surgical excision for deep partial or full thickness burns remains controversial. Objectives: To determine if early surgical intervention (excision and grafting within 7 days) improves outcomes when compared to delayed surgical intervention (excision and grafting after 7 days) in adults with thermal burns. Methods: We searched the following electronic databases: Cochrane Wound Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL. We hand searched the references of included studies and major review articles. We contacted authors of included trials for information about any ongoing trials or unpublished studies. Selection criteria: We included randomized controlled trials, both published and unpublished, comparing early versus delayed surgical intervention for treatment of thermal burns of all degrees and percent total body surface areas (%TBSA) in adult patients. Data collection and analysis: Two authors independently, and in duplicate, screened the titles abstracts and then full texts of all citations for possible inclusion. Data from eligible studies were extracted independently and in duplicate using Microsoft Excel. We pooled outcome data according to the guidelines of the Cochrane Collaboration using Review Manager 5.3 software and random effects model. We assessed Risk of Bias (RoB) in individual studies using the Cochrane Collaboration’s tool and overall certainty of evidence for each outcome using the GRADE framework. Main results: A total of 9 RCTs were included in the systematic review; 6 in the quantitative meta-analysis. Early surgical intervention may result in a small albeit imprecise reduction in mortality (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.53 to 1.14, I2 = 46%, very low certainty) and a reduction in length of hospital stay (days) (mean difference (MD) 12.66 days fewer; 95% CI 9.80 days fewer to 15.53 days fewer, I2 = 88%, low certainty), but increased need for red blood cell (RBC) units (MD 27.11; 95% CI 20.17 to 34.06 units, I2 = 99%, low certainty) compared to delayed surgical intervention. Additionally, early excision and grafting may result in better functional and cosmetic outcomes; both based on low certainty evidence. However, no difference in scar quality and proportion of burns requiring re-operation was found (both low certainty). Conclusion: Early excision and grafting may reduce mortality and improve other patient important outcomes in adults with thermal burns, however most outcomes are based on low or very low certainty evidence. Higher quality, methodologically rigorous studies examining health-related quality of life are warranted in order to best inform this clinical question.

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counterintuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfvén waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, α = 2 as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed >600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: preflare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that α = 1.63 ± 0.03. This is below the critical threshold, suggesting that Alfvén waves are an important driver of coronal heating.

Background Nitrate supplementation is thought to improve performance in endurance sports. Objective To meta-analyze studies evaluating the effect of nitrate supplementation on endurance sports performance among adults. Data sources We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science and CINAHL without language restrictions. Methods We included studies that: 1) compared nitrate supplementation with placebo; 2) enrolled adults engaging in an endurance-based activity; and 3) reported a performance measure or surrogate physiologic outcome. We evaluated risk of bias using the Cochrane Collaboration tool and pooled data with a random-effects model. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate confidence in estimates. Results We included 73 studies (n = 1061). Nitrate supplementation improved power output (MD 4.6 watts, P

Background. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for the early detection of organ transplant rejection and other causes of graft injury. For nonrejection renal injuries, there is little information about the performance characteristics of this biomarker. We highlight some of the possible causes of kidney injury that may arise in patients with normal dd-cfDNA levels. Methods. We performed a retrospective analysis of solitary renal transplant cases between January 2017 and November 2019. Those who had an abnormal laboratory or pathological finding within 1 mo of a normal dd-cfDNA test were selected. Subgroups were stratified for those who had normal or abnormal/rising serum creatinine, and differences between the groups were analyzed. Results. Of 414 individuals who received a kidney transplant, 24 (7.5%) had a total of 41 normal dd-cfDNA values and 51 abnormal laboratory tests or histologic findings. The most common graft-injuring event was BK virus viremia (24 of 51). Other abnormal findings included urinary traction infections (n = 4), CMV viremia (n = 4), and biopsies demonstrating antibody-mediated rejection (AMR) (n = 2), T cell–mediated rejection (n = 1), focal segmental glomerulosclerosis (n = 2), nondonor-specific antibody chronic AMR (n = 1), and interstitial fibrosis and tubular atrophy (n = 7). Subgroup analysis of those with normal dd-cfDNA and normal/stable versus abnormal/rising creatinine showed that BK virus viremia was the most common abnormal finding in both groups at 53% and 38% respectively. On biopsy, 1 case of acute T cell–mediated rejection (1B and 2B) was seen with normal/stable creatinine, whereas 1 of nonspecific C4d focally positive and 1 of nondonor-specific antibody AMR were seen with abnormal/rising creatinine. Conclusions. Low levels of serum dd-cfDNA do not preclude detection of active graft-injuring events and that subclinical injuries may be developing. Context is important in the interpretation of dd-cfDNA, so renal biopsy remains a part of the diagnostic pathway for allograft dysfunction and maintenance of allograft health.

The ultrasonic sound guide system presents the audio broadcasting system based on the inaudible ultrasonic sound to assist the indoor and outdoor navigation of the visually impaired. The transmitters are placed at the point of interest to propagate the frequency modulated voice signal in ultrasonic sound range. The dual channel receiver device is carried by the visually impaired person in the form of eyeglasses to receive the ultrasonic sound for the voice signal via demodulation. Since the ultrasonic sound demonstrates the acoustic properties, the velocity, directivity, attenuation, and superposition of ultrasonic sound provide the acoustic clue to the user for localizing the multiple transmitter positions by binaural localization capability. The visually impaired hear the designated voice signal and follow the signal attributions to arrive at the specific location. Due to the low microphone gain from side addressing, the time delay between the receiver channels demonstrates the high variance and high bias in end directions. However, the perception experiment shows the further prediction accuracy in end directions as compared to the center direction outcomes. The overall evaluations show the precise directional prediction for narrow- and wide-angle situations. The ultrasonic sound guide system is a useful device to localize places in the near field without touching braille.

Purpose To report the visual and refractive results of small incision lenticule extraction (SMILE) with low energy settings in the United States (US) and to evaluate outcomes for low astigmatism treatment. Setting Private clinical practice. Design Retrospective cohort study. Methods This study retrospectively reviewed 462 consecutive eyes that underwent SMILE with lower energy settings. Inclusion criteria included all patients between the ages of 19–39 with myopic astigmatism up to -11.25 diopters (D) spherical equivalent (sphere up to -10.00 D, astigmatism up to -3.00 D), and corrected distance visual acuity of at least 20/25. Eyes with low astigmatism (0.25 D-0.50 D) were also included. Outcome analysis was performed according to the Standard Graphs for Reporting Refractive Surgery at postoperative month (POM) 1, and POM 3–6 when data were available. Results The mean preoperative spherical equivalent treated was -4.96 ± 2.07; at POM 1, 92% of eyes achieved uncorrected visual acuity (UCVA) of 20/20 or better and maintained visual stability throughout the remainder of the study. At last visit, 431 eyes (93%) achieved UCVA of 20/20 or better, and 461 eyes (99.8%) were 20/25 or better. Ninety-seven (21%) eyes gained at least 1 Snellen line of corrected distance visual acuity and no eyes lost 2 or more lines. Almost all eyes (n = 453, 98%) were within 0.5D of target; 85% of eyes with low astigmatism had ≤0.25 D at last visit compared to 80% of eyes with moderate astigmatism. Conclusions SMILE with U.S.-approved low energy settings is safe, predictable, and efficacious and provides patients with a fast visual recovery.

Parental iron replacement is given to patients with severe iron deficiency or intolerance to oral iron. Hypophosphataemia has been reported to occur as a complication of parental iron replacement, and is postulated to be related to the carbohydrate moieties used in the parenteral preparations. Hypophosphataemia is under-diagnosed as symptoms such as fatigue, muscle weakness and poor effort tolerance mimic anaemia. Severe hypophosphataemia (

Patients with liver cirrhosis are at increased risk of developing hepatocellular carcinoma (HCC) and are placed on routine surveillance for HCC. Diagnosis algorithms are in place to guide clinicians in the evaluation of liver lesions detected during surveillance. Radiological assessments are critical with diagnostic criteria based on identification of typical hallmarks of HCCs on multiphasic computed tomography (CT) and dynamic contrast-enhanced magnetic resonance imaging (MRI). We report a patient with a hypervascular exophytic lesion indeterminate for HCC on CT imaging. While the detection of an exophytic arterially-enhancing lesion in an at-risk patient on CT imaging may prompt clinicians to treat the lesion as HCC without further evaluation, the patient underwent contrast-enhanced MRI with the lesion being eventually diagnosed as an exophytic haemangioma. Thus, no further action was necessary and the patient was continued on routine HCC surveillance.

Background and study aims Using personal protective equipment (PPE) can reduce risk of disease transmission. During the COVID-19 pandemic, enhanced PPE (EPPE) is recommended when performing endoscopy. We aimed to evaluate the impact of EPPE on colonoscopy performance when compared to standard PPE (SPPE). Patients and methods A review of electronic medical records and endoscopy reports of consecutive patients who underwent colonoscopy during two similar one-month time periods (in 2019 and during the COVID-19 pandemic in 2020) was performed. SPPE was used in 2019 and EPPE was used in 2020. Patient clinical data and procedure-related information were captured and analyzed. The primary outcomes were time to cecum (TTC) and total procedure time. Secondary outcomes were adenoma detection rate (ADR), polyp detection rate (PDR) and cecal intubation rate (CIR). Statistical analysis was performed using STATA v16.1. Results Two hundred and forty-seven colonoscopy procedures were analyzed. Baseline demographics and indications for colonoscopy of patients in both groups were similar. There were no significant differences in median TTC (10.0 vs 10.0 min, P = 0.524) or total procedure time (22.5 vs 23.0 min, P = 0.946) between colonoscopy performed in SPPE and EPPE. The ADR, PDR and CIR were also similar. Conclusion Our findings suggest that use of EPPE does not affect colonoscopy performance.

BackgroundGulf War (GW) Illness (GWI) is a debilitating condition with a complex constellation of immune, endocrine and neurological symptoms, including cognitive impairment, anxiety and depression. We studied a novel model of GWI based on 3 known common GW exposures (GWE): (i) intranasal lipopolysaccharide, to which personnel were exposed during desert sand storms; (ii) pyridostigmine bromide, used as prophylaxis against chemical warfare; and (iii) chronic unpredictable stress, an inescapable element of war. We used this model to evaluate prophylactic treatment with the PPARγ agonist, rosiglitazone (ROSI).MethodsRats were subjected to the three GWE for 33 days. In series 1 and 2, male and female GWE-rats were compared to naïve rats. In series 3, male rats with GWE were randomly assigned to prophylactic treatment with ROSI (GWE-ROSI) or vehicle. After the 33-day exposures, three neurofunctional domains were evaluated: cognition (novel object recognition), anxiety-like behaviors (elevated plus maze, open field) and depression-like behaviors (coat state, sucrose preference, splash test, tail suspension and forced swim). Brains were analyzed for astrocytic and microglial activation and neuroinflammation (GFAP, Iba1, tumor necrosis factor and translocator protein). Neurofunctional data from rats with similar exposures were pooled into 3 groups: naïve, GWE and GWE-ROSI.ResultsCompared to naïve rats, GWE-rats showed significant abnormalities in the three neurofunctional domains, along with significant neuroinflammation in amygdala and hippocampus. There were no differences between males and females with GWE. GWE-ROSI rats showed significant attenuation of neuroinflammation and of some of the neurofunctional abnormalities.ConclusionThis novel GWI model recapitulates critical neurofunctional abnormalities reported by Veterans with GWI. Concurrent prophylactic treatment with ROSI was beneficial in this model.

Here we describe the methods for production of a recombinant viral capsid protein and subsequent use in an indirect enzyme linked immunosorbent assay (ELISA), and for use in production of a rabbit polyclonal antibody. These reagents were utilized in development and optimization of an ELISA, which established the extent of exposure of free ranging raccoons to a newly described polyomavirus (RacPyV) [1]. Production of a polyclonal antibody has allowed for further characterization of RacPyV, including immunohistochemistry and immunocytochemistry techniques, in order to answer questions about pathogenesis of this virus.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by binding to sequences within the 3′ UTR of mRNAs. Because miRNAs bind to short sequences with partial complementarity, target identification is challenging. To complement the existing target prediction algorithms, we devised a systematic “reverse approach” screening platform that allows the empirical prediction of miRNA-target interactions. Using Drosophila cells, we screened the 3′ untranslated regions (3′ UTRs) of the Hedgehog pathway genes against a genome-wide miRNA library and identified both predicted and many nonpredicted miRNA-target interactions. We demonstrate that miR-14 is essential for maintaining the proper level of Hedgehog signaling activity by regulating its physiological target, hedgehog. Furthermore, elevated levels of miR-14 suppress Hedgehog signaling activity by cotargeting its apparent nonphysiological targets, patched and smoothened. Altogether, our systematic screening platform is a powerful approach to identifying both physiological and apparent nonphysiological targets of miRNAs, which are relevant in both normal and diseased tissues.

Cellular and systemic responses to low oxygen levels are principally mediated by Hypoxia Inducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors, whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIFα is hydroxylated by specific prolyl-4-hydroxylases, targeting it for proteasomal degradation, while in hypoxia the activity of these hydroxylases decreases due to low oxygen availability, leading to HIFα accumulation and expression of HIF target genes. To identify microRNAs required for maximal HIF activity, we conducted an overexpression screen in Drosophila melanogaster, evaluating the induction of a HIF transcriptional reporter. miR-190 overexpression enhanced HIF-dependent biological responses, including terminal sprouting of the tracheal system, while in miR-190 loss of function embryos the hypoxic response was impaired. In hypoxic conditions, miR-190 expression was upregulated and required for induction of HIF target genes by directly inhibiting the HIF prolyl-4-hydroxylase Fatiga. Thus, miR-190 is a novel regulator of the hypoxia response that represses the oxygen sensor Fatiga, leading to HIFα stabilization and enhancement of hypoxic responses.

Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic.We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome.Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients.BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation.

Hepatic veno-occlusive disease (VOD)/sinusoidal obstructive syndrome (SOS) is a severe complication that can occur following haematopoietic stem cell transplant (HSCT) with high-intensity conditioning chemotherapy regimens. Severe VOD/SOS, often characterised by multiorgan failure, is associated with a high mortality rate. This case report details the complex clinical course of a male patient in his mid-20s, recently diagnosed with B cell acute lymphoblastic leukaemia, who underwent allogeneic HSCT. Based on the 2023 European Society for Blood and Marrow Transplantation (EBMT) criteria, the patient developed very severe VOD/SOS, prompting immediate treatment with defibrotide. Unexpectedly, he developed profound hyperammonaemia exceeding 900 µmol/L, leading to encephalopathy and cerebral oedema. Despite aggressive interventions including defibrotide, lactulose, rifampin and haemodialysis, the patient passed away due to cerebral oedema and pulseless electrical activity arrest. We theorise the hyperammonaemia is disproportionate to his hepatic dysfunction and is possibly secondary to an acquired defect of the urea synthesis consistent with idiopathic hyperammonaemia, a rare complication in patients receiving intense conditioning chemotherapy. [ABSTRACT FROM AUTHOR]