Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle.

Neutrophils are predominantly glycolytic cells that derive little ATP from oxidative phosphorylation; however, they possess an extensive mitochondrial network and maintain a mitochondrial membrane potential. Although studies have shown neutrophils need their mitochondria to undergo apoptosis and regulate NETosis, the metabolic role of the respiratory chain in these highly glycolytic cells is still unclear. Recent studies have expanded on the role of reactive oxygen species (ROS) released from the mitochondria as intracellular signaling molecules. Our study shows that neutrophils can use their mitochondria to generate ROS and that mitochondrial ROS release is increased in hypoxic conditions. This is needed for the stabilization of a high level of the critical hypoxic response factor and pro-survival protein HIF-1α in hypoxia. Further, we demonstrate that neutrophils use the glycerol 3-phosphate pathway as a way of directly regulating mitochondrial function through glycolysis, specifically to maintain polarized mitochondria and produce ROS. This illustrates an additional pathway by which neutrophils can regulate HIF-1α stability and will therefore be an important consideration when looking for treatments of inflammatory conditions in which HIF-1α activation and neutrophil persistence at the site of inflammation are linked to disease severity.

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE).

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020-002230-32).

Fish Erythrocyte Extracellular Traps (FEETs) are an evolutionarily conserved cellular process triggered by different stimuli.

Fish erythrocytes remain nucleated, unlike mammalian erythrocytes that undergo enucleation during maturation. Besides oxygen transport, fish erythrocytes are capable of several immune defence processes and thus these cells are candidates for carrying out ETotic responses. ETosis is an evolutionarily conserved innate immune defence process found in both vertebrates and invertebrates, which involves the extrusion of DNA studded with antimicrobial effector proteins into the extracellular space that traps and kills microorganisms. In this present report, we demonstrate that erythrocytes from Danio rerio (zebrafish) produce ETotic-like responses when exposed to both chemical and physiological inducers of ETosis. Furthermore, erythrocytes from Salmo salar (Atlantic salmon) behaved in a similar way. We have termed these ET-like formations, as Fish Erythrocyte Extracellular Traps (FEETs). Several inducers of mammalian ETosis, such as the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin, induced FEETs. Moreover, we found that FEETs depend on the activation of PKC and generation of mitochondrial reactive oxygen species (mROS). This present report is the first demonstration that fish erythrocytes can exhibit ETotic-like responses, unveiling a previously unknown function, which sheds new light on the innate immune arsenal of these cells.

A Systematic Review and a Meta-analysis of Randomized Controlled Trials' Control Groups in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

PURPOSE OF REVIEW: Determining the risk for progression or survival after standard androgen deprivation treatment (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) is essential for stratifying patients according to expected outcomes in future studies of treatment combination. This systematic review and meta-analysis aims to estimate the progression-free survival (PFS) and overall survival (OS) probabilities in the control group of randomized controlled trials (RCTs) of different regimens of standard androgen deprivation treatment (ADT) in mHSPC and to identify possible predictors of outcomes. RECENT FINDINGS: Studies reporting time-dependent outcomes (progression or death) after standard ADT treatment of mHSPC were searched in MEDLINE, CANCERLIT, the Cochrane Controlled Trials Register, and the Cochrane Library from inception through June 2021. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using a distribution-free summary survival curve. Primary outcomes were actuarial probabilities of disease progression and survival. Fifteen studies met the inclusion criteria. The pooled estimate of the actuarial PFS rate was 35.2% at two years. The pooled actuarial OS rate was 62.5% at three years. Heterogeneity among studies was highly significant for all outcomes. By univariate meta-regression analyses, high-volume disease and the presence of visceral metastases were associated with shorter survival. Our findings show that PFS and OS are highly variable in patients with mHSPC treated with ADT, providing a helpful benchmark for indirect comparisons of the benefits of the combination of chemotherapy and second-generation hormonotherapy.

Triple pass laser therapy for recalcitrant facial port wine stains.

Patients with recalcitrant facial port wine stains (rfPWS) can be challenging to manage, often leaving the clinician with difficult decisions for treatment options. 'Triple therapy' consists of using three different laser wavelengths at each treatment setting. The evidence on outcomes is limited as this treatment approach has not been previously reported to the best of our knowledge. Children who received triple therapy at least once for rfPWS, and for whom SIAscopy readings had been taken, were retrospectively identified. SIAscope readings were compared before the first triple therapy treatment and at final the most recent clinical follow-up. The clinical appearance was also assessed using a Visual Analogue Scale comparing clinical photographs taken before triple therapy to those taken at the most recent clinical follow-up. A total of 47 children were identified and included in our review. The SIAscope readings showed an overall significant (p < 0.001) lightening with 39 (83%) showing lightening and 8 (17%) patients showing a darkening. Scores using the VAS also showed improvement with 55% experiencing an improvement in their clinical appearance, 38% showing no visible change and 6% appearing to have worsened. Triple therapy can offer improvement of rfPWS which have failed to respond to single wavelength laser therapy. SIAscopy and VAS scores correlate well in assessing clinical response; however, the added clinical benefit of SIAscopy in vascular laser clinics remains uncertain.

Roxadustat (FG-4592) treatment for anemia in dialysis-dependent (DD) and not dialysis-dependent (NDD) chronic kidney disease patients: A systematic review and meta-analysis.

The effect of roxadustat (FG-4592) on individuals with chronic kidney diseases (CKD) patients receiving or not receiving the dialysis was unclear. The aim of this study was to evaluate the efficacy of roxadustat for the treatment of anemia in patients who are dialysis dependent (DD) or dialysis independent (NDD) CKD. We performed a systematic review of randomised controlled trials (RCTs) comparing treatment with roxadustat versus placebo or epoetin alfa up to November 2019. We investigated the efficacy of roxadustat in the levels of hemoglobin and other clinical parameters in renal anemia in patients with NDD and DD-CKD. We estimated weighted-mean difference (WMD) using random effect models. We included six RCTs comprising 1001 patients of whom 70.6 % were treated with roxadustat and 294 controls. The control group for studies of NDD-CKD patients was placebo whereas an active control of epoetin-alfa was used in studies of DD-CKD patients. Median follow-up time was 8 weeks. All trials were industry-sponsored. Overall, roxadustat increased hemoglobin levels by 1.20 g/dl (95 % CI:0.66, 1.75,P < 0.0001,I2 = 99.3 %). Hemoglobin levels increased by 1.99 g/dl in NDD-CKD patients versus placebo and 0.52 g/dl in DD-CKD patients versus epoetin-alfa. Roxadustat was associated with a decrease the levels of hepcidin by -49.3 ng/dl (-38.5 ng/dl in NDD patients versus placebo and -27.7 ng/dl in DD patients versus epoetin alfa), a decrease in ferritin of -49.7 µmol/l (-52.2 µmol/l in NDD patients versus placebo and -7.3 µmol/l in DD patients versus epoetin alfa), and increase in total iron-binding capacity of 32.2 µmol/l (14.1 µmol/l in NDD patients versus placebo and 13.6 µmol/l in DD patients versus epoetin alfa). The percentage change in the transferrin saturation levels was -2.07 % (-6%, NDD patients versus placebo, and +3.7 % in DD patients versus epoetin alfa) in anemia associated CKD patients. This review found roxadustast increases the levels of hemoglobin, serum transferrin, intestinal iron absorption, and reduces hepcidin in both NDD and DD-CKD patients. Safety data is still emerging.

Postmenopausal exogenous hormone therapy and Melanoma risk in women: A systematic review and time-response meta-analysis.

A favourable option to management symptoms during menopausal transition is menopausal hormone therapy (MHT) but relation among MHT and risk of melanoma is controversial. This study aims to identify, analyse and present the evidence surrounding post-menopausal exogenous hormone therapy and the risk for melanoma in women. A systematic searches of database was conducted in PubMed/MEDLINE, Scopus, and Cochrane without time, region, and language restrictions from inception to April 2020. The DerSimonian and Laird random-effects model was used to estimate combined risk ratio (RR) and 95% confidence intervals (CI). Subgroup analysis and time-response analysis was conducted based on the formulation of used hormone and length of hormone therapy. Combined results from fourteen studies that containing 19 arms with 1,164,077 participants which 4273 of them had melanoma cancer showed increase risk of melanoma in the hormone-treated versus control group 1.14 (95% CI 1.05-1.24, I2: 21%). The stronger and significant relationship between MHT and risk of melanoma was in participants who used oestrogen formulation (RR 1.32, 95% CI 1.17-1.49, I2 = 0%). Moreover, a significant non-linear time-response relation between MHT and melanoma was also in initial three years of MHT (Coef1 = 0.2423, p1 < 0.01). This study reveals a significant direct relationship between the MHT and risk of melanoma in postmenopausal women.

Temporal trend and regional disparity in osteoarthritis hospitalisations in Sweden 1998-2015.

AIM: This study investigated time trend and regional disparities in hospitalisations due to osteoarthritis (OA) among people aged ≥20 years in Sweden from 1998 through 2015. METHODS: National and regional data on hospital admissions with a primary diagnosis of OA were collected from the National Patient Register. The absolute and relative regional disparities were assessed using the absolute weighted mean difference from overall mean and the index of disparity. We applied joinpoint regression for temporal trend analysis of hospitalisations and the Mann-Kendall trend test for disparity measures. Changes in number of OA hospitalisations between 1998-2000 and 2013-2015 were analysed using two counterfactual scenarios. RESULTS: During 1998-2015, OA hospitalisations constituted 2.0% of all hospitalisations, with higher proportions among women (58.7%) and those aged 70-74 years (18.0%). The age-standardised rate of OA hospitalisation and its proportions from all and musculoskeletal disorders hospitalisations rose, on average, by >2.0% per year during the study period. OA hospitalisation rates rose statistically significantly in all age groups except for the youngest and oldest age groups. The proportion of hip OA from all OA hospitalisations declined, while the opposite was observed for knee OA. The relative regional disparities declined in men, and the absolute regional disparities rose among women over time. The population growth and ageing could explain only about one third of the observed increases in the absolute number of OA hospitalisations between 1998-2000 and 2013-2015. CONCLUSIONS: OA hospitalisations have increased substantially, suggesting the need to improve OA prevention and primary-care management in Sweden.

Socio-demographic and economics factors associated with suicide mortality in Iran, 2001-2010: application of a decomposition model.

BACKGROUND: Suicide is a major global health problem, especially among youth. Suicide is known to be associated with a variety of social, economic, political and religious factors, vary across geographical and cultural regions. The current study aimed to investigate the effects of socioeconomic factors on suicide mortality rate across different regions in Iran. METHODS: The data on distribution of population and socio-economic factors (such as unemployment rate, divorce rate, urbanization rate, average household expenditure etc.) at province level were obtained from the Statistical Centre of Iran and the National Organization for Civil Registration. The data on the annual number of deaths caused by suicide in each province was extracted from the published reports of the Iranian Forensic Medicine Organization. We used a decomposition model to distinguish between spatial and temporal variation in suicide mortality. RESULTS: The average rate of suicide mortality was 5.5 per 100,000 population over the study period. Across the provinces (spatial variation), suicide mortality rate was positively associated with household expenditure and the proportion of people aged 15-24 and older than 65 years and was negatively associated with the proportion of literate people. Within the provinces (temporal variation), higher divorce rate was associated with higher suicide mortality. By excluding the outlier provinces, the results showed that in addition to the proportion of people aged 15-24 and older than 65, divorce and unemployment rates were also significant predictors of spatial variation in suicide mortality while divorce rate was associated with higher suicide mortality within provinces. CONCLUSION: The findings indicate that both spatial and temporal variations in suicide mortality rates across the provinces and over time are determined by a number of socio-economic factors. The study provides information that can be of importance in developing preventive strategies.

Cost effectiveness of HIV and sexual reproductive health interventions targeting sex workers: a systematic review.

BACKGROUND: Sex workers have high incidences of HIV and other sexually transmitted diseases. Although, interventions targeting sex workers have shown to be effective, evidence on which strategies are most cost-effective is limited. This study aims to systematically review evidence on the cost-effectiveness of sexual health interventions for sex workers on a global level. It also evaluates the quality of available evidence and summarizes the drivers of cost effectiveness. METHODS: A search of published articles until May 2018 was conducted. A search strategy consisted of key words, MeSH terms and other free text terms related to economic evaluation, sex workers and sexual and reproductive health (SRH) was developed to conduct literature search on Medline, Web of Science, Econlit and the NHS Economic Evaluation Database. The quality of reporting the evidence was evaluated using the CHEERS checklist and drivers of cost-effectiveness were reported. RESULTS: Overall, 19 studies met the inclusion criteria. The majority of the studies were based in middle-income countries and only three in low-income settings. Most of the studies were conducted in Asia and only a handful in Sub-Saharan Africa and Latin America. The reviewed studies mainly evaluated the integrated interventions, i.e. interventions consisted a combination of biomedical, structural or behavioural components. All interventions, except for one, were highly cost-effective. The reporting quality of the evidence was relatively good. The strongest drivers of cost-effectiveness, reported in the studies, were HIV prevalence, number of partners per sex worker and commodity costs. Furthermore, interventions integrated into existing health programs were shown to be most cost-effective. CONCLUSION: This review found that there is limited economic evidence on HIV and SRH interventions targeting sex workers. The available evidence indicates that the majority of the HIV and SRH interventions targeting sex workers are highly cost-effective, however, more effort should be devoted to improving the quality of conducting and reporting cost-effectiveness evidence for these interventions to make them usable in policy making. This review identified potential factors that affect the cost-effectiveness and can provide useful information for policy makers when designing and implementing such interventions.

An unusual case of spleen metastasis from carcinoma ex pleomorphic adenoma of the parotid gland.

Carcinoma ex pleomorphic adenoma is a rare tumor arising from the salivary glands that spreads through direct extension, through the lymphatic vessels, and, rarely, hematogenously. When distant metastases have been found, they have been reported mainly in the lung. We present an unusual case of carcinoma ex pleomorphic adenoma of the parotid gland with splenic metastases. The patient presented with a primary carcinoma ex pleomorphic adenoma of the parotid gland and he underwent a total parotidectomy with laterocervical lymphadenectomy ipsilateral and adjuvant radiation therapy to the right parotid area. One year later, the patient showed an ipsilateral supraclavicular lymph node recurrence, treated with surgery and radiation therapy. Two more years later, the patient developed lung and splenic lesions, detected through CT and PET. He underwent splenectomy and pathologic assessment of the specimen showed metastatic carcinoma ex pleomorphic adenoma. To our knowledge, there is no reported case of a carcinoma ex pleomorphic adenoma metastasizing to the spleen. Patients treated for carcinoma ex pleomorphic adenoma should be investigated for distant metastases with a long-term follow-up examination for local and distant metastases and new splenic lesions in these patients should be investigated.

Systemic and local effect of oxidative stress on recurrent aphthous stomatitis: systematic review.

Recurrent aphthous stomatitis (RAS) is a chronic and recurrent inflammatory disease of the mouth. It is characterised by the appearance of painful ulcers in the oral mucosa. RAS is believed to be a multifactorial disease with genetic predisposition, environmental factors and alterations in the immune system. Oxidative stress, caused by an imbalance between free radicals and the antioxidant system, also appears to be involved in the pathogenesis of RAS. Several risk factors, such as smoking, iron and vitamin deficiency and anxiety, may contribute to the development of the disease. Understanding the underlying mechanisms may help in the prevention and treatment of RAS. We searched PubMed, Scopus and Web of Science databases for articles on oxidative stress in patients with RAS from 2000 to 2023. Studies analysing oxidant and antioxidant levels in the blood and saliva of RAS patients and healthy controls were selected. Of 170 potentially eligible articles, 24 met the inclusion criteria: 11 studies on blood samples, 6 on salivary samples and 7 on both blood and salivary samples. Multiple oxidative and antioxidant markers were assessed in blood and saliva samples. Overall, statistically significant differences were found between RAS patients and healthy controls for most markers. In addition, increased oxidative DNA damage was observed in patients with RAS. Patients with RAS show elevated levels of oxidative stress compared to healthy controls, with a significant increase in oxidative markers and a significant decrease in antioxidant defences in saliva and blood samples.

Exploring the complex relationships between coping strategies, locus of control and self-esteem with psychopathology: structural equation modeling with a special focus on clinical high-risk of psychosis.

BACKGROUND: Coping strategies, competence, and locus of control (LOC) beliefs are important predictors of mental health (MH). However, research into their complex interactions has produced mixed results. Our study investigated them further in the previously unexplored context of clinical high-risk (CHR) of psychosis. METHODS: We tested six alternative structural equation models in a community sample (N = 523), hypothesizing a mediating role of coping and treating CHR symptoms as (i) an additional mediator or (ii) a specific outcome. Our measurement model included two latent factors of MH: (1) psychopathology (PP), consisting of presence of mental disorders, global and psychosocial functioning, and (2) self-rated health (SRH) status. RESULTS: In the model with the best Akaike Information Criterion and the latent factors as outcome variables, maladaptive coping completely mediated the impact of maladaptive LOC on PP and SRH. Additionally, CHR symptoms partially mediated the effect of maladaptive coping on PP and SRH in the community sample, as long as sex was not entered into the model. In the clinical sample (N = 371), the model did not support a mediation by CHR symptoms, despite significant pathways with both coping and MH outcomes; further, competence beliefs directly impacted SRH. CONCLUSIONS: Coping strategies are an important intervention target for MH promotion, especially in the community. In clinical populations, interventions focusing on coping strategies may improve CHR symptoms, thus potentially supporting better MH, especially SRH. Additionally, due to their mostly cascading effects on MH, improving competence and LOC beliefs may also promote psychological well-being.

In Silico and In Vitro Analysis of IL36RN Alterations Reveals Critical Residues for the Function of the Interleukin-36 Receptor Complex.

Generalized pustular psoriasis is a potentially life-threatening skin disease, associated with IL36RN disease alleles. IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), a protein that downregulates the activity of IL-36 cytokines by blocking their receptor (IL-36R). Although generalized pustular psoriasis can be treated with IL-36R inhibitors, the structural underpinnings of the IL-36Ra/IL-36R interaction remain poorly understood. In this study, we sought to address this question by systematically investigating the effects of IL36RN sequence changes. We experimentally characterized the effects of 30 IL36RN variants on protein stability. In parallel, we used a machinelearning tool (Rhapsody) to analyze the IL-36Ra three-dimensional structure and predict the impact of all possible amino acid substitutions. This integrated approach identified 21 amino acids that are essential for IL-36Ra stability. We next investigated the effects of IL36RN changes on IL-36Ra/IL-36R binding and IL-36R signaling. Combining invitro assays and machine learning with a second program (mCSM), we identified 13 amino acids that are critical for IL-36Ra/IL36R engagement. Finally, we experimentally validated three representative predictions, further confirming the reliability of Rhapsody and mCSM. These findings shed light on the structural determinants of IL-36Ra activity, with potential to facilitate the design of new IL-36 inhibitors and aid the interpretation of IL36RN variants in diagnostic settings.

Real-World Implementation and Outcomes of Adalimumab Therapeutic Drug Monitoring in Psoriasis: A National Specialized Center Experience.

Serum adalimumab concentration is a biomarker of treatment response but therapeutic drug monitoring (TDM) is yet to be implemented in routine psoriasis care. We incorporated adalimumab TDM in a national specialized psoriasis service and evaluated it using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) implementation science framework. We undertook pre-implementation planning (validating local assays) and implementation interventions targeted to patients (pragmatic sampling at routine reviews), clinicians (introduction of a TDM protocol), and healthcare systems (adalimumab TDM as a key performance indicator). Over 5 months, 170 of 229 (74%) individuals treated with adalimumab received TDM. Clinical improvement after TDM-guided dose escalation occurred in 13 of 15 (87%) nonresponders with serum drug concentrations <8.3 µg/ml (median PASI reduction of 3.2 [interquartile range = 2.2-8.2] after 23.4 weeks) and in all nonresponders who had TDM-guided switch in biologic due to supratherapeutic drug concentrations (>8.3 µg/ml; n = 2) or positive antidrug antibody (n = 2) (PASI reduction of 7.8 [interquartile range = 7.5-12.9] after 20.0 weeks). Proactive TDM led to dose reduction in five individuals with clear skin and subtherapeutic or supratherapeutic drug concentrations; four (80%) sustained clear skin after 50 weeks (range = 42-52). Adalimumab TDM based on pragmatic serum sampling is clinically viable and may lead to patient benefit. Context-specific implementation interventions and systematic implementation assessment may bridge the biomarker research-to-practice gap.

A new diagnosis of myelodysplastic syndrome in hemochromatosis in an elderly man.

Hemochromatosis is associated with increased risk of hematological neoplasias, but studies showing hemochromatosis gene mutations in myelodysplastic syndrome (MDS) are scanty, particularly in the elderly. The onset of MDS in hemochromatosis usually occurs between 60 and 70 years of age, while cases with advanced age are very rare. We report a case of a 78- year-old man with hemochromatosis who developed refractory anemia with excess of blasts. Our case suggests that in the elderly with hemochromatosis, myelodysplasia should be considered a possible cause of anemia.

Low fat diet versus low carbohydrate diet for management of non-alcohol fatty liver disease: A systematic review.

Although there is a consensus on beneficial effects of a low calorie diet in management of non-alcoholic fatty liver disease, the optimal composition of diet has not yet been elucidated. The aim of this review is to summarize the results of current randomized controlled trials evaluating the effects of low fat diet (LFD) vs. low carbohydrate diet (LCD) on NAFLD. This is a systematic review of all the available data reported in published clinical trials up to February 2022. The methodological quality of eligible studies was assessed, and data were presented aiming specific standard measurements. A total of 15 clinical trial studies were included in this systematic review. There is an overall lack of consensus on which dietary intervention is the most beneficial for NAFLD patients. There is also an overall lack of consensus on the definition of the different restrictive diets and the percentage of macronutrient restriction recommended. It seems that low calorie diets, regardless of their fat and carbohydrate composition, are efficient for liver enzyme reduction. Both LCD and LFD have similar effects on liver enzymes change; however, this improvement tends to be more marked in LFD. All calorie restrictive dietary interventions are beneficial for reducing weight, liver fat content and liver enzymes in individuals with NAFLD. Low fat diets seem to be markedly successful in reducing transaminase levels. Further research is needed to explore diet intensity, duration and long-term outcome.

Outcomes of Locally Advanced Rectal Cancer Patients Treated with Total Neoadjuvant Treatment: A Meta-Anaysis of Randomized Controlled Trials.

BACKGROUND & AIMS: Determining outcomes using the total neoadjuvant therapy (TNT) in patients with local advanced rectal cancer is important for stratifying patients according to expected outcomes in future studies in the era of treatment combination. The present meta-analysis estimated the pathological complete response, disease-free survival, and overall survival probabilities of rectal cancer patients and identified predictors of outcomes. METHODS: Studies reporting pathological complete response rate and time-dependent outcomes (progression or death) after total neoadjuvant treatment of locally advanced rectal cancer (LARC) were identified in MEDLINE through January 2022. Three independent observers extracted data on patient populations and outcomes and combined the data using a distribution-free summary survival curve. The primary outcomes were actuarial probabilities of recurrence and survival. RESULTS: Fourteen RCTs, including 18 TNT arms, met the inclusion criteria. The pooled estimate of pathological complete response (pCR) probability was 23.6%, with moderate heterogeneity between studies. The pooled estimates of actuarial disease-free survival rate were 70.6% at 3 years and 65.4% at 5 years. The pooled estimates of actuarial survival rates were 93% at 3 years and 81.6% at 5 years. In both these outcomes, heterogeneity between studies was highly significant. CONCLUSION: This meta-analysis showed that Total Neoadjuvant Therapy is an optimal approach for LARC patients. The results provide a useful benchmark for future comparisons of the benefits of combinations of other drug families as target therapies or immunotherapies.

Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics.

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).

Peripheral quantitative computed tomography: optimization of reproducibility measures of bone density, geometry, and strength at the radius and tibia.

The aim of this study was to determine the reproducibility for in vivo measurements at the radius and tibia for trabecular and cortical parameters, bone geometry, and bone strength indices with the peripheral quantitative computed tomography (pQCT) XCT 3000. We performed 3 repeated scans within 2mo at the radius (N=18) and tibia (N=16) on healthy, premenopausal women, aged 22-35 yrs and report precision measures including %coefficient of variation (%CV) and least significant changes (LSCs). For the radius, we studied 2 sections (4% and 33% of total length) and for the tibia, 3 sections (4%, 38%, and 66% of total length). Reproducibility for radius at 33% and tibia at every site was good (%CV ranged from 0.02% to 2.19%). The precision error for the distal 4% radius was, however, higher. The reproducibility at the distal radius improved when we considered only the scans with a change of ± 10mm(2) in the radius total area at this site (%CV from 0.87% to 2.25%). This study showed that, when follow-up measurements are carefully obtained, pQCT yields excellent reproducibility at both the radius and tibia. These precision errors, in conjunction with changes in LSC for the pQCT measures, are useful for research and potential clinical applications.