A new elpistostegalian from the Late Devonian of the Canadian Arctic.

A fundamental gap in the study of the origin of limbed vertebrates lies in understanding the morphological and functional diversity of their closest relatives. Whereas analyses of the elpistostegalians Panderichthys rhombolepis, Tiktaalik roseae and Elpistostege watsoni have revealed a sequence of changes in locomotor, feeding and respiratory structures during the transition1-9, an isolated bone, a putative humerus, has controversially hinted at a wider range in form and function than now recognized10-14. Here we report the discovery of a new elpistostegalian from the Late Devonian period of the Canadian Arctic that shows surprising disparity in the group. The specimen includes partial upper and lower jaws, pharyngeal elements, a pectoral fin and scalation. This new genus is phylogenetically proximate to T. roseae and E. watsoni but evinces notable differences from both taxa and, indeed, other described tetrapodomorphs. Lacking processes, joint orientations and muscle scars indicative of appendage-based support on a hard substrate13, its pectoral fin shows specializations for swimming that are unlike those known from other sarcopterygians. This unexpected morphological and functional diversity represents a previously hidden ecological expansion, a secondary return to open water, near the origin of limbed vertebrates.

The axial skeleton of Tiktaalik roseae.

The axial columns of the earliest limbed vertebrates show distinct patterns of regionalization as compared to early tetrapodomorphs. Included among their novel features are sacral ribs, which provide linkage between the vertebral column and pelvis, contributing to body support and propulsion by the hindlimb. Data on the axial skeletons of the closest relatives of limbed vertebrates are sparce, with key features of specimens potentially covered by matrix. Therefore, it is unclear in what sequence and under what functional context specializations in the axial skeletons of tetrapods arose. Here, we describe the axial skeleton of the elpistostegalian Tiktaalik roseae and show that transformations to the axial column for head mobility, body support, and pelvic fin buttressing evolved in finned vertebrates prior to the origin of limbs. No atlas-axis complex is observed; however, an independent basioccipital-exoccipital complex suggests increased mobility at the occipital vertebral junction. While the construction of vertebrae in Tiktaalik is similar to early tetrapodomorphs, its ribs possess a specialized sacral domain. Sacral ribs are expanded and ventrally curved, indicating likely attachment to the expanded iliac blade of the pelvis by ligamentous connection. Thus, the origin of novel rib types preceded major alterations to trunk vertebrae, and linkage between pelvic fins and axial column preceded the origin of limbs. These data reveal an unexpected combination of post-cranial skeletal characters, informing hypotheses of body posture and movement in the closest relatives of limbed vertebrates.

Inhaled Fluticasone Furoate for Outpatient Treatment of Covid-19.

BACKGROUND: The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a decentralized, double-blind, randomized, placebo-controlled platform trial in the United States to assess the use of repurposed medications in outpatients with confirmed coronavirus disease 2019 (Covid-19). Nonhospitalized adults 30 years of age or older who had at least two symptoms of acute infection that had been present for no more than 7 days before enrollment were randomly assigned to receive inhaled fluticasone furoate at a dose of 200 µg once daily for 14 days or placebo. The primary outcome was the time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Key secondary outcomes included hospitalization or death by day 28 and a composite outcome of the need for an urgent-care or emergency department visit or hospitalization or death through day 28. RESULTS: Of the 1407 enrolled participants who underwent randomization, 715 were assigned to receive inhaled fluticasone furoate and 692 to receive placebo, and 656 and 621, respectively, were included in the analysis. There was no evidence that the use of fluticasone furoate resulted in a shorter time to recovery than placebo (hazard ratio, 1.01; 95% credible interval, 0.91 to 1.12; posterior probability of benefit [defined as a hazard ratio >1], 0.56). A total of 24 participants (3.7%) in the fluticasone furoate group had urgent-care or emergency department visits or were hospitalized, as compared with 13 participants (2.1%) in the placebo group (hazard ratio, 1.9; 95% credible interval, 0.8 to 3.5). Three participants in each group were hospitalized, and no deaths occurred. Adverse events were uncommon in both groups. CONCLUSIONS: Treatment with inhaled fluticasone furoate for 14 days did not result in a shorter time to recovery than placebo among outpatients with Covid-19 in the United States. (Funded by the National Center for Advancing Translational Sciences and others; ACTIV-6 ClinicalTrials.gov number, NCT04885530.).

Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

BACKGROUND: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. RESULTS: A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. CONCLUSIONS: In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).

The origin of blinking in both mudskippers and tetrapods is linked to life on land.

Blinking, the transient occlusion of the eye by one or more membranes, serves several functions including wetting, protecting, and cleaning the eye. This behavior is seen in nearly all living tetrapods and absent in other extant sarcopterygian lineages suggesting that it might have arisen during the water-to-land transition. Unfortunately, our understanding of the origin of blinking has been limited by a lack of known anatomical correlates of the behavior in the fossil record and a paucity of comparative functional studies. To understand how and why blinking originates, we leverage mudskippers (Oxudercinae), a clade of amphibious fishes that have convergently evolved blinking. Using microcomputed tomography and histology, we analyzed two mudskipper species, Periophthalmus barbarus and Periophthalmodon septemradiatus, and compared them to the fully aquatic round goby, Neogobius melanostomus. Study of gross anatomy and epithelial microstructure shows that mudskippers have not evolved novel musculature or glands to blink. Behavioral analyses show the blinks of mudskippers are functionally convergent with those of tetrapods: P. barbarus blinks more often under high-evaporation conditions to wet the eye, a blink reflex protects the eye from physical insult, and a single blink can fully clean the cornea of particulates. Thus, eye retraction in concert with a passive occlusal membrane can achieve functions associated with life on land. Osteological correlates of eye retraction are present in the earliest limbed vertebrates, suggesting blinking capability. In both mudskippers and tetrapods, therefore, the origin of this multifunctional innovation is likely explained by selection for increasingly terrestrial lifestyles.

Bayesian transition models for ordinal longitudinal outcomes.

Ordinal longitudinal outcomes are becoming common in clinical research, particularly in the context of COVID-19 clinical trials. These outcomes are information-rich and can increase the statistical efficiency of a study when analyzed in a principled manner. We present Bayesian ordinal transition models as a flexible modeling framework to analyze ordinal longitudinal outcomes. We develop the theory from first principles and provide an application using data from the Adaptive COVID-19 Treatment Trial (ACTT-1) with code examples in R. We advocate that researchers use ordinal transition models to analyze ordinal longitudinal outcomes when appropriate alongside standard methods such as time-to-event modeling.

A systematic review of case-control studies of cytokines in blister fluid and skin tissue of patients with Stevens Johnson syndrome and toxic epidermal necrolysis.

Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions characterised by keratinocyte apoptosis, necroptosis and epidermal detachment. Several cytokines and cytotoxic proteins have been shown to be elevated in the blood and skin of SJS/TEN sufferers and biologics such as intravenous immune globulin and tumour necrosis factor (TNF)-alpha inhibitors have demonstrated good therapeutic potential. The exact pathogenic model of SJS/TEN however remains elusive. This systematic review aimed to evaluate the case-control studies of cytokines and cytotoxic proteins in the blister fluid and skin of adults with Stevens Johnson syndrome and/or toxic epidermal necrolysis. This review was registered with INPLASY and conducted in accordance with the PRISMA reporting guidelines. Potential bias was assessed using the NIH criteria. Eleven articles describing results from 96 cases and 170 controls were included. Fas, Fas ligand, Interleukin (IL)-8 and B-cell lymphoma (Bcl)-2 were elevated in SJS/TEN blister fluid and skin tissue, compared with healthy controls. IL-2, IL-6, TNF-alpha, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon-gamma and matrix metalloproteinase-2 were elevated in SJS/TEN blister fluid compared with fluid sampled from lesional controls. Granulysin, IL-33, TGF-beta-1 and IL-13 were elevated in SJS/TEN skin tissue compared with lesional lichen planus tissue, as was IL-13, IFN-gamma, IL-2 and IL-5, when compared with erythema multiforme tissue. A wide array of cytokines and cytotoxic proteins are present at higher concentrations in the blister fluid and skin tissue of SJS/TEN patients compared with healthy and lesional controls. Our findings suggest that these proteins may be pathogenic, as well as possibly markers for diagnosis, disease severity and course. They may also prove to be useful therapeutic targets. More research is needed.

A new paradigm for leprosy diagnosis based on host gene expression.

Transcriptional profiling is a powerful tool to investigate and detect human diseases. In this study, we used bulk RNA-sequencing (RNA-Seq) to compare the transcriptomes in skin lesions of leprosy patients or controls affected by other dermal conditions such as granuloma annulare, a confounder for paucibacillary leprosy. We identified five genes capable of accurately distinguishing multibacillary and paucibacillary leprosy from other skin conditions. Indoleamine 2,3-dioxygenase 1 (IDO1) expression alone was highly discriminatory, followed by TLR10, BLK, CD38, and SLAMF7, whereas the HS3ST2 and CD40LG mRNA separated multi- and paucibacillary leprosy. Finally, from the main differentially expressed genes (DEG) and enriched pathways, we conclude that paucibacillary disease is characterized by epithelioid transformation and granuloma formation, with an exacerbated cellular immune response, while multibacillary leprosy features epithelial-mesenchymal transition with phagocytic and lipid biogenesis patterns in the skin. These findings will help catalyze the development of better diagnostic tools and potential host-based therapeutic interventions. Finally, our data may help elucidate host-pathogen interplay driving disease clinical manifestations.

High tissue-sodium associates with systemic inflammation and insulin resistance in obese individuals.

BACKGROUND AND AIMS: High sodium intake is associated with obesity and insulin resistance, and high extracellular sodium content may induce systemic inflammation, leading to cardiovascular disease. In this study, we aim to investigate whether high tissue sodium accumulation relates with obesity-related insulin resistance and whether the pro-inflammatory effects of excess tissue sodium accumulation may contribute to such association. METHODS AND RESULTS: In a cross-sectional study of 30 obese and 53 non-obese subjects, we measured insulin sensitivity determined as glucose disposal rate (GDR) using hyperinsulinemic euglycemic clamp, and tissue sodium content using 23Na magnetic resonance imaging. Median age was 48 years, 68% were female and 41% were African American. Median (interquartile range) BMI was 33 (31.5, 36.3) and 25 (23.5, 27.2) kg/m2 in the obese and non-obese individuals, respectively. In obese individuals, insulin sensitivity negatively correlated with muscle (r = -0.45, p = 0.01) and skin sodium (r = -0.46, p = 0.01). In interaction analysis among obese individuals, tissue sodium had a greater effect on insulin sensitivity at higher levels of high-sensitivity C-reactive protein (p-interaction = 0.03 and 0.01 for muscle and skin Na+, respectively) and interleukin-6 (p-interaction = 0.024 and 0.003 for muscle and skin Na+, respectively). In interaction analysis of the entire cohort, the association between muscle sodium and insulin sensitivity was stronger with increasing levels of serum leptin (p-interaction = 0.01). CONCLUSIONS: Higher muscle and skin sodium are associated with insulin resistance in obese patients. Whether high tissue sodium accumulation has a mechanistic role in the development of obesity-related insulin resistance through systemic inflammation and leptin dysregulation remains to be examined in future studies. CLINICALTRIALS: gov registration: NCT02236520.

Fin ray patterns at the fin-to-limb transition.

The fin-to-limb transition was marked by the origin of digits and the loss of dermal fin rays. Paleontological research into this transformation has focused on the evolution of the endoskeleton, with little attention paid to fin ray structure and function. To address this knowledge gap, we study the dermal rays of the pectoral fins of 3 key tetrapodomorph taxa-Sauripterus taylori (Rhizodontida), Eusthenopteron foordi (Tristichopteridae), and Tiktaalik roseae (Elpistostegalia)-using computed tomography. These data show several trends in the lineage leading to digited forms, including the consolidation of fin rays (e.g., reduced segmentation and branching), reduction of the fin web, and unexpectedly, the evolution of asymmetry between dorsal and ventral hemitrichia. In Eusthenopteron, dorsal rays cover the preaxial endoskeleton slightly more than ventral rays. In Tiktaalik, dorsal rays fully cover the third and fourth mesomeres, while ventral rays are restricted distal to these elements, suggesting the presence of ventralized musculature at the fin tip analogous to a fleshy "palm." Asymmetry is also observed in cross-sectional areas of dorsal and ventral rays. Eusthenopteron dorsal rays are slightly larger than ventral rays; by contrast, Tiktaalik dorsal rays can be several times larger than ventral rays, and degree of asymmetry appears to be greater at larger sizes. Analysis of extant osteichthyans suggests that cross-sectional asymmetry in the dermal rays of paired fins is plesiomorphic to crown group osteichthyans. The evolution of dermal rays in crownward stem tetrapods reflects adaptation for a fin-supported elevated posture and resistance to substrate-based loading prior to the origin of digits.

Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear. Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US. Interventions: Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. Results: Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19: A Randomized Clinical Trial.

Importance: It is unknown whether ivermectin, with a maximum targeted dose of 600 µg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19. Objective: To evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 µg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to evaluate repurposed therapies among outpatients with mild to moderate COVID-19. A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022. Interventions: Participants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 µg/kg (n = 602) daily, or placebo (n = 604) for 6 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28. Results: Among 1206 randomized participants who received study medication or placebo, the median (IQR) age was 48 (38-58) years, 713 (59.1%) were women, and 1008 (83.5%) reported receiving at least 2 SARS-CoV-2 vaccine doses. The median (IQR) time to sustained recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (posterior probability of benefit) for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.13; P = .68). Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P = .53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 µg/kg daily for 6 days, compared with placebo did not improve time to sustained recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain. Objective: To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19. Design, Setting, and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less. Interventions: Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607). Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28. Results: Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Update on the efficacy and safety of intravenous tranexamic acid in hip fracture surgery: a systematic review and meta-analysis.

AIM: The aim of this meta-analysis was to assess the safety and efficacy of tranexamic acid (TXA) in the management of hip fracture surgeries in comparison with placebo. METHODS: A systematic search was conducted from August 6, 2021. Eligible studies included randomized clinical trials and prospective studies comparing the use of intravenous TXA in patients treated for hip fractures, in comparison with placebo. Review Manager was used for the meta-analysis. RESULTS: Eighteen prospective studies including 14 RCTs met the eligibility criteria. The results favored the TXA group in the quantity of total blood loss (MD = - 196.91 mL, 95% CI - 247.59, - 146.23, I2 = 92%), intraoperative blood loss (MD = - 26.86 mL, 95% CI - 36.96, - 16.78, I2 = 62%), and rate of blood transfusion (OR 0.35, 95% CI 0.28, 0.42, I2 = 0%). TXA also exhibited higher hemoglobin level at day 1 (MD = 6.77 g/L, 95% CI 4.30, 9.24, I2 = 83%) and day 3 (MD = 7.02 g/L, 95% CI 3.30, 10.74, I2 = 82%) postoperatively. There was no significant difference found in the incidence of thromboembolic events from occurring between the two groups, such as deep vein thrombosis (OR 1.22, 95% CI 0.73, 2.02, I2 = 0%) and pulmonary embolism (OR 0.82, 95% CI 0.33, 2.05, I2 = 0%). CONCLUSION: Administration of intravenous TXA appears to reduce blood loss, rate of blood transfusions and pose no increased risk of thromboembolic events. Therefore, TXA should be considered by physicians when managing hip fracture patients.

Effects of caloric restriction and aerobic exercise on circulating cell-free mitochondrial DNA in patients with moderate to severe chronic kidney disease.

Circulating cell-free mitochondrial DNA (ccf-mtDNA) may induce systemic inflammation, a common condition in chronic kidney disease (CKD), by acting as a damage-associated molecular pattern. We hypothesized that in patients with moderate to severe CKD, aerobic exercise would reduce ccf-mtDNA levels. We performed a post hoc analysis of a multicenter randomized trial (NCT01150851) measuring plasma concentrations of ccf-mtDNA at baseline and 2 and 4 mo after aerobic exercise and caloric restriction. A total of 99 participants had baseline ccf-mtDNA, and 92 participants completed the study. The median age of the participants was 57 yr, 44% were female and 55% were male, 23% had diabetes, and 92% had hypertension. After adjusting for demographics, blood pressure, body mass index, diabetes, and estimated glomerular filtration rate, median ccf-mtDNA concentrations at baseline, 2 mo, and 4 mo were 3.62, 3.08, and 2.78 pM for the usual activity group and 2.01, 2.20, and 2.67 pM for the aerobic exercise group, respectively. A 16.1% greater increase per month in ccf-mtDNA was seen in aerobic exercise versus usual activity (P = 0.024), which was more pronounced with the combination of aerobic exercise and caloric restriction (29.5% greater increase per month). After 4 mo of intervention, ccf-mtDNA increased in the aerobic exercise group by 81.6% (95% confidence interval: 8.2-204.8, P = 0.024) compared with the usual activity group and was more marked in the aerobic exercise and caloric restriction group (181.7% increase, 95% confidence interval: 41.1-462.2, P = 0.003). There was no statistically significant correlation between markers of oxidative stress and inflammation with ccf-mtDNA. Our data indicate that aerobic exercise increased ccf-mtDNA levels in patients with moderate to severe CKD.NEW & NOTEWORTHY The effects of prolonged exercise on circulating cell-free mitochondrial DNA (ccf-mtDNA) have not been explored in patients with chronic kidney disease (CKD). We showed that 4-mo aerobic exercise is associated with an increase in plasma ccf-mtDNA levels in patients with stages 3 or 4 CKD. These changes were not associated with markers of systemic inflammation. Future studies should determine the mechanisms by which healthy lifestyle interventions influence biomarkers of inflammation and oxidative stress in patients with CKD.

Dupilumab-associated head and neck dermatitis is associated with elevated pretreatment serum Malassezia-specific IgE: a multicentre, prospective cohort study.

Dupilumab associated head and neck dermatitis is incompletely understood. This prospective multicentre prospective study identified baseline Malassezia-specific IgE as associated with the development of Dupilumab associated head and neck dermatitis.

Effect of Lowering Vt on Mortality in Acute Respiratory Distress Syndrome Varies with Respiratory System Elastance.

Rationale: If the risk of ventilator-induced lung injury in acute respiratory distress syndrome (ARDS) is causally determined by driving pressure rather than by Vt, then the effect of ventilation with lower Vt on mortality would be predicted to vary according to respiratory system elastance (Ers). Objectives: To determine whether the mortality benefit of ventilation with lower Vt varies according to Ers. Methods: In a secondary analysis of patients from five randomized trials of lower- versus higher-Vt ventilation strategies in ARDS and acute hypoxemic respiratory failure, the posterior probability of an interaction between the randomized Vt strategy and Ers on 60-day mortality was computed using Bayesian multivariable logistic regression. Measurements and Main Results: Of 1,096 patients available for analysis, 416 (38%) died by Day 60. The posterior probability that the mortality benefit from lower-Vt ventilation strategies varied with Ers was 93% (posterior median interaction odds ratio, 0.80 per cm H2O/[ml/kg]; 90% credible interval, 0.63-1.02). Ers was classified as low (<2 cm H2O/[ml/kg], n = 321, 32%), intermediate (2-3 cm H2O/[ml/kg], n = 475, 46%), and high (>3 cm H2O/[ml/kg], n = 224, 22%). In these groups, the posterior probabilities of an absolute risk reduction in mortality ≥ 1% were 55%, 82%, and 92%, respectively. The posterior probabilities of an absolute risk reduction ≥ 5% were 29%, 58%, and 82%, respectively. Conclusions: The mortality benefit of ventilation with lower Vt in ARDS varies according to elastance, suggesting that lung-protective ventilation strategies should primarily target driving pressure rather than Vt.

IncobotulinimtoxinA (Xeomin) for the treatment of adductor laryngeal dystonia: A prospective, open-label clinical trial.

OBJECTIVES: Demonstrate an understanding of incobotulinumtoxinA efficacy in the treatment of adductor spasmodic dysphonia (SD). Understand that incobotulinumtoxinA can successfully be used as an alternative to onabotulinumtoxinA and for secondary non-responders. METHODS: We conducted a prospective open-label trial from 2016 until 2019 regarding the use of incobotulinimtoxinA for the treatment of adductor spasmodic dysphonia. Exclusion criteria included pregnant/nursing women, botulinum toxin for other indications, known allergy, neuromuscular or systemic diseases, use of aminoglycoside antibiotics, substance abuse, litigation regarding prior therapy, or other confounding conditions. Sixty-four injection sessions with completed with sixteen patients who were enrolled in the study and underwent EMG-guided incobotulinumtoxinA injections to the thyroarytenoid (TA) muscle using a hollow monopolar Teflon-coated needle via a trans-cricothyroid membrane approach. Dosages to each TA muscle were recorded and patients completed a Voice Handicap Index-10 (VHI-10), a validated worksheet regarding their perceived percent of normal function (PNF) following treatment, and a side effect profile. Outcomes were analyzed using the paired t-test. RESULTS: For primary transitioners to incobotulinimtoxinA, VHI-10 scores and best percent normal function did not significantly change. For non-responders, VHI-10 decreased from 32.5 on Botox to 19.5 on incobotulinimtoxinA and best PNF increased from 37.6 to 90 %, which was statistically significant. Transient side effects included breathiness. CONCLUSIONS: Our study demonstrates that incobotulinimtoxinA may be used successfully for adductor SD either as first line treatment or in secondary non-responders to onabotulinumtoxinA.

Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown. Objective: To evaluate the efficacy of ivermectin, 400 µg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19. Design, Setting, and Participants: ACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 93 sites in the US. Interventions: Participants were randomized to receive ivermectin, 400 µg/kg (n = 817), daily for 3 days or placebo (n = 774). Main Outcomes and Measures: Time to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28. Results: Among 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5]). Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Perioperative Blood Transfusions Are Associated With Worse Overall Survival But Not Disease-Free Survival After Curative Rectal Cancer Resection: A Propensity Score-Matched Analysis.

BACKGROUND: The effects of blood transfusions on oncologic outcomes after surgery remain inconclusive. Thus, we examined the association between receiving a perioperative blood transfusion and oncologic outcomes in patients undergoing curative rectal cancer resection. OBJECTIVE: The purpose of this study was to assess the association between receiving a perioperative blood transfusion with disease-free and overall survival in patients undergoing curative resection of clinical stage I to III rectal cancer. We hypothesized that blood transfusion is associated with worse disease-free and overall survival in this patient cohort. DESIGN: This was a retrospective cohort study using a propensity score-matched analysis. SETTINGS: The study involved 6 tertiary academic medical centers in the United States contributing to the United States Rectal Cancer Consortium. PATIENTS: Patients who underwent curative resection for rectal cancer from 2010 to 2018 were included. MAIN OUTCOME MEASURES: The primary outcome was disease-free survival. The secondary outcomes were overall survival, intensive care unit length of stay, hospital length of stay, surgical site infection, and readmission. RESULTS: Of the 924 patients eligible for matching, 312 patients were matched, including 100 patients who received a transfusion and 212 who did not. In a propensity score-matched analysis, receiving a perioperative blood transfusion was not associated with worse 5-year disease-free survival (transfused, 78%; not transfused, 83%; p = 0.32) but was associated with worse 5-year overall survival (transfused 65% vs not transfused 86%; p < 0.001) and increased hospital length of stay (transfused, 9.9 d; not transfused, 7.6 d; p = 0.001). LIMITATIONS: Despite propensity matching, confounding may remain. Propensity matching may limit the power to detect a difference in disease-free survival. CONCLUSIONS: Receiving a perioperative blood transfusion is not associated with worse disease-free survival but is associated with worse overall survival. Such findings are important for clinicians and patients to understand when considering perioperative blood transfusions. See Video Abstract at http://links.lww.com/DCR/B531. LAS TRANSFUSIONES DE SANGRE PERIOPERATORIAS SE ASOCIAN CON UNA PEOR SOBREVIDA GLOBAL, PERO NO CON LA SOBREVIDA LIBRE DE ENFERMEDAD POSTERIOR A LA RESECCIN CURATIVA DEL CNCER DE RECTO UN PUNTAJE DE PROPENSIN POR ANLISIS DE CONCORDANCIA: ANTECEDENTES:El impacto de las transfusiones de sangre en los resultados oncológicos posteriores a la cirugía no son concluyentes. Por lo anterior, estudiamos la asociación entre recibir una transfusión de sangre perioperatoria y los resultados oncológicos en pacientes llevados a resección curativa de cáncer de recto.OBJETIVO:El propósito de este estudio fue evaluar la asociación entre recibir una transfusión de sangre perioperatoria con la sobrevida libre de enfermedad y la sobrevida general en pacientes llevados a resección curativa de cáncer de recto en estadio clínico I-III. Nuestra hipótesis es que la transfusión de sangre se asocia con una peor sobrevida global y libre de enfermedad en esta cohorte de pacientes.DISEÑO:Es un estudio de cohorte retrospectivo que utilizó un puntaje de propensión por análisis de concordancia.AMBITO:El estudio se realizó en seis centros médicos académicos de tercer nivel en los Estados Unidos que contribuían al Consorcio de Cáncer de Recto de los Estados Unidos.PACIENTES:Se incluyeron pacientes que fueron llevados a resección curativa por cáncer de recto entre 2010 y 2018.PRINCIPALES VARIABLES EVALUADAS:El objeitvo principal fue la sobrevida libre de enfermedad. Los objetivos secundarios fueron la sobrevida global, el tiempo de estancia en la unidad de cuidados intensivos, el tiempo de la estancia hospitalaria, la infección del sitio quirúrgico y el reingreso.RESULTADOS:De los 924 pacientes elegibles para el emparejamiento, se emparejaron 312 pacientes, incluidos 100 pacientes que recibieron una transfusión y 212 que no. En el puntaje de propensión por análisis de concordancia, recibir una transfusión de sangre perioperatoria no se asoció con una peor sobrevida libre de enfermedad a 5 años (TRANSFUSIÓN 78%; NO TRANSFUSIÓN 83%; p = 0,32), pero se asoció con una peor sobrevida global a 5 años (TRANSFUSION 65% vs NO TRANSFUSION 86%; p <0,001) y aumento de la estancia hospitalaria (TRANSFUSIÓN 9,9 días; NO TRANSFUSION 7,6 días; p = 0,001).LIMITACIONES:A pesar de la concordancia de propensión, pueden existir desviaciones. El emparejamiento de propensión puede limitar el poder para detectar una diferencia en la sobrevida libre de enfermedad.CONCLUSIONES:Recibir una transfusión de sangre perioperatoria no se asocia con una peor sobrevida libre de enfermedad, pero sí con una peor sobrevida global. Es importante que los médicos y los pacientes comprendan estos hallazgos al considerar las transfusiones de sangre perioperatorias. Consulte Video Resumen en http://links.lww.com/DCR/B531. (Traducción-Dr Lisbeth Alarcon-Bernes).