Spillover of highly pathogenic avian influenza H5N1 virus to dairy cattle.

Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b virus has caused the death of millions of domestic birds and thousands of wild birds in the U.S. since January, 20221-4 Throughout this outbreak, spillovers to mammals have been frequently documented5-12. We report spillover of HPAI H5N1 virus in dairy cattle herds across several states in the U.S. The affected cows displayed clinical signs encompassing decreased feed intake, altered fecal consistency, respiratory distress, and decreased milk production with abnormal milk. Infectious virus and viral RNA were consistently detected in milk from affected cows. Viral distribution in tissues via immunohistochemistry and in situ hybridization revealed a distinct tropism of the virus for the epithelial cells lining the alveoli of the mammary gland in cows. Whole viral genome sequences recovered from dairy cows, birds, domestic cats, and a raccoon from affected farms indicated multidirectional interspecies transmissions. Epidemiologic and genomic data revealed efficient cow-to-cow transmission after apparently healthy cows from an affected farm were transported to a premise in a different state. These results demonstrate the transmission of HPAI H5N1 clade 2.3.4.4b virus at a non-traditional interface underscoring the ability of the virus to cross species barriers.

Localization of lattice dynamics in low-angle twisted bilayer graphene.

Twisted bilayer graphene is created by slightly rotating the two crystal networks in bilayer graphene with respect to each other. For small twist angles, the material undergoes a self-organized lattice reconstruction, leading to the formation of a periodically repeated domain1-3. The resulting superlattice modulates the vibrational3,4 and electronic5,6 structures within the material, leading to changes in the behaviour of electron-phonon coupling7,8 and to the observation of strong correlations and superconductivity9. However, accessing these modulations and understanding the related effects are challenging, because the modulations are too small for experimental techniques to accurately resolve the relevant energy levels and too large for theoretical models to properly describe the localized effects. Here we report hyperspectral optical images, generated by a nano-Raman spectroscope10, of the crystal superlattice in reconstructed (low-angle) twisted bilayer graphene. Observations of the crystallographic structure with visible light are made possible by the nano-Raman technique, which reveals the localization of lattice dynamics, with the presence of strain solitons and topological points1 causing detectable spectral variations. The results are rationalized by an atomistic model that enables evaluation of the local density of the electronic and vibrational states of the superlattice. This evaluation highlights the relevance of solitons and topological points for the vibrational and electronic properties of the structures, particularly for small twist angles. Our results are an important step towards understanding phonon-related effects at atomic and nanometric scales, such as Jahn-Teller effects11 and electronic Cooper pairing12-14, and may help to improve device characterization15 in the context of the rapidly developing field of twistronics16.

Early Treatment with Pegylated Interferon Lambda for Covid-19.

BACKGROUND: The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 µg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization. RESULTS: A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19-related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424.).

White-tailed deer (Odocoileus virginianus) may serve as a wildlife reservoir for nearly extinct SARS-CoV-2 variants of concern.

The spillover of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to white-tailed deer (WTD) and its ability to transmit from deer to deer raised concerns about the role of WTD in the epidemiology and ecology of the virus. Here, we present a comprehensive cross-sectional study assessing the prevalence, genetic diversity, and evolution of SARS-CoV-2 in WTD in the State of New York (NY). A total of 5,462 retropharyngeal lymph node samples collected from free-ranging hunter-harvested WTD during the hunting seasons of 2020 (Season 1, September to December 2020, n = 2,700) and 2021 (Season 2, September to December 2021, n = 2,762) were tested by SARS-CoV-2 real-time RT-PCR (rRT-PCR). SARS-CoV-2 RNA was detected in 17 samples (0.6%) from Season 1 and in 583 samples (21.1%) from Season 2. Hotspots of infection were identified in multiple confined geographic areas of NY. Sequence analysis of SARS-CoV-2 genomes from 164 samples demonstrated the presence of multiple SARS-CoV-2 lineages and the cocirculation of three major variants of concern (VOCs) (Alpha, Gamma, and Delta) in WTD. Our analysis suggests the occurrence of multiple spillover events (human to deer) of the Alpha and Delta lineages with subsequent deer-to-deer transmission and adaptation of the viruses. Detection of Alpha and Gamma variants in WTD long after their broad circulation in humans in NY suggests that WTD may serve as a wildlife reservoir for VOCs no longer circulating in humans. Thus, implementation of continuous surveillance programs to monitor SARS-CoV-2 dynamics in WTD is warranted, and measures to minimize virus transmission between humans and animals are urgently needed.

Effect of Early Treatment with Ivermectin among Patients with Covid-19.

BACKGROUND: The efficacy of ivermectin in preventing hospitalization or extended observation in an emergency setting among outpatients with acutely symptomatic coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unclear. METHODS: We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2-positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 µg per kilogram of body weight) once daily for 3 days or placebo. (The trial also involved other interventions that are not reported here.) The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization. RESULTS: A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16). Of the 211 primary-outcome events, 171 (81.0%) were hospital admissions. Findings were similar to the primary analysis in a modified intention-to-treat analysis that included only patients who received at least one dose of ivermectin or placebo (relative risk, 0.89; 95% Bayesian credible interval, 0.69 to 1.15) and in a per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen (relative risk, 0.94; 95% Bayesian credible interval, 0.67 to 1.35). There were no significant effects of ivermectin use on secondary outcomes or adverse events. CONCLUSIONS: Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19. (Funded by FastGrants and the Rainwater Charitable Foundation; TOGETHER ClinicalTrials.gov number, NCT04727424.).

Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

From Deer-to-Deer: SARS-CoV-2 is efficiently transmitted and presents broad tissue tropism and replication sites in white-tailed deer.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) in humans, has a broad host range, and is able to infect domestic and wild animal species. Notably, white-tailed deer (WTD, Odocoileus virginianus), the most widely distributed cervid species in the Americas, were shown to be highly susceptible to SARS-CoV-2 in challenge studies and reported natural infection/exposure rates approaching 30-40% in free-ranging WTD in the U.S. Thus, understanding the infection and transmission dynamics of SARS-CoV-2 in WTD is critical to prevent future zoonotic transmission to humans, at the human-WTD interface during hunting or venison farming, and for implementation of effective disease control measures. Here, we demonstrated that following intranasal inoculation with SARS-CoV-2 B.1 lineage, WTD fawns (~8-month-old) shed infectious virus up to day 5 post-inoculation (pi), with high viral loads shed in nasal and oral secretions. This resulted in efficient deer-to-deer transmission on day 3 pi. Consistent a with lack of infectious SARS-CoV-2 shedding after day 5 pi, no transmission was observed to contact animals added on days 6 and 9 pi. We have also investigated the tropism and sites of SARS-CoV-2 replication in adult WTD (3-4 years of age). Infectious virus was detected up to day 6 pi in nasal secretions, and from various respiratory-, lymphoid-, and central nervous system tissues, indicating broad tissue tropism and multiple sites of virus replication. The study provides important insights on the infection and transmission dynamics of SARS-CoV-2 in WTD, a wild animal species that is highly susceptible to infection and with the potential to become a reservoir for the virus in the field.

The impact of revascularization strategy on clinical failure, hemodynamic failure, and chronic limb-threatening ischemia symptoms in the BEST-CLI Trial.

OBJECTIVE: Sustained clinical and hemodynamic benefit after revascularization for chronic limb-threatening ischemia (CLTI) is needed to resolve symptoms and prevent limb loss. We sought to compare rates of clinical and hemodynamic failure as well as resolution of initial and prevention of recurrent CLTI after endovascular (ENDO) vs bypass (OPEN) revascularization in the Best-Endovascular-versus-best-Surgical-Therapy-in-patients-with-CLTI (BEST-CLI) trial. METHODS: As planned secondary analyses of the BEST-CLI trial, we examined the rates of (1) clinical failure (a composite of all-cause death, above-ankle amputation, major reintervention, and degradation of WIfI stage); (2) hemodynamic failure (a composite of above-ankle amputation, major and minor reintervention to maintain index limb patency, failure to an initial increase or a subsequent decrease in ankle brachial index of 0.15 or toe brachial index of 0.10, and radiographic evidence of treatment stenosis or occlusion); (3) time to resolution of presenting CLTI symptoms; and (4) incidence of recurrent CLTI. Time-to-event analyses were performed by intention-to-treat assignment in both trial cohorts (cohort 1: suitable single segment great saphenous vein [SSGSV], N = 1434; cohort 2: lacking suitable SSGSV, N = 396), and multivariate stratified Cox regression models were created. RESULTS: In cohort 1, there was a significant difference in time to clinical failure (log-rank P < .001), hemodynamic failure (log-rank P < .001), and resolution of presenting symptoms (log-rank P = .009) in favor of OPEN. In cohort 2, there was a significantly lower rate of hemodynamic failure (log-rank P = .006) favoring OPEN, and no significant difference in time to clinical failure or resolution of presenting symptoms. Multivariate analysis revealed that assignment to OPEN was associated with a significantly lower risk of clinical and hemodynamic failure in both cohorts and a significantly higher likelihood of resolving initial and preventing recurrent CLTI symptoms in cohort 1, including after adjustment for key baseline patient covariates (end-stage renal disease [ESRD], prior revascularization, smoking, diabetes, age >80 years, WIfI stage, tissue loss, and infrapopliteal disease). Factors independently associated with clinical failure included age >80 years in cohort 1 and ESRD across both cohorts. ESRD was associated with hemodynamic failure in cohort 1. Factors associated with slower resolution of presenting symptoms included diabetes in cohort 1 and WIfI stage in cohort 2. CONCLUSIONS: Durable clinical and hemodynamic benefit after revascularization for CLTI is important to avoid persistent and recurrent CLTI, reinterventions, and limb loss. When compared with ENDO, initial treatment with OPEN surgical bypass, particularly with available saphenous vein, is associated with improved clinical and hemodynamic outcomes and enhanced resolution of CLTI symptoms.

Tuning Molecular Motion Enhances Intrinsic Fluorescence in Peptide Amphiphile Nanofibers.

Peptide amphiphiles (PAs) are highly tunable molecules that were recently found to exhibit aggregation-induced emission (AIE) when they self-assemble into nanofibers. Here, we leverage decades of molecular design and self-assembly study of PAs to strategically tune their molecular motion within nanofibers to enhance AIE, making them a highly useful platform for applications such as sensing, bioimaging, or materials property characterization. Since AIE increases when aggregated molecules are rigidly and closely packed, we altered the four most closely packed amino acids nearest to the hydrophobic core by varying the order and composition of glycine, alanine, and valine pairs. Of the six PA designs studied, C16VVAAK2 had the highest quantum yield at 0.17, which is a more than 10-fold increase from other PA designs including the very similar C16AAVVK2, highlighting the importance of precise amino acid placement to anchor rigidity closest to the core. We also altered temperature to increase AIE. C16VVAAK2 exhibited an additional 4-fold increase in maximum fluorescence intensity when the temperature was raised from 5 to 65 °C. As the temperature increased, the secondary structure transitioned from ß-sheet to random coil, indicating that further packing an already aligned molecular system makes it even more readily able to transfer energy between the electron-rich amides. This work both unveils a highly fluorescent AIE PA system design and sheds insights into the molecular orientation and packing design traits that can significantly enhance AIE in self-assembling systems.

Individualized telehealth home programme for children with cerebral palsy during the COVID-19 pandemic.

AIM: To analyse the effects of an individualized telehealth home programme on the performance of functional goals of children and adolescents with cerebral palsy (CP) during the COVID-19 pandemic. METHOD: A prospective single-group intervention study with children/adolescents with CP (n = 144; median age = 92 months [Q1 = 44.0, Q3 = 148.8]; 74 males, 70 females), representing all Gross Motor Function Classification System (GMFCS) levels participated in a 4-month home programme in Brazil. An interdisciplinary team encouraged families to choose a functional goal to be trained. The Canadian Occupational Performance Measure (COPM) was used at pre-intervention (T1), post-intervention (T2), and 3-month follow-up (T3). The differences in COPM scores at T1, T2, and T3 were evaluated using Friedman's test. The effect size was calculated using Cohen's d. Univariate analysis was included. RESULTS: Significant improvements were observed after the intervention, with maintenance of scores after 3 months (p < 0.001, dperformance = 1.33; dsatisfaction = 1.31). None of the tested variables (child's abilities, age, caregiver's educational level, perception of family-centredness, and type of goal) were significantly related to the change scores. INTERPRETATION: The individualized remote telehealth home programme can be a potential intervention, especially for children with CP classified in GMFCS levels IV and V. Also, this intervention provided a possible solution to help some children and their families in performing prioritized functional goals during the pandemic period.

Literature reviews and global neurosurgery: a powerful way of doing more with less.

INTRODUCTION: Neurosurgery is an intensely competitive field. With the USMLE Step 1 transitioning to a pass/fail system, research has become a crucial component of the neurosurgery residency application process. This emphasis on research is particularly critical for international medical graduates (IMGs), who often face greater challenges compared to their U.S. counterparts. IMGs typically need more publications and higher H-indices to stand out. However, accessing quality research opportunities is significantly more difficult for those from low- and middle-income countries. This mini-review aims to provide a new perspective for IMGs, demonstrating that publishing in prestigious neurosurgical journals is possible even with limited resources. METHODS: We searched Scopus and reviewed Brazilian publications from 2014 to 2023 in Neurosurgery and the Journal of Neurosurgery. We extracted the methodological designs of the studies and the graduation status of the first authors. RESULTS: In 2023-2024, four Brazilian medical students published systematic reviews in major neurosurgical journals as first authors, marking a revolutionary change in the Brazilian neurosurgical landscape not seen in the past decade. These achievements illustrate that high-impact publications are attainable without geographical proximity, substantial financial support, or access to extensive institutional databases. Letters to the editor also represented a considerable Brazilian contribution. CONCLUSION: Literature reviews and letters to the editor are accessible methods for IMGs to engage in impactful research. IMGs can maximize their abilities and significantly contribute to neurosurgery by embracing literature reviews and meta-analyses. These approaches can open doors for those without other avenues to begin their research careers.

Maxillary artery utilization in subcranial-intracranial bypass procedures: a comprehensive systematic review and pooled analysis.

The utilization of the internal maxillary artery (IMAX) in subcranial-intracranial bypass for revascularization in complex aneurysms, tumors, or refractory ischemia shows promise. However, robust evidence concerning its outcomes is lacking. Hence, the authors embarked on a systematic review with pooled analysis to elucidate the efficacy of this approach. We systematically searched PubMed, Embase, and Web of Science databases following PRISMA guidelines. Included articles used the IMAX as a donor vessel for revascularizing an intracranial area and reported at least one of the following outcomes: patency, complications, or clinical data. Favorable outcomes were defined as the absence of neurologic deficits or improvement in the baseline condition. Complications were considered any adverse event directly related to the procedure. Out of 418 retrieved articles, 26 were included, involving 183 patients. Among them, 119 had aneurysms, 41 experienced ischemic strokes (transient or not), 2 had arterial occlusions, and 3 had neoplasia. Furthermore, 91.8% of bypasses used radial artery grafts, and 87.9% revascularized the middle cerebral artery territory. The median average follow-up period was 12 months (0.3-53.1). The post-operation patency rate was 99% (95% CI: 97-100%; I2=0%), while the patency rate at follow-up was 82% (95% CI: 68-96%; I2=77%). Complications occurred in 21% of cases (95% CI: 9-32%; I2=58%), with no significant procedure-related mortality in 0% (95% CI: 0-2%; I2=0%). Favorable outcomes were observed in 88% of patients (95% CI: 81-96%; I2=0%), and only 3% experienced ischemia (95% CI: 0-6%; I2=0%). The subcranial-intracranial bypass with the IMAX shows excellent postoperative patency and considerable favorable clinical outcomes. While complications exist, the procedure carries a minimal risk of mortality. However, long-term patency presents heterogeneous findings, warranting additional research.

STA-MCA Double-Barrel Bypass: A Systematic Review of Technique and Single-Arm Meta-Analysis of Outcomes.

INTRODUCTION: Conventionally, one branch of the superficial temporal artery (STA) is utilized to revascularize the middle cerebral artery (MCA). However, there is the possibility of utilizing both branches of the STA when performing the bypass, characterizing the double-barrel (DB) STA-MCA bypass. Notably, a lack of studies evaluating this technique led the authors to conduct a systematic review and single-arm meta-analysis. METHODS: PubMed, Embase and Web of Science were searched systematically for publications of DB-STA-MCA bypass on November 1st, 2023. The findings were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Case reports were not included for statistical analysis purposes. RESULTS: The review included 408 patients and 534 bypasses from 34 studies. The main etiology was Moyamoya disease (64.6%), followed by cerebral ischemia (22.2%) and aneurysms (12.5%). The median of the mean follow-ups of each study was 12.8 months (range 1.5-87.9). The postoperative patency was 100%. The follow-up patency was 98% (95% CI: 96%-100%; I2 = 0%). The procedure-related mortality was 0% (95% CI: 0%-1%; I2 = 0%). Aneurysms obtained 87% (95% CI: 72%-100%; I2 = 4%) of good clinical outcomes, while Moyamoya disease yielded a rate of 70% (95% CI: 10%-100%; I2 = 97%). Ischemic complications occurred at a rate of 6% (95% CI: 2%-11%; I2 = 36%), while hemorrhagic occurred at 6% (95% CI: 1%-11%; I2 = 56%). Hyperperfusion syndrome rate was calculated as 18% (7%-30%; I2 = 55%) for Moyamoya disease. CONCLUSIONS: The procedure appears to be safe, with excellent patency rates. The clinical efficacy for ischemic and Moyamoya diseases warrants further standardized robust investigation with a broader number of patients, and aneurysm studies are required to enhance sample sizes. The main complication for the Moyamoya subgroup is hyperperfusion syndrome.

Fractal structures in the chaotic advection of passive scalars in leaky planar hydrodynamical flows.

The advection of passive scalars in time-independent two-dimensional incompressible fluid flows is an integrable Hamiltonian system. It becomes non-integrable if the corresponding stream function depends explicitly on time, allowing the possibility of chaotic advection of particles. We consider for a specific model (double gyre flow), a given number of exits through which advected particles can leak, without disturbing the flow itself. We investigate fractal escape basins in this problem and characterize fractality by computing the uncertainty exponent and basin entropy. Furthermore, we observe the presence of basin boundaries with points exhibiting the Wada property, i.e., boundary points that separate three or more escape basins.

Spatially Coherent Tip-Enhanced Raman Spectroscopy Measurements of Electron-Phonon Interaction in a Graphene Device.

Coherence length (Lc) of the Raman scattering process in graphene as a function of Fermi energy is obtained with spatially coherent tip-enhanced Raman spectroscopy. Lc decreases when the Fermi energy is moved into the neutrality point, consistent with the concept of the Kohn anomaly within a ballistic transport regime. Since the Raman scattering involves electrons and phonons, the observed results can be rationalized either as due to unusually large variation of the longitudinal optical phonon group velocity vg, reaching twice the value for the longitudinal acoustic phonon, or due to changes in the electron energy uncertainty, both properties being important for optical and transport phenomena that might not be observable by any other technique.

Antioxidants in Photoaging: From Molecular Insights to Clinical Applications.

Photoaging (PA) is considered a silent disease affecting millions of people globally and is defined as skin damage due to prolonged exposure to ultraviolet radiation (UVR) from the sun. Physiologically, the skin is in a state of renewal and synthesis of components of the extracellular matrix (ECM). However, exposure to UVR affects the production of the ECM, and the functioning and response of skin cells to UVR begins to change, thus expressing clinical and phenotypic characteristics of PA. The primary mechanisms involved in PA are direct damage to the DNA of skin cells, increases in oxidative stress, the activation of cell signaling pathways responsible for the loss of skin integrity, and cytotoxicity. The medical and scientific community has been researching new therapeutic tools that counteract PA, considering that the damage caused by UVR exceeds the antioxidant defense mechanisms of the skin. Thus, in recent years, certain nutraceuticals and phytochemicals have been found to exhibit potential antioxidant and photoprotective effects. Therefore, the main objective of this review is to elucidate the molecular bases of PA and the latest pharmaceutical industry findings on antioxidant treatment against the progression of PA.

The Omicron Variant BA.1.1 Presents a Lower Pathogenicity than B.1 D614G and Delta Variants in a Feline Model of SARS-CoV-2 Infection.

Omicron (B.1.1.529) is the most recent SARS-CoV-2 variant of concern, which emerged in late 2021 and rapidly achieved global predominance by early 2022. In this study, we compared the infection dynamics, tissue tropism, and pathogenesis and pathogenicity of SARS-CoV-2 D614G (B.1), Delta (B.1.617.2), and Omicron BA.1.1 (B.1.1.529) variants in a highly susceptible feline model of infection. Although D614G- and Delta-inoculated cats became lethargic and showed increased body temperatures between days 1 and 3 postinfection (pi), Omicron-inoculated cats remained subclinical and, similar to control animals, gained weight throughout the 14-day experimental period. Intranasal inoculation of cats with D614G- and the Delta variants resulted in high infectious virus shedding in nasal secretions (up to 6.3 log10 TCID50.Ml-1), whereas strikingly lower level of viruses shedding (<3.1 log10 TCID50.Ml-1) was observed in Omicron-inoculated animals. In addition, tissue distribution of the Omicron variant was markedly reduced in comparison to the D614G and Delta variants, as evidenced by lower in situ viral RNA detection, in situ viral immunofluorescence staining, and viral loads in tissues on days 3, 5, and 14 pi. Nasal turbinate, trachea, and lung were the main-but not the only-sites of replication for all three viral variants. However, only scarce virus staining and lower viral titers suggest lower levels of viral replication in tissues from Omicron-infected animals. Notably, while D614G- and Delta-inoculated cats presented pneumonia, histologic examination of the lungs from Omicron-infected cats revealed mild to modest inflammation. Together, these results demonstrate that the Omicron variant BA.1.1 is less pathogenic than D614G and Delta variants in a highly susceptible feline model. IMPORTANCE The SARS-CoV-2 Omicron (B.1.1.529) variant of concern emerged in South Africa late in 2021 and rapidly spread across the world causing a significant increase in the number of infections. Importantly, this variant was also associated with an increased risk of reinfections. However, the number of hospitalizations and deaths due to COVID-19 did not follow the same trends. These early observations suggested effective protection conferred by immunizations and/or overall lower virulence of the highly mutated variant virus. In this study we present novel evidence demonstrating that the Omicron BA.1.1 variant of concern presents a lower pathogenicity when compared to D614G- or Delta variants in cats. Clinical, virological, and pathological evaluations revealed lower disease severity, viral replication, and lung pathology in Omicron-infected cats when compared with D614G and Delta variant inoculated animals, confirming that Omicron BA.1.1 is less pathogenic in a highly susceptible feline model of infection.

Baseline modern medical management in the BEST-CLI trial.

OBJECTIVES: The use of optimal medical therapy (OMT) in patients with chronic limb-threatening ischemia (CLTI) has not been well-studied. The Best Endovascular vs Best Surgical Therapy in Patients with CLTI study (BEST-CLI) is a multicenter, randomized, controlled trial sponsored by the National Institutes of Health comparing revascularization strategies in patients with CLTI. We evaluated the use of guideline-based OMT among patients with CLTI at the time of their enrollment into the trial. METHODS: A multidisciplinary committee defined OMT criteria related to blood pressure and diabetic management, lipid-lowering and antiplatelet medication use, and smoking status for patients enrolled in BEST-CLI. Status reports indicating adherence to OMT were provided to participating sites at regular intervals. Baseline demographic characteristics, comorbid medical conditions, and use of OMT at trial entry were evaluated for all randomized patients. A linear regression model was used to identify the relationship of predictors to the use of OMT. RESULTS: At the time of randomization (n = 1830 total enrolled), 87% of patients in BEST-CLI had hypertension, 69% had diabetes, 73% had hyperlipidemia, and 35% were currently smoking. Adherence to four OMT components (controlled blood pressure, not currently smoking, use of one lipid-lowering medication, and use of an antiplatelet agent) was modest. Only 25% of patients met all four OMT criteria; 38% met three, 24% met two, 11% met only one, and 2% met none. Age ≥80 years, coronary artery disease, diabetes, and Hispanic ethnicity were positively associated, whereas Black race was negatively associated, with the use of OMT. CONCLUSIONS: A significant proportion of patients in BEST-CLI did not meet OMT guideline-based recommendations at time of entry. These data suggest a persistent major gap in the medical management of patients with advanced peripheral atherosclerosis and CLTI. Changes in OMT adherence over the course of the trial and their impact on clinical outcomes and quality of life will be assessed in future analyses.

Relationship between WIfI stage and quality of life at revascularization in the BEST-CLI trial.

OBJECTIVE: The WIfI (Wound, Ischemia, foot Infection) stage measures the extent of wounds, ischemia, and foot infection in patients with chronic limb threatening ischemia (CLTI) and has been associated with the risk of major amputation. Patients with CLTI have impaired health-related quality of life (HRQoL), which can be multifactorial. We hypothesized that the severity of the limb threat (WIfI stage) would be associated with poor HRQoL among patients with CLTI presenting for revascularization. METHODS: The dataset of the BEST-CLI (best endovascular versus best surgical therapy in patients with CLTI) trial, a prospective, randomized trial comparing open and endovascular revascularization strategies, was queried for HRQoL assessments at patient enrollment. The HRQoL assessments included (1) Vascular Quality of Life; (2) 12-item short form survey (SF-12), containing the utility index score (short-form six-dimension R2 utility index, incorporating physical, emotional, and mental well-being) and mental and physical components; and (3) the EQ-5D. Multivariable regression analysis was used to identify the independent associations with the baseline HRQoL assessments. RESULTS: A total of 1568 patients with complete WIfI data were analyzed, of whom 71.5% were men. The WIfI distribution was 35.5% with stage 4, 29.6% with stage 3, 28.6% with stage 2, and 6.3% with stage 1. Patients presenting with WIfI stage 4, compared with stage 1 to 3, were more often men (74.9% vs 69.6%) and current smokers (25.4% vs. 17.6%), had had end-stage renal disease (13.3% vs 8.5%) and diabetes (83.6% vs 60.2%), were not independently ambulatory (56.8% vs 38.5%), and had had higher median morbidity scores (4 vs 3; P < .05 for all). On multivariable analysis, WIfI stage 4, compared with stage 1 to 3, was associated with lower SF-12 mental component scale scores (estimate, -2.43; 95% confidence interval, -3.73 to -1.13; P < .001) and short-form six-dimension R2 utility index scores (estimate, -0.02; 95% confidence interval, -0.03 to 0.001; P = .04). The WIfI stage was not independently associated with the baseline Vascular Quality of Life, SF-12 physical component scale, or EQ-5D assessments. CONCLUSIONS: WIfI stage was independently associated with poorer quality of life because of mental, rather than physical, health for patients with CLTI. Clinicians should be aware of the burden of mental stress borne by those with the greatest limb impairment.

Initial Clinical Outcomes Using Umbilical Cord-Derived Tissue Grafts to Repair Anovaginal Fistula.

BACKGROUND: Perianal fistula is a debilitating disease and challenging condition to treat. Recently, the use of stem cells has been shown to improve healing of fistulas. OBJECTIVE: The aim was to examine the use of an umbilical cord-derived stem cell graft in a pilot study as a novel scaffold/stem inlay implanted into fistula repairs for anovaginal fistula to examine healing rates. DESIGN: This was a pilot study. SETTINGS: This study took place in a colorectal surgery practice. PATIENTS: Patients with anovaginal fistula consented to participate. Cryopreserved umbilical cord tissue graft with viable cells was incorporated as an inlay using a previously reported technique by the authors. Demographic data including history of previous repairs and IBD were included. All patients were followed for a minimum of 6 weeks. MAIN OUTCOME MEASURES: The primary measures were safety and efficacy of novel stem cell graft in the treatment of anovaginal fistula. RESULTS: From September 2017 to September 2019, 15 patients underwent anovaginal fistula repair. Three of these patients underwent a second repair, for a total of 18 repairs. No patient was intentionally diverted, but 3 patients presented for repair with a preexisting stoma. The majority of repairs were previous repair failures (12; 67%), and 7 repairs were performed on 5 patients with IBD. Median follow-up was 30 (6-104) weeks. The safety profile for cryopreserved umbilical cord tissue graft was excellent as no adverse events occurred. Overall complete healing rate was 39%, and 12 (67%) repairs resulted in improvement of symptoms. LIMITATIONS: This was a small pilot study. CONCLUSIONS: This is the largest series using cryopreserved umbilical cord graft for anovaginal fistula repair. The use of umbilical cord was safe and effective at closing defects. Randomized studies are necessary to determine added benefits over current standard of care. See Video Abstract at http://links.lww.com/DCR/B896 . RESULTADOS CLNICOS INICIALES DEL USO DE INJERTOS DE TEJIDO DERIVADO DE PLACENTA PARA REPARACIN DE FSTULAS ANOVAGINALES: ANTECEDENTES:La fístula perianal es una enfermedad debilitante y una afección difícil de tratar. Recientemente, se ha demostrado que el uso de células madre mejora la curación de las fístulas.OBJETIVO:Deseamos examinar el uso de un injerto de células madre derivadas de cordón umbilical en un estudio piloto como una nueva matriz/injerto de células madre implantado en reparaciones de fístula para fístula anovaginal para examinar las tasas de curación.DISEÑO:Este fue un estudio piloto.ESCENARIO:Este estudio se llevó a cabo en una clínica de cirugía colorrectal.PACIENTES:Se obtuvo consentimiento informado de pacientes con fístula anovaginal. El injerto de tejido de cordón umbilical criopreservado con células viables se incorporó como incrustación utilizando una técnica previamente informada por los autores. Se incluyeron datos demográficos que incluían antecedentes de reparaciones previas y enfermedad inflamatoria intestinal. Todos los pacientes fueron seguidos durante un mínimo de 6 semanas.PRINCIPALES MEDIDAS DE RESULTADO:Las principales medidas fueron la seguridad y la eficacia del nuevo injerto de células madre en el tratamiento de la fístula anovaginal.RESULTADOS:Desde 9/2017-9/2019, 15 pacientes fueron sometidas a reparación de fístula anovaginal. Tres de estos pacientes fueron sometidos a una segunda reparación, para un total de 18 reparaciones. Ningún paciente fue derivado intencionalmente mientras que 3 pacientes se presentaron para reparación con un estoma preexistente. La mayoría de las reparaciones fueron fallas de reparaciones previas (12, 67%) y se realizaron siete reparaciones en 5 pacientes con enfermedad inflamatoria intestinal (EII). La mediana de seguimiento fue de 30 semanas (6-104). El perfil de seguridad del injerto de tejido de cordón umbilical criopreservado fue excelente ya que no se produjeron efectos adversos. La tasa general de curación completa fue del 39% y 12 (67%) reparaciones dieron como resultado una mejoría de los síntomas.LIMITACIONES:Este fue un pequeño estudio piloto.CONCLUSIÓNES:Ésta es la serie más grande de utilización de injerto de cordón umbilical criopreservado para la reparación de una fístula anovaginal. La utilización del cordón umbilical resultó segura y eficaz para cerrar defectos. Se necesitan estudios aleatorizados para determinar los beneficios adicionales sobre el estándar de atención actual. Consulte Video Resumen en http://links.lww.com/DCR/B896 . (Traducción-Dr. Jorge Silva Velazco ).