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This study provides new information about the influence of the contraction pattern (i.e., continuous and intermittent) on the development of neuromuscular fatigability when exercise is performed until exhaustion. Maximal torque production is similarly reduced by both exercises, whereas maximal torque sustainability is impaired only after the continuous exercise. To evaluate neuromuscular fatigability, we then recommend using a sustained maximal voluntary contraction since this measure allows to concurrently collect information on complementary aspects of neuromuscular fatigability.

Las vasculitis asociadas a ANCA representan un grupo de enfermedades autoinmunes, multisistémicas, que afectan principalmente a los vasos de pequeño calibre, pudiendo comprometer el tracto respiratorio superior e inferior, el aparato otorrinolaringológico, riñón y piel, aunque eventualmente cualquier órgano puede estar involucrado. Son enfermedades con potencial y severo compromiso de órganos y elevada morbimortalidad. El objetivo de estas guías fue desarrollar las primeras recomendaciones argentinas para su tratamiento, basadas en la revisión de la literatura mediante metodología GRADE. Un panel de expertos en vasculitis elaboró las preguntas en formato PICO (población, intervención, comparador y outcomes), y luego un panel de expertos en metodología efectuó la revisión de la bibliografía con la extracción de la evidencia para cada una de las preguntas. Se realizó un focus group de pacientes para conocer sus preferencias y experiencias. Finalmente, con la información recabada, el panel de expertos en vasculitis procedió a la votación de las recomendaciones que a continuación se presentan.

La arteritis de células gigantes (ACG) es una vasculitis sistémica que afecta a personas adultas; compromete vasos arteriales de mediano y gran calibre, con potenciales complicaciones de gravedad, como la ceguera, y es considerada una emergencia médica. El objetivo de estas guías fue desarrollar las primeras recomendaciones argentinas para su tratamiento, basadas en la revisión de la literatura mediante metodología GRADE. Un panel de expertos en vasculitis elaboró las preguntas en formato PICO (población, intervención, comparador y outcomes), y luego un panel de expertos en metodología efectuó la revisión de la bibliografía con la extracción de la evidencia para cada una de las preguntas. Se realizó un focus group de pacientes para conocer sus preferencias y experiencias. Finalmente, con la información recabada, el panel de expertos en vasculitis procedió a la votación de las recomendaciones que a continuación se presentan.

La arteritis de células gigantes (ACG) es una vasculitis sistémica que afecta a personas adultas; compromete vasos arteriales de mediano y gran calibre, con potenciales complicaciones de gravedad, como la ceguera, y es considerada una emergencia médica. El objetivo de estas guías fue desarrollar las primeras recomendaciones argentinas para su tratamiento, basadas en la revisión de la literatura mediante metodología GRADE. Un panel de expertos en vasculitis elaboró las preguntas en formato PICO (población, intervención, comparador y outcomes), y luego un panel de expertos en metodología efectuó la revisión de la bibliografía con la extracción de la evidencia para cada una de las preguntas. Se realizó un focus group de pacientes para conocer sus preferencias y experiencias. Finalmente, con la información recabada, el panel de expertos en vasculitis procedió a la votación de las recomendaciones que a continuación se presentan.

La arteritis de células gigantes (ACG) es una vasculitis sistémica que afecta a personas adultas; compromete vasos arteriales de mediano y gran calibre, con potenciales complicaciones de gravedad, como la ceguera, y es considerada una emergencia médica. El objetivo de estas guías fue desarrollar las primeras recomendaciones argentinas para su tratamiento, basadas en la revisión de la literatura mediante metodología GRADE. Un panel de expertos en vasculitis elaboró las preguntas en formato PICO (población, intervención, comparador y outcomes), y luego un panel de expertos en metodología efectuó la revisión de la bibliografía con la extracción de la evidencia para cada una de las preguntas. Se realizó un focus group de pacientes para conocer sus preferencias y experiencias. Finalmente, con la información recabada, el panel de expertos en vasculitis procedió a la votación de las recomendaciones que a continuación se presentan.

Magnetically actuated endoscopes are currently transitioning in to clinical use for procedures such as colonoscopy, presenting numerous benefits over their conventional counterparts. Intelligent and easy-to-use control strategies are an essential part of their clinical effectiveness due to the un-intuitive nature of magnetic field interaction. However, work on developing intelligent control for these devices has mainly been focused on general purpose endoscope navigation. In this work, we investigate the use of autonomous robotic control for magnetic colonoscope intervention via biopsy, another major component of clinical viability. We have developed control strategies with varying levels of robotic autonomy, including semi-autonomous routines for identifying and performing targeted biopsy, as well as random quadrant biopsy. We present and compare the performance of these approaches to magnetic endoscope biopsy against the use of a standard flexible endoscope on bench-top using a colonoscopy training simulator and silicone colon model. The semi-autonomous routines for targeted and random quadrant biopsy were shown to reduce user workload with comparable times to using a standard flexible endoscope.

Martin and his colleagues in 1989 described for the first time a fasciocutaneous flap based on a posterior branch of the anterior interosseous artery (AIA). Despite its promising characteristics, this flap never achieved popularity and the literature about it is limited. The aim of the present study is to share our experience with the AIA flap both as a local and free flap in reconstructing defects of various body regions.A retrospective review of 26 consecutive patients operated between January2001 and August 2020 was conducted. Seventeen male and nine female patients, mean age 52 years, underwent reconstruction of local and distant soft tissue defects using the AIA flap. Fourteen flaps were raised as free flap and 12 as local flaps for a total of 26 flaps. The locations of the defects included the face, the lower limb, the hand dorsum, and fingers.Twenty-four out of 26 flaps survived completely, and two pedicled flaps presented partial necrosis, with one requiring a new free flap procedure. One free anterior interosseous flap required revision of the venous anastomosis. Two donor site dehiscence were observed, and they both healed by secondary intention healing. Follow-ups were conducted for a mean of 18 months. All patients showed good contour restoration of the affected body part.The AIA flap, either free or pedicled, represents a reliable tool to perform "like-with-like" reconstructions of hand defects. In some occasions, it is well suited for shallow defects in other body parts.

Em decorrência das mudanças climáticas estão ficando cada vez mais comuns as tempestades, inundações, secas, ocasionando os eventos extremos. O objetivo foi identificar os eventos extremos de excesso e déficit de precipitação na Bacia Hidrográfica do Camaquã situada no Rio Grande do Sul (RS), no período de 1991 a 2020, e analisar o ambiente sinótico associado ao evento de chuva mais intensa da série. Foi realizado o levantamento dos desastres naturais, dados de precipitação máxima diária, imagens de satélite e dados estimados do modelo ERA5, e relacionados com El niño Oscilação Sul. Foram observados 197 desastres naturais, sendo que 61% foram de excesso e 39% por déficit de precipitação. Destes, 27% dos anos estavam sob influência de El Niño, 20% por La Niña e 53% por anos neutros. Dos eventos extremos 28 casos ultrapassaram o percentil de 99% (133 mm), sendo quatro sistemas frontais, oito ciclones e dez sistemas convectivos de mesoescala. O evento mais intenso ocorreu em Camaquã e Cristal no dia 24/12/1995, apresentando forçantes dinâmica e térmica de um ciclone extratropical. Podemos concluir que estudos como este, se tornam cada vez mais relevante, visto a importância dessa região ao Estado do RS.

The healthcare is often considered one of the sectors most prone to corruption, and transparency policies have been proposed in several countries to fight bribery and corruption. Indeed, the transparency of public bodies potentially plays a relevant role in preventing misbehaviour and favouring accountability. This study contributes to a broader understanding of the role of transparency in the healthcare sector using Italy as a case study. For this purpose, we first built a composite indicator to assess the differences in transparency, performance, and integrity between Italian local health authorities (LHAs) retrieving the administrative data available on their websites. Then, we used both non-parametric method and multivariate regression to explore the relationship between the performance of different expenditure functions (total production costs, administrative costs, and medical and non-medical-related service costs) at the LHA level and the transparency index. Our results show a wide difference in transparency, performance, and integrity among LHAs that does not always follow the classic north–south divide in Italy. In addition, we find results consistent with the idea that transparency is generally associated with a better capability of LHAs in the containment of healthcare expenditure while imposing larger administrative burdens. Overall, reforms promoting transparency impose administrative costs, which policymakers should bear in mind to develop less burdensome transparency measures, as they might not be a ‘free lunch’.

Background: Low back pain (LBP) is the leading cause of years lived with disability worldwide. Public safety workers are highly exposed to physically demanding activities and inappropriate postures, which can increase the LBP experience in this population. Smartphone app-based self-managed interventions may be an alternative for chronic non-specific LBP (CNSLBP) treatment. This study aims to develop and test the effectiveness of an 8-week smartphone app-based self-managed exercise program plus health education, compared to a health education program alone, on neuromuscular and perceptual outcomes in police officers and firefighters with CNSLBP. Methods: This is a parallel, two-armed, blinded evaluator randomized clinical trial. Police officers and firefighters (from public safety institutions in the Rio Grande do Sul state, Brazil) will be randomly assigned to m-health self-managed exercise program (twice a week) plus health education or health education alone. Self-management exercise program components are mobility and core resistance exercises, available on the app. Follow-ups will be conducted post-treatment (8 weeks) and 16 weeks after randomization. The primary outcomes will be pain intensity and disability post-treatment (8 weeks). Secondary outcomes will be biopsychosocial factors related to CNSLBP. Discussion: Our hypothesis is of superiority for the effects of a smartphone app-based self-managed exercise program on primary and secondary outcomes, compared to the effects of only the health education intervention in police officers and firefighters with CNSLBP. Trial registration: The study was prospectively registered at ClinicalTrials.gov (NCT05481996. Registered on August 01, 2022).

PDF file - 2662K, Tumor burden in LSL Kras mice.

Supplementary Figure 2 PDF file - 182K, This Figure shows the activation status of RhoA and Rac1 in mouse lungs and validation of RhoA-GTP antibody on mouse lung tissue by IHC

Supplementary Figure 6 PDF file - 141K, This Figure shows that FAK is co-expressed with RHOA in lung adenocarcinomas. In addition, we provide the validation of RHOA-GTP antibody on human specimens by IHC

PDF file - 2336K, Analysis of tumors and survival in Kras-GFP mice.

Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes medium-chain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM.Significance:MCAD exerts a protective role to prevent accumulation of toxic metabolic by-products in glioma cells, actively catabolizing lipid species that would otherwise affect mitochondrial integrity and induce cell death. This work represents a first demonstration of a nonenergetic role for dependence on fatty acid metabolism in cancer.This article is highlighted in the In This Issue feature, p. 2659

Supplementary Figure 1 PDF file - 311K, This Figure shows that the KrasG12D;Ink4a/Arf -/- mice show increased tumor burden, increased Ki-67, Cyclin D1 expression and decreased survival compared to KrasG12D;Ink4a/Arf +/+ mice

Supplementary Figure 7 PDF file - 205K, This Figure shows that pharmacological inhibition of FAK results in suppression of NSCLC in vivo

Lung cancer commonly displays a number of recurrent genetic abnormalities, and about 30% of lung adenocarcinomas carry activating mutations in the Kras gene, often concomitantly with inactivation of tumor suppressor genes p16INK4A and p14ARF of the CDKN2AB locus. However, little is known regarding the function of p15INK4B translated from the same locus. To determine the frequency of CDKN2AB loss in human mutant KRAS lung cancer, The Cancer Genome Atlas (TCGA) database was interrogated. Two-hit inactivation of CDKN2A and CDKN2B occurs frequently in patients with mutant KRAS lung adenocarcinoma. Moreover, p15INK4B loss occurs in the presence of biallelic inactivation of p16INK4A and p14ARF, suggesting that p15INK4B loss confers a selective advantage to mutant KRAS lung cancers that are p16INK4A and p14ARF deficient. To determine the significance of CDKN2AB loss in vivo, genetically engineered lung cancer mouse models that express mutant Kras in the respiratory epithelium were utilized. Importantly, complete loss of CDKN2AB strikingly accelerated mutant Kras–driven lung tumorigenesis, leading to loss of differentiation, increased metastatic disease, and decreased overall survival. Primary mutant Kras lung epithelial cells lacking Cdkn2ab had increased clonogenic potential. Furthermore, comparative analysis of mutant Kras;Cdkn2a null with Kras;Cdkn2ab null mice and experiments with mutant KRAS;CDKN2AB–deficient human lung cancer cells indicated that p15INK4B is a critical tumor suppressor. Thus, the loss of CDKN2AB is of biologic significance in mutant KRAS lung tumorigenesis by fostering cellular proliferation, cancer cell differentiation, and metastatic behavior.Implications: These findings indicate that mutant Kras;Cdkn2ab null mice provide a platform for accurately modeling aggressive lung adenocarcinoma and testing therapeutic modalities. Mol Cancer Res; 12(6); 912–23. ©2014 AACR.

PDF file - 1846K, Lung specific expression of Kras and GFP in the mouse.

PDF file - 102K, Metastatic disease in LSL Kras mice.

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Supplementary Figures S1 through S3

PDF file - 4413K, Progression in CDKN2AB lung tumors.

Supplementary Methods PDF file - 123K, This file contains the Supplementary materials and methods linked to the manuscript. In addition the references associated with the materials are reported

Supplementary Figure 4 PDF file - 169K, This Figure shows that RHOA activation is essential for the survival of NSCLC expressing mutant KRAS in association with INK4a/ARF or p53 deficiency

Oculocutaneous albinism (OCA) is a group of rare, genetic disorders caused by absent/reduced melanin biosynthesis. The aim of this study was to explore the neurovisual, cognitive, adaptive, and behavioral profile of children affected by OCA, also evaluating any possible effect of the visual acuity deficit on the clinical profile and genotype–phenotype correlations. Eighteen children (9 males, mean age 84 months ± 41; range 18–181 months) with a molecular confirmed diagnosis of OCA were enrolled in the study. We collected data on clinical history, neurodevelopmental profile, neurological and neurovisual examination, and cognitive, adaptive, and emotional/behavioral functioning. A global neurodevelopmental impairment was detected in 56% of the children, without evolving into an intellectual disability. All the patients showed signs and symptoms of visual impairment. Low adaptive functioning was observed in 3 cases (17%). A risk for internalizing behavioral problems was documented in 6 cases (33%), for externalizing problems in 2 (11%), and for both in 5 (28%). Twelve children (67%) showed one or more autistic-like features. Correlation analyses revealed significant associations between the visual acuity level and performance intelligence quotient (p = 0.001), processing speed index (p = 0.021), Vineland total score (p = 0.020), Vineland communication (p = 0.020), and socialization (p = 0.037) domains. No significant correlations were found between genotype and phenotype.Conclusion: Children with OCA may present a global neurodevelopmental delay that seems to improve with age and emotional/behavioral difficulties, along with the well-known visual impairment. An early neuropsychiatric evaluation and habilitative training are recommended to improve vision-related performance, neurodevelopment, and any psychological difficulties. What is Known:• Children with oculocutaneous albinism show dermatological and ophthalmological problems.• An early visual impairment may have negative implications on motor, emotional, and cognitive processes that would allow the child to organize his or her experiences. What is New:• In addition to a variable combination of ocular signs and symptoms, children with oculocutaneous albinism may present an early neurodevelopmental delay and emotional/behavioral difficulties.• An early visual treatment is recommended to improve vision-related performance, neurodevelopment, and any psychological difficulties.

PDF file - 2931K, Evaluation of primary mouse cell lines.

PDF file - 1036K, Progression-Free and overall survival of patients with CDKN2A or CDKN2AB mutant lung cancer.

Supplementary Figure 5 PDF file - 199K, This Figure shows that FAK is a critical target of RHOA in mutant KRAS;INK4a/ARF deficient NSCLC cells

Supplementary Figure 3 PDF file - 76K, This Figure shows the knockdown efficiency of shRNAs against KRAS and that MEK1/2 inhibition suppresses RHOA

Supplementary Figure 4. Radiosensitization induced by FAK blockade is accompanied by persistence of DNA damage foci.

Supplementary Materials and Methods

Purpose: Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide due to the limited availability of effective therapeutic options. For instance, there are no effective strategies for NSCLCs that harbor mutant KRAS, the most commonly mutated oncogene in NSCLC. Thus, our purpose was to make progress toward the generation of a novel therapeutic strategy for NSCLC.Experimental Design: We characterized the effects of suppressing focal adhesion kinase (FAK) by RNA interference (RNAi), CRISPR/CAS9 gene editing or pharmacologic approaches in NSCLC cells and in tumor xenografts. In addition, we tested the effects of suppressing FAK in association with ionizing radiation (IR), a standard-of-care treatment modality.Results: FAK is a critical requirement of mutant KRAS NSCLC cells. With functional experiments, we also found that, in mutant KRAS NSCLC cells, FAK inhibition resulted in persistent DNA damage and susceptibility to exposure to IR. Accordingly, administration of IR to FAK-null tumor xenografts causes a profound antitumor effect in vivo.Conclusions: FAK is a novel regulator of DNA damage repair in mutant KRAS NSCLC and its pharmacologic inhibition leads to radiosensitizing effects that could be beneficial in cancer therapy. Our results provide a framework for the rationale clinical testing of FAK inhibitors in NSCLC patients. Clin Cancer Res; 22(23); 5851–63. ©2016 AACR.

Supplementary Figure 2. Suppression of FAK did not affect p-AKT, p-ERK and p-S6.

Supplementary Table 1. The table shows the mutations reported by the COSMIC database for every cell line used in our study.

Supplementary Figure 5. Ionizing radiations and FAK blockade increase the number and persistence of DNA damage foci.

Supplementary Figure 1. Suppression of FAK leads to loss of viability in mutant KRAS NSCLC cells.

Supplementary Figure 3. Inhibition of FAK causes upregulation of γ-H2AX.

Supplementary Figure 4 from Aldehyde Dehydrogenase Activity Selects for Lung Adenocarcinoma Stem Cells Dependent on Notch Signaling

Supplementary Figure 2 from Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Blockade Is an Effective Radiosensitizing Strategy for the Treatment of Non–Small Cell Lung Cancer Harboring K-RAS Mutations

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Aldehyde dehydrogenase (ALDH) is a candidate marker for lung cancer cells with stem cell-like properties. Immunohistochemical staining of a large panel of primary non–small cell lung cancer (NSCLC) samples for ALDH1A1, ALDH3A1, and CD133 revealed a significant correlation between ALDH1A1 (but not ALDH3A1 or CD133) expression and poor prognosis in patients including those with stage I and N0 disease. Flow cytometric analysis of a panel of lung cancer cell lines and patient tumors revealed that most NSCLCs contain a subpopulation of cells with elevated ALDH activity, and that this activity is associated with ALDH1A1 expression. Isolated ALDH+ lung cancer cells were observed to be highly tumorigenic and clonogenic as well as capable of self-renewal compared with their ALDH− counterparts. Expression analysis of sorted cells revealed elevated Notch pathway transcript expression in ALDH+ cells. Suppression of the Notch pathway by treatment with either a γ-secretase inhibitor or stable expression of shRNA against NOTCH3 resulted in a significant decrease in ALDH+ lung cancer cells, commensurate with a reduction in tumor cell proliferation and clonogenicity. Taken together, these findings indicate that ALDH selects for a subpopulation of self-renewing NSCLC stem-like cells with increased tumorigenic potential, that NSCLCs harboring tumor cells with ALDH1A1 expression have inferior prognosis, and that ALDH1A1 and CD133 identify different tumor subpopulations. Therapeutic targeting of the Notch pathway reduces this ALDH+ component, implicating Notch signaling in lung cancer stem cell maintenance. Cancer Res; 70(23); 9937–48. ©2010 AACR.

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