Acute physiological responses and muscle recovery in females: a randomised controlled trial of muscle damaging exercise in hypoxia.

BACKGROUND: Studies have investigated the effects of training under hypoxia (HYP) after several weeks in a male population. However, there is still a lack of knowledge on the acute hypoxic effects on physiology and muscle recovery in a female population. METHODS: This randomized-controlled trial aimed to investigate the acute effects of muscle damaging exercise, performed in HYP and normoxia (CON), on physiological responses and recovery characteristics in healthy females. Key inclusion criteria were recreationally active female participants between the age of 18 to 35 years without any previous surgeries and injuries, whilst key exclusion criteria were acute pain situations, pregnancy, and medication intake. The females conducted a muscle-damaging protocol, comprising 5 × 20 drop-jumps, in either HYP (FiO2: 12%) or CON (FiO2: 21%). Physiological responses, including capillary oxygenation (SpO2), muscle oxygenation (SmO2), heart rate (HR), core- (Tcore) and skin- (Tskin) temperature were assessed at the end of each exercise set. Recovery characteristics were quantified by taking venous blood samples (serum creatine-kinase [CK], C-reactive protein [CRP] and blood sedimentation rate [BSR]), assessing muscle swelling of the quadriceps femoris muscle, maximum voluntary isometric contraction (MVIC) of the knee extensor muscles, countermovement jump (CMJ) performance and muscle soreness ratings (DOMS) at 24-, 48- and 72-hrs post-exercise. RESULTS: SpO2 (HYP: 76.7 ± 3.8%, CON: 95.5 ± 1.7%, p < 0.001) and SmO2 (HYP: 60.0 ± 9.3, CON: 73.4 ± 5.8%, p = 0.03) values were lower (p < 0.05) in HYP compared to CON at the end of the exercise-protocol. No physiological differences between HYP and CON were observed for HR, Tcore, and Tskin (all p > 0.05). There were also no differences detected for any recovery variable (CK, CRP, BSR, MVIC, CMJ, and DOMS) during the 72-hrs follow-up period between HYP and CON (all p > 0.05). CONCLUSION: In conclusion, our results showed that muscle damaging exercise under HYP leads to reduced capillary and muscle oxygenation levels compared to normoxia with no difference in inflammatory response and muscle recovery during 72 h post-exercise. TRIAL REGISTRATION: NCT04902924, May 26th 2021.

Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2- advanced breast cancer receiving first-line ribociclib plus fulvestrant.

BACKGROUND: The phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2- ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population. METHODS: Postmenopausal patients with HR+/HER2- ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan-Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615). RESULTS: At data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50-0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed. CONCLUSIONS: This analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2- ABC.

Asymptomatic bacteriuria in candidates for active treatment of renal stones: results from an international multicentric study on more than 2600 patients.

The occurrence of asymptomatic bacteriuria concomitant to urolithiasis is an issue for patients undergoing renal stone treatment. Disposing of a preoperative urine culture is essential to reduce the risk of septic events. The endpoint of the study is to report which characteristics of candidates for renal stone treatment are frequently associated with positive urine culture. 2605 patients were retrospectively enrolled from 14 centers; inclusion criteria were age > 18 and presence of a single renal stone 1-2 cm in size. The variables collected included age, gender, previous renal surgery, comorbidities, skin-to-stone distance, stone size, location, density, presence of hydronephrosis. After a descriptive analysis, the association between continuous and categorical variables and the presence of positive urine culture was assessed using a logistic regression model. Overall, 240/2605 patients (9%) had preoperative bacteriuria. Positive urine culture was more frequent in females, patients with previous renal interventions, chronic kidney disease, congenital anomalies, larger stones, increased density. Multivariate analysis demonstrated that previous renal interventions (OR 2.6; 95% CI 1.9-3.4; p < 0.001), renal-related comorbidities (OR 1.31; 95% CI 1.19-1.4; p < 0.001), higher stone size (OR 1.06; 95% CI 1.02-1.1; p = 0.01) and density (OR 1.00; 95% CI 1.0-1.00; p = 0.02) were associated with bacteriuria; male gender and lower caliceal location were inversely related to it. Beyond expected risk factors, such as female gender, other parameters are seemingly favoring the presence of positive urine culture. The awareness of variables associated with bacteriuria allows to assess which individuals are at increased risk of presenting bacteriuria and reduce the rate of septic complications.

Early stage breast cancer follow-up in real-world clinical practice: the added value of cell free circulating tumor DNA.

PURPOSE: Physical examinations and annual mammography (minimal follow-up) are as effective as laboratory/imaging tests (intensive follow-up) in detecting breast cancer (BC) recurrence. This statement is now challenged by the availability of new diagnostic tools for asymptomatic cases. Herein, we analyzed current practices and circulating tumor DNA (ctDNA) in monitoring high-risk BC patients treated with curative intent in a comprehensive cancer center. PATIENTS AND METHODS: Forty-two consecutive triple negative BC patients undergoing neoadjuvant therapy and surgery were prospectively enrolled. Data from plasma samples and surveillance procedures were analyzed to report the diagnostic pattern of relapsed cases, i.e., by symptoms, follow-up procedures and ctDNA. RESULTS: Besides minimal follow-up, 97% and 79% of patients had at least 1 non-recommended imaging and laboratory tests for surveillance purposes. During a median follow-up of 5.1(IQR, 4.1-5.9) years, 13 events occurred (1 contralateral BC, 1 loco-regional recurrence, 10 metastases, and 1 death). Five recurrent cases were diagnosed by intensive follow-up, 5 by symptoms, and 2 incidentally. ctDNA antedated disseminated disease in all evaluable cases excepted two with bone-only and single liver metastases. The mean time from ctDNA detection to suspicious findings at follow-up imaging was 3.81(SD, 2.68), and to definitive recurrence diagnosis 8(SD, 2.98) months. ctDNA was undetectable in the absence of disease and in two suspected cases not subsequently confirmed. CONCLUSIONS: Some relapses are still symptomatic despite the extensive use of intensive follow-up. ctDNA is a specific test, sensitive enough to detect recurrence before other methods, suitable for clarifying equivocal imaging, and exploitable for salvage therapy in asymptomatic BC survivors.

α-catenin switches between a slip and an asymmetric catch bond with F-actin to cooperatively regulate cell junction fluidity.

α-catenin is a crucial protein at cell junctions that provides connection between the actin cytoskeleton and the cell membrane. At adherens junctions (AJs), α-catenin forms heterodimers with ß-catenin that are believed to resist force on F-actin. Outside AJs, α-catenin forms homodimers that regulates F-actin organization and directly connect the cell membrane to the actin cytoskeleton, but their mechanosensitive properties are inherently unknown. By using ultra-fast laser tweezers we found that a single α-ß-catenin heterodimer does not resist force but instead slips along F-actin in the direction of force. Conversely, the action of 5 to 10 α-ß-catenin heterodimers together with force applied toward F-actin pointed end engaged a molecular switch in α-catenin, which unfolded and strongly bound F-actin as a cooperative catch bond. Similarly, an α-catenin homodimer formed an asymmetric catch bond with F-actin triggered by protein unfolding under force. Our data suggest that α-catenin clustering together with intracellular tension engage a fluid-to-solid phase transition at the membrane-cytoskeleton interface.

Cardiac involvement in athletes infected by SARS COV-2 disease.

Objectives: The aim of the present study was to conduct a review of the current literature evaluating the available evidence to date in terms of epidemiology, pathophysiology and clinical presentation of COVID-19 in relation to cardiovascular involvement, with a special focus on the myocarditis model, in the population of athletes (professional and recreational) who are preparing to return to competitions, with the ultimate aim of guaranteeing maximum safety for resuming sports activities. News: The COVID-19 pandemic has resulted in the inevitable cancellation of most sports activities, practiced at both a professional and amateur level, in order to minimize the risk of spreading the infection. Since the number of athletes who tested positive was rather high, the potential cardiac involvement in this peculiar population of subjects contracting the disease in a mild (asymptomatic, slightly symptomatic) or moderate form, has recently raised concerns following the observation of cases of recorded myocardial damage, myocarditis, arrhythmias and a first reported case of Sudden Cardiac Death (SCD) in a 27-year-old professional basketball player. Several studies even seem to confirm the possibility of permanent impairment of the cardiorespiratory system following the infection. Medical history, biomarkers, electrocardiographical and cardiac imaging features appear to be crucial in distinguishing cardiovascular alterations related to COVID-19 infection from typical adaptations to exercise related to athletes' heart. Prospects and Projects: Clarifications and prospective data based on long-term follow-ups on larger populations of athletes are still needed to exclude the development of myocardial damage capable of negatively affecting prognosis and increasing cardiovascular risk in athletes recovered from COVID-19 in asymptomatic (simple positivity to SARS-COV-2) or in a mild form. Conclusion: From a clinical point of view extreme caution is necessary when planning the return to sport (Return To Play-RTP) of athletes recovered from a mild or asymptomatic form of COVID-19: a careful preliminary medical-sports evaluation should be carried out in order to assess the potential development of myocardial damage that would increase their cardiovascular risk.

Objectifs: Le but cette étude était de mener une revue de la littérature actuelle évaluant les différents éléments disponibles en termes d'épidémiologie, de physiopathologie et de présentation clinique de l'atteinte cardio-vasculaire du COVID-19. Une attention particulière sera donnée aux lésions myocardiques dans la population des athlètes, à la fois de niveau professionnel et amateur, qui s'apprêtent à reprendre la compétition, dans le but de garantir une sécurité maximale dans la reprise des activités sportives. Actualités: La pandémie de COVID-19 a entraîné l'annulation inévitable de la plupart des activités sportives, pratiquées à la fois à un niveau professionnel et amateur, afin de minimiser le risque de propagation de l'infection. Le nombre d'athlètes testés positifs étant plutôt élevé, les répercussions cardiaques potentielles dans cette population particulière de sujets contractant la maladie sous une forme légère (asymptomatique, légèrement symptomatique) ou modérée, a récemment soulevé des inquiétudes suite à l'observation de cas de lésions myocardiques, de myocardites, d'arythmies et d'un premier cas signalé de mort subite chez un basketteur professionnel de 27 ans. De plus, plusieurs études semblent confirmer la possibilité d'une altération permanente du système cardiorespiratoire suite à l'infection. Les antécédents médicaux, les biomarqueurs, les caractéristiques électrocardiographiques et à l'imagerie cardiaque semblent ainsi être des éléments cruciaux pour pouvoir distinguer les altérations cardiovasculaires liées à l'infection au COVID-19 des adaptations typiques à l'exercice des cœurs d'athlètes. Perspectives et projets: Des précisions et des données prospectives basées sur des suivis à long terme sur des populations plus importantes d'athlètes sont encore nécessaires pour exclure le développement de lésions myocardiques capables d'affecter négativement le pronostic et d'augmenter le risque cardiovasculaire chez les athlètes en rémission d'une infection au COVID-19 asymptomatique (positivité simple au SARS-COV-2) ou sous une forme légère. Conclusion: D'un point de vue clinique, une extrême prudence est nécessaire lors de la planification du retour au sport des athlètes en rémission d'une forme légère ou asymptomatique de COVID-19: une évaluation médico-sportive minutieuse de ces patients doit être effectuée afin d'évaluer le développement potentiel de lésions myocardiques qui augmenteraient leur risque cardiovasculaire.

Mammographic density to predict response to neoadjuvant systemic breast cancer therapy.

BACKGROUND: Mammographic density (MD) is a risk factor for breast cancer (BC) development, and recurrence. However, its predictive value has been less studied. Herein, we challenged MD as a biomarker associated with response in patients treated with neoadjuvant therapy (NAT). METHODS: Data on all NAT treated BC patients prospectively collected in the registry of Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy (2009-2019) were identified. Diagnostic mammograms were used to evaluate and score MD as categorized by the Breast Imaging-Reporting and Data System (BI-RADS), which identifies 4 levels of MD in keeping with relative increase of fibro-glandular over fat tissue. Each case was classified according to the following categories a (MD < 25%), b (26-50%), c (51-75%), and d (> 75%). The association between MD and pathological complete response (pCR), i.e., absence of BC cells in surgical specimens, was analyzed in multivariable setting used logistic regression models with adjustment for clinical and pathological variables. RESULTS: A total of 442 patients were analyzed, 120 of which (27.1%) attained a pCR. BI-RADS categories a, b, c, and d accounted for 10.0%, 37.8%, 37.1% and 15.2% of cases. Corresponding pCR were 20.5%, 26.9%, 30.5%, 23.9%, respectively. At multivariable analysis, when compared to cases classified as BI-RADS a, those with denser breast showed an increased likelihood of pCR with odds ratio (OR) of 1.70, 2.79, and 1.47 for b, c and d categories, respectively (p = 0.0996), independently of age, BMI [OR underweight versus (vs) normal = 3.76], clinical nodal and tumor status (OR T1/Tx vs T4 = 3.87), molecular subtype (HER2-positive vs luminal = 10.74; triple-negative vs luminal = 8.19). In subgroup analyses, the association of MD with pCR was remarkable in triple-negative (ORs of b, c and d versus a: 1.85, 2.49 and 1.55, respectively) and HER2-positive BC cases (ORs 2.70, 3.23, and 1.16). CONCLUSION: Patients with dense breast are more likely to attain a pCR at net of other predictive factors. The potential of MD to assist decisions on BC management and as a stratification factor in neoadjuvant clinical trials should be considered.

Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival.

BACKGROUND: Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Here we present a new landmark in survival follow-up for a phase III cyclin-dependent kinases 4 and 6 inhibitor clinical trial in patients with ABC (median, 56.3 months). PATIENTS AND METHODS: This phase III, randomized, double-blind, placebo-controlled trial was conducted at 174 sites (30 countries). Patients were men and postmenopausal women (age ≥18 years) with histologically/cytologically confirmed HR+/HER2- ABC. Patients could have received ≤1 line of endocrine therapy (ET) but no chemotherapy for ABC. Patients, assigned 2:1, were stratified by the presence/absence of liver/lung metastases and previous ET. Patients received intramuscular fulvestrant (500 mg, day 1 of each 28-day cycle plus day 15 of cycle 1) with oral ribociclib (600 mg/day, 3 weeks on, 1 week off) or placebo. Efficacy analyses were by intention to treat. Safety was assessed in patients receiving ≥1 dose study treatment. OS was a secondary endpoint. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615; no longer enrolling). RESULTS: Between 18 June 2015 and 10 June 2016, 726 patients were randomly assigned (484, ribociclib; 242, placebo). At data cut-off (30 October 2020), median OS (mOS) was 53.7 months (ribociclib) versus 41.5 months (placebo) [hazard ratio (HR), 0.73; 95% confidence interval (CI) 0.59-0.90]. Subgroup analyses were consistent with overall population. In the first-line setting, most patients in the ribociclib arm (∼60%) lived longer than median follow-up; mOS was 51.8 months in the placebo arm (HR, 0.64; 95% CI 0.46-0.88). In the second-line setting, mOS was 39.7 months (ribociclib) versus 33.7 months (placebo) (HR, 0.78; 95% CI 0.59-1.04). No apparent drug-drug interaction between ribociclib and fulvestrant or new safety signals were observed. CONCLUSIONS: This analysis reported extended OS follow-up in MONALEESA-3. mOS was ∼12 months longer in patients with HR+/HER2- ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy.

The novel Mechanical Ventilator Milano for the COVID-19 pandemic.

This paper presents the Mechanical Ventilator Milano (MVM), a novel intensive therapy mechanical ventilator designed for rapid, large-scale, low-cost production for the COVID-19 pandemic. Free of moving mechanical parts and requiring only a source of compressed oxygen and medical air to operate, the MVM is designed to support the long-term invasive ventilation often required for COVID-19 patients and operates in pressure-regulated ventilation modes, which minimize the risk of furthering lung trauma. The MVM was extensively tested against ISO standards in the laboratory using a breathing simulator, with good agreement between input and measured breathing parameters and performing correctly in response to fault conditions and stability tests. The MVM has obtained Emergency Use Authorization by U.S. Food and Drug Administration (FDA) for use in healthcare settings during the COVID-19 pandemic and Health Canada Medical Device Authorization for Importation or Sale, under Interim Order for Use in Relation to COVID-19. Following these certifications, mass production is ongoing and distribution is under way in several countries. The MVM was designed, tested, prepared for certification, and mass produced in the space of a few months by a unique collaboration of respiratory healthcare professionals and experimental physicists, working with industrial partners, and is an excellent ventilator candidate for this pandemic anywhere in the world.

Blood-based genomics of triple-negative breast cancer progression in patients treated with neoadjuvant chemotherapy.

BACKGROUND: As neoadjuvant chemotherapy (NAC) is increasingly used in triple-negative breast cancer (TNBC), we investigated the value of circulating tumor DNA (ctDNA) for patient monitoring prior, during, and after NAC, and circulating tumor cells (CTCs) for disease characterization at clinical progression. MATERIALS AND METHODS: Forty-two TNBC patients undergoing NAC were prospectively enrolled. Primary tumor mutations identified by targeted-gene sequencing were validated and tracked in 168 plasma samples longitudinally collected at multiple time-points by droplet digital polymerase chain reaction. At progression, plasma DNA underwent direct targeted-gene assay, and CTCs were collected and analyzed for copy number alterations (CNAs) by low-pass whole genome sequencing. RESULTS: ctDNA detection after NAC was associated with increased risk of relapse, with 2-year event-free survival estimates being 44.4% [95% confidence interval (CI) 21.4%-92.3%] versus 77.4% (95% CI 57.8%-100%). ctDNA prognostic value remained worthy even after adjusting for age, residual disease, systemic inflammatory indices, and Ki-67 [hazard ratio (HR) 1.91; 95% CI 0.51-7.08]. During follow-up, ctDNA was undetectable in non-recurrent cases with the unique exception of one showing a temporary peak over eight samples. Conversely, ctDNA was detected in 8/11 recurrent cases, and predated the clinical diagnosis up to 13 months. Notably, recurrent cases without ctDNA developed locoregional, contralateral, and bone-only disease. At clinical progression, CTCs presented chromosome 10 and 21q CNAs whose network analysis showed connected modules including HER/PI3K/Ras/JAK signaling and immune response. CONCLUSION: ctDNA is not only associated with but is also predictive of prognosis in TNBC patients receiving NAC, and represents an exploitable tool, either alone or with CTCs, for personalized TNBC management.

[Osteoarthicular injuries in orthopedic surgeons. How do we deal with it?] / Lesiones osteoarticulares en cirujanos ortopédicos. ¿Cómo lo afrontamos?

INTRODUCTION: Therapeutic decision-making is a complex process in which multiple variables must be considered. There is a growing trend towards surgical indication, although scientific evidence is not always blunt. Understanding how surgeons make decisions can improve our understanding of treatment variability. OBJECTIVES: To expose the demographic situation of osteoarticular injuries in orthopedic surgeons in Uruguay and how they deal with their own injury and identify those variables that influence therapeutic decision-making in the orthopedist. MATERIAL AND METHODS: Using the Uruguayan Society of Orthopedics and Traumatology database, residents and surgeons who had at least one osteoarticular injury were identified. Each of the selected ones was interviewed by telephone, obtaining the variables of interest. RESULTS: In a total of 274 residents and Orthopedic surgeons, we include 56 professionals and 69 osteoarticular injuries. We highlight the existence of multiple injuries of controversial treatment, according to current scientific evidence. The surgeon did not always indicate the same treatment to himself, in respect of the one that would indicate a patient with the same injury. Fear of complications, rapid job reimbursement, opinion of an expert colleague, among others were some of the variables found in the therapeutic decision. CONCLUSIONS: When the lesion settles on the surgeon itself, a different action was observed with respect to a patient with equal injury.

INTRODUCCIÓN: La toma de decisiones terapéuticas es un proceso complejo en la cual deben considerarse múltiples variables. Existe una tendencia cada vez mayor hacia la indicación quirúrgica, aunque no siempre la evidencia científica sea contundente. Entender cómo los cirujanos toman decisiones puede mejorar nuestra comprensión de la variabilidad de los tratamientos. OBJETIVOS: exponer la situación demográfica de las lesiones osteoarticulares en los cirujanos ortopédicos de Uruguay y cómo afrontan su propia lesión e identificar aquellas variables que influyen en la toma de decisiones terapéuticas en el ortopedista. MATERIAL Y MÉTODOS: Utilizando la base de datos de la Sociedad de Ortopedia y Traumatología del Uruguay se identificaron residentes y cirujanos que presentaron al menos una lesión osteoarticular. Se entrevistó telefónicamente a cada uno de los seleccionados, obteniendo las variables de interés. RESULTADOS: En un total de 274 residentes y traumatólogos, incluimos 56 profesionales y 69 lesiones osteoarticulares. Destacamos la existencia de múltiples lesiones de tratamiento controvertido, según la evidencia científica actual. El cirujano no siempre indicó el mismo tratamiento a sí mismo respecto al que indicaría a un paciente con la misma lesión. Miedo a las complicaciones, rápida reintegración laboral, opinión de un colega experto, entre otras, fueron algunas de las variables halladas en la decisión terapéutica. CONCLUSIONES: Cuando la lesión asienta en el propio cirujano, se observó un accionar distinto con respecto a un paciente con igual lesión.

Can the Charlson Comorbidity Index be used to predict the ASA grade in patients undergoing spine surgery?

BACKGROUND: The American Society of Anaesthesiologists' Physical Status Score (ASA) is a key variable in predictor models of surgical outcome and "appropriate use criteria". However, at the time when such tools are being used in decision-making, the ASA rating is typically unknown. We evaluated whether the ASA class could be predicted statistically from Charlson Comorbidy Index (CCI) scores and simple demographic variables. METHODS: Using established algorithms, the CCI was calculated from the ICD-10 comorbidity codes of 11'523 spine surgery patients (62.3 ± 14.6y) who also had anaesthetist-assigned ASA scores. These were randomly split into training (N = 8078) and test (N = 3445) samples. A logistic regression model was built based on the training sample and used to predict ASA scores for the test sample and for temporal (N = 341) and external validation (N = 171) samples. RESULTS: In a simple model with just CCI predicting ASA, receiver operating characteristics (ROC) analysis revealed a cut-off of CCI ≥ 1 discriminated best between being ASA ≥ 3 versus < 3 (area under the curve (AUC), 0.70 ± 0.01, 95%CI,0.82-0.84). Multiple logistic regression analyses including age, sex, smoking, and BMI in addition to CCI gave better predictions of ASA (Nagelkerke's pseudo-R2 for predicting ASA class 1 to 4, 46.6%; for predicting ASA ≥ 3 vs. < 3, 37.5%). AUCs for discriminating ASA ≥ 3 versus < 3 from multiple logistic regression were 0.83 ± 0.01 (95%CI, 0.82-0.84) for the training sample and 0.82 ± 0.01 (95%CI, 0.81-0.84), 0.85 ± 0.02 (95%CI, 0.80-0.89), and 0.77 ± 0.04 (95%CI,0.69-0.84) for the test, temporal and external validation samples, respectively. Calibration was adequate in all validation samples. CONCLUSIONS: It was possible to predict ASA from CCI. In a simple model, CCI ≥ 1 best distinguished between ASA ≥ 3 and < 3. For a more precise prediction, regression algorithms were created based on CCI and simple demographic variables obtainable from patient interview. The availability of such algorithms may widen the utility of decision aids that rely on the ASA, where the latter is not readily available.

Lesiones osteoarticulares en cirujanos ortopédicos. ¿Cómo lo afrontamos? / Osteoarthicular injuries in orthopedic surgeons. How do we deal with it?

Resumen: Introducción: La toma de decisiones terapéuticas es un proceso complejo en la cual deben considerarse múltiples variables. Existe una tendencia cada vez mayor hacia la indicación quirúrgica, aunque no siempre la evidencia científica sea contundente. Entender cómo los cirujanos toman decisiones puede mejorar nuestra comprensión de la variabilidad de los tratamientos. Objetivos: exponer la situación demográfica de las lesiones osteoarticulares en los cirujanos ortopédicos de Uruguay y cómo afrontan su propia lesión e identificar aquellas variables que influyen en la toma de decisiones terapéuticas en el ortopedista. Material y métodos: Utilizando la base de datos de la Sociedad de Ortopedia y Traumatología del Uruguay se identificaron residentes y cirujanos que presentaron al menos una lesión osteoarticular. Se entrevistó telefónicamente a cada uno de los seleccionados, obteniendo las variables de interés. Resultados: En un total de 274 residentes y traumatólogos, incluimos 56 profesionales y 69 lesiones osteoarticulares. Destacamos la existencia de múltiples lesiones de tratamiento controvertido, según la evidencia científica actual. El cirujano no siempre indicó el mismo tratamiento a sí mismo respecto al que indicaría a un paciente con la misma lesión. Miedo a las complicaciones, rápida reintegración laboral, opinión de un colega experto, entre otras, fueron algunas de las variables halladas en la decisión terapéutica. Conclusiones: Cuando la lesión asienta en el propio cirujano, se observó un accionar distinto con respecto a un paciente con igual lesión.

Abstract: Introduction: Therapeutic decision-making is a complex process in which multiple variables must be considered. There is a growing trend towards surgical indication, although scientific evidence is not always blunt. Understanding how surgeons make decisions can improve our understanding of treatment variability; Objectives: To expose the demographic situation of osteoarticular injuries in orthopedic surgeons in Uruguay and how they deal with their own injury and identify those variables that influence therapeutic decision-making in the orthopedist. Material and methods: Using the Uruguayan Society of Orthopedics and Traumatology database, residents and surgeons who had at least one osteoarticular injury were identified. Each of the selected ones was interviewed by telephone, obtaining the variables of interest. Results: In a total of 274 residents and Orthopedic surgeons, we include 56 professionals and 69 osteoarticular injuries. We highlight the existence of multiple injuries of controversial treatment, according to current scientific evidence. The surgeon did not always indicate the same treatment to himself, in respect of the one that would indicate a patient with the same injury. Fear of complications, rapid job reimbursement, opinion of an expert colleague, among others were some of the variables found in the therapeutic decision. Conclusions: When the lesion settles on the surgeon itself, a different action was observed with respect to a patient with equal injury.

PRESBYOPIA MANAGEMENT WITH DIFFRACTIVE PHAKIC POSTERIOR CHAMBER IOL.

OBJECTIVE: To evaluate safety and refractive efficiency after posterior chamber diffractive implantable phakic contact lens (IPCL) surgery. MATERIAL AND METHODS: A prospective non-randomized case-series study was performed on 54 myopic eyes of 27 patients who had undergone diffractive IPCL surgery. Corneal endothelial cell density (ECD), central corneal thickness (CCT), intra-ocular pressure (IOP), vault, uncorrected distance (UDVA), spherical equivalent (SE) and defocus curve, were all evaluated twelve months after surgery. The presence of cataracts was evaluated by slit-lamp during a postoperative follow-up. RESULTS: Mean age was 47 ± 2.62 years-old. Mean SE decreased, from -5.95 ± 2.56 D in a pre-operative stage, to -0.25 ± 0.25 D twelve months after surgery. Achieved UDVA was 20/20 in 24.1% of all cases, 20/25 in 74.1% of them, and 20/32 in all remaining cases. No eyes suffered lost lines of vision. The binocular defocus curve was 0.06 ± 0.05 logMAR for a -3.0 D of defocus; 0.11 ± 0.04 logMAR for a -1.5 D of defocus, and 0.08 ± 0.03 logMAR for a 0 D of defocus. Twelve months after surgery, mean ECD had decreased by 1.43 %, whereas mean CCT had increased by 0.06 %, without any significant statistical difference (p = 0.28 and p = 0.93 respectively). No difference (p: 0.86) in the vault was observed at 6 months vs.12 months, as well as between IOP measurements (p = 0.22). There were no non-intra or postoperative complications, and, specifically, no cataracts developed either. CONCLUSIONS: Diffractive IPCL was implanted safely. Corneal endothelial CD, CCT, vault, and IOP remained stable twelve months after surgery. Visual acuity for distance, intermediate and near sight were achieved without spectacles.

Timing of oral feeding changes in premature infants who underwent osteopathic manipulative treatment.

BACKGROUND: The delayed transition from gavage-to-nipple feeding is one of the most significant factors that may prolong hospital length of stay (LOS). Osteopathic manipulative treatment (OMT) has been demonstrated to be effective regarding LOS reduction, but no investigations have documented its clinical validity for attaining oral feeding. OBJECTIVES: To assess OMT utility regarding the timing of oral feeding in healthy preterm infants. DESIGN: Preliminary propensity score-matched retrospective cohort study. SETTING: Data were extrapolated from the neonatal intensive care unit (NICU) of Del Ponte Hospital in Varese, Italy, during the period between March 2012 and December 2013. INTERVENTIONS: Two propensity score-matched groups of healthy preterm infants aged 28+0 to 33+6 were compared, observing those supported with OMT until hospital discharge and control subjects. MAIN OUTCOME MEASURES: Days from birth to the attainment of oral feeding was the primary endpoint. Body weight, body length, head circumference and LOS were considered as secondary endpoints. RESULTS: Seventy premature infants were included in the study as the control group (n = 35; body weight (BW) = 1457.9 ± 316.2 g; gestational age (GA) = 31.5 ± 1.73 wk) and the osteopathic group (n = 35; BW = 1509.6 ± 250.8 g; GA = 31.8 ± 1.64 wk). The two groups had analogous characteristics at study entry. In this cohort, we observed a significant reduction in TOF (-5.00 days; p = 0.042) in the osteopathic group with a greater effect in very low birth weight infants. CONCLUSIONS: These data demonstrate the utility and potential efficacy of OMT for the attainment of oral feeding. Further adequately powered clinical trials are recommended.

De-escalated therapy for HR+/HER2+ breast cancer patients with Ki67 response after 2-week letrozole: results of the PerELISA neoadjuvant study.

BACKGROUND: In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole. PATIENTS AND METHODS: PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon's design, to reject the null hypothesis, at least 8/43 pCR had to be documented. RESULTS: Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042). CONCLUSIONS: The primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared. EUDRACT NUMBER: 2013-002662-40. CLINICALTRIALS.GOV IDENTIFIER: NCT02411344.

Radiofrequency echographic multispectrometry compared with dual X-ray absorptiometry for osteoporosis diagnosis on lumbar spine and femoral neck.

An innovative, non-ionizing technique to diagnose osteoporosis on lumbar spine and femoral neck was evaluated through a multicenter study involving 1914 women. The proposed method showed significant agreement with reference gold standard method and, therefore, a potential for early osteoporosis diagnoses and possibly improved patient management. INTRODUCTION: To assess precision (i.e., short term intra-operator precision) and diagnostic accuracy of an innovative non-ionizing technique, REMS (Radiofrequency Echographic Multi Spectrometry), in comparison with the clinical gold standard reference DXA (dual X-ray absorptiometry), through an observational multicenter clinical study. METHODS: In a multicenter cross-sectional observational study, a total of 1914 postmenopausal women (51-70 years) underwent spinal (n = 1553) and/or femoral (n = 1637) DXA, according to their medical prescription, and echographic scan of the same anatomical sites performed with the REMS approach. All the medical reports (DXA and REMS) were carefully checked to identify possible errors that could have caused inaccurate measurements: erroneous REMS reports were excluded, whereas erroneous DXA reports were re-analyzed where possible and otherwise excluded before assessing REMS accuracy. REMS precision was independently assessed. RESULTS: In the spinal group, quality assessment on medical reports produced the exclusion of 280 patients because of REMS errors and 78 patients because of DXA errors, whereas 296 DXA reports were re-analyzed and corrected. Analogously, in the femoral group there were 205 exclusions for REMS errors, 59 exclusions for DXA errors, and 217 re-analyzed DXA reports. In the resulting dataset (n = 1195 for spine, n = 1373 for femur) REMS outcome showed a good agreement with DXA: the average difference in bone mineral density (BMD, bias ± 2SD) was -0.004 ± 0.088 g/cm2 for spine and - 0.006 ± 0.076 g/cm2 for femur. Linear regression showed also that the two methods were well correlated: standard error of the estimate (SEE) was 5.3% for spine and 5.8% for femur. REMS precision, expressed as RMS-CV, was 0.38% for spine and 0.32% for femur. CONCLUSIONS: The REMS approach can be used for non-ionizing osteoporosis diagnosis directly on lumbar spine and femoral neck with a good level of accuracy and precision. However, a more rigorous operator training is needed to limit the erroneous acquisitions and to ensure the full clinical practicability.