Problematic meta-analyses: Bayesian and frequentist perspectives on combining randomized controlled trials and non-randomized studies.

PURPOSE: In the literature, the propriety of the meta-analytic treatment-effect produced by combining randomized controlled trials (RCT) and non-randomized studies (NRS) is questioned, given the inherent confounding in NRS that may bias the meta-analysis. The current study compared an implicitly principled pooled Bayesian meta-analytic treatment-effect with that of frequentist pooling of RCT and NRS to determine how well each approach handled the NRS bias. MATERIALS & METHODS: Binary outcome Critical-Care meta-analyses, reflecting the importance of such outcomes in Critical-Care practice, combining RCT and NRS were identified electronically. Bayesian pooled treatment-effect and 95% credible-intervals (BCrI), posterior model probabilities indicating model plausibility and Bayes-factors (BF) were estimated using an informative heavy-tailed heterogeneity prior (half-Cauchy). Preference for pooling of RCT and NRS was indicated for Bayes-factors > 3 or < 0.333 for the converse. All pooled frequentist treatment-effects and 95% confidence intervals (FCI) were re-estimated using the popular DerSimonian-Laird (DSL) random effects model. RESULTS: Fifty meta-analyses were identified (2009-2021), reporting pooled estimates in 44; 29 were pharmaceutical-therapeutic and 21 were non-pharmaceutical therapeutic. Re-computed pooled DSL FCI excluded the null (OR or RR = 1) in 86% (43/50). In 18 meta-analyses there was an agreement between FCI and BCrI in excluding the null. In 23 meta-analyses where FCI excluded the null, BCrI embraced the null. BF supported a pooled model in 27 meta-analyses and separate models in 4. The highest density of the posterior model probabilities for 0.333 < Bayes factor < 1 was 0.8. CONCLUSIONS: In the current meta-analytic cohort, an integrated and multifaceted Bayesian approach gave support to including NRS in a pooled-estimate model. Conversely, caution should attend the reporting of naïve frequentist pooled, RCT and NRS, meta-analytic treatment effects.

When Can Nonrandomized Studies Support Valid Inference Regarding Effectiveness or Safety of New Medical Treatments?

The randomized controlled trial (RCT) is the gold standard for evaluating the causal effects of medications. Limitations of RCTs have led to increasing interest in using real-world evidence (RWE) to augment RCT evidence and inform decision making on medications. Although RWE can be either randomized or nonrandomized, nonrandomized RWE can capitalize on the recent proliferation of large healthcare databases and can often answer questions that cannot be answered in randomized studies due to resource constraints. However, the results of nonrandomized studies are much more likely to be impacted by confounding bias, and the existence of unmeasured confounders can never be completely ruled out. Furthermore, nonrandomized studies require more complex design considerations which can sometimes result in design-related biases. We discuss questions that can help investigators or evidence consumers evaluate the potential impact of confounding or other biases on their findings: Does the design emulate a hypothetical randomized trial design? Is the comparator or control condition appropriate? Does the primary analysis adjust for measured confounders? Do sensitivity analyses quantify the potential impact of residual confounding? Are methods open to inspection and (if possible) replication? Designing a high-quality nonrandomized study of medications remains challenging and requires broad expertise across a range of disciplines, including relevant clinical areas, epidemiology, and biostatistics. The questions posed in this paper provide a guiding framework for assessing the credibility of nonrandomized RWE and could be applied across many clinical questions.

Advantages of multi-arm non-randomised sequentially allocated cohort designs for Phase II oncology trials.

BACKGROUND: Efficient trial designs are required to prioritise promising drugs within Phase II trials. Adaptive designs are examples of such designs, but their efficiency is reduced if there is a delay in assessing patient responses to treatment. METHODS: Motivated by the WIRE trial in renal cell carcinoma (NCT03741426), we compare three trial approaches to testing multiple treatment arms: (1) single-arm trials in sequence with interim analyses; (2) a parallel multi-arm multi-stage trial and (3) the design used in WIRE, which we call the Multi-Arm Sequential Trial with Efficient Recruitment (MASTER) design. The MASTER design recruits patients to one arm at a time, pausing recruitment to an arm when it has recruited the required number for an interim analysis. We conduct a simulation study to compare how long the three different trial designs take to evaluate a number of new treatment arms. RESULTS: The parallel multi-arm multi-stage and the MASTER design are much more efficient than separate trials. The MASTER design provides extra efficiency when there is endpoint delay, or recruitment is very quick. CONCLUSIONS: We recommend the MASTER design as an efficient way of testing multiple promising cancer treatments in non-comparative Phase II trials.

Efecto del uso de mensajes de texto en dispositivos de telefonía móvil en la adherencia al tratamiento de hipertensión arterial / Effect of mobile phone text messaging on adherence to hypertension treatment

La hipertensión arterial es una de las enfermedades crónicas de mayor incidencia a nivel mundial, produce una importante mortalidad y discapacidad. Este trabajo tuvo por objetivo evaluar el efecto del uso de mensajes de texto en dispositivos de telefonía móvil en la adherencia al tratamiento de hipertensión arterial. Se efectuó un estudio de intervención cuasiexperimental, de antes y después, en el cual se entrevistó a pacientes que pertenecían a un programa ambulatorio de enfermedades crónicas. Se formaron 4 grupos, uno de ellos, el grupo control. A los grupos intervenidos se les remitieron mensajes de texto (educativos/motivadores), con diferentes frecuencias de envío, por un período de 2 meses. Al término de la intervención, se pidió llenar el cuestionario Martín-Bayarre-Grau para determinar su adherencia al tratamiento antihipertensivo antes y después de la intervención. Se realizó un análisis bivariado, en el cual se comparó la variable adherencia al tratamiento, antes y después de la intervención, de los cuatro grupos del estudio. Se encontró solo una diferencia significativa en el grupo 3 (p = 0,011), al cual se le enviaron 8 mensajes al mes (2 por semana). También se comparó, después de los 2 meses, a los grupos sometidos a intervención versus el grupo control; se halló una diferencia significativa en el grupo 3 (p = 0,022). La intervención ha demostrado ser útil para mejorar la adherencia en esta población de estudio. Se obtuvo una respuesta positiva en el grupo 3, que recibió 8 mensajes al mes(AU)

Hypertension is one of the chronic diseases with the highest incidence worldwide and a cause of considerable mortality and disability. This paper aims to evaluate the effect of mobile phone text messaging on adherence to hypertension treatment. A quasi-experimental before-after intervention was conducted based on interviews with patients from a chronic disease outpatient program. Four groups were formed, one of which was the control group. The groups intervened were sent encouraging educational text messages at varying frequencies for a period of two months. At the close of the intervention, participants were asked to fill in the Martín Bayarre Grau questionnaire to determine their adherence to antihypertensive treatment before and after the intervention. A bivariate analysis was performed comparing the variable adherence to treatment before and after the intervention in the four study groups. A significant difference was only found in Group 3 (p = 0.011). This group was sent eight messages per month (two messages per week). Additionally, a comparison between the intervention groups and the control group conducted at two months found a significant difference in Group 3 (p = 0.022). The intervention proved was useful to improve adherence in the study population. A positive response was obtained in Group 3, who received eight messages per month(AU)

Patients with Moderate Non-Culprit Coronary Lesions of Recent Acute Coronary Syndrome.

Fractional flow reserve (FFR) measurement was compared to dobutamine stress echocardiography (DSE) instable angina (SA) with stable coronary lesion (s) (SCL (s) ) in a few trials; however, similar comparisons in patients with acute coronary syndrome (ACS) with non-culprit lesion (s) (NCL (s) ) are lacking. Our objectives were to prospectively evaluate the diagnostic performance of FFR with two different cutoff values (< 0.80 and < 0.75) relative to DSE in moderate (30%-70% diameter stenosis) NCLs (ACS group) and to compare these observations with those measured in SCLs (SA group). One hundred seventy-five consecutive patients with SA (n = 86) and ACS (n = 89) with 225 coronary lesions (109 SCLs and 116 NCLs) were enrolled. In contrast to the ACS cohort in SA patients, normal DSE was associated with higher FFR values compared to those with abnormal DSE (P = 0.051 versus P = 0.006). In addition, in the SA group, a significant correlation was observed between DSE (regional wall motion score index at peak stress) and FFR (r = -0.290; P = 0.002), whereas a similar association was absent (r = -0.029; P = 0.760) among ACS patients. In the SA group, decreasing the FFR cutoff value (< 0.80 versus < 0.75) improved the concordance of FFR with DSE (70.6% versus 81.7%) without altering its discriminatory power (area under the curve; 0.68 versus 0.63; P = 0.369), whereas in the ACS group, concordance remained similar (69.0% versus 71.6%) and discriminatory power decreased (0.62 versus 0.51; P = 0.049), respectively. In conclusion, lesion-specific FFR assessment may have different relevance in patients with moderate NCLs than in patients with SCLs.

The effect of care transition pathway implementation on patients undergoing joint replacement during the COVID-19 pandemic: a quasi-experimental study from a tertiary care hospital orthopedic department in Beijing, China.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has had a massive impact on individuals globally. The Chinese government has formulated effective response measures, and medical personnel have been actively responding to challenges associated with the epidemic prevention and control strategies. This study aimed to evaluate the effect of the implementation of a care transition pathway on patients that underwent joint replacement during the COVID-19 pandemic. METHODS: A quasi-experimental study was designed to evaluate the effect of implementing a care transition pathway for patients who underwent joint replacement during the COVID-19 pandemic in the orthopedic department of a tertiary care hospital in Beijing, China. Using a convenient sampling method, a total of 96 patients were selected. Of these, 51 patients who had undergone joint replacement in 2019 and received treatment via the routine nursing path were included in the control group. The remaining 45 patients who underwent joint replacement during the COVID-19 epidemic in 2020 and received therapy via the care transition pathway due to the implementation of epidemic prevention and control measures were included in the observation group. The quality of care transition was assessed by the Care Transition Measure (CTM), and patients were followed up 1 week after discharge. RESULTS: The observation group was determined to have better general self-care preparation, written planning materials, doctor-patient communication, health monitoring, and quality of care transition than the control group. CONCLUSIONS: A care transition pathway was developed to provide patients with care while transitioning through periods of treatment. It improved the patient perceptions of nursing quality. The COVID-19 pandemic is a huge challenge for health professionals, but we have the ability to improve features of workflows to provide the best possible patient care.

Feeding during neonatal therapeutic hypothermia, assessed using routinely collected National Neonatal Research Database data: a retrospective, UK population-based cohort study.

BACKGROUND: Therapeutic hypothermia is standard of care in high-income countries for babies born with signs of hypoxic ischaemic encephalopathy, but optimal feeding during treatment is uncertain and practice is variable. This study aimed to assess the association between feeding during therapeutic hypothermia and clinically important outcomes. METHODS: We did a population-level retrospective cohort study using the UK National Neonatal Research Database. We included all babies admitted to National Health Service neonatal units in England, Scotland, and Wales between Jan 1, 2010, and Dec 31, 2017, who received therapeutic hypothermia for 72 h or died during this period. For analysis, we created matched groups using propensity scores and compared outcomes in babies who were fed versus unfed enterally during therapeutic hypothermia. The primary outcome was severe necrotising enterocolitis, either confirmed at surgery or causing death. Secondary outcomes include pragmatically defined necrotising enterocolitis (a recorded diagnosis of necrotising enterocolitis in babies who received at least 5 consecutive days of antibiotics while also nil by mouth during their neonatal unit stay), late-onset infection (pragmatically defined as 5 consecutive days of antibiotic treatment commencing after day 3), survival to discharge, measures of breastmilk feeding, and length of stay in neonatal unit. FINDINGS: 6030 babies received therapeutic hypothermia, of whom 1873 (31·1%) were fed during treatment. Seven (0·1%) babies were diagnosed with severe necrotising enterocolitis and the number was too small for further analyses. We selected 3236 (53·7%) babies for the matched feeding analysis (1618 pairs), achieving a good balance for all recorded background variables. Pragmatically defined necrotising enterocolitis was rare in both groups (incidence 0·5%, 95% CI 0·2-0·9] in the fed group vs 1·1% [0·7-1·4] in the unfed group). The enterally fed group had fewer pragmatically defined late-onset infections (difference -11·6% [95% CI -14·0 to -9·3]; p<0·0001), higher survival to discharge (5·2% [3·9-6·6]; p<0·0001), higher proportion of breastfeeding at discharge (8·0% [5·1-10·8]; p<0·0001), and shorter neonatal unit stays (-2·2 [-3·0 to -1·2] days; p<0·0001) compared with the unfed group. INTERPRETATION: Necrotising enterocolitis is rare in babies receiving therapeutic hypothermia. Enteral feeding during hypothermia is safe and associated with beneficial outcomes compared with not feeding, although residual confounding could not be completely ruled out. Our findings support starting milk feeds during therapeutic hypothermia. FUNDING: UK National Institute for Health Research Health Technology Assessment programme 16/79/13.

Safety of Allogeneic Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Complex Perianal Fistulas Not Associated With Crohn's Disease: A Phase I Clinical Trial.

BACKGROUND: Anal fistula treatment aims to eradicate the fistula, preserve the sphincter, prevent recurrence, and allow an early return to daily activities for the patient. Because of the difficulty of achieving these goals, stem cell-based therapy has emerged for the treatment of complex perianal fistula with promising results. OBJECTIVE: The objective of this study was to evaluate the safety of allogeneic mesenchymal stem cells in the treatment of complex anal fistula in patients without Crohn's disease. DESIGN: This was a prospective nonrandomized phase I clinical trial. SETTINGS: This study was conducted at a second-level hospital. PATIENTS: Twenty consecutive patients diagnosed with a complex fistula were included. INTERVENTIONS: All patients received 40 × 106 allogeneic mesenchymal stem cells. In patients with 2 tracts, 20 × 106 stem cells were applied on each tract. MAIN OUTCOME MEASURES: The patients were discharged 24 hours after the procedure and were evaluated at 1, 2, 4, 8, 16, and 24 weeks after the application. The long-term follow-up was performed 1 year after the procedure. RESULTS: The procedure was performed in a total of 20 patients from October 1, 2016, to October 31, 2017; 1 patient was eliminated from the final data analysis. No adverse effects were reported within the first 24 hours, and all the patients were discharged asymptomatic. Three patients (15%) presented with perianal abscess. In 1 patient, the abscess appeared at the fourth week, and, in the other 2 patients, the abscess was diagnosed at week 8. Complete closure was achieved in 13 (69%) patients. LIMITATIONS: This was a nonrandomized controlled trial. CONCLUSION: The use of allogeneic mesenchymal stem cells as a treatment is a safe option for the management of complex perianal fistula not associated with Crohn's disease. See Video Abstract at http://links.lww.com/DCR/B443. SEGURIDAD DE LAS CLULAS MADRE MESENQUIMALES ALOGNICAS DERIVADAS DEL TEJIDO ADIPOSO PARA EL TRATAMIENTO DE FSTULAS PERIANALES COMPLEJAS NO ASOCIADAS CON LA ENFERMEDAD DE CROHN ENSAYO CLNICO DE FASE I: ANTECEDENTES:El tratamiento de la fístula anal tiene como objetivo erradicar la fístula, preservar el esfínter, prevenir la recurrencia y permitir un retorno temprano a las actividades diarias del paciente. Debido a la dificultad de alcanzar estos objetivos, ha surgido una terapia basada en células madre para el tratamiento de la fístula perianal compleja con resultados prometedores.OBJETIVO:El objetivo de este estudio fue evaluar la seguridad de las células madre mesenquimales alogénicas en el tratamiento de la fístula anal compleja en pacientes sin enfermedad de Crohn.DISEÑO:Este fue un ensayo clínico prospectivo no aleatorizado de fase I.AMBIENTE:Este estudio se realizó en un hospital de segundo nivel.PACIENTES:Veinte pacientes consecutivos diagnosticados de fístula compleja.INTERVENCIONES:Todos los pacientes recibieron 40 x 106 células madre mesenquimales alogénicas, en pacientes con dos tractos, se aplicaron 20 x 106 células madre en cada tracto.PRINCIPALES MEDIDAS DE RESULTADO:Los pacientes fueron dados de alta 24 horas después del procedimiento y fueron evaluados 1, 2, 4, 8, 16, 24 semanas después de la aplicación. El seguimiento a largo plazo se realizó un año después del procedimiento.RESULTADOS:El procedimiento se realizó en un total de 20 pacientes desde el 1 de octubre de 2016 al 31 de octubre de 2017; un paciente fue eliminado del análisis de datos final. No se informaron efectos adversos en las primeras 24 horas, todos los pacientes fueron dados de alta asintomáticos. Tres pacientes (15%) presentaron absceso perianal. En un paciente, el absceso apareció a la cuarta semana y en los otros dos pacientes el absceso se diagnosticó en la octava semana. El cierre completo se logró en 13 (69%) de los pacientes.LIMITACIONES:Este fue un ensayo controlado no aleatorio.CONCLUSIÓN:El uso de células madre mesenquimales alogénicas como tratamiento es una opción segura para el manejo de la fístula perianal compleja no asociada con la enfermedad de Crohn. Consulte Video Resumen en http://links.lww.com/DCR/B443.

The Revised WIC Food Package and Child Development: A Quasi-Experimental Study.

BACKGROUND AND OBJECTIVES: The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), one of the largest US safety net programs, was revised in 2009 to be more congruent with dietary guidelines. We hypothesize that this revision led to improvements in child development. METHODS: Data were drawn from a cohort of women and children enrolled in the Conditions Affecting Neurocognitive Development and Learning in Early Childhood study from 2006 to 2011 (Shelby County, TN; N = 1222). Using quasi-experimental difference-in-differences analysis, we compared measures of growth, cognitive, and socioemotional development between WIC recipients and nonrecipients before and after the policy revision. RESULTS: The revised WIC food package led to increased length-for-age z scores at 12 months among infants whose mothers received the revised food package during pregnancy (ß = .33, 95% confidence interval: 0.05 to 0.61) and improved Bayley Scales of Infant Development cognitive composite scores at 24 months (ß = 4.34, 95% confidence interval: 1.11 to 7.57). We observed no effects on growth at age 24 months or age 4 to 6 years or cognitive development at age 4 to 6 years. CONCLUSIONS: This study provides some of the first evidence that children of mothers who received the revised WIC food package during pregnancy had improved developmental outcomes in the first 2 years of life. These findings highlight the value of WIC in improving early developmental outcomes among vulnerable children. The need to implement and expand policies supporting the health of marginalized groups has never been more salient, particularly given the nation's rising economic and social disparities.

Exploring the Contributions of Combined Model Regional Medical Education Campuses to the Physician Workforce.

PURPOSE: Physician shortages and maldistribution, particularly within family medicine, have led many medical schools worldwide to create regional medical campuses (RMCs) for clerkship training. However, Canadian medical schools have developed a number of RMCs in which all years of training (i.e., a combined model that includes both preclerkship and clinical training) are provided geographically separate from the main campus. This study addresses the question: Are combined model RMC graduates more likely to enter postgraduate training in family medicine and rural-focused programs relative to main campus graduates? METHOD: The authors used a quasi-experimental research design and analyzed 2006-2016 data from the Canadian Resident Matching Service (CaRMS). Graduating students (N = 26,525) from 16 Canadian medical schools who applied for the CaRMS match in their year of medical school graduation were eligible for inclusion. The proportions of graduates who matched to postgraduate training in (1) family medicine and (2) rural-focused programs were compared for combined model RMCs and main campuses. RESULTS: Of RMC graduates, 48.4% matched to family medicine (95% confidence interval [CI] = 46.1-50.7) compared with 37.1% of main campus graduates (95% CI = 36.5-37.7; P < .001). Of RMC graduates, 23.9% matched to rural-focused training programs (95% CI = 21.8-25.9) compared with 10.4% of main campus graduates (95% CI = 10.0-10.8; P < .001). Subanalyses ruled out a variety of potentially confounding variables. CONCLUSIONS: Combined model RMCs, in which all years of training take place away from the medical school's main campus, are associated with greater proportions of medical students entering family medicine postgraduate training and rural-focused training programs. These findings should encourage policymakers, health services agencies, and medical schools to continue seeking complements to academic medical center-based medical education.

Pride and Prejudice during the COVID-19 Pandemic: The Misfortune of Inappropriate Clinical Trial Design.

Coronavirus Disease 2019 (COVID-19) is a rapidly evolving global pandemic for which more than a thousand clinical trials have been registered to secure therapeutic effectiveness, expeditiously. Most of these are single-center non-randomized studies rather than multi-center, randomized controlled trials. Single-arm trials have several limitations and may be conducted when spontaneous improvement is not anticipated, small placebo effect exists, and randomization to a placebo is not ethical. In an emergency where saving lives takes precedence, it is ethical to conduct trials with any scientifically proven design, however, safety must not be compromised. A phase II or III trial can be conducted directly in a pandemic with appropriate checkpoints and stopping rules. COVID-19 has two management paradigms- antivirals, or treatment of its complications. Simultaneous assessment of two different treatments can be done using 2 × 2 factorial schema. World Health Organization's SOLIDARITY trial is a classic example of the global research protocol which can evaluate the preferred treatment to combat COVID-19 pandemic. Short of that, a trial design must incorporate the practicality of the intervention used, and an appropriate primary endpoint which should ideally be a clinical outcome. Collaboration between institutions is needed more than ever to successfully execute and accrue in randomized trials.

Methodological approaches to the design and analysis of nonrandomized intervention studies for the prevention of child and adolescent obesity.

OBJECTIVES: Interventions for child obesity prevention are needed and it is unclear whether evidence from nonrandomized intervention studies is adequate. The objective of this research was to review the methods for the design, analysis and reporting of nonrandomized intervention studies for child obesity prevention and to assess potential for bias. METHODS: We conducted a review of nonrandomized intervention studies, including population health interventions, quasi-experimental studies and natural experiments, published from 2013 to 2017 that were identified in a recent systematic review. Data on study design, intervention and control groups, outcome measures, and statistical analyses, were extracted. Risk of bias was evaluated using the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool. RESULTS: All identified studies (n = 23) included a school or community-based intervention and had a concurrent control group. Participants were 3-18 years and sample sizes were 100 to > 1 million. Study designs were described inconsistently, and interventions ranged from 14 weeks to 5 years. Obesity was compared between control and intervention groups using logistic or linear regression, analysis of variance and mixed effects regression. Only 48% of studies accounted for clustering, and methods to control for confounding and repeated measures varied substantially. Overall risk of bias was moderate to serious for all studies. CONCLUSION: There are substantial opportunities to improve the methods for nonrandomized intervention studies and reduce bias. Future studies should use advanced statistical and causal epidemiology methods, including better control for confounding and clustering, to generate higher quality evidence and certainty regarding which obesity prevention interventions are effective.

Effect of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intravenous Rivipansel.

Two studies evaluated the effects of renal and hepatic impairment on pharmacokinetics and safety of rivipansel (NCT02813798, NCT02871570). A single intravenous 840-mg rivipansel dose was administered to subjects with renal impairment or normal renal function in study 1005 and subjects with moderate hepatic impairment or normal hepatic function in study 1006. Plasma (both studies) and urine (study 1005) samples were collected for 96 hours postdose. All subjects in studies 1005 (n = 28) and 1006 (n = 16) completed all study procedures. Rivipansel exposure (AUCinf ) was 47%, 124%, and 437% higher and total clearance 30%, 57%, and 82% lower in the mild, moderate, and severe renal impairment groups, respectively, than in the normal renal function group. Overall rivipansel exposure was 20% lower and total clearance 31% higher in the moderate hepatic impairment group than in the normal hepatic function group. Ten treatment-emergent adverse events occurred in studies 1005 and 1006; no event was considered treatment related. As expected, clearance of rivipansel decreased with increasing renal impairment. The difference observed between rivipansel pharmacokinetics in subjects with moderate hepatic impairment and subjects with normal hepatic function was not considered clinically significant. Single doses of rivipansel were well tolerated in subjects with either renal or hepatic impairment.

Sofosbuvir plus ribavirin and sofosbuvir plus ledipasvir in patients with genotype 1 or 3 hepatitis C virus and severe renal impairment: a multicentre, phase 2b, non-randomised, open-label study.

BACKGROUND: There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4-5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis. METHODS: This phase 2b, open-label, non-randomised, multicentre study in the USA and New Zealand investigated three sequentially enrolled cohorts of patients. Patients were recruited from ten hospitals and clinical research centres and were included if they had genotype 1 or 3 HCV infection, a creatinine clearance less than or equal to 30 mL/min, and were not on dialysis. In cohorts 1 and 2, patients received sofosbuvir (200 mg in cohort 1 and 400 mg in cohort 2) plus ribavirin 200 mg once per day for 24 weeks. In cohort 3, 18 patients received ledipasvir combined with sofosbuvir (90 mg ledipasvir and 400 mg sofosbuvir) once per day for 12 weeks. The primary efficacy endpoint was the proportion of patients achieving sustained virological response 12 weeks after the end of treatment (SVR12). Safety and pharmacokinetic data were also collected. The trial is registered with ClinicalTrials.gov, number NCT01958281, and is completed. FINDINGS: This study was done between Oct 7, 2013, and Oct 29, 2017. In the sofosbuvir plus ribavirin cohorts, 32 patients were screened, of whom 20 were enrolled and assessed for efficacy and safety (ten patients in each cohort). In the ledipasvir plus sofosbuvir cohort, 33 patients were screened, of whom 18 were enrolled and assessed for treatment efficacy and safety. Four (40%, 95% CI 12-74) of ten patients in cohort 1 and six (60%, 26-88) of ten patients in cohort 2 achieved SVR12. All 18 (100%, 82-100) patients in cohort 3 achieved SVR12. Adverse events were mostly mild or moderate in severity. The most commonly reported adverse events overall were headache (eight [21%] of 38 patients), anaemia (seven [18%] of 38 patients), and fatigue (six [16%] of 38 patients). Eight patients had serious adverse events, none of which were treatment related. There were no treatment-related cardiac events or clinically significant changes in echocardiographic parameters or creatinine clearance by Cockcroft-Gault. INTERPRETATION: In this phase 2b study, ledipasvir combined with sofosbuvir for 12 weeks was safe and effective in patients with genotype 1 HCV infection and stage 4-5 chronic kidney disease who were not on dialysis. FUNDING: Gilead Sciences.

Estimation of historical control rate for a single arm de-escalation study - Application to the POSITIVE trial.

BACKGROUND: Although randomized controlled clinical trials are optimal to evaluate the effect of an experimental therapy, single-arm trials are required whenever randomization is unethical or not feasible, such as de-escalation studies. We propose using prospectively identified historical controls to place results of single-arm, de-escalation trials into context. METHODS: POSITIVE is a prospective, single-arm study in young women with hormone-receptor-positive early breast cancer to determine if temporarily interrupting adjuvant endocrine therapy in order to become pregnant increases the risk of a breast cancer event. After 272 women enrolled in POSITIVE, we identified a cohort of 1499 SOFT/TEXT patients potentially eligible to enroll in POSITIVE who did not interrupt endocrine therapy. Method I used the SOFT/TEXT cohort to calculate annualized hazard rates by a piecewise exponential model. Method II used the SOFT/TEXT cohort to group-match SOFT/TEXT patients to POSITIVE patients; sample sets of SOFT/TEXT patients were randomly drawn 5000 times to obtain sets having patient, disease, and treatment characteristics more balanced with POSITIVE participants. RESULTS: Compared with SOFT/TEXT, POSITIVE participants were younger, less likely to be overweight/obese, had fewer positive nodes, and fewer received aromatase inhibitor or chemotherapy. The estimated 3-year breast cancer free interval event rates were 9.5% (95% CI: 7.9%,11.1%) for Method I and 9.4% (95% CI: 7.8%,10.9%) for Method II, compared with 5.8% initially assumed when POSITIVE was designed. CONCLUSION: External control datasets should be identified before launching single-arm, de-escalation trials and methods applied during their conduct to provide context for interim monitoring and interpretation of the final analysis.

Estabilidad y nivel óseo periimplantario de implantes postextractivos en pacientes de la tercera edad / Stability and peri-implant bone level of post-extractive implants in elderly patients

Introducción: Los implantes postextractivos acortan el tiempo en lograr la rehabilitación del paciente, resulta esta condicionante un factor esencial para devolver la calidad de vida en corto plazo a un adulto mayor y mejorar rápidamente su función masticatoria. Objetivo: Determinar los valores de estabilidad y la pérdida ósea periimplantaria en implantes postextractivos en pacientes de la tercera edad. Material y Método: Se realizó un estudio cuasi-experimental en 99 pacientes de la tercera edad en la Facultad de Estomatología ¨Raúl González Sánchez¨, 2017-2019. Bajo su consentimiento se colocaron 173 implantes postextractivos. Se determinó tipo de hueso de soporte, estabilidad primaria y secundaria según análisis de frecuencia de resonancia con Osstel Mentor. Se midió el nivel óseo periimplantario y la pérdida ósea hasta 12 meses de colocada la rehabilitación. Resultados: Se posicionaron mayoritariamente implantes en el sitio de implantación incisivo maxilar en 43,3 por ciento de los casos. Los valores promedio de estabilidad primaria y secundaria fueron 48 ISQ y 68 ISQ respectivamente. La pérdida ósea promedio tras un año de rehabilitación fue de 1,04±0,22mm. Conclusiones: Los implantes dentales postextractivos en pacientes de la tercera edad se insertaron preferentemente en el grupo incisivo maxilar y en hueso tipo D2, registraron una estabilidad primaria promedio moderada y una estabilidad secundaria promedio substancial. La pérdida ósea vertical periimplantaria exhibió valores semejantes a los implantes en zonas curadas y dentro del valor estandarizado para pérdida ósea periimplantaria para el primer año tras su colocación(AU)

Introduction: Post-extractive implants shorten the time in achieving the rehabilitation of the patient, being this condition an essential factor to restore the quality of life to elderly patients at short term. Objective: To determine the stability values and peri-implant bone loss in post-extractive implants in elderly patients. Material and Method: A cohort study was carried out in 99 elderly patients at Raúl González Sánchez Dental School of Havana from 2017 to 2019. Under the consent of the patients, 173 post-extractive implants were placed. Bone support type, and primary and secondary stability were determined on the basis of a resonance frequency analysis with Ostell Mentor®. The peri-implant bone level and peri-implant bone loss were measured until 12 months after rehabilitation. Results: Implants were mainly positioned in the maxillary incisive site in 43,3 percent of the cases. The average values of primary and secondary stability were 48 ISQ and 68 ISQ, respectively. The average bone loss after 12 months of rehabilitation was 1,04 ± 0,22 mm. Conclusions: Post-extractive dental implants were inserted preferably in the maxillary incisive site and in D2 bone type, registering moderated average values of primary stability and substantial average values of secondary stability. The peri-implant vertical bone loss exhibited implants with similar values than those in the healed areas and within the standardized value for peri-implant bone loss within the first year after implant placement(AU)

Pharmacokinetics of Gepotidacin in Renal Impairment.

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. In this phase 1, nonrandomized, open-label, parallel-group, multicenter, multipart study, the pharmacokinetics, safety, and tolerability of a single intravenous (IV) dose of gepotidacin 750 mg over 2 hours were evaluated in subjects with normal renal function, in those with moderate and severe renal impairment, and in end-stage renal disease (ESRD) on and not on dialysis. Administration of IV gepotidacin 750 mg was safe and generally tolerated in the study subjects. Dosing in severe renal impairment with and without hemodialysis resulted in significant increases in plasma drug levels and decreases in clearance. The geometric mean elimination half-life (t½ ) was minimally impacted (range 9.45 to 11.5 hours) in all the renal-impairment groups relative to normal renal function. Regardless of renal function, urine gepotidacin concentrations remained considerably high over a 12-hour period. Saliva concentrations displayed a linear relationship with plasma concentrations. The t½ in saliva was not impacted in the moderate-impairment and ESRD subjects and was comparable to t½ in plasma. Over a 4-hour dialysis, approximately 6% of the gepotidacin dose was removed. Overall, subjects with severe renal impairment and ESRD with and without hemodialysis may require adjustment in dose or dosing frequency.

The problem of axillary staging in breast cancer after neoadjuvant chemotherapy. Role of targeted axillary dissection and types of lymph node markers. / El problema de la estadificación axilar en el cáncer de mama tras quimioterapia neoadyuvante. Papel de la disección axilar dirigida y tipos de marcadores ganglionares.

Targeted axillary dissection (TAD) consists of a new axillary staging technique that combines sentinel lymph node biopsy (SLNB) and clipped lymph node biopsy (CLNB) in the same surgery, in order to re-stage patients with breast cancer and positive axillary lymph nodes undergoing neoadjuvant chemotherapy (NAQT). Prior to the NAQT, the affected lymph node is punctured and a solid marker is left inside echo-guided, in order to biopsy it in the subsequent surgery. There are numerous types of markers: metallic (steel, titanium or polyglycolic acid clips), radioiodine or ferromagnetic seeds, which differ in the method of location (wire, gamma-detection or magnetic probe). The aim of this study is to perform a systematic review about the current status of the TAD, as well as to explain the different techniques and types of axillary marking, based on the current available evidence.

Endoscopic Step Up: A Colon-Sparing Alternative to Colectomy to Improve Outcomes and Reduce Costs for Patients With Advanced Neoplastic Polyps.

BACKGROUND: The optimal strategy for colonic polyps not amenable to traditional endoscopic polypectomy is unknown. Endoscopic step up is a promising strategy for definitive treatment. OBJECTIVE: The purpose of this study was to determine whether endoscopic step up leads to improved outcomes and decreased costs compared with planned colectomy for endoscopically unresectable colon polyps. DESIGN: This was a retrospective review of a prospective database. SETTING: The study was conducted at a tertiary referral center. PATIENTS: Consecutive patients referred for endoscopically unresectable colon polyps 15 to 50 mm in size were included. INTERVENTIONS: Patients underwent planned colectomy or endoscopic step up at the surgeon's discretion. Endoscopic step up began with diagnostic colonoscopy in the operating room. If the polyp was amenable to endoscopic removal, endoscopic mucosal resection or endoscopic submucosal dissection was performed with progression to combined endoscopic-laparoscopic surgery or laparoscopic colectomy, as indicated. MAIN OUTCOME MEASURES: The primary outcome was 30-day adverse events. We also examined length of stay, hospital charges, insurer payments, and polyp recurrence. RESULTS: A total of 52 patients underwent planned colectomy (48 laparoscopic), and 38 underwent endoscopic step up (28 endoscopic mucosal resection, 2 endoscopic submucosal dissection, 6 combined endoscopic-laparoscopic surgery, and 2 colectomy). Compared with planned colectomy, endoscopic step-up patients had fewer complications (13% vs 33%; p = 0.03) and shorter length of stay (median, 0 vs 4 d; p < 0.001). There was 1 readmission in the endoscopic step-up group and 5 in the planned colectomy group. Endoscopic step-up patients had lower hospital costs ($4790 vs $13,004; p < 0.001) and insurer payments ($2431 vs $19,951; p < 0.001). One-year polyp recurrence-free survival was 84% (95% CI, 67%-93%) in endoscopic step-up patients. All of the recurrences were benign, <1 cm, and managed endoscopically. LIMITATIONS: The study was limited by its nonrandomized design and short follow-up. CONCLUSIONS: An endoscopic step-up approach to colon polyps is associated with less morbidity, decreased healthcare costs, and colon preservation in 95% of patients. Additional studies are needed to evaluate long-term quality of life and polyp recurrence in this group. See Video Abstract at http://links.lww.com/DCR/B188. ENDOSCOPIC STEP UP: UNA ALTERNATIVA A COLECTOMíA PARA PRESERVACIóN DE COLON CON LOS PROPóSITOS DE MEJORAR RESULTADOS Y REDUCIR COSTOS EN PACIENTES CON PóLIPOS NEOPLáSICOS AVANZADOS: Se desconoce la estrategia óptima para los pólipos de colon no susceptibles a la polipectomia endoscópica tradicional. Endoscopic Step Up es una estrategia prometedora para el tratamiento definitivo.Determinar si Endoscopic Step Up produce mejores resultados y menores costos en comparación con la colectomía programada para pólipos de colon endoscópicamente no resecables.Revisión retrospectiva de una base de datos prospectiva.Centro de referencia de tercer nivel.Pacientes consecutivos remitidos para pólipos de colon endoscópicamente irresecables de tamaño 15-50 mm.Los pacientes se sometieron a colectomía programada o Endoscópico Step Up a discreción del cirujano. Endoscopic Step Up comenzó con una colonoscopia diagnóstica en el quirófano. Si el pólipo era susceptible de extirpación endoscópica, la resección endoscópica de la mucosa o la disección submucosa endoscópica se realizaba con progresión a cirugía endoscópica-laparoscópica combinada o colectomía laparoscópica, según a cosnideraciones clínicas en el transoperatorio.El resultado primario fue los eventos adversos a 30 días. Duración de la estadía hospitalaria, los cargos hospitalarios, los pagos de las aseguradoras y la recurrencia de pólipos también fueron examinados.Un total de 52 pacientes se sometieron a colectomía programada (48 laparoscópicas) y 38 se sometieron a Endoscopic Step Up (28 resección endoscópica de la mucosa, 2 disección submucosa endoscópica, 6 cirugía endoscópica-laparoscópica combinada y 2 colectomía). En comparación con la colectomía programada los pacientes endoscópicos Step Up tuvieron menos complicaciones (13% versus 33%, p = 0.03) y una estadía hospitalaria más corta (mediana 0 versus 4 días, p <0.001). Hubo 1 reingreso hospitalario en el grupo Endoscopic Step Up y 5 en el grupo de colectomía programada. Los pacientes endoscópicos Step Up tuvieron costos hospitalarios más bajos ($ 4,790 versus $ 13,004, p <0,001) y pagos de la aseguradora ($ 2,431 versus $ 19,951, p <0,001). La supervivencia libre de recurrencia de pólipos a un año fue del 84% (IC 95% 67-93) en pacientes endoscópicos Step Up. Todas las recurrencias fueron benignas, <1 cm, y manejadas endoscópicamente.Diseño no aleatorizado y seguimiento corto.El abordaje endoscópico Step Up para pólipos de colon se asocia con menos morbilidad, disminución de los costos de atención médica y preservación del colon en el 95% de los pacientes. Se ocupan más estudios para evaluar la calidad de vida a largo plazo y la recurrencia de pólipos en este grupo. Consulte Video Resumen en http://links.lww.com/DCR/B188. (Traducción-Dr Adrián Ortega Robles).

Radiofrequency Ablation of the Surgical Bed After Lumpectomy in Breast-conserving Surgery. / Ablación por radiofrecuencia del lecho quirúrgico tras tumorectomía en cirugía conservadora del cáncer de mama.

INTRODUCTION: Obtaining tumor-free margins during breast conservative surgery (BCS) is essential to avoid local recurrence and frequently requires reoperation. Radiofrequency ablation (RFA) of surgical margins after lumpectomy seems to be a helpful tool to avoid reoperations, but evidence is insufficient. This study analyzes the efficacy and safety of RFA after BCS to obtain free surgical margins. METHODS: Non-randomized experimental study performed in an intervention group of 40 patients assigned to receive RFA after lumpectomy and successive resection of surgical margins, and a historical control group of 40 patients treated with BCS alone. In the intervention group, the RFA effect on tumor cell viability in the surgical margins was analyzed. Also, reoperation rate, complications and cosmetic results were compared in both groups. RESULTS: A total of 240 excised margins were analyzed after RFA, obtaining a high number of tumor-free margins. Compared to the control group, the reoperation rate decreased significantly (0% vs 12%; P=.02), without differences in terms of postoperative complications (10% vs 5%; P=.67) or cosmetic results (excellent or good 92.5% vs 95%; P=.3). CONCLUSIONS: RFA after lumpectomy is a reliable, safe and successful procedure to obtain tumor-free surgical margins and to decrease the reoperation rate without affecting complications or compromising cosmetic results.