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BACKGROUND: Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear. METHODS: We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety. RESULTS: A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively. CONCLUSIONS: Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).
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Antineoplásicos , Piridinas , Neoplasias da Glândula Tireoide , Humanos , Progressão da Doença , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/genética , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Quinazolinas/efeitos adversos , Quinazolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Monoclonal antibodies (mAbs) are utilized broadly to treat cancer and infectious diseases, and mAb exposure (serum concentration over time) is one predictor of overall treatment efficacy. Herein, we present findings from a clinical trial evaluating the pharmacokinetics (PK) of the long-acting mAb sotrovimab targeting SARS-CoV-2 in hematopoietic cell transplant (HCT) recipients. METHODS: All participants received an intravenous infusion of sotrovimab within one week prior to initiating the pre-transplant preparative regimen. The serum concentration of sotrovimab was measured longitudinally for up to 24 weeks post-transplant. RESULTS: Compared to non-HCT participants, we found that mAb clearance was 10% and 26% higher in autologous and allogeneic HCT recipients, respectively. Overall sotrovimab exposure was approximately 15% lower in HCT recipients compared to non-HCT recipients. Exposure was significantly reduced in HCT recipients who developed diarrhea and lower gastrointestinal (GI) graft-versus-host disease (GVHD) post-transplant. CONCLUSIONS: These data show that sotrovimab exposure may be reduced in HCT recipients, possibly related to increased GI clearance in patients with GVHD. This phenomenon has implications for dose selection and duration of efficacy with sotrovimab and potentially other mAbs in this vulnerable patient population. Thus, mAb dose regimens developed in non-HCT populations may have to be optimized when applied to HCT populations.
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There is a growing appreciation for differences in epidemiology, treatment, and outcomes of cardiovascular conditions by sex. Historically, cardiovascular clinical trials have under-represented females, but findings have nonetheless been applied to clinical care in a sex-agnostic manner. Thus, much of the collective knowledge about sex-specific cardiovascular outcomes result from post hoc and secondary analyses. In some cases, these investigations have revealed important sex-based differences with implications for optimizing care for female patients with arrhythmias. This review explores the available evidence related to cardiac arrhythmia care among females, with emphasis on areas in which important sex differences are known or suggested. Considerations related to improving female enrollment in clinical trials as a way to establish more robust clinical evidence for the treatment of females are discussed. Areas of remaining evidence gaps are provided, and recommendations for areas of future research and specific action items are suggested. The overarching goal is to improve appreciation for sex-based differences in cardiac arrhythmia care as 1 component of a comprehensive plan to optimize arrhythmia care for all patients.
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Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/terapia , Gerenciamento Clínico , Caracteres Sexuais , Arritmias Cardíacas/fisiopatologia , Terapia de Ressincronização Cardíaca/métodos , Ensaios Clínicos como Assunto/métodos , Desfibriladores Implantáveis , Feminino , Humanos , Incidência , Gravidez , Complicações Cardiovasculares na Gravidez/epidemiologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Complicações Cardiovasculares na Gravidez/terapiaRESUMO
BACKGROUND: Microbially induced calcium carbonate precipitation has been extensively researched for geoengineering applications as well as diverse uses within the built environment. Bacteria play a crucial role in producing calcium carbonate minerals, via enzymes including carbonic anhydrase-an enzyme with the capability to hydrolyse CO2, commonly employed in carbon capture systems. This study describes previously uncharacterised carbonic anhydrase enzyme sequences capable of sequestering CO2 and subsequentially generating CaCO3 biominerals and suggests a route to produce carbon negative cementitious materials for the construction industry. RESULTS: Here, Bacillus subtilis was engineered to recombinantly express previously uncharacterised carbonic anhydrase enzymes from Bacillus megaterium and used as a whole cell catalyst allowing this novel bacterium to sequester CO2 and convert it to calcium carbonate. A significant decrease in CO2 was observed from 3800 PPM to 820 PPM upon induction of carbonic anhydrase and minerals recovered from these experiments were identified as calcite and vaterite using X-ray diffraction. Further experiments mixed the use of this enzyme (as a cell free extract) with Sporosarcina pasteurii to increase mineral production whilst maintaining a comparable level of CO2 sequestration. CONCLUSION: Recombinantly produced carbonic anhydrase successfully sequestered CO2 and converted it into calcium carbonate minerals using an engineered microbial system. Through this approach, a process to manufacture cementitious materials with carbon sequestration ability could be developed.
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Bacillus subtilis , Carbonato de Cálcio , Dióxido de Carbono , Anidrases Carbônicas , Sporosarcina , Carbonato de Cálcio/metabolismo , Carbonato de Cálcio/química , Bacillus subtilis/metabolismo , Bacillus subtilis/genética , Bacillus subtilis/enzimologia , Dióxido de Carbono/metabolismo , Anidrases Carbônicas/metabolismo , Anidrases Carbônicas/genética , Sporosarcina/metabolismo , Sporosarcina/enzimologia , Sporosarcina/genética , Bacillus megaterium/metabolismo , Bacillus megaterium/genética , Bacillus megaterium/enzimologia , Sequestro de Carbono , Precipitação Química , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genéticaRESUMO
BACKGROUND: Cytomegalovirus (CMV) is a driver of negative outcomes after lung transplant (LTX) and primary prophylaxis (PPX) with valganciclovir (VGC) is standard-of-care. VGC is associated with myelosuppression, prompting interest in letermovir (LTV). METHODS: Adults receiving LTX between April 1, 2015, and July 30, 2022, at our institution were evaluated. Patients were excluded if low CMV risk (D-/R-), survived <90 days post-LTX, or transferred care before PPX withdrawal. Primary outcomes were leukopenia (white blood cell count [WBC] ≤ 3.0 × 109/L), severe leukopenia (WBC ≤ 2.0 × 109/L), and neutropenia (absolute neutrophil count ≤ 1500 cells/µL) requiring granulocyte-colony stimulating factor (GCSF) on PPX. Secondary outcomes included breakthrough CMV infection and post-PPX CMV infection. RESULTS: 204 patients met inclusion criteria: 175 patients on VGC and 29 patients on LTV (after VGC conversion). Most patients received bilateral LTX (62.7%) with non-lymphocyte-depleting induction (96.6%) and moderate-risk serostatus (D+/R+, 48.5%). Patients transitioned from VGC to LTV after a mean of 178 days (SD 80.8 days) post-transplant. Patients on VGC experienced significantly more leukopenia (82.3% vs. 58.6%, p = 0.008), severe leukopenia (57.1% vs. 31.0%, p = 0.016), and neutropenia requiring GCSF (70.9% vs. 51.7%, p = 0.048). Breakthrough (5.7% vs. 3.4%, p = 0.955) and post-PPX (24.6% vs. 37.9%, p = 0.199) infections were similar. A subgroup analysis of patients with high-risk serostatus showed similar trends, though did not reach statistical significance. CONCLUSIONS: In this single-center study, the incidence of leukopenia and neutropenia requiring GCSF were reduced with LTV compared to VGC. Breakthrough and post-PPX infections were not significantly different. This evidence suggests that LTV has comparable efficacy with reduced myelosuppression compared to VGC in LTX recipients, and may be an appropriate alternative for PPX.
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BACKGROUND: Many studies reporting neonatal outcomes in birth centers include births with risk factors not acceptable for birth center care using the evidence-based CABC criteria. Accurate comparisons of outcomes by birth setting for low-risk patients are needed. METHODS: Data from the public Natality Detailed File from 2018 to 2021 were used. Logistic regression, including adjusted and unadjusted odds ratios, compared neonatal outcomes (chorioamnionitis, Apgar scores, resuscitation, intensive care, seizures, and death) between centers and hospitals. Covariates included maternal diabetes, body mass index, age, parity, and demographic characteristics. RESULTS: The sample included 8,738,711 births (8,698,432 (99.53%) in hospitals and 40,279 (0.46%) in birth centers). There were no significant differences in neonatal deaths (aOR 1.037; 95% CI [0.515, 2.088]; p-value 0.918) or seizures (aOR 0.666; 95% CI [0.315, 1.411]; p-value 0.289). Measures of morbidity either not significantly different or less likely to occur in birth centers compared to hospitals included chorioamnionitis (aOR 0.032; 95% CI [0.020, 0.052]; p-value < 0.001), Apgar score < 4 (aOR 0.814, 95% CI [0.638, 1.039], p-value 0.099), Apgar score < 7 (aOR 1.075, 95% CI [0.979, 1.180], p-value 0.130), ventilation >6 h (aOR 0.349; [0.281,0.433], p-value < 0.001), and intensive care admission (aOR 0.356; 95% CI [0.328, 0.386], p-value < 0.001). Birth centers had higher odds of assisted neonatal ventilation for <6 h as compared to hospitals (aOR 1.373; 95% CI [1.293, 1.457], p-value < 0.001). CONCLUSION: Neonatal deaths and seizures were not significantly different between freestanding birth centers and hospitals. Chorioamnionitis, Apgar scores < 4, and intensive care admission were less likely to occur in birth centers.
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Índice de Apgar , Centros de Assistência à Gravidez e ao Parto , Mortalidade Infantil , Humanos , Recém-Nascido , Feminino , Estados Unidos/epidemiologia , Centros de Assistência à Gravidez e ao Parto/estatística & dados numéricos , Gravidez , Mortalidade Infantil/tendências , Adulto , Lactente , Fatores de Risco , Modelos Logísticos , Masculino , Corioamnionite/epidemiologia , Convulsões/epidemiologia , Convulsões/mortalidadeRESUMO
NEW FINDINGS: What is the central question of this study? Does non-freezing cold injury (NFCI) alter normal peripheral vascular function? What is the main finding and its importance? Individuals with NFCI were more cold sensitive (rewarmed more slowly and felt more discomfort) than controls. Vascular tests indicated that extremity endothelial function was preserved with NFCI and that sympathetic vasoconstrictor response might be reduced. The pathophysiology underpinning the cold sensitivity associated with NFCI thus remains to be identified. ABSTRACT: The impact of non-freezing cold injury (NFCI) on peripheral vascular function was investigated. Individuals with NFCI (NFCI group) and closely matched controls with either similar (COLD group) or limited (CON group) previous cold exposure were compared (n = 16). Peripheral cutaneous vascular responses to deep inspiration (DI), occlusion (PORH), local cutaneous heating (LH) and iontophoresis of acetylcholine and sodium nitroprusside were investigated. The responses to a cold sensitivity test (CST) involving immersion of a foot in 15°C water for 2 min followed by spontaneous rewarming, and a foot cooling protocol (footplate cooled from 34°C to 15°C), were also examined. The vasoconstrictor response to DI was lower in NFCI compared to CON (toe: 73 (28)% vs. 91 (17)%; P = 0.003). The responses to PORH, LH and iontophoresis were not reduced compared to either COLD or CON. During the CST, toe skin temperature rewarmed more slowly in NFCI than COLD or CON (10 min: 27.4 (2.3)°C vs. 30.7 (3.7)°C and 31.7 (3.9)°C, P < 0.05, respectively); however, no differences were observed during the footplate cooling. NFCI were more cold-intolerant (P < 0.0001) and reported colder and more uncomfortable feet during the CST and footplate cooling than COLD and CON (P < 0.05). NFCI showed a decreased sensitivity to sympathetic vasoconstrictor activation than CON and greater cold sensitivity (CST) compared to COLD and CON. None of the other vascular function tests indicated endothelial dysfunction. However, NFCI perceived their extremities to be colder and more uncomfortable/painful than the controls.
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Lesão por Frio , Humanos , Temperatura Baixa , Temperatura Cutânea , Temperatura , VasoconstritoresRESUMO
NEW FINDINGS: What is the central question of this study? Is peripheral sensory function impaired in the chronic phase of non-freezing cold injury (NFCI)? What is the main finding and its importance? Warm and mechanical detection thresholds are elevated and intraepidermal nerve fibre density is reduced in individuals with NFCI in their feet when compared to matched controls. This indicates impaired sensory function in individuals with NFCI. Interindividual variation was observed in all groups, and therefore a diagnostic cut-off for NFCI has yet to be established. Longitudinal studies are required to follow NFCI progression from formation to resolution ABSTRACT: The aim of this study was to compare peripheral sensory neural function of individuals with non-freezing cold injury (NFCI) with matched controls (without NFCI) with either similar (COLD) or minimal previous cold exposure (CON). Thirteen individuals with chronic NFCI in their feet were matched with the control groups for sex, age, race, fitness, body mass index and foot volume. All undertook quantitative sensory testing (QST) on the foot. Intraepidermal nerve fibre density (IENFD) was assessed 10 cm above the lateral malleolus in nine NFCI and 12 COLD participants. Warm detection threshold was higher at the great toe in NFCI than COLD (NFCI 45.93 (4.71)°C vs. COLD 43.44 (2.72)°C, P = 0.046), but was non-significantly different from CON (CON 43.92 (5.01)°C, P = 0.295). Mechanical detection threshold on the dorsum of the foot was higher in NFCI (23.61 (33.59) mN) than in CON (3.83 (3.69) mN, P = 0.003), but was non-significantly different from COLD (10.49 (5.76) mN, P > 0.999). Remaining QST measures did not differ significantly between groups. IENFD was lower in NFCI than COLD (NFCI 8.47 (2.36) fibre/mm2 vs. COLD 11.93 (4.04) fibre/mm2 , P = 0.020). Elevated warm and mechanical detection thresholds may indicate hyposensitivity to sensory stimuli in the injured foot for individuals with NFCI and may be due to reduced innervation given the reduction in IENFD. Longitudinal studies are required to identify the progression of sensory neuropathy from the formation of injury to its resolution, with appropriate control groups employed.
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Lesão por Frio , Humanos , Sensação , Pé , Temperatura BaixaRESUMO
NEW FINDINGS: What is the central question of this study? Are biomarkers of endothelial function, oxidative stress and inflammation altered by non-freezing cold injury (NFCI)? What is the main finding and its importance? Baseline plasma [interleukin-10] and [syndecan-1] were elevated in individuals with NFCI and cold-exposed control participants. Increased [endothelin-1] following thermal challenges might explain, in part, the increased pain/discomfort experienced with NFCI. Mild to moderate chronic NFCI does not appear to be associated with either oxidative stress or a pro-inflammatory state. Baseline [interleukin-10] and [syndecan-1] and post-heating [endothelin-1] are the most promising candidates for diagnosis of NFCI. ABSTRACT: Plasma biomarkers of inflammation, oxidative stress, endothelial function and damage were examined in 16 individuals with chronic NFCI (NFCI) and matched control participants with (COLD, n = 17) or without (CON, n = 14) previous cold exposure. Venous blood samples were collected at baseline to assess plasma biomarkers of endothelial function (nitrate, nitrite and endothelin-1), inflammation [interleukin-6 (IL-6), interleukin-10 (IL-10), tumour necrosis factor alpha and E-selectin], oxidative stress [protein carbonyl, 4-hydroxy-2-nonenal (4-HNE), superoxide dismutase and nitrotyrosine) and endothelial damage [von Willebrand factor, syndecan-1 and tissue type plasminogen activator (TTPA)]. Immediately after whole-body heating and separately, foot cooling, blood samples were taken for measurement of plasma [nitrate], [nitrite], [endothelin-1], [IL-6], [4-HNE] and [TTPA]. At baseline, [IL-10] and [syndecan-1] were increased in NFCI (P < 0.001 and P = 0.015, respectively) and COLD (P = 0.033 and P = 0.030, respectively) compared with CON participants. The [4-HNE] was elevated in CON compared with both NFCI (P = 0.002) and COLD (P < 0.001). [Endothelin-1] was elevated in NFCI compared with COLD (P < 0.001) post-heating. The [4-HNE] was lower in NFCI compared with CON post-heating (P = 0.032) and lower than both COLD (P = 0.02) and CON (P = 0.015) post-cooling. No between-group differences were seen for the other biomarkers. Mild to moderate chronic NFCI does not appear to be associated with a pro-inflammatory state or oxidative stress. Baseline [IL-10] and [syndecan-1] and post-heating [endothelin-1] are the most promising candidates for diagnosing NFCI, but it is likely that a combination of tests will be required.
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Lesão por Frio , Interleucina-10 , Humanos , Ativador de Plasminogênio Tecidual , Sindecana-1 , Nitratos , Nitritos , Interleucina-6 , Endotelina-1 , Estresse Oxidativo , Inflamação , Biomarcadores , Temperatura BaixaRESUMO
BACKGROUND: Racial and ethnic disparities in cesarean rates in the United States are well documented. This study investigated whether cesarean inequities persist in midwife-led birth center care, including for individuals with the lowest medical risk. METHODS: National registry records of 174,230 childbearing people enrolled in care in 115 midwifery-led birth center practices between 2007 and 2022 were analyzed for primary cesarean rates and indications by race and ethnicity. The lowest medical risk subsample (n = 70,521) was analyzed for independent drivers of cesarean birth. RESULTS: Primary cesarean rates among nulliparas (15.5%) and multiparas (5.7%) were low for all enrollees. Among nulliparas in the lowest-risk subsample, non-Latinx Black (aOR = 1.37; 95% CI, 1.15-1.63), Latinx (aOR = 1.51; 95% CI, 1.32-1.73), and Asian participants (aOR = 1.48; 95% CI, 1.19-1.85) remained at higher risk for primary cesarean than White participants. Among multiparas, only Black participants experienced a higher primary cesarean risk (aOR = 1.49; 95% CI, 1.02-2.18). Intrapartum transfers from birth centers were equivalent or lower for Black (14.0%, p = 0.345) and Latinx (12.7%, p < 0.001) enrollees. Black participants experienced a higher proportion of primary cesareans attributed to non-reassuring fetal status, regardless of risk factors. Place of admission was a stronger predictor of primary cesarean than race or ethnicity. CONCLUSIONS: Place of first admission in labor was the strongest predictor of cesarean. Racism as a chronic stressor and a determinant of clinical decision-making reduces choice in birth settings and may increase cesarean rates. Research on components of birth settings that drive inequitable outcomes is warranted.
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OBJECTIVES: Interest in expanding access to the birth center model is growing. The purpose of this research is to describe birth center staffing models and business characteristics and explore relationships to perinatal outcomes. METHODS: This descriptive analysis includes a convenience sample of all 84 birth center sites that participated in the AABC Site Survey and AABC Perinatal Data Registry between 2012 and 2020. Selected independent variables include staffing model (CNM/CM or CPM/LM), legal entity status, birth volume/year, and hours of midwifery call/week. Perinatal outcomes include rates of induction of labor, cesarean birth, exclusive breastfeeding, birthweight in pounds, low APGAR scores, and neonatal intensive care admission. RESULTS: The birth center model of care is demonstrated to be safe and effective, across a variety of staffing and business models. Outcomes for both CNM/CM and CPM/LM models of care exceed national benchmarks for perinatal quality with low induction, cesarean, NICU admission, and high rates of breastfeeding. Within the sample of medically low-risk multiparas, variations in clinical outcomes were correlated with business characteristics of the birth center, specifically annual birth volume. Increased induction of labor and cesarean birth, with decreased success breastfeeding, were present within practices characterized as high volume (>200 births/year). The research demonstrates decreased access to the birth center model of care for Black and Hispanic populations. CONCLUSIONS FOR PRACTICE: Between 2012 and 2020, 84 birth centers across the United States engaged in 90,580 episodes of perinatal care. Continued policy development is necessary to provide risk-appropriate care for populations of healthy, medically low-risk consumers.
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Centros de Assistência à Gravidez e ao Parto , Trabalho de Parto , Tocologia , Gravidez , Recém-Nascido , Feminino , Humanos , Estados Unidos , Modelos Logísticos , Recursos HumanosRESUMO
A complex biological and psychological series of events commence at fertilization and continue through parturition between the preborn human organism and his or her mother, which extends far beyond the physical connection between an adult patient and contained tissue. This guideline reviews evidence in support of various aspects of this bond and its implications for care of the maternal patient.
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Parto Obstétrico , Mães , Humanos , Adulto , Feminino , Masculino , Gravidez , Apego ao Objeto , Parto , Exame FísicoRESUMO
BACKGROUND: Selpercatinib is a first-in-class, highly selective RET kinase inhibitor with CNS activity that has shown efficacy in RET fusion-positive lung and thyroid cancers. RET fusions occur rarely in other tumour types. We aimed to investigate the efficacy and safety of selpercatinib in a diverse group of patients with RET fusion-positive non-lung or thyroid advanced solid tumours (ie, a tumour-agnostic population). METHODS: LIBRETTO-001 is an ongoing phase 1/2, single-group, open-label, basket trial of selpercatinib in patients aged 18 years and older (or ≥12 years, where permitted by regulatory authorities) with RET-altered cancers. The trial is being conducted at 89 sites in 16 countries; the tumour-agnostic population was enrolled at 30 sites (outpatient and inpatient medical facilities) across eight countries. A prespecified interim analysis of LIBRETTO-001 was planned to investigate the efficacy and safety of selpercatinib in a tumour-agnostic population of patients with RET fusion-positive advanced solid tumours; the data cutoff date was Sept 24, 2021. Eligible patients had disease progression on or after previous systemic therapies or no satisfactory therapeutic options and an Eastern Cooperative Oncology Group performance status of 0-2. Selpercatinib was orally administered in a continuous 28-day cycle. Patients enrolled in the phase 1 dose-escalation portion received between 20 mg once daily or 20-240 mg twice daily; the phase 2 recommended dose was 160 mg twice daily. The primary endpoint was the objective response rate as determined by the independent review committee. The efficacy-evaluable tumour-agnostic population was defined as patients with RET fusion-positive cancer, other than non-small-cell lung cancer and thyroid cancer, who had at least 6 months of follow-up from the first study dose at the time of data cutoff (all responders at the time of data cutoff were followed up for at least 6 months from the onset of response unless they progressed or died earlier). Safety was analysed in the tumour-agnostic population of patients who had been enrolled and received selpercatinib on or before the data cutoff date. This study is registered with ClinicalTrials.gov (NCT03157128) and is still recruiting participants. FINDINGS: Between Dec 4, 2017, and Aug 4, 2021, 45 patients with RET fusion-positive tumour-agnostic cancers were enrolled from the phase 1 dose-escalation and phase 2 dose-expansion cohorts of the trial. 43 (96%) of 45 patients received a starting dose of selpercatinib at the recommended dose of 160 mg twice daily. Of the two patients who did not, one received a dose of 160 mg twice daily via intra-patient dose escalation (as allowed per protocol for patients enrolled in the phase 1 portion of the study at lower doses) and the other patient's starting dose of 120 mg twice daily was never escalated. Of the 41 efficacy-evaluable patients, the objective response rate as per the independent review committee was 43·9% (95% CI 28·5-60·3; 18 of 41 patients). The most common grade 3 or worse treatment-emergent adverse events were hypertension (ten [22%] of 45 patients), increased alanine aminotransferase (seven [16%]), and increased aspartate aminotransferase (six [13%]). Treatment-emergent serious adverse events occurred in 18 (40%) of 45 patients. No treatment-related deaths occurred. INTERPRETATION: Selpercatinib showed clinically meaningful activity in the RET fusion-positive tumour-agnostic population, with a safety profile consistent with that observed in other indications. Comprehensive genomic testing that includes RET fusions will be crucial for identifying patients who might benefit from selpercatinib. FUNDING: Loxo Oncology.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias da Glândula Tireoide , Alanina Transaminase , Aspartato Aminotransferases , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis , Piridinas , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genéticaRESUMO
Longer wavelength lasers will be needed for future gravitational wave detectors that use cryogenic cooling of silicon based test-mass optics. Diode lasers with a 1550 nm wavelength output are potential seed light sources for such a detector, however diode laser devices have a different spectral profile and higher frequency noise than the solid state lasers used in current detectors. We present a frequency stabilisation system for a 1550 nm external cavity diode laser capable of reducing the laser frequency noise to a level of 0.1HzHz up to 1 kHz with a unity gain frequency of 535 kHz using a hybrid analogue-digital servo with in-loop cancellation of resonant features. In addition, a method of high speed digital filter optimisation and automated design is demonstrated.
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BACKGROUND: Total shoulder arthroplasty (TSA) has become the gold-standard treatment to relieve joint pain and disability in patients with glenohumeral osteoarthritis who do not respond to conservative treatment. An adverse reaction to metal debris released due to fretting corrosion has been a major concern in total hip arthroplasty. To date, it is unclear how frequently implant corrosion occurs in TSA and whether it is a cause of implant failure. This study aimed to characterize and quantify corrosion and fretting damage in a single anatomic TSA design and to compare the outcomes to the established outcomes of total hip arthroplasty. METHODS: We analyzed 21 surgically retrieved anatomic TSAs of the same design (Tornier Aequalis Pressfit). The retrieved components were microscopically examined for taper corrosion, and taper damage was scored. Head and stem taper damage was quantitatively measured with a non-contact optical coordinate-measuring machine. In selected cases, damage was further characterized at high magnifications using scanning electron microscopy. Energy-dispersive x-ray spectroscopy and metallographic evaluations were performed to determine underlying alloy microstructure and composition. Comparisons between groups with different damage features were performed with independent-samples t tests; Mann-Whitney tests and multivariate linear regression were conducted to correlate damage with patient factors. The level of statistical significance was set at P < .05. RESULTS: The average material loss for head and stem tapers was 0.007 mm3 and 0.001 mm3, respectively. Material loss was not correlated with sex, age, previous implant, or time in situ (P > .05). We observed greater volume loss in head tapers compared with stem tapers (P = .002). Implants with evidence of column damage had larger volumetric material loss than those without such evidence (P = .003). Column damage aligned with segregation bands within the alloy (preferential corrosion sites). The average angular mismatch was 0.03° (standard deviation, 0.0668°), with negative values indicating distal engagement and positive values indicating proximal engagement. Implants with proximal engagement were significantly more likely to have column damage than those with distal engagement (P = .030). DISCUSSION: This study has shown not only that the metal components of TSA implants can corrode but also that the risk of corrosion can be reduced by (1) eliminating preferential corrosion sites and (2) ensuring distal engagement to prevent fluid infiltration into the modular junction.
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Artroplastia do Ombro , Prótese de Quadril , Humanos , Ligas , Metais , Desenho de Prótese , Falha de PróteseRESUMO
PURPOSE: The purpose of this study was to describe sociodemographic variations in client preference for birthplace and relationships to perinatal health outcomes. METHODS: Descriptive data analysis (raw number, percentages, and means) showed that preference for birthplace varied across racial and ethnic categories as well as sociodemographic categories including educational status, body mass index, payer status, marital status, and gravidity. A subsample of medically low-risk childbearing people, qualified for birth center admission in labor, was analyzed to assess variations in maternal and newborn outcomes by site of first admission in labor. RESULTS: While overall clinical outcomes exceeded national benchmarks across all places of admission in the sample, disparities were noted including higher cesarean birth rates among Black and Hispanic people. This variation was larger within the population of people who preferred to be admitted to the hospital in labor in the absence of medical indication. CONCLUSION: This study supports that the birth center model provides safe delivery care across the intersections of US sociodemographics. Findings from this study highlight the importance of increased access and choice in place of birth for improving health equity, including decreasing cesarean birth and increasing breastfeeding initiation.
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Centros de Assistência à Gravidez e ao Parto , Cesárea , Feminino , Hispânico ou Latino , Humanos , Recém-Nascido , Parto , Gravidez , Sistema de Registros , Estados Unidos/epidemiologiaRESUMO
PURPOSE: Survivorship care plans (SCPs) are used to facilitate communication between oncology and primary care providers (PCPs) after cancer treatment and to assist cancer survivors with healthcare decisions. We evaluated pediatric oncology providers' experiences creating and delivering SCPs. We also evaluated PCPs' opinions of SCPs. METHODS: Together, oncology nurses and oncologists created individualized SCPs for leukemia patients treated at a children's hospital in Utah, with nurses in charge of inputting the majority of SCP content. We surveyed providers after each SCP was completed. We also mailed SCPs to PCPs with a survey on SCP content and their knowledge and comfort level caring for cancer survivors. Descriptive statistics were used to summarize survey content. RESULTS: A total of 6 nurses and 8 oncologists created 21 SCPs. On average, nurses assisted with 3.5 SCPs and spent 209 min (range 100-600 min) on completing their sections of each SCP, whereas oncologists assisted with 2.6 SCPs and spent 47.4 min (range 15-120). For most SCPs, there was agreement that they should be shared with PCPs (nurse surveys 71.4%, oncologist surveys 100%). Of the 15 participating PCPs, only 28% felt prepared to manage long-term effects in pediatric cancer survivors. They agreed that the SCP would improve communication with their patient's oncologist (80%) and their knowledge for future care (100%). CONCLUSIONS: SCPs require substantial clinician time to create, but are seen as useful by PCPs. PCPs require specific guidelines and resources concerning ongoing care for pediatric cancer survivors.
Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Pessoal de Saúde/normas , Neoplasias/mortalidade , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/terapia , Projetos Piloto , Inquéritos e Questionários , SobrevivênciaRESUMO
LESSONS LEARNED: The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. BACKGROUND: Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. METHODS: Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. RESULTS: Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92-3.67) months for regorafenib versus 2.07 (95% CI, 1.64-3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16-23.48) months for regorafenib and 4.89 (95% CI, 3.02-9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31-1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. CONCLUSION: Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.
Assuntos
Lipossarcoma , Compostos de Fenilureia , Piridinas , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Lipossarcoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases , Piridinas/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: To explore the role of the birth center model of care in rural health and maternity care delivery in the United States. METHODS: All childbearing families enrolled in care at an American Association of Birth Centers Perinatal Data RegistryTM user sites between 2012 and 2020 are included in this descriptive analysis. FINDINGS: Between 2012 and 2020, 88 574 childbearing families enrolled in care with 82 American Association of Birth Centers Perinatal Data RegistryTM user sites. Quality outcomes exceeded national benchmarks across all geographic regions in both rural and urban settings. A stable and predictable rate of transfer to a higher level of care was demonstrated across geographic regions, with over half of the population remaining appropriate for birth center level of care throughout the perinatal episode of care. Controlling for socio demographic and medical risk factors, outcomes were as favorable for clients in rural areas compared with urban and suburban communities. CONCLUSIONS: Rural populations cared for within the birth center model of care experienced high-quality outcomes. HEALTH POLICY IMPLICATIONS: A major focus of the United States maternity care reform should be the expansion of access to birth center models of care, especially in underserved areas such as rural communities.
Assuntos
Centros de Assistência à Gravidez e ao Parto/organização & administração , Acessibilidade aos Serviços de Saúde , Serviços de Saúde Materna/organização & administração , Saúde da População Rural/normas , Feminino , Humanos , Recém-Nascido , Modelos Logísticos , Serviços de Saúde Materna/normas , Modelos Organizacionais , Gravidez , População Rural , Estados UnidosRESUMO
Importance: Patients with advanced soft tissue sarcoma (STS) have a median overall survival of less than 2 years. In a phase 2 study, an overall survival benefit in this population was observed with the addition of olaratumab to doxorubicin over doxorubicin alone. Objective: To determine the efficacy of doxorubicin plus olaratumab in patients with advanced/metastatic STS. Design, Setting, and Participants: ANNOUNCE was a confirmatory, phase 3, double-blind, randomized trial conducted at 110 sites in 25 countries from September 2015 to December 2018; the final date of follow-up was December 5, 2018. Eligible patients were anthracycline-naive adults with unresectable locally advanced or metastatic STS, an Eastern Cooperative Oncology Group performance status of 0 to 1, and cardiac ejection fraction of 50% or greater. Interventions: Patients were randomized 1:1 to receive doxorubicin, 75 mg/m2 (day 1), combined with olaratumab (n = 258), 20 mg/kg in cycle 1 and 15 mg/kg in subsequent cycles, or placebo (n = 251) on days 1 and 8 for up to 8 21-day cycles, followed by olaratumab/placebo monotherapy. Main Outcomes and Measures: Dual primary end points were overall survival with doxorubicin plus olaratumab vs doxorubicin plus placebo in total STS and leiomyosarcoma (LMS) populations. Results: Among the 509 patients randomized (mean age, 56.9 years; 58.2% women; 46.0% with LMS), all were included in the primary analysis and had a median length of follow-up of 31 months. No statistically significant difference in overall survival was observed between the doxorubicin plus olaratumab group vs the doxorubicin plus placebo group in either population (total STS: hazard ratio, 1.05 [95% CI, 0.84-1.30], P = .69, median overall survival, 20.4 months vs 19.7 months; LMS: hazard ratio, 0.95 [95% CI, 0.69-1.31], P = .76, median overall survival, 21.6 months vs 21.9 months). Adverse events of grade 3 or greater reported in 15% or more of total patients with STS were neutropenia (46.3% vs 49.0%), leukopenia (23.3% vs 23.7%), and febrile neutropenia (17.5% vs 16.5%). Conclusions and Relevance: In this phase 3 clinical trial of patients with advanced STS, treatment with doxorubicin plus olaratumab vs doxorubicin plus placebo resulted in no significant difference in overall survival. The findings did not confirm the overall survival benefit observed in the phase 2 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02451943.