[Injury mechanism, clinical status and prospects of traumatic brain injury].

Traumatic brain injury (TBI) is an important in the world's public health and an important subject of basic and clinical research in the medical field. In the past 30 years, the epidemiology, injury mechanism, safety prevention, medical strategies, nursing measures and other aspects of TBI have made great progress, and the level of treatment has also been continuously improved, but it still faces many challenges. The focus of research on the injury mechanism of TBI has gradually shifted from the classic signaling pathways of primary injury to the study of secondary injury mechanisms. Pharmacological research on various therapeutic targets has also made significant progress, which is expected to be transformed into new TBI therapeutic drugs. On the other hand, many new clinical concepts, new systems, and new methods are constantly being integrated into the diagnosis and treatment of TBI, which has gradually transformed from the original treatment of acute neurological injury to the comprehensive treatment of chronic systemic diseases. This paper is based on the latest research progress in the basic and clinical aspects of TBI, and provides a review of its current status and development trends, providing reference for the medical treatment and research of TBI.

Event-free survival by residual cancer burden with pembrolizumab in early-stage TNBC: exploratory analysis from KEYNOTE-522.

BACKGROUND: KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group. PATIENTS AND METHODS: A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model. RESULTS: Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group. CONCLUSIONS: Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR.

Impact of Exercise and Cognitive Stimulation Therapy on Physical Function, Cognition and Muscle Mass in Pre-Frail Older Adults in the Primary Care Setting: A Cluster Randomized Controlled Trial.

OBJECTIVES: Multicomponent exercise program have shown to improve function and cognition in older adults but studies on pre-frail older adults in the primary care setting are limited. This study aimed i) to evaluate impact of 6 months exercise (Ex) versus complementary effect of 3 months of cognitive stimulation therapy (CST) to 6 months of Ex (Ex+CST) on physical function, muscle mass and cognition versus control group at 3, 6 and 12 months ii) inflammatory biomarkers such as Interleukin-6 (IL-6) and Tumor Necrosis Factor Alpha (TNF-α). DESIGN: Cluster randomised control trial. SETTING AND INTERVENTION: Pre-frail older adults ≥ 65 years attending primary care clinic. Two intervention groups i) Ex 6 months ii) CST 3 months with Ex 6 months. MEASUREMENTS: At 0, 3, 6 and 12 months, questionnaires (on demographics, physical function, cognition, and depression) were administered and physical function assessment (gait speed, short physical performance battery (SPPB) test, handgrip strength, five times sit-to-stand (5x-STS)) was conducted. Muscle mass and its surrogates such as phase angle and body cell mass were measured using bioelectrical impedance analysis machine. Inflammatory biomarkers were measured at 0 and 3 months. RESULTS: Data from 190 participants was analysed at 3 months (111 control, 37 Ex and 41 Ex+CST). At 3 months, significant improvement in cognition was seen only in the Ex+CST group whereas improvements in depression, gait speed, SPPB and 5x-STS were seen in both the Ex and Ex+CST groups. At 6 months, the Ex+CST group improved in cognition and depression whereas improvement in frailty and muscle mass indices were seen in both the interventions groups. At 12 months, both the interventions groups had better perceived health, gait speed and less decline in muscle mass compared with control groups. Both the Ex and Ex+CST had significant association with TNF-α at 3 months (ß -2.71 (95% CI -4.80 - -0.62); p = 0.012 and ß -1.74 (95% CI -3.43 - -0.06); p = 0.043 respectively). CONCLUSION: Combined Ex+CST had significant improvement in cognition whereas the intervention groups improved in depression, physical function, muscle mass, frailty, perceived health and TNF-α levels. With growing evidence of the benefits of multicomponent interventions at primary care level, incorporating it into mainstream care with action plans on long-term sustainability and scalability should be a priority for every country.

Outcomes with durvalumab after chemoradiotherapy in stage IIIA-N2 non-small-cell lung cancer: an exploratory analysis from the PACIFIC trial.

BACKGROUND: The phase III PACIFIC trial (NCT02125461) established consolidation durvalumab as standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC) and no disease progression following chemoradiotherapy (CRT). In some cases, patients with stage IIIA-N2 NSCLC are considered operable, but the relative benefit of surgery is unclear. We report a post hoc, exploratory analysis of clinical outcomes in the PACIFIC trial, in patients with or without stage IIIA-N2 NSCLC. MATERIALS AND METHODS: Patients with unresectable, stage III NSCLC and no disease progression after ≥2 cycles of platinum-based, concurrent CRT were randomized 2 : 1 to receive durvalumab (10 mg/kg intravenously; once every 2 weeks for up to 12 months) or placebo, 1-42 days after CRT. The primary endpoints were progression-free survival (PFS; assessed by blinded independent central review according to RECIST version 1.1) and overall survival (OS). Treatment effects within subgroups were estimated by hazard ratios (HRs) from unstratified Cox proportional hazards models. RESULTS: Of 713 randomized patients, 287 (40%) had stage IIIA-N2 disease. Baseline characteristics were similar between patients with and without stage IIIA-N2 NSCLC. With a median follow-up of 14.5 months (range: 0.2-29.9 months), PFS was improved with durvalumab versus placebo in both patients with [HR = 0.46; 95% confidence interval (CI), 0.33-0.65] and without (HR = 0.62; 95% CI 0.48-0.80) stage IIIA-N2 disease. Similarly, with a median follow-up of 25.2 months (range: 0.2-43.1 months), OS was improved with durvalumab versus placebo in patients with (HR = 0.56; 95% CI 0.39-0.79) or without (HR = 0.78; 95% CI 0.57-1.06) stage IIIA-N2 disease. Durvalumab had a manageable safety profile irrespective of stage IIIA-N2 status. CONCLUSIONS: Consistent with the intent-to-treat population, treatment benefits with durvalumab were confirmed in patients with stage IIIA-N2, unresectable NSCLC. Prospective studies are needed to determine the optimal treatment approach for patients who are deemed operable.

Fetoscopy-guided bipolar cord coagulation in selective fetal reduction with complicated monochorionic diamniotic twins: a prospective cohort study.

OBJECTIVE: To assess the feasibility of fetoscopy-guided bipolar umbilical cord coagulation for selective fetal reduction in complicated monochorionic diamniotic (MCDA) twin pregnancies. METHODS: MCDA twins undergoing fetoscopy-guided bipolar cord coagulation (BCC) were enrolled prospectively between December 2015 to March 2020 in a fetal medicine center. RESULTS: Twenty-three cases undergoing fetoscopy-guided BCC were finally analyzed, including 11 cases for type 2 selective intrauterine growth restriction, 4 cases for twin-twin transfusion syndrome, and 8 cases for a severe discordant anomaly. The overall survival rate was 78.3% (18/23). CONCLUSIONS: Fetoscopy-guided BCC is effective for selective fetal reduction in complicated monochorionic twin pregnancies.

Machine Learning Approach for Automated Detection of Irregular Walking Surfaces for Walkability Assessment with Wearable Sensor.

The walkability of a neighborhood impacts public health and leads to economic and environmental benefits. The condition of sidewalks is a significant indicator of a walkable neighborhood as it supports and encourages pedestrian travel and physical activity. However, common sidewalk assessment practices are subjective, inefficient, and ineffective. Current alternate methods for objective and automated assessment of sidewalk surfaces do not consider pedestrians' physiological responses. We developed a novel classification framework for the detection of irregular walking surfaces that uses a machine learning approach to analyze gait parameters extracted from a single wearable accelerometer. We also identified the most suitable location for sensor placement. Experiments were conducted on 12 subjects walking on good and irregular walking surfaces with sensors attached at three different locations: right ankle, lower back, and back of the head. The most suitable location for sensor placement was at the ankle. Among the five classifiers trained with gait features from the ankle sensor, Support Vector Machine (SVM) was found to be the most effective model since it was the most robust to subject differences. The model's performance was improved with post-processing. This demonstrates that the SVM model trained with accelerometer-based gait features can be used as an objective tool for the assessment of sidewalk walking surface conditions.

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189.

BACKGROUND: In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. PATIENTS AND METHODS: Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. RESULTS: After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. CONCLUSIONS: Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.

The risk of anti-osteoporotic agent-induced severe cutaneous adverse drug reactions and their association with HLA.

BACKGROUND: There is increasing use of anti-osteoporotic agents (AOA) worldwide for prevention or management of patients with osteoporosis. However, there have been reports of severe cutaneous adverse reactions (SCAR) induced by AOA. A recent study showed weak association between HLA and strontium ranelate (SR)-SCAR. OBJECTIVE: To characterize patients with AOA-SCAR and investigate the HLA association and utility of in vitro diagnostic methods. METHODS: We enrolled 16 cases with AOA-cutaneous adverse drug reactions (cADR), including SCAR (n = 10: 8 with Stevens-Johnson syndrome [SJS] and 2 with drug rash with eosinophilia and systemic symptoms [DRESS]) and maculopapular exanthema (MPE) (n = 6) from Taiwan and Hong Kong. We analysed the clinical characteristics, outcomes, HLA alleles and in vitro testing of AOA-SCAR, and tolerability to alternative drugs. We further performed literature review and meta-analysis on the HLA association of AOA-SCAR. RESULTS: Our data showed strontium ranelate is the most common causality of AOA-SCAR in Asian populations. There was no cross-hypersensitivity of SR-SCAR with other AOA. HLA genotyping showed that SR-SJS was most significantly associated with HLA-A*33:03 (Pc = 5.17 × 10-3 , OR: 25.97, 95% CI: 3.08-219.33). Meta-analysis showed that HLA-A*33:03 was associated with SR-SJS (P = 5.01 × 10-5 ; sensitivity: 85.7%) in Asians. The sensitivity of lymphocyte activation test (LAT) for identifying the culprit drug of SR-SJS was 83.3%. CONCLUSIONS: Strontium ranelate is identified as the most notorious AOA associated with SCAR. The HLA-A*33:03 genetic allele and LAT testing may add benefits to the diagnosis of SR-SCAR in patients whose reaction developed while taking multiple drugs.

Planning for groundwater sustainability accounting for uncertainty and costs: An application to California's Central Valley.

In regions experiencing aquifer depletion, planning for groundwater sustainability requires both accurate accounting of current groundwater budgets and an assessment of future conditions, with changes in recharge and pumping. Hydrologic variability, climate change effects on water flows, changing water infrastructure operations, and inherent uncertainties in modeling, challenge the plans to achieve groundwater sustainability. This paper examines the importance, magnitude, and policy implications of uncertainties in groundwater overdraft estimation for water management in California. We review water balance estimates from two regional-scale groundwater models-C2VSim and CVHM-for sub-regions within California's Central Valley, and examine the variability and uncertainty in historical and future estimates of groundwater overdraft. Assuming reductions in agricultural water use for sub-regions with overdraft, we estimate the probabilities of ending groundwater overdraft for different periods. We also obtain the economic costs associated with these reductions in agricultural production. Results from both groundwater models show significant inter-annual variability in flows affecting groundwater storage, and our model comparison highlights the uncertainty in water budget estimates for Central Valley sub-regions given the differences between models. The analysis of the probabilities of achieving sustainability at the sub-regional scale show that the average overdraft rate is important and that greater variance in annual groundwater storage increases uncertainties in ending overdraft, especially for shorter periods. Greater reductions in annual net water increases the reliability of achieving groundwater sustainability, but rising rapidly agricultural economic losses. Setting management thresholds below groundwater levels can ease meeting sustainability criteria, but also can introduce a false pathway to sustainability. Finally, we discuss policy implications for the design of local groundwater sustainability plans and state assessment and regulation of local plans.

Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial.

BACKGROUND: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. PATIENTS AND METHODS: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians). RESULTS: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. CONCLUSIONS: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

Atypical femur fracture incidence in women increases with duration of bisphosphonate exposure.

In a northern California population of older women who were treated with oral bisphosphonate drugs, the incidence of atypical femur fracture, a rare complication of treatment, increased with longer duration of bisphosphonate exposure. These findings align with those previously reported in an independent southern California population. INTRODUCTION: The age-adjusted incidence of atypical femur fracture (AFF) reported in southern California increased with bisphosphonate (BP) exposure, ranging up to 113 per 100,000 person-years for 8-10-year exposure. This study examines the incidence of AFF in a northern California population. METHODS: Women age 45-89 years who initiated oral BP during 2002-2014 in Kaiser Permanente Northern California were followed for AFF outcome, defined by a primarily transverse diaphyseal femur fracture through both cortices, with focal periosteal/endosteal hypertrophy, minimal trauma, and minimal/no comminution. Total BP exposure was determined from dispensed prescriptions. The incidence of AFF, calculated for 2-year BP categories ranging from < 2 to > 10 years, was age-adjusted using the 2000 US Census. RESULTS: Among 94,542 women, 107 experienced an AFF during or < 1 year after BP cessation (mean exposure 6.6 ± 3.0 years and total days' supply 5.7 ± 2.8 years at AFF). A strong relationship between AFF incidence and increasing BP exposure was seen, more than doubling for each 2-year category until 8-10 years. Among women with 2- to < 4-year BP, the crude and age-adjusted incidence was 18 and 9 per 100,000 person-years but increased over 2- and 5-fold for women with 4- to < 6- and 6- to < 8-year BP, respectively. For those receiving ≥ 8-year BP, the crude and age-adjusted incidence peaked at 196 and 112 per 100,000 person-years exposure. CONCLUSION: Incidence of AFF increases markedly after 4-6 years of BP. These trends align with southern California and confirm a strong BP duration-related risk of this rare but serious event.

Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study.

BACKGROUND: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. PATIENTS AND METHODS: Eligible patients had centrally confirmed mTNBC, ≥1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1-positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), progression-free survival, and overall survival. RESULTS: All enrolled patients (N = 170) were women, 61.8% had PD-L1-positive tumors, and 43.5% had received ≥3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7-9.9) in the total and 5.7% (2.4-12.2) in the PD-L1-positive populations. Disease control rate (95% CI) was 7.6% (4.4-12.7) and 9.5% (5.1-16.8), respectively. Median duration of response was not reached in the total (range, 1.2+-21.5+) and in the PD-L1-positive (range, 6.3-21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9-2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6-11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. CONCLUSIONS: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02447003.

Contribution of the Fetal Cardiac Axis and V-Sign Angle in First-Trimester Screening for Major Cardiac Defects.

OBJECTIVE: To estimate the potential value of fetal assessment for the cardiac axis (CAx) and V-sign angle (VSA) in the first trimester in the prediction of fetal major cardiac defects. METHODS: A cohort study was conducted from December 2015 to June 2016. Patients with singleton pregnancies and crown-rump length from 45 to 84 mm were recruited to undergo nuchal translucency sonography. The CAx on the 4-chamber view and the VSA on the 3-vessel and trachea view with Doppler mapping were measured. The estimated performance of different combinations of increased fetal nuchal translucency, CAx, and VSA in screening for major cardiac defects was examined. RESULTS: The study population of fetuses included 30 fetuses with major cardiac defects and 1538 normal fetuses. The CAx and VSA were 30° to 60° and 30° to 40°, respectively, according to the 2.5th and 97.5th percentiles in normal fetuses. When cases of isolated septal wall defects and an isolated right aortic arch were excluded, nuchal translucency above the 95th percentile, an abnormal CAx, and an abnormal VSA were observed in 63.3% (19 of 30), 63.3% (19 of 30), and 66.7% (20 of 30) of fetuses with major cardiac defects, respectively, and in 4.6% (71 of 1538), 2.0% (30 of 1538), and 5.6% (86 of 1538) of those without cardiac defects. Either an abnormal CAx or VSA was found in 93.3% (28 of 30) of the fetuses with cardiac defects and in 7.3% (113 of 1538) of those without cardiac defects. CONCLUSION: Assessment of the CAx and VSA is helpful in defining a population at risk for major cardiac defects in the first trimester.