Effect of propranolol on pharmacokinetics of clozapine in schizophrenic patients: a meta-analysis.

PURPOSE: Clozapine is the effective therapy for treatment-refractory schizophrenia. However, the use of clozapine is limited by its adverse effects. As propranolol is frequently used for the prevention and treatment of clozapine-induced tachycardia, we performed a meta-analysis to evaluate the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients. METHODS: We included 16 retrospective studies on the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients, with data from both generic and brand name treatment phases in eight clozapine bioequivalence studies conducted in a single center in China from 2018 to 2022. Review Manager 5.4 was used for meta-analysis of the included studies. RESULTS: The SMDs with 95% CIs of AUC0-12, Cmax,ss, C, and C were calculated to be 0.44 (0.23, 0.64), 0.40 (0.20, 0.61), 0.43 (0.22, 0.63), and 0.44 (0.23, 0.64), respectively. These findings proved that combination with propranolol would increase the systemic exposure of clozapine. T1/2 of clozapine was significantly longer in the presence of propranolol than in the absence of propranolol (SMD = 0.32, 95% CI [0.12, 0.52], p = 0.002). There was no statistically significant difference for T of clozapine in the presence or absence of propranolol (SMD = - 0.05, 95% CI [- 0.25, 0.15], p = 0.63). CONCLUSION: The combination with propranolol could significantly increase systemic exposure and extended T1/2 of clozapine, and thus need to be considered in prescribing decisions.

Pharmacokinetics and bioequivalence of two metoprolol succinate extended release tablets in healthy Chinese subjects under fasting and fed conditions.

AIMS: The aims of this study were to evaluate and compare the pharmacokinetic profiles and establish bioequivalence of test and reference metoprolol succinate extended-release (ER) tablets in healthy Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS: Subjects were randomly assigned to either the fasting or the fed group and also to one of the two treatment sequences (test-reference or reference-test), according to which they received a single 47.5-mg dose of the test or reference metoprolol ER tablet in the study periods. During each period, blood samples were collected at pre-dose and at intervals up to 48 hours after dosing. Plasma concentrations of metoprolol were determined by liquid chromatography. The safety of both ER tablets was monitored throughout the study. RESULTS: 60 subjects were enrolled and all completed the study, with 30 participants each in the fasting and fed groups. In both groups, the 90% confidence intervals for AUC0-48h, AUC0-inf, and Cmax were within the acceptable bioequivalence range (80 - 125%). There were no significant differences in adverse event (AE) reporting between the subjects receiving test or reference ER tablet. No serious AEs occurred during the study period. CONCLUSION: The test metoprolol ER tablet was bioequivalent to the reference metoprolol ER tablet (Betaloc ZOK) in healthy Chinese subjects measured under both fasting and fed conditions. Both formulations were well tolerated by all study participants.

FTH1 protects against osteoarthritis by MAPK pathway inhibition of extracellular matrix degradation.

OBJECTIVE: Ferritin heavy chain 1 (FTH1) is an important subunit of ferro-storing proteins and is indispensable for iron metabolism. Though it has been extensively studied in numerous organs and diseases, the relationship between FTH1 and osteoarthritis (OA) is unclear. DESIGN: Primary murine chondrocytes and cartilage explants were treated with FTH1 siRNA for 72 h. Mice were injected with adenovirus expressing FTH1 after destabilized medial meniscus (DMM) surgery. These approaches were used to determine the effect of FTH1 expression on the pathophysiology of OA. RESULTS: FTH1 expression was down regulated in OA patients and mice after DMM surgery. Knock down of FTH1 induced articular cartilage damage and extracellular matrix degradation in cartilage explants. Further, over expression of FTH1 reduced the susceptibility of chondrocytes to ferroptosis and reversed decrements in SOX9 and aggrecan after DMM surgery. Moreover, FTH1 relieved OA by inhibition of the chondrocyte MAPK pathway. CONCLUSION: This study found FTH1 to play an essential role in extracellular matrix degradation, ferroptosis, and chondrocytes senescence during OA progression. Further, injection of adenovirus expressing FTH1 may be a potential strategy for OA prevention and therapy.

Prognostic Interplay Between COVID-19 and Heart Failure With Reduced Ejection Fraction.

BACKGROUND: COVID-19 may negatively impact the prognosis of patients with chronic HFrEF and vice versa. METHODS: This study included 2 parallel analyses of patients in the United States who were in the TriNetX health database and who underwent polymerase chain reaction testing for SARS-CoV-2 as an inpatient or outpatient between January and September of 2020. Analysis A included patients with positive tests for COVID-19 and compared patients with histories of worsening heart failure with reduced ejection fraction (HFrEF) (hospitalization due to heart failure (HF) or IV diuretic use during the prior 12 months), HFrEF without worsening, and no prior HF. Analysis B included patients with histories of HFrEF and compared patients with positive vs negative COVID-19 tests. Outcomes included mortality and worsening HF. In both analyses, prespecified subgroup analyses were stratified by inpatient vs outpatient settings of the COVID-19 tests. RESULTS: In Analysis A, of 99,052 patients with positive COVID-19 tests, 514 (0.5%) and 524 (0.5%) patients had histories of worsening HFrEF and HFrEF without worsening, respectively. After adjustment, compared to patients without HF, worsening HFrEF (risk ratio [RR] 1.42, 95% CI 1.10-1.83; P< 0.001) and HFrEF without worsening (RR 1.33, 95% CI 0.96-1.84; P= 0.06) were associated with higher 30-day mortality rates. Excess risk of mortality tended to be pronounced in patients initially diagnosed with COVID-19 as outpatients (P for interaction, 0.12 and 0.006, respectively). In Analysis B, of 14,838 patients with HFrEF tested for COVID-19, 1038 (7.0%) had positive tests. After adjustment, testing positive was associated with excess 30-day mortality risk (RR 1.67, 95% CI 1.38-2.02; P< 0.001) and worsening HF (RR 1.33, 95% CI 1.17-1.51; P< 0.001). Mortality risk was nominally more pronounced among patients presenting as outpatients (P for interaction 0.07). CONCLUSION: In this large cohort of patients tested for COVID-19, among patients testing positive, a history of HFrEF with or without worsening was associated with excess mortality rates, particularly among patients diagnosed with COVID-19 as outpatients. Among patients with established HFrEF, compared with testing negative, testing positive for COVID-19 was independently associated with higher risk of death and worsening HF.

Real-world homologous recombination repair mutation testing in metastatic castration-resistant prostate cancer in the USA, Europe and Japan.

Aim: To assess homologous recombination repair mutation (HRRm) testing patterns in metastatic castration-resistant prostate cancer. Methods: A point-in-time, international survey conducted January-August 2020. Results: Three-quarters of physicians (oncologists, urologists, specialist surgeons) globally reported access to genetic/genomic testing and just over half were HRRm testers. Surveyed physicians reported HRRm testing and positivity rates for 1913 patients, which were 18.1% and 33.7%, respectively. Of patients tested (n = 347), the most common HRR genes tested were BRCA (91.6%) and ATM (47.3%). Conclusion: Overall testing rates were low, with physicians mostly testing patients they considered higher risk. Increased awareness and education are needed to encourage broader testing, to understand familial risk and to identify patients with worse outcomes or those eligible for life-prolonging treatments.

Metastatic castration-resistant prostate cancer (mCRPC) is cancer that has spread beyond the prostate gland and that no longer responds to hormone therapy. Genetic testing is now recommended for patients with mCRPC to help doctors understand familial risk and identify patients who may benefit from new treatments. The authors asked doctors questions about their patients, such as their age, symptoms and genetic testing. The authors found that overall genetic testing rates were low, with doctors mostly testing patients they thought were at higher risk of developing cancer. Increased doctor awareness and education are needed to encourage more genetic testing in mCRPC patients. However, doctors claimed that the cost of these tests was a challenge to conducting genetic testing.

Impact of next-generation hormonal agents on treatment patterns among patients with metastatic hormone-sensitive prostate cancer: a real-world study from the United States, five European countries and Japan.

BACKGROUND: Until five years ago, the metastatic hormone-sensitive prostate cancer (mHSPC) treatment landscape was dominated by the use of androgen deprivation therapy (ADT) alone. However, novel hormonal agents (NHAs) and chemotherapy are now approved for male patients with mHSPC. This study aimed to understand the impact NHA approvals had on mHSPC real-world treatment patterns and to identify the key factors associated with NHA or chemotherapy (± ADT) usage vs ADT alone. METHODS: Data were collected from the Adelphi Prostate Cancer Disease Specific Programme (DSP)™, a point-in-time survey of physicians and their consulting patients conducted in the United States (US), five European countries (France, Germany, Italy, Spain, and the United Kingdom), and Japan between January and August 2020. Data were analysed using descriptive statistics for individual countries, regions, and all countries combined. Pairwise analyses were used to further investigate differences between treatment groups at global level. RESULTS: 336 physicians provided data on 1195 mHSPC patients. Globally, at data collection, the most common mHSPC regimen initiated first was ADT alone (47%), followed by NHAs (± ADT) (31%, of which 21% was abiraterone, 8% was enzalutamide, and 2% was apalutamide) and chemotherapy (± ADT) (19%). The highest rates of ADT alone usage were observed in Japan (78%) and Italy (66%), and the lowest in Spain (34%) and in the US (36%). Our results showed that clinical decision making was driven by patient fitness, compliance, tolerance of adverse events, and balance of impact on quality of life vs overall survival. CONCLUSIONS: This real-world survey offered early insights into the evolving mHSPC treatment paradigm. It showed that in 2020, ADT alone remained the most common initial mHSPC therapy, suggesting that physicians may prefer using treatments which they are familiar and have experience with, despite clinical trial evidence of improved survival with NHAs or chemotherapy (± ADT) vs ADT alone. Results also indicated that physicians prescribed specific mHSPC treatments primarily based on the following criteria: patient preference, disease burden/severity, and the performance status and comorbidities of the patient. To fully appreciate the rapidly changing mHSPC treatment landscape and monitor NHA uptake, additional real-world studies are required.

Medication use by US patients with pulmonary hypertension associated with chronic obstructive pulmonary disease: a retrospective study of administrative data.

BACKGROUND: Pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD). While clinical guidelines recommend specific drug therapies for pulmonary arterial hypertension (PAH), these drug therapies are not recommended for PH due to lung disease. METHODS: This was a retrospective cohort study using the Optum® Clinformatics® Data Mart from January 2009-September 2019. An algorithm was designed to identify adults with ≥ 2 ICD-9-CM or ICD-10-CM diagnosis codes for PH and with ≥ 2 diagnosis codes for COPD. Sensitivity analyses were conducted among subgroups of patients with evidence of a right heart catheterization (RHC) or pulmonary function test (PFT). Patient characteristics, medications used, and durations of use of PAH and COPD medications were analyzed. RESULTS: A total of 25,975 patients met the study inclusion criteria. Their mean age was 73.5 (SD 10.0) years and 63.8% were female. Medications targeting PAH were prescribed to 643 (2.5%) patients, most frequently a phosphodiesterase-5 inhibitor (2.1%) or an endothelin receptor antagonist (0.75%). Medications for COPD were prescribed to 17,765 (68.4%) patients, most frequently an inhaled corticosteroid (57.4%) or short-acting beta agonist (50.4%). The median durations of use ranged from 4.9 to 12.8 months for PAH medications, and from 0.4 to 5.9 months for COPD medications. Of the subgroup of patients with RHC (N = 2325), 257 (11.1%) were prescribed a PAH medication and 1670 (71.8%) used a COPD medication. Of the subgroup with a PFT (N = 2995), 58 (1.9%) were prescribed a PAH medication and 2100 (70.1%) a COPD medication. CONCLUSIONS: Patients with PH associated with COPD were identified in a US administrative claims database. Very few of these patients received any of the medications recommended for PAH, and only about two thirds received medications for COPD.

Representativeness of the VICTORIA Trial Population in Clinical Practice: Analysis of the PINNACLE Registry.

BACKGROUND: In the VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial, vericiguat reduced the risk of mortality due to cardiovascular problems and of hospitalization due to heart failure (HF) among patients with HF with reduced ejection fraction (HFrEF) and recent worsening HF events (WHFEs). The representativeness of the VICTORIA population of patients with WHFE in clinical practice is unknown. METHODS AND RESULTS: Patients with HF and ejection fraction <45% were identified in the Practice Innovation And Clinical Excellence (PINNACLE) registry and were stratified by the occurrence of WHFEs. Characteristics and outcomes of patients in the PINNACLE registry with and without WHFEs were compared to the VICTORIA population. Of the 14,180 PINNACLE patients identified with HFrEF, 26.5% had had a WHFE. The VICTORIA population was similar to PINNACLE patients with WHFEs in mean age (67.3 vs 66.7), ejection fraction (28.9% vs 28.3%), body mass index (26.8 vs 27.6), and comorbidity burden. The rate of hospitalization because of HF at 1 year was 29.6% in the placebo group of VICTORIA, compared to 35.8% in PINNACLE patients with WHFEs and 13.3% in patients without WHFEs. CONCLUSIONS: The PINNACLE patients with WHFEs meeting the VICTORIA definition resembled the VICTORIA population in characteristics and outcomes, suggesting that VICTORIA's population may be generalizable to patients with WHFEs in clinical practice.

Factors associated with switching from sulphonylureas to dipeptidyl peptidase 4 inhibitors among patients with type 2 diabetes in the United States.

AIMS: Studies examining the prevalence of and factors associated with switching from sulphonylureas (SUs) to dipeptidyl peptidase 4 (DPP-4) inhibitors in real-world settings are lacking. We assessed the factors associated with switching from SUs to DPP-4 inhibitors in the United States. MATERIALS AND METHODS: This retrospective cohort study was conducted using the Optum Clinformatics® Data Mart (2009-2018). Adults with type 2 diabetes and newly prescribed at least two SUs were included and were followed for 2 years after the initiation of SU (index date). We compared the characteristics of those who switched from SUs to DPP-4 inhibitors (only; no additional antidiabetic drugs) with those who continued with SUs (without adding other antidiabetic drugs) using multivariate logistic regression. Multinomial regression analyses were also conducted to assess the factors associated with switching to different drug classes versus continuation with SUs. RESULTS: In a sample of 119 107 new SU users, 2.2% (2633) switched to DPP-4 inhibitors, 3.8% (4542) switched to antidiabetic drugs other than DPP-4 inhibitors, 68.3% (81 394) discontinued SUs but did not switch to another antidiabetic drug, 12.9% (15 345) continued with SUs and added other antidiabetic drugs, and 12.8% (15 193) continued with SUs only. Multivariate logistic regression showed that those who had significantly higher likelihood of switching were younger, female [vs. males; adjusted odds ratio (AOR) = 0.70], and living in the south; had previous use of DPP-4 inhibitors (AOR = 1.71); were not using antidiabetic drugs at baseline; had more baseline diabetes-related emergency room visits (AOR = 1.13), depression (AOR = 1.34), post-index hypoglycaemia (AOR = 2.20), and an earlier index year; and were glyburide users (vs. glimepiride users; AOR = 1.29). CONCLUSIONS: The discontinuation rate for SUs is high. Factors associated with switching from SUs to DPP-4 inhibitors included age, sex, geographic region, baseline antidiabetic drug use, type of SU, baseline diabetes-related emergency room visits, hypoglycaemia and depression.

Systemic therapy, survival and end-of-life costs for metastatic triple-negative breast cancer: retrospective SEER-Medicare study of women age ≥65 years.

Aim: To analyze therapy for metastatic triple-negative breast cancer (mTNBC), factors contributing to survival and costs. Patients & methods: Using 2010-2016 SEER-Medicare data, we identified women (≥65 years) with mTNBC. Results: Of 302 eligible patients, 152 (50%) received systemic therapy. In multivariable regression analyses, only age <75 years was associated with therapy receipt (odds ratio: 2.91; 95% CI: 1.79-4.74); and only systemic therapy significantly reduced risk of death (hazard ratio: 0.34; 95% CI: 0.26-0.44). Median overall survival was 13.4 (95% CI: 11.3-15.1) vs 3.3 months (95% CI: 2.7-3.9) in therapy vs no-therapy cohorts. Mean per-patient-per-month costs <30 days before end-of-life/follow-up were $14,100 and $15,600 (2019 USD), respectively. Conclusion: Poor outcomes and high costs indicate need for more effective mTNBC therapy.

Early triple-negative breast cancer in women aged ≥65: retrospective study of outcomes, resource use and costs, 2010-2016.

Aim: To examine real-world treatment patterns and outcomes in neoadjuvant and adjuvant settings for early-stage triple-negative breast cancer (TNBC). Patients & methods: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients (≥65 years) with newly diagnosed stage II/III TNBC in 2010-2015 who had surgery plus neoadjuvant and/or adjuvant (systemic and/or radiation) therapy. Treatment, survival, healthcare resource use and costs were assessed through 2016. Results: Of 1569 patients (>99% women), 6%/74%/20% received neoadjuvant-only/adjuvant-only/both (neo + adj) therapies, respectively. Median overall survival was 23 months/not reached (NR)/78 months, with longer survival at stage II (NR/NR/78 months) than stage III (22/43/38 months). Mean per patient per month costs were $10,620 and $17,872 in neoadjuvant and adjuvant periods. Conclusion: These findings provide insights into clinical and economic outcomes for early-stage TNBC in 2010-2016.

Real-world genetic testing patterns in metastatic castration-resistant prostate cancer.

Aim: To assess the patterns of genetic testing for homologous recombination repair mutations in patients with metastatic castration-resistant prostate cancer (mCRPC) pre-PARP inhibitors approval. Patients & methods: mCRPC patients were selected in an oncology electronic medical records database. Patterns and predictors of testing for ATM, BRCA1/2, CDK12, PALB2 and FANCA gene alterations were assessed. Results: Of 5213 mCRPC patients, 674 (13%) had a documented genetic test. The number of tested patients increased from 1 in 2013 to 313 in 2018 (out of 3161 and 3010 clinically active patients, respectively). Receiving care in an academic oncology center (versus a community-based center) strongly predicted genetic testing (hazard ratio = 2.41). Conclusion: The use of and access to genetic testing pre-PARP inhibitor approval was suboptimal.

Lay abstract In 2017, US guidelines recommended the use of genetic testing in patients with metastatic castration-resistant prostate cancer (mCRPC). While the initial goal of genetic testing was to guide referral to genetic counselling and clinical trial enrollment, it is now also used to identify patients who could benefit from new drugs that target specific molecular defects. Using medical record data of US patients with mCRPC, we found that the rates of genetic testing and the breadth of molecular defects tested were suboptimal from 2013 to 2019. We also found lower rates of genetic testing in patients treated in community-based centers compared with those treated in academic oncology centers. These results underscore the importance of increasing the take up rate of genetic testing in patients with mCRPC to help guide treatment decisions.

Evaluation of bioequivalence between generic and brand-name clozapine in Chinese schizophrenic patients: A randomized, two-period, crossover study.

OBJECTIVE: Clozapine is the most effective therapy for schizophrenia. This study compared the bioequivalence of a generic formulation of clozapine (ChangZhou Pharmaceutical Factory Co. Ltd. Jiangsu, China) to the brand name formulation (Clozaril, HLS Therapeutics, Inc., Philadelphia, PA, USA) after multiple doses in Chinese schizophrenic patients. MATERIALS AND METHODS: This was a randomized, open-label, multiple-dose, 2-way crossover study in which patients with schizophrenia received the generic clozapine or Clozaril 100 mg twice daily for 10 days before crossing over to the alternate formulation for the next 10 days. Blood samples were collected at regular intervals during each treatment period, and plasma concentration of clozapine was determined by high-performance liquid chromatography. RESULTS: 26 patients were enrolled, of whom 24 completed the study and were included in the steady-state analyses. The mean AUC0-12 was 6,003.29 h×ng/mL for generic clozapine and 6,347.53 h×ng/mL for Clozaril. The mean Cmax,ss was 698.52 ng/mL for generic clozapine and 739.75 ng/mL for Clozaril. The ratio of the adjusted geometric means and its 90% CI of the ratios for AUC0-12 was 96.24% (89.60 - 103.36%), and for Cmax,ss was 95.90% (88.91 - 103.44%). A total of 66 adverse events were reported by 22 (84.62%) subjects. Among them, 34 occurred in 17 (65.38%) patients during dosing of generic clozapine, and 32 occurred in 16 (61.54%) patients during dosing of brand-name clozapine. CONCLUSION: The result demonstrated that the generic clozapine was bioequivalent to brand-name clozapine (Clozaril). This would provide physicians with reassurance that patients who receive the studied generic clozapine will achieve similar plasma drug concentrations to those of brand-name clozapine (Clozaril).

Outcomes at 7 years post-transplant in black vs nonblack kidney transplant recipients administered belatacept or cyclosporine in BENEFIT and BENEFIT-EXT.

Clinical outcomes are generally worse for black vs nonblack renal allograft recipients. In BENEFIT and BENEFIT-EXT, recipients were randomized to belatacept more intense-based, belatacept less intense-based, or cyclosporine-based immunosuppression. At year 7, belatacept was associated with superior graft survival vs cyclosporine in BENEFIT (recipients of living or standard criteria deceased donor kidneys); belatacept was associated with similar graft survival vs cyclosporine in BENEFIT-EXT (recipients of extended criteria donor kidneys). In both studies, renal function was superior for belatacept-treated vs cyclosporine-treated patients. Seven-year outcomes were examined by race post hoc in each study. The effect of race and treatment on time to death or graft loss was compared using Cox regression. The interaction between treatment and race was also considered. Glomerular filtration rate (GFR) was estimated from months 1 to 84 using a repeated-measures model. In total, 8.3% (55/666) and 13.1% (71/543) of patients in BENEFIT and BENEFIT-EXT, respectively, were black. Time to death or graft loss was similar in blacks and nonblacks. For both subgroups, estimated mean GFR increased over 7 years for belatacept, but declined for cyclosporine. Outcomes were similar in belatacept-treated black and nonblack patients. Due to the small number of black patients, these results must be interpreted with caution.

Macrophage-derived ectosomal miR-350-3p promotes osteoarthritis progression through downregulating chondrocyte H3K36 methyltransferase NSD1.

Mechanical overloading can promote cartilage senescence and osteoarthritis (OA) development, but its impact on synovial macrophages and the interaction between macrophages and chondrocytes remain unknown. Here, we found that macrophages exhibited M1 polarization under mechanical overloading and secreted ectosomes that induced cartilage degradation and senescence. By performing miRNA sequencing on ectosomes, we identified highly expressed miR-350-3p as a key factor mediating the homeostatic imbalance of chondrocytes caused by M1-polarized macrophages, this result being confirmed by altering the miR-350-3p level in chondrocytes with mimics and inhibitor. In experimental OA mice, miR-350-3p was increased in synovium and cartilage, while intra-articular injection of antagomir-350-3p inhibited the increase of miR-350-3p and alleviated cartilage degeneration and senescence. Further studies showed that macrophage-derived ectosomal miR-350-3p promoted OA progression by inhibiting nuclear receptor binding SET domain protein 1(NSD1) in chondrocytes and regulating histone H3 lysine 36(H3K36) methylation. This study demonstrated that the targeting of macrophage-derived ectosomal miRNAs was a potential therapeutic method for mechanical overload-induced OA.

Generalized Focal Loss: Towards Efficient Representation Learning for Dense Object Detection.

Object detection is a fundamental computer vision task that simultaneously predicts the category and localization of the targets of interest. Recently one-stage (also termed "dense") detectors have gained much attention over two-stage ones due to their simple pipeline and friendly application to end devices. Dense object detectors basically formulate object detection as dense classification and localization (i.e., bounding box regression). The classification is usually optimized by Focal Loss and the box location is commonly learned under Dirac delta distribution. A recent trend for dense detectors is to introduce an individual prediction branch to estimate the quality of localization, which facilitates the classification to improve detection performance. This paper delves into the representations of the above three fundamental elements: quality estimation, classification and localization. Three problems are discovered in existing practices, including (1) the inconsistent usage of the quality estimation and classification between training and inference, (2) the inflexible Dirac delta distribution for localization, and (3) the deficient and implicit guidance for accurate quality estimation. To address these problems, we design new representations for these elements. Specifically, we merge the quality estimation into the class prediction vector to form a joint representation, use a vector to represent arbitrary distribution of box locations, and extract discriminant feature descriptors from the distribution vector for more reliable quality estimation. The improved representations eliminate the inconsistency risk and accurately depict the flexible distribution in real data, but contain continuous labels, which is beyond the scope of Focal Loss. We then propose Generalized Focal Loss (GFocal) that generalizes Focal Loss from its discrete form to the continuous version for successful optimization. Extensive experiments demonstrate the effectiveness of our method, without sacrificing the efficiency both in training and inference. Based on GFocal, we construct a considerably fast and lightweight detector termed NanoDet under mobile settings, which is 1.8 AP higher, 2x faster and 6x smaller than scaled YoloV4-Tiny.

First-in-human phase I studies of YJ001 spray applied to local skin in healthy subjects and patients with diabetic neuropathic pain.

BACKGROUND: The study aimed to investigate the safety, pharmacokinetics (PK), and efficacy of YJ001 spray, a candidate drug for diabetic neuropathic pain (DNP) therapy. RESEARCH DESIGN & METHODS: Forty-two healthy subjects received one of four single doses (240, 480, 720, 960 mg) of YJ001 spray or placebo, and 20 patients with DNP received repeated doses (240 and 480 mg) of YJ001 spray or placebo via topical route of administration to the local skin of both feet. Safety, and efficacy assessments were performed, and blood samples were collected for PK analyses. RESULTS: The pharmacokinetic results revealed that the concentrations of YJ001 and its metabolites were low, and most of them were lower than the lower limit of quantitation. In patients with DNP, treatment with a 480 mg YJ001 spray dose significantly reduced pain and improved sleep quality compared with placebo. No serious adverse events (SAEs) or clinically significant findings of the safety parameters were observed. CONCLUSION: Systemic exposure to YJ001 and its metabolites is low after YJ001 spray is applied locally to the skin, which will reduce systemic toxicity and adverse reactions. YJ001 appears to be well tolerated and potentially effective in the management of DNP and is a promising new remedy for DNP.

Multiple doses of SHR-1222, a sclerostin monoclonal antibody, in postmenopausal women with osteoporosis: A randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial.

SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50-400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned. Twenty-one received placebo and eighty-four received SHR-1222 sequentially (100 mg QM, n=4; 200 or 300 mg QM, n=20; and 400 or 600 mg Q2M, n=20). The most common adverse events included increased blood parathyroid hormone, increased low-density lipoprotein, increased blood alkaline phosphatase, increased blood cholesterol, back pain, and arthralgia, the majority of which were mild in severity without noticeable safety concerns. Serum SHR-1222 exposure (Cmax,ss and AUC0-tau,ss) increased in a greater than dose-proportional manner. Following multiple doses of SHR-1222, the bone formation markers (terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and osteocalcin) increased in a dose-dependent manner, whereas the bone resorption marker (ß-C-telopeptide) was downregulated. Accordingly, BMD gains in the lumbar spine, total hip, and femoral neck were observed. The maximum BMD increase from baseline at the lumbar spine was detected in the 300 mg QM cohort (14.6% vs. 0.6% in the placebo group on day 169). Six (6/83; 7.2%) subjects developed anti-SHR-1222 antibodies with no discernible effects on PKs, PDs, and safety. Thus, multiple doses of SHR-1222 showed an acceptable safety profile and dose-dependent plasma exposure in women with POP, and could improve their BMD rapidly and prominently by promoting bone formation and inhibiting bone resorption. These findings further support SHR-1222 as a potential alternative agent for the treatment of POP.

Long-Term Real-World Outcomes of First-Line Pembrolizumab Monotherapy for Metastatic Non-Small Cell Lung Cancer With ≥50% Expression of Programmed Cell Death-Ligand 1.

Objectives: Immune checkpoint inhibitors (ICIs) of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) have been rapidly adopted in US clinical practice for first-line therapy of metastatic non-small cell lung cancer (NSCLC) since regulatory approval in October 2016, and a better understanding is needed of long-term outcomes of ICI therapy administered in real-world settings outside of clinical trials. Our aim was to describe long-term outcomes of first-line pembrolizumab monotherapy at US oncology practices for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status. Methods: This retrospective two-cohort study used technology-enabled abstraction of deidentified electronic health records (EHR cohort) plus enhanced manual chart review (spotlight cohort) to study adult patients with stage IV NSCLC, PD-L1 expression ≥50%, no documented EGFR/ALK/ROS1 genomic aberration, and ECOG performance status 0-1 who initiated first-line pembrolizumab monotherapy from 1-November-2016 to 31-March-2020 (EHR cohort, with data cutoff 31-March-2021) or from 1-December-2016 to 30-November-2017 (spotlight cohort, with data cutoff 31-August-2020). Kaplan-Meier analysis was used to determine overall survival (OS; both cohorts) and, for the spotlight cohort, real-world progression-free survival (rwPFS) and real-world tumor response (rwTR). Results: The EHR cohort included 566 patients (298 [53%] men); the spotlight cohort included 228 (105 [46%] men); median age in both cohorts was 71. Median follow-up from pembrolizumab initiation to data cutoff was 35.1 months (range, 12.0-52.7) and 38.4 months (range, 33.1-44.9) in EHR and spotlight cohorts, respectively. Median OS was 19.6 months (95% CI, 16.6-24.3) and 21.1 months (95% CI, 16.2-28.9), respectively; 3-year OS rates were 36.2% and 38.2% in EHR and spotlight cohorts, respectively. In the spotlight cohort, median rwPFS was 7.3 months (95% CI, 5.7-9.2); 88 patients (38.6%; 95% CI, 32.2-45.2) experienced rwTR of complete or partial response. For 151/228 patients (66%) who discontinued pembrolizumab, the most common reasons were disease progression (70 [46%]) and therapy-related adverse effects (35 [23%]). Conclusions: Real-world outcomes remain consistent with outcomes observed in clinical trials, supporting long-term benefits of first-line pembrolizumab monotherapy for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status.

Real-World Treatment Patterns in Metastatic Castration-Resistant Prostate Cancer Across Europe (France, Germany, Italy, Spain, and the United Kingdom) and Japan.

INTRODUCTION: Prostate cancer (PC) is the second most common cancer, and the fifth most common cause of cancer-related mortality among male patients, worldwide. In Europe and Japan, the incidence of PC in men in 2020 exceeded that of lung cancer. Although national and regional clinical guidelines for the treatment of metastatic castration-resistant prostate cancer (mCRPC) are available in Europe and Japan, a literature review did not identify a published comparison of differing guidelines, but identified a lack of studies reporting treatment patterns of approved mCRPC treatments in Europe and Japan in normal clinical practice. The objective of this real-world study was to compare national treatment guidelines and real-world treatment for mCRPC in Europe and Japan. METHODS: Physician-reported demographics, clinical characteristics, and treatment data of patients with mCRPC were drawn from the Adelphi Prostate Cancer Disease Specific Programme™, conducted in five European countries and Japan (2020) and analysed descriptively. RESULTS: All current treatment guidelines recommended the use of novel hormonal agents (NHA-abiraterone/enzalutamide) and chemotherapy (mainly docetaxel), with some intercountry differences, with NHA rechallenge accepted in Germany, Italy and Japan, but not in France, Spain or the United Kingdom. Overall, 271 physicians provided data for 1753 patients. At 1st-line (1L), the most common treatment was NHAs followed by (→) chemotherapy, in all countries. Chemotherapy was the most common 2nd-line (2L) treatment, except in Japan, where 2L NHA use was preferred, and Spain, where both were used equally. NHA â†’ chemotherapy and chemotherapy â†’ NHA were the first and second usual 1L â†’ 2L sequence in most countries, except for France, where the second most common sequence was NHA â†’ NHA, and Japan, with androgen deprivation therapy alone â†’ NHA. CONCLUSION: Real-world mCRPC treatment patterns largely reflected national guidelines. It is expected that guidelines and treatment patterns will change with the development of new treatment options.