Evaluation of non-additive genetic effects on carcass and meat quality traits in Korean Hanwoo cattle using genomic models.

The traditional genetic evaluation methods generally consider additive genetic effects only and often ignore non-additive (dominance and epistasis) effects that may have contributed to genetic variation of complex traits of livestock species. The available dense single nucleotide polymorphisms (SNPs) panels offer to investigate the potential benefits of including non-additive genetic effects in the genomic evaluation models. Data from 16 971 genotyped (Illumina Bovine 50 K SNP chip) Korean Hanwoo cattle were used to estimate genetic variance components and prediction accuracy of genomic breeding values (GEBVs) for four carcass and meat quality traits: carcass weight (CWT), eye muscle area (EMA), back fat thickness (BFT) and marbling score (MS). Five different genetic models were evaluated through including additive, dominance and epistatic interactions (additive by additive, A × A; additive by dominance, A × D and dominance by dominance, D × D) successively in the models. The estimates of additive genetic variances and narrow sense heritabilities (ha2) were found similar across the evaluated models and traits except when additive interaction (A × A) was included. The dominance variance estimates relative to phenotypic variance ranged from 1.7-3.4% for CWT and MS traits, whereas, they were close to zero for EMA and BFT traits. The magnitude of A × A epistatic heritability (haa2) ranged between 14.8 and 27.7% in all traits. However, heritability estimates for A × D and D × D epistatic interactions (had2 and hdd2) were quite low compared to haa2 and were contributed only 0.0-9.7% of the total phenotypic variation. In general, broad sense heritability (hG2) estimates were almost twice (ranging between 0.54 and 0.68) the ha2 for all of the investigated traits. The inclusion of dominance effects did not improve the prediction accuracy of GEBV but improved 2.0-3.0% when epistatic effects were included in the model. More importantly, rank correlation revealed that partitioning of variance components considering dominance and epistatic effects in the model would enable to re-rank of top animals with better prediction of GEBV. The present result suggests that dominance and epistatic effects could be included in the genomic evaluation model for better estimates of variance components and more accurate prediction of GEBV for carcass and meat quality traits in Korean Hanwoo cattle.

Effectiveness of next-generation sequencing for patients with advanced non-small-cell lung cancer: a population-based registry study.

BACKGROUND: Despite the growing use of next-generation sequencing (NGS) in the management of advanced non-small-cell lung cancer (NSCLC), there is little evidence that its use leads to improved clinical outcomes. This study aimed to compare the effectiveness of NGS with that of single-gene testing (SGT) alone in patients with advanced NSCLC. MATERIALS AND METHODS: This was a retrospective cohort study conducted on patients diagnosed with advanced lung adenocarcinoma between 2017 and 2018 from a nationwide, population-based database. We identified patients who had SGT exclusively (SGT group) or underwent upfront NGS or NGS following SGT as an initial evaluation (NGS group). Patients were followed up until death or the end of the study (31 December 2019). The adjusted hazard ratio (aHR) for death was estimated using the Cox proportional hazards model. The factors affecting the adoption of NGS were identified. RESULTS: Of 8566 patients diagnosed with advanced lung adenocarcinoma, 402 and 6932 patients were assigned to the NGS and SGT groups, respectively. More NGS was carried out in younger patients, those with higher incomes, and those living in urban areas. After balancing these confounders through matching, no difference was observed in the median overall survival and risk of death between the NGS and SGT groups [18.5 versus 19.7 months, log-rank P = 0.783; aHR 0.98, 95% confidence interval (CI) 0.84-1.14, respectively]. Only in a subgroup for whom epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitors were not indicated, NGS was associated with better survival outcomes (14.1 versus 9.0 months, log-rank P = 0.006; aHR 0.82, 95% CI 0.69-0.97). CONCLUSIONS: In the real world, NGS for all-comers in patients with advanced NSCLC did not increase survival outcomes. When health care resources to support equal access to NGS are limited, upfront SGT followed by NGS may be a more efficient strategy.

Improved diagnostic performance of susceptibility-weighted imaging with compressed sensing-sensitivity encoding and neuromelanin-sensitive MRI for Parkinson's disease and atypical Parkinsonism.

AIM: To verify the diagnostic performance of the loss of nigrosome-1 on susceptibility-weighted imaging (SWI) with compressed sensing-sensitivity encoding (CS-SENSE) and neuromelanin on neuromelanin-sensitive (NM) magnetic resonance imaging (MRI) for the diagnosis of Parkinson's disease (PD) and atypical Parkinsonism. MATERIALS AND METHODS: A total of 195 patients who underwent MRI between October 2019 and February 2020, including SWI, with or without CS-SENSE, and NM-MRI, were reviewed retrospectively. Two neuroradiologists assessed the loss of nigrosome-1 on SWI and neuromelanin on the NM-MRI. The result of N-3-fluoropropyl-2-beta-carbomethoxy-3-beta-(4-iodophenyl) nortropane positron-emission tomography (PET) was set as the reference standard. RESULTS: When CS-SENSE was applied for nigrosome-1 imaging on SWI, the non-diagnostic scan rate was lowered significantly from 19.3% (17/88) to 5.6% (6/107; p=0.004). Diagnosis of PD and atypical Parkinsonism based on the loss of nigrosome-1 on SWI and based on NM-MRI showed good diagnostic value (area under the curve [AUC] 0.821, 95% confidence interval [CI] = 0.755-0.875: AUC 0.832, 95% CI = 0.771-0.882, respectively) with a substantial inter-reader agreement (κ = 0.791 and 0.681, respectively). Combined SWI and neuromelanin had a similar discriminatory ability (AUC 0.830, 95% CI = 0.770-0.880). Similarly, the diagnosis of PD was excellent. CONCLUSIONS: CS-SENSE may add value to the diagnostic capability of nigrosome-1 on SWI to reduce the nondiagnostic scan rates. Furthermore, loss of nigrosome-1 on SWI or volume loss of neuromelanin on NM-MRI may be helpful for diagnosing PD.

Search for Boosted Dark Matter in COSINE-100.

We search for energetic electron recoil signals induced by boosted dark matter (BDM) from the galactic center using the COSINE-100 array of NaI(Tl) crystal detectors at the Yangyang Underground Laboratory. The signal would be an excess of events with energies above 4 MeV over the well-understood background. Because no excess of events are observed in a 97.7 kg·yr exposure, we set limits on BDM interactions under a variety of hypotheses. Notably, we explored the dark photon parameter space, leading to competitive limits compared to direct dark photon search experiments, particularly for dark photon masses below 4 MeV and considering the invisible decay mode. Furthermore, by comparing our results with a previous BDM search conducted by the Super-Kamionkande experiment, we found that the COSINE-100 detector has advantages in searching for low-mass dark matter. This analysis demonstrates the potential of the COSINE-100 detector to search for MeV electron recoil signals produced by the dark sector particle interactions.

A phase II open-label trial of avelumab plus axitinib in previously treated non-small-cell lung cancer or treatment-naïve, cisplatin-ineligible urothelial cancer.

BACKGROUND: We hypothesized that avelumab plus axitinib could improve clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC) or urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled previously treated patients with advanced or metastatic NSCLC, or untreated, cisplatin-ineligible patients with advanced or metastatic UC. Patients received avelumab 800 mg every 2 weeks (Q2W) and axitinib 5 mg orally two times daily. The primary endpoint was objective response rate (ORR). Immunohistochemistry was used to assess programmed death-ligand 1 (PD-L1) expression (SP263 assay) and the presence of CD8+ T cells (clone C8/144B). Tumor mutational burden (TMB) was assessed by whole-exome sequencing. RESULTS: A total of 61 patients were enrolled and treated (NSCLC, n = 41; UC, n = 20); 5 remained on treatment at data cut-off (26 February 2021). The confirmed ORR was 31.7% in the NSCLC cohort and 10.0% in the UC cohort (all partial responses). Antitumor activity was observed irrespective of PD-L1 expression. In exploratory subgroups, ORRs were higher in patients with higher (≥median) CD8+ T cells in the tumor. ORRs were higher in patients with lower TMB (

Clinical outcomes of sinonasal inverted papilloma: a retrospective analysis of 139 cases.

OBJECTIVES: Sinonasal inverted papilloma has a high tendency for recurrence, local bone destruction and risk of malignant transformation. Therefore, complete resection of the tumour is required, and close follow up is essential. This article describes the clinical outcomes, recurrence rate and malignant transformation rate of sinonasal inverted papilloma. METHODS: In this study, 139 patients diagnosed with sinonasal inverted papilloma in our hospital from December 2010 to May 2022 were retrospectively analysed. All patients underwent endoscopic surgery. RESULTS: Sinonasal inverted papilloma occurred more often in males than in females. The mean age of patients with sinonasal inverted papilloma was 67.3 ± 5.7 years at diagnosis. The most prevalent site of origin was the maxillary sinus (50.4 per cent). The recurrence rate was 5.75 per cent, and the malignant transformation rate was 6.5 per cent. CONCLUSION: All patients in this study underwent endoscopic surgery. Meticulous resection and regular long-term follow ups are crucial to reducing sinonasal inverted papilloma recurrence after surgery.

Effects of genomic estimated breeding value and dietary energy to protein ratio on growth performance, carcass trait, and lipogenic gene expression in Hanwoo steer.

"Genome-based precision feeding" is a concept that involves the application of customised diets to different genetic groups of cattle. We investigated the effects of the genomic estimated breeding value (gEBV) and dietary energy to protein ratio (DEP) on growth performance, carcass traits, and lipogenic gene expression in Hanwoo (Korean cattle) steers. Forty-four Hanwoo steers (BW = 636 kg, age = 26.9 months) were genotyped using the Illumina Bovine 50 K BeadChip. The gEBV was calculated using genomic best linear unbiased prediction. Animals were separated into high gEBV of marbling score or low-gMS groups based on the upper and lower 50% groupings of the reference population, respectively. Animals were assigned to one of four groups in a 2 × 2 factorial arrangement: high gMS/high DEP (0.084 MJ/g), high gMS/low DEP (0.079 MJ/g), low gMS/high DEP, and low gMS/low DEP. Steers were fed concentrate with a high or low DEP for 31 weeks. The BW tended to be higher (0.05 < P < 0.1) in the high-gMS groups compared to the low-gMS groups at 0, 4, 8, 12, and 20 weeks. The average daily gain (ADG) tended to be lower (P = 0.08) in the high-gMS group than in the low-gMS group. Final BW and measured carcass weight (CW) were positively correlated with the gEBV of carcass weight (gCW). The DEP did not affect ADG. Neither the gMS nor the DEP affected the MS and beef quality grade. The intramuscular fat (IMF) content in the longissimus thoracis (LT) tended to be higher (P = 0.08) in the high-gMS groups than in the low-gMS groups. The mRNA levels of lipogenic acetyl-CoA carboxylase and fatty acid binding protein 4 genes in the LT were higher (P < 0.05) in the high-gMS group than in the low-gMS group. Overall, the IMF content tended to be affected by the gMS, and the genetic potential (i.e., gMS) was associated with the functional activity of lipogenic gene expression. The gCW was associated with the measured BW and CW. The results demonstrated that the gMS and the gCW may be used as early prediction indexes for meat quality and growth potential of beef cattle.

Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.

BACKGROUND: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

Vitamin D supplementation and total cancer incidence and mortality by daily vs. infrequent large-bolus dosing strategies: a meta-analysis of randomised controlled trials.

BACKGROUND: Efficacy of vitamin D supplementation may vary by dosing strategies and adiposity. To address such heterogeneity, we performed a meta-analysis of randomised controlled trials of vitamin D supplementation and total cancer outcomes. METHODS: PubMed and Embase were searched through January 2022. Summary relative risk (SRR) and 95% confidence interval (CI) were estimated using the DerSimonian-Laird random-effects model. RESULTS: For total cancer incidence (12 trials), the SRR for vitamin D supplementation vs. control group was 0.99 (95% CI, 0.94-1.03; P = 0.54; I2 = 0%). No significant association was observed regardless of whether the supplement was given daily or infrequently in a large-bolus. Yet, among trials testing daily supplementation, a significant inverse association was observed among normal-weight individuals (SRR, 0.76; 95% CI, 0.64-0.90; P = 0.001, I2 = 0%), but not among overweight or obese individuals (Pheterogeneity = 0.02). For total cancer mortality (six trials), the SRR was 0.92 (95% CI, 0.82-1.03; P = 0.17; I2 = 33%). A significant inverse association emerged (SRR, 0.87; 95% CI, 0.78-0.96; P = 0.007; I2 = 0%) among studies testing daily supplementations but not among studies that testing infrequent large-bolus supplementations (Pheterogeneity = 0.09). CONCLUSIONS: For vitamin D supplementation, daily dosing, but not infrequent large-bolus dosing, reduced total cancer mortality. For total cancer incidence, bolus dosing did not reduce the risk and the benefits of daily dosing were limited to normal-weight individuals.

A simplified cranial cavity model to understand the relationship between intracranial pressure and dural sinus pressure.

Although accurate intracranial pressure (ICP) monitoring is essential for the diagnosis and treatment of severe brain diseases, current methods are performed invasively. Therefore, a safe and less invasive ICP measurement is required. The purpose of our study was to develop a simplified cranial cavity model for a better understanding of the relationship between the ICP and the pressure measurement within the dural venous sinus (DVS) to support the validity of using sinus pressure as the surrogate of the ICP. The in-house cranial cavity model had three components: the brain part, the DVS part, and the subarachnoid space (SAS) part. Pressure in other parts was measured when the pressure in the SAS part and, separately, brain part was increased from 0 (baseline) to 50 mmHg at intervals of 10 mmHg. When the pressure in the SAS part was increased from 10 to 50 mmHg at 10 mmHg interval, pressures of both the brain and DVS parts increased without significant difference (all P > 0.05). However, pressures in both the SAS and DVS parts differed while the pressure in the brain part was increased. The pressures in both parts showed about 70% of the increase in the brain part. Nevertheless, the pressures in the SAS and DVS parts were not significantly different (P > 0.05). A simplified in-house cranial cavity model was developed consisting of three compartments to represent the actual intracranial spaces. The pressure measurement within the DVS was feasible to use as a surrogate for the ICP measurement.

Facial erythema in patients with atopic dermatitis treated with Dupilumab - a descriptive study of morphology and Aetiology.

BACKGROUND: The development of dermatitis on face and neck, which was not described in phase 3 clinical trials, has been reported in the literature in patients treated with dupilumab. Little is known regarding the causes or defining features of the facial dermatitis. OBJECTIVES: We conducted surveys of consecutive patients with AD on dupilumab to describe its clinical features, morphology and aetiology. METHODS: A multi-centre prospective cohort study was conducted from 1 January 2020, to 31 December 31 2020. A total of 162 patients under dupilumab treatment were asked to complete a questionnaire and patients were evaluated by dermatologists. RESULTS: Of all 162 patients, 137 (84.6%) patients reported pre-existing facial dermatitis prior to dupilumab therapy. One hundred and twenty-one (88.3%) patients with pre-existing facial dermatitis reported improvement of their facial dermatitis with dupilumab therapy, nine (6.6%) patients reported no change after the treatment and seven (4.3%) patients of them got worse after the treatment (exacerbation group). Of 25 patients who reported no pre-existing active facial dermatitis, six (24%) patients reported new-onset facial erythema after the starting dupilumab therapy (new-onset group). A large proportion of the patients in both the exacerbation (86%) and new-onset groups (67%) had a history of facial TCS use. Both groups showed similar clinical manifestations and distribution with few differences. CONCLUSIONS: The vast majority of patients treated with dupilumab in academic institutions from Korea and the United States experienced improvement in their facial dermatitis with dupilumab therapy. A small proportion of patients had new onset and exacerbation. Although the mechanisms of this adverse event remain unclear, steroid withdrawal should be considered as a diagnosis of the erythema in some patients.

Minocycline suppresses lipogenesis via inhibition of p300 histone acetyltransferase activity in human SZ95 sebocytes.

BACKGROUND: Minocycline is a second-generation tetracycline drug, which is widely used to treat diverse infectious and inflammatory diseases such as acne vulgaris. The effects of minocycline on acne vulgaris have been mainly attributed to its anti-inflammatory effect; however, its sebum-regulating effect and the relevance to epigenetic regulation in human sebaceous glands remain uninvestigated. OBJECTIVES: To identify the potential underlying epigenetic mechanism of sebum-inhibitory effects of minocycline in human SZ95 sebocytes. METHODS: The quantity of lipid droplets and the expression of key lipogenic genes were analysed in minocycline-treated SZ95 sebocytes. To examine whether the sebum-inhibitory effects of minocycline are relevant to histone acetylation, we analysed the effects of minocycline on p300 HAT and total HDAC activity. To elucidate the functional implication of p300 HAT inhibition by minocycline in sebocytes, we assessed the effect of p300 knockdown, inhibition and overexpression on lipid accumulation in SZ95 sebocytes. RESULTS: Minocycline suppressed the insulin and liver X receptor agonist-induced lipid accumulation and the expression of the key lipogenic transcription factor sterol regulatory element-binding protein 1 (SREBP1) and its downstream genes, fatty acid synthase (FAS) and acetyl-CoA carboxylase α (ACCα). Minocycline inhibited p300 HAT activity in a concentration-dependent manner, but demonstrated no effect on global HDAC activity, resulting in a significant decrease in histone acetylation. Downregulation of p300 by knockdown or inhibition significantly suppressed SREBP1 expression, histone acetylation and lipid accumulation, whereas p300 overexpression enhanced these effects. Moreover, p300 overexpression rescued minocycline-inhibited SREBP1 expression and lipid synthesis. CONCLUSIONS: Our findings revealed a novel sebum-regulating effect of minocycline. Moreover, as p300 HAT is a key epigenetic regulator of sebaceous lipogenesis, its inhibitors could be used for the treatment of acne vulgaris.

Attenuation of intrinsic ageing of the skin via elimination of senescent dermal fibroblasts with senolytic drugs.

BACKGROUND: Skin ageing is caused by numerous factors that result in structural and functional changes in cutaneous components. Research has shown that senescent cells are known to accumulate in skin ageing, however, the role of senescent cells in skin ageing has not been defined. OBJECTIVES: To elucidate the role of the senescent cell in skin ageing, we evaluated the effect of known senolytic drugs on senescent dermal fibroblasts. METHODS: Primary human dermal fibroblasts (HDFs) were induced to senescence by long-term passaging, UV irradiation, and H2 O2 treatment. Cell viability was measured after treatment of ABT-263 and ABT-737 on HDFs. Young and aged hairless mice were intradermally injected with drugs or vehicle on the dorsal skin for 10 days. Skin specimens were obtained and reverse-transcription quantitative PCR, western blotting, and histological analysis were performed. RESULTS: We found that ABT-263 and ABT-737 induced selective clearance of senescent dermal fibroblasts, regardless of the method of senescence induction. Aged mouse skin treated with ABT-263 or ABT-737 showed increased collagen density, epidermal thickness, and proliferation of keratinocytes, as well as decreased senescence-associated secretory phenotypes, such as MMP-1 and IL-6. CONCLUSIONS: Taken together, our results indicate that selective clearance of senescent skin cells can attenuate and improve skin ageing phenotypes and that senolytic drugs may be of potential use as new therapeutic agents for treating ageing of the skin.

Consensus for HER2 alterations testing in non-small-cell lung cancer.

Human epidermal growth factor receptor 2 (HER2) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity. Its alterations, including mutation, amplification and overexpression, could result in oncogenic potential and have been detected in many cancers such as non-small-cell lung cancer (NSCLC). Such alterations are, in general, considered markers of poor prognosis. Anti-HER2 antibody-drug conjugates, e.g. trastuzumab deruxtecan (T-DXd, DS-8201) and disitamab vedotin (RC48), were recently approved for HER2-positive breast and gastric cancers. Meanwhile, several HER2-targeted drugs, such as T-DXd, neratinib, afatinib, poziotinib and pyrotinib, have been evaluated in patients with advanced NSCLC, with several of them demonstrating clinical benefit. Therefore, identifying HER2 alterations is pivotal for NSCLC patients to benefit from these targeted therapies. Recent guidelines on HER2 testing were developed for breast and gastric cancer, however, and have not been fully established for NSCLC. The expert group here reached a consensus on HER2 alteration testing in NSCLC with the focus on clinicopathologic characteristics, therapies, detection methods and diagnostic criteria for HER2-altered NSCLC patients. We hope this consensus could improve the clinical management of NSCLC patients with HER2 alterations.

Bilobed flap reconstruction for skin defects after parotid carcinoma surgery.

OBJECTIVE: To analyse the treatment results of bilobed flap reconstruction performed for skin defects after parotid carcinoma surgery. METHOD: Ten patients who underwent bilobed flap reconstruction for skin defects after parotid carcinoma surgery in our hospital, from 2014 to 2020, were retrospectively enrolled. RESULTS: All patients underwent bilobed flap reconstruction for skin defects after parotid carcinoma surgery. The size of the skin defect was 2.7 × 2.2 cm in the smallest dimension and 9.0 × 6.3 cm in the largest dimension. All bilobed flaps except one healed without any problems. One patient developed partial flap necrosis in the retroauricular region, and was treated with skin grafts after removal of the necrotic tissue under local anaesthesia. All bilobed flaps, including the cases in which skin grafts were performed, survived after post-operative radiotherapy or chemotherapy. CONCLUSION: A bilobed flap is a good reconstruction option for skin defects after parotid carcinoma surgery in some cases.

Female reproductive factors and risk of joint replacement arthroplasty of the knee and hip due to osteoarthritis in postmenopausal women: a nationwide cohort study of 1.13 million women.

OBJECTIVES: Previous studies of the relationships between female reproductive factors and osteoarthritis (OA) have shown conflicting results. In this study, we aimed to explore the relationships between reproductive factors and joint replacement arthroplasty of the knee (TKRA) and hip (THRA) in a large nationwide population-based cohort of postmenopausal Korean women. METHODS: We included 1,134,680 subjects who participated in national health examinations in 2009 in the study. The study outcomes were incident THRA or TKRA due to severe hip or knee OA. The relationships between reproductive factors and THRA or TKRA were evaluated using a multivariable-adjusted proportional hazards model. RESULTS: During a mean follow-up duration of 8.2 years, 1,610 incident THRA cases and 60,670 incident TKRA cases were observed. Later age at menarche, longer breastfeeding, HRT and OC use were associated with increased risk of TKRA for severe knee OA, while later age at menopause and longer reproductive span were associated with decreased risk. With regard to THRA for severe hip OA, later menarche, longer breastfeeding, HRT more than 5 years, and OC use more than 1 year were associated with higher risk. The associations between reproductive factors and severe OA were more pronounced in underweight and younger subjects. CONCLUSION: We found that shorter estrogen exposure was associated with higher risk of TKRA due to severe knee OA, and such associations were more pronounced in underweight and younger subjects. The association between shorter estrogen exposure and THRA was not robust.

First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆.

BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Mask-induced dermatoses during the COVID-19 pandemic: a questionnaire-based study in 12 Korean hospitals.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, various adverse skin reactions to long-term mask wearing have been reported. AIM: To assess the clinical features of mask-induced dermatoses and to recommend prevention and treatment options. METHODS: From April to August 2020, questionnaires including topics such as demographic information, pre-existing skin disorders, reported mask-related symptoms, daily mask-wearing duration and frequency, types of masks used and whether the participant was a healthcare worker, were distributed to patients in 12 hospitals. Dermatologists assessed skin lesions, confirmed diagnosis and recorded treatments. RESULTS: Itchiness was the most frequent symptom, mostly affecting the cheeks. The most common skin disease was new-onset contact dermatitis (33.94%), followed by new-onset acne (16.97%) and worsening of pre-existing acne (16.97%). Daily wearing of masks was significantly (P = 0.02) associated with new-onset contact dermatitis. More than half of patients with pre-existing skin problems experienced disease worsening while wearing masks. Longer duration of wearing (> 6 h/day, P = 0.04) and use of cotton masks (P < 0.001) significantly increased acne flare-up. Healthcare workers had a higher incidence of skin disease. Skin lesions were generally mild and well tolerated with topical treatment. The study had some limitations: the effect of seasonal characteristics and other risk factors were not assessed, and the patients were visiting dermatological clinics and had interest in their skin status, thus, there may have been selection bias. CONCLUSION: Mask-induced/-triggered dermatoses contribute to increase the dermatological burden during the pandemic.

Early diagnosis of chyle fistula with SD LipidoCare after neck dissection.

OBJECTIVE: This study aimed to analyse the results of chyle fistula testing using the SD LipidoCare system in patients who had undergone neck dissections performed in our hospital in 2019. METHOD: Sixty patients who underwent neck dissections from March 2019 to November 2019 were identified based on their medical records. RESULTS: Post-operative chyle fistulas were observed in 3 of 60 patients (5 per cent). All patients who developed chyle fistulas had undergone left-sided neck dissections. Within 3 minutes, the SD LipidoCare test had produced triglyceride results of 49, 56 and 207 mg/dl in the three patients. The remaining 57 patients measured 'low' for triglycerides on the SD LipidoCare test system. CONCLUSION: The SD LipidoCare test quickly and accurately diagnosed chyle fistulas in patients who had undergone neck dissections. All patients improved with conservative treatment following the early diagnosis of chyle fistulas.