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Purpose: To investigate the outcomes of patients who underwent surgical correction of congenital superior oblique muscle paralysis in adulthood.Methods: We retrospectively analyzed the medical records of 35 patients who underwent surgical correction of congenital superior oblique muscle paralysis after the age of 18 years. At the final follow-up, success was defined as residual hypertropia < 4 prism diopters (PD), whereas failure was defined as residual hypertropia ≥ 5 PD or overcorrection. Clinical features were compared between the success and failure groups to identify factors affecting the surgical outcome. At the final follow-up, the resolution of symptoms, such as head tilt and diplopia, was also recorded.Results: Of the 35 patients, 24 (68.6%) and 11 (31.4%) were classified into the success and failure groups, respectively. Preoperative vertical deviation was larger in the failure group compared to the success group (23.1 vs. 15.2 PD, respectively; p < 0.05). Of the 31 patients with preoperative head tilt, head tilt resolved in 29 (93.5%). Of the 19 patients with diplopia, it resolved in all except 1 who was overcorrected.Conclusions: The preoperative vertical angle of the superior oblique muscle may affect the outcome of surgery performed in adulthood for correcting congenital superior oblique paralysis. Head tilt, diplopia, and subjective symptoms are typically resolved postoperatively.

Heritability of stroke is assumed not to be low, especially in the young-age stroke population. However, most genetic studies have been performed in highly selected patients with typical clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population.We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGV) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP) using a customized, targeted next-generation sequencing panel.Among 1,033 patients, 131 (12.7%) had 28 CRGV, most frequently in RNF213 (n=59), followed by ABCC6 (n=53) and NOTCH3 (n=15). The frequency of CRGV differed by ischemic stroke subtypes (p0.01)-highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51-55 years (17.1% vs. 9.3%, p=0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUS) were found in 15.4% patients.CRGV in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGV did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGV or VUS should be explored. This article is protected by copyright. All rights reserved.

Background: We aimed to evaluate covert brain infarction (CBI), frequently encountered during the diagnostic work-up of acute ischemic stroke, as a risk factor for stroke recurrence in patients with atrial fibrillation (AF). Methods: For this prospective cohort study, from patients with acute ischemic stroke hospitalized at 14 centers between 2017 and 2019, we enrolled AF patients without history of stroke or transient ischemic attack and divided them into the CBI (+) and CBI (−) groups. The 2 groups were compared regarding the 1-year cumulative incidence of recurrent ischemic stroke and all-cause mortality using the Fine and Gray subdistribution hazard model with nonstroke death as a competing risk and the Cox frailty model, respectively. Each CBI lesion was also categorized into either embolic-appearing (EA) or non-EA pattern CBI. Adjusted hazard ratios and 95% CIs of any CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were estimated. Results: Among 1383 first-ever stroke patients with AF, 578 patients (41.8%) had CBI. Of these 578 with CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were 61.8% (n=357), 21.8% (n=126), and 16.4% (n=95), respectively. The estimated 1-year cumulative incidence of recurrent ischemic stroke was 5.2% and 1.9% in the CBI (+) and CBI (−) groups, respectively ( P =0.001 by Gray test). CBI increased the risk of recurrent ischemic stroke (adjusted hazard ratio [95% CI], 2.91 [1.44–5.88]) but did not the risk of all-cause mortality (1.32 [0.97–1.80]). The EA pattern CBI only and both CBIs elevated the risk of recurrent ischemic stroke (2.76 [1.32–5.77] and 5.39 [2.25–12.91], respectively), while the non-EA pattern only did not (1.44 [0.40–5.16]). Conclusions: Our study suggests that AF patients with CBI might have increased risk of recurrent stroke. CBI could be considered when estimating the stroke risk in patients with AF.

Low-fluence, multisession therapy of Nd:YAG laser has been widely used for treating melasma.To evaluate the efficacy and safety of low-fluence Nd:YAG laser toning for melasma using a systematic review and meta-analysis.The PubMed, Web of Science, Embase, and Cochrane Library databases were searched till December 2020. A total of 50 studies (1,772 patients) and 66 studies were selected for the evaluation of the efficacy and complications, retrospectively.The mean Melasma Area and Severity Index/modified Melasma Area and Severity Index scores for laser toning as monotherapy at4, 4 to8, 8 to12, 12 to24, and ≥24 weeks after treatment compared with that at pretreatment were -0.51, -0.91, -0.97, -0.92, 0.01 SD, whereas those as combination therapy were -1.64, -1.26, -0.94, not available, -1.45 SD, respectively. An increase in light value and a decrease in relative lightness index have remained up to 8 weeks after laser toning. Complications including hypopigmentation/leukoderma, postinflammatory hyperpigmentation, and recurrence were noted. The incidence of hypopigmentation/leukoderma correlated with the number of laser sessions (p = .036).Low-fluence Nd:YAG laser toning as combination therapy has shown better efficacy than monotherapy and the efficacy seems to diminish with time. This study suggests the positive correlation of hypopigmentation/leukoderma with the number of laser sessions.

The vitamin-C-synthesizing enzyme senescent marker protein 30 (SMP30) is a cold resistance gene in Drosophila, and vitamin C concentration increases in brown adipose tissue post-cold exposure. However, the roles of SMP30 in thermogenesis are unknown. Here, we tested the molecular mechanism of thermogenesis using wild-type (WT) and vitamin C-deficient SMP30-knockout (KO) mice. SMP30-KO mice gained more weight than WT mice without a change in food intake in response to short-term high-fat diet feeding. Indirect calorimetry and cold-challenge experiments indicated that energy expenditure is lower in SMP30-KO mice, which is associated with decreased thermogenesis in adipose tissues. Therefore, SMP30-KO mice do not lose weight during cold exposure, whereas WT mice lose weight markedly. Mechanistically, the levels of serum FGF21 were notably lower in SMP30-KO mice, and vitamin C supplementation in SMP30-KO mice recovered FGF21 expression and thermogenesis, with a marked reduction in body weight during cold exposure. Further experiments revealed that vitamin C activates PPARα to upregulate FGF21. Our findings demonstrate that SMP30-mediated synthesis of vitamin C activates the PPARα/FGF21 axis, contributing to the maintenance of thermogenesis in mice.

Although the production of several founder animals (F0) for gene editing in livestock has been reported in cattle, very few studies have assessed germline transmission to the next generation due to the long sexual maturation and gestation periods. The present study aimed to assess the germline transmission of MSTN mutations (-12bps deletion) in MSTN mutant F0 male and female cattle. For this purpose, oocytes and semen were collected after the sexual maturation of MSTN cattle, and embryos produced by in vitro fertilization were analyzed. In addition, the embryos were subjected to additional gene (PRNP) editing using electroporation. Embryos produced by in vitro fertilization with MSTN male and female cattle were transferred to a surrogate, and one calf was successfully born. MSTN heterozygous mutation was shown by sequencing of the F1 calf, which had no health issues. As a further experiment, using electroporation, additional gene-edited embryos fertilized with the MSTN male sperm showed a high mutation rate of PRNP (86.2 ± 3.4%). These data demonstrate that the cattle produced through gene editing matured without health issues and had transmitted MSTN mutation from the germ cells. Also, additional mutation of embryos fertilized with the MSTN male sperm could enable further mutagenesis using electroporation.

BACKGROUND: Frailty is present in ≥50% of older adults receiving dialysis. Our objective was to a develop an administrative data–based frailty index and assess the frailty index’s predictive validity for mortality and future hospitalizations. METHODS: We used United States Renal Data System data to establish two cohorts of adults aged ≥65 years, initiating dialysis in 2013 and in 2017. Using the 2013 cohort (development dataset), we applied the deficit accumulation index approach to develop a frailty index. Adjusting for age and sex, we assessed the extent to which the frailty index predicts the hazard of time until death and time until first hospitalization over 12 months. We assessed the Harrell’s C-statistic of the frailty index, a comorbidity index, and jointly. The 2017 cohort was used as a validation dataset. RESULTS: Using the 2013 cohort (n=20,974), we identified 53 deficits for the frailty index across seven domains: disabilities, diseases, equipment, procedures, signs, tests, and unclassified. Among those with ≥1 deficit, the mean (SD) frailty index was 0.30 (0.13), range 0.02–0.72. Over 12 months, 18% (n=3842) died, and 55% (n=11,493) experienced a hospitalization. Adjusted hazard ratios for each 0.1-point increase in frailty index in models of time to death and time to first hospitalization were 1.41 (95% confidence interval, 1.37 to 1.44) and 1.33 (95% confidence interval, 1.31 to 1.35), respectively. For mortality, C-statistics for frailty index, comorbidity index, and both indices were 0.65, 0.65, and 0.66, respectively. For hospitalization, C-statistics for frailty index, comorbidity index, and both indices were 0.61, 0.60, and 0.61, respectively. Data from the 2017 cohort were similar. CONCLUSIONS: We developed a novel frailty index for older adults receiving dialysis. Further studies are needed to improve on this frailty index and validate its use for clinical and research applications.

Despite the growing literature on the importance of identifying and managing frailty, its assessment has been limited in clinical settings. With the goal of integrating frailty assessment into routine clinical practice, this quality improvement project aimed to determine the feasibility, acceptability, and utility of administering a telephone-based frailty assessment.Between 9/2020 and 6/2021, we identified 169 established patients with serious illnesses in an academic primary care-geriatric clinic. Patients were contacted via telephone, and their current medical, functional, nutritional, cognitive, and mood statuses were assessed using validated screening tools. A deficit-accumulation frailty score was then calculated using an electronic medical record-based frailty index calculator and standardized documentation with recommendations was generated for providers. The primary outcome was feasibility, measured as the proportion of patients successfully assessed. Secondary outcomes included completion rates of each domain, administration time, providers' perception, and clinical utility of the assessment.A total of 139 (82.2%) patients, mean age of 82 years, 63.3% frail were successfully assessed. Of the 139 assessments, medical and functional domains were completed for all, while nutrition, mood, and cognition were completed by 88.5% (n = 123), 68.3% (n = 95), and 59.7% (n = 83) of the time, respectively. Conducting the full assessment took an average (standard deviation) time of 26.1 (7.3) minutes. Without the cognitive and mood domain, assessment took an average of 15.7 (7.5) minutes. Patients' providers found the information from the assessment helpful in evaluating and managing their patients. Care plans of 51.8% and 65.0% of patients who had mobility and mind issues, respectively, addressed these domains within 30 days after the assessment.Implementation of the telephone-based frailty assessment is feasible, acceptable, and has the potential to influence the care plans of older adults. This work demonstrated how frailty assessment can be integrated with the outpatient setting.

Objective: Unilateral biportal endoscopic (UBE) discectomy and tubular microdiscectomy (TMD) are widely practiced methods for treatment of lumbar disc herniation. Good clinical outcomes of these methods are reported in many papers, but there are a few comparative studies. This study reports the clinical outcomes of UBE and TMD as minimally invasive surgery methods for lumbar disc herniations and discusses the effectiveness of UBE.Methods: Sixty-seven patients who had undergone single-level discectomy using one of two methods, UBE or TMD, underwent a prospective follow-up examination. Thirty-four of these patients underwent discectomy using UBE, and the remaining 33 patients underwent TMD. In addition to the traditional measures of outcome, the improvement of generic health-related quality of life and disease-specific measurements like Visual Analogue Scale (VAS) score, Short-form 36 (SF-36), and Oswestry Disability Index (ODI) were evaluated and compared.Results: Sixty-seven patients with more than 6 months of post-operative follow-up evaluations were included. The mean improvements in the VAS scores for back pain and leg pain and ODI were 2.0, 3.7, and 26.5 for the UBE group and 1.6, 3.0, and 19.4 for the TMD group. The SF-36 physical health component subscale score improved from 35.4 pre-operatively to 54.8 at the last follow-up in the UBE group, and the mental health score improved from 43.5 to 55.1 (TMD group: from 34.9 to 54.3 and 44.2 to 57.1, respectively). Conclusion: The clinical outcomes of the UBE group are comparable to those of the TMD group. The results indicate that UBE for lumbar disc herniation can be performed safely and effectively as a treatment modality.

Postharvest loss of vegetables and fruits is higher in developing countries due to the lack of post-processing equipment. Although the production of ginger and turmeric is high in Nepal, farmers practices open sun drying, which leads to poor quality, and the products do not get to the market at reasonable prices. In this study, a simple, easy to assemble and disassemble mixed-mode solar dryer has been designed, fabricated, and biochemical and performance analyses were done. The dryer was designed considering the solar irradiation, sunshine hours, latitude of the location, locally available materials, moisture content (MC) of the product, and drying capacity. The Computational Fluid Dynamics (CFD) analysis was performed using ANSYS Fluent simulation software to predict the dryer’s temperature and air flow behavior. The experiment was carried out in November in the harvesting season of ginger. The dryer performance is compared with the open sun drying using ginger and turmeric. The biochemical properties such as Oleoresin and Essential oil were determined using Soxhlet and Steam distillation methods and compared with the product of open sun drying. The experiment results showed that ginger and turmeric took only about 14 sunshine hours to reach from 88% to 10-12% moisture content. The maximum collector and drying efficiency were recorded at about 45.32% and 31.364%, respectively. The temperature distribution inside the dryer obtained from the experiment correlated with the results obtained from the CFD analysis. The retention of essential oil was found more in product drying with dryer than open sun drying. Among the various drying models, Wang and Singh model was found suitable for describing the drying model. It is concluded that the designed dryer is suitable for ginger and turmeric drying into a safe moisture level, ensuring product quality. BIBECHANA 19 (2021) 40-60

The pharmacological effectiveness of loquat leaf extract (LE) and its important component, ursolic acid (UA), in the treatment of diabetes mellitus, has been well established in traditional medicine; however, the mechanism underlying their action is still unclear. We evaluated the protective effects of LE and UA against hyperglycemia-induced advanced glycation end product (AGE) formations and hepatic pro-inflammation. Oral administration of UA and LE at a dose of 50 mg/kg/day for 15 days yielded no significant hypoglycemic effect in diabetic db/db mice. UA and LE suppressed hepatic oxidative stress and AGE formation in diabetic mice, and this was followed by the downregulated mitogen-activated protein kinase signaling and nuclear factor κ B (NF-κB) activity. To identify the molecular target of LE and UA, a docking simulation was performed, and this predicted UA to bind to liver kinase B1 (LKB1), an upstream of AMP-activated protein kinase (AMPK)/transcription factor forkhead box O3 (FOXO3) axis. UA reversed the high-glucose-induced downregulation of LKB1-AMPK1-FOXO3 activation and antioxidant gene transcription. These findings demonstrated the antioxidant and anti-inflammatory effects of UA and LE against hyperglycemia-induced hepatic inflammation. Furthermore, we speculate that the LKB1/AMPK/FOXO3 pathway is a potential target responsible for these beneficial effects of LE and UA.

Communication of the benefits and harms of blood pressure lowering strategy is crucial for shared decision-making.To quantify the effect of intensive versus standard systolic blood pressure lowering in terms of the number of event-free days DESIGN: Post hoc analysis of the Systolic Blood Pressure Intervention Trial PARTICIPANTS: A total of 9361 adults 50 years or older without diabetes or stroke who had a systolic blood pressure of 130-180 mmHg and elevated cardiovascular risk INTERVENTIONS: Intensive (systolic blood pressure goal120 mmHg) versus standard blood pressure lowering (140 mmHg) MAIN MEASURES: Days free of major adverse cardiovascular events (MACE), serious adverse events (SAE), and monitored adverse events (hypotension, syncope, bradycardia, electrolyte abnormalities, injurious falls, or acute kidney injury) over a median follow-up of 3.33 years KEY RESULTS: The intensive treatment group gained 14.7 more MACE-free days over 4 years (difference, 14.7 [95% confidence interval: 5.1, 24.4] days) than the standard treatment group. The benefit of the intensive treatment varied by cognitive function (normal: difference, 40.7 [13.0, 68.4] days; moderate-to-severe impairment: difference, -15.0 [-56.5, 26.4] days; p-for-interaction=0.009) and self-rated health (excellent: difference, -22.7 [-51.5, 6.1] days; poor: difference, 156.1 [31.1, 281.2] days; p-for-interaction=0.001). The mean overall SAE-free days were not significantly different between the treatments (difference, -14.8 [-35.3, 5.7] days). However, the intensive treatment group had 28.5 fewer monitored adverse event-free days than the standard treatment group (difference, -28.5 [-40.3, -16.7] days), with significant variations by frailty status (non-frail: difference, 38.8 [8.4, 69.2] days; frail: difference, -15.5 [-46.6, 15.7] days) and self-rated health (excellent: difference, -12.9 [-45.5, 19.7] days; poor: difference, 180.6 [72.9, 288.4] days; p-for-interaction0.001).Over 4 years, intensive systolic blood pressure lowering provides, on average, 14.7 more MACE-free days than standard treatment, without any difference in SAE-free days. Whether this time-based effect summary improves shared decision-making remains to be elucidated.ClinicalTrials.gov Registration: NCT01206062.

Although the optimal use of prescribed medications for stroke survivors is critical for preventing secondary stroke, longitudinal observations of the natural course of medication persistence and adherence in Korean stroke survivors are rare. Furthermore, studies are needed to identify strong predictors influencing medication adherence and to determine whether these predictors change over time.To evaluate the longitudinal medication persistence and adherence at 3 months and 1 year after discharge in all stroke patients and to identify predictors of long-term medication adherence in patients who can self-medicate.A multicentre, prospective, longitudinal descriptive study.A total of 600 consecutive ischaemic stroke patients were recruited from three stroke centres across Korea, from 1 September, 2017 to 28 February, 2019. Various factors related to medication adherence suggested by the World Health Organisation were investigated through face-to-face interviews at each centre during hospitalisation. Medication persistence and adherence were assessed at 3 months and 1 year after discharge using the eight-item Morisky Medication Adherence Scale through telephone interviews.Of 537 survivors at 3 months, 526 (98.0%) were persistent and 472 (89.7%) were adherent. Of 493 survivors at 1 year, 477 (96.8%) were persistent and 392 (82.2%) were adherent. Medication belief, income and health literacy were statistically significant predictors of three-month medication adherence, which predicted one-year medication adherence with older age and low income.Among Korean stroke survivors, three-month and one-year medication persistence and adherence were relatively good. Medication beliefs and three-month medication adherence were important and modifiable factors predicting three-month adherence and one-year adherence, respectively.To increase long-term adherence to medication, various strategies are needed to improve beliefs about medication, taking into account the patient's age and level of knowledge. These interventions need to be initiated during hospitalisation to form early medication habits after discharge.

This study evaluated the effects of four different gibberellin-pastes (GAP) on fruit quality and storability of niitaka pear in 2014 and 2015 consecutive years. Pear fruit stalks were treated with dongbu GA gold, nebaekeo, busa, and GA hyeophwa-pastes at 35 and 37 days after full bloom, respectively. After harvest time, the fruits were stored at 0°C for up to 180 days. In both years, fruit weight was 6.2-21.3% higher in GAP-treated fruits than the control fruits at harvest. In 2014 year, flesh firmness was higher in control (70.6 N) than the GAP-treated fruits (54.4-64.6 N) at harvest, but it was not different in all treatments in 2015 year. The titratable acidity (TA) at harvest was also higher in control than the GAP treated fruits in 2014 year. The soluble solids content (SSC) at harvest was slightly lower in control than the GAP treated fruits in both years. During cold storage, flesh firmness was decreased in all treatments, whereas the fruits treated with nebaekeo GAP had the lowest flesh firmness (39.4 N) after 135 days of the storage. TA was a slightly higher in control (0.19%) than the GAP-treated fruits (0.14-0.17%) after 180 days of storage. However, SSC was higher in the fruits treated with dongbu GA gold and GA hyeophwa-pastes than the control fruits during storage. Therefore, GAP-treatments increased fruit weight and SSC than control, but flesh firmness and TA of GAP-treated fruits were reduced after 180 days of the storage.

This randomized clinical trial was performed to compare pain scales between intravenous patient-controlled analgesia (IV-PCA) and patient-controlled epidural analgesia (PCEA) in patients undergoing open surgical resection of major pancreatobiliary malignancies.One hundred ten patients were randomly assigned to the PCEA or IV-PCA group. We compared the numeric rating scale pain score during ambulation on postoperative day (PD) 2 and at rest (at 06:00, 12:00, and 18:00) from PD 1 to 7, the serum level of troponin I on PD 1, and the incidence of postoperative complications between the two groups.There were no significant differences in the pain scores during ambulation on PD 2, at rest up to PD 7, serum troponin I level, and postoperative complication rates. The incidences of nausea (20.4% vs. 6.3%; p = 0.039) and drowsiness (20.4% vs. 0%; p = 0.001) were higher in the IV-PCA group and the rate of dysuria (0% vs. 14.6%; p = 0.004) was higher in the PCEA group.PCEA showed no superiority over IV-PCA in terms of postoperative pain relief or morbidity after major open surgery for pancreatobiliary malignancies. The method of analgesia should be considered based the characteristics of the patient, surgeon, anesthesiologist, and institute.

Categorizing clinical risk amidst heterogeneous multimorbidity in older people living with HIV/AIDS (PLWH) may help prioritize and optimize health care engagements.PLWH and their prevalent conditions in 8 health domains diagnosed before January 1, 2015 were identified using 2014-2016 Medicare claims and the Chronic Conditions Data Warehouse. Latent profile analysis identified 4 distinct clinical subgroups based on the likelihood of conditions occurring together [G1: healthy, G2: substance use (SU), G3: pulmonary (PULM), G4: cardiovascular conditions (CV)]. Restricted mean survival time regression estimated the association of each subgroup with the 365 day mean event-free days until death, first hospitalization, and nursing home admission. Zero-inflated Poisson regression estimated hospitalization frequency in 2-year follow-up.Of 11,196 older PLWH, 71% were male, and the average age was 61 (SD 9.2) years. Compared with healthy group, SU group had a mean of 30 [95% confidence interval: (19.0 to 40.5)], PULM group had a mean of 28 (22.1 to 34.5), and CV group had a mean of 22 (15.0 to 22.0) fewer hospitalization-free days over 1 year. Compared with healthy group (2.8 deaths/100 person-years), CV group (8.4) had a mean of 4 (3.8 to 6.8) and PULM group (7.9) had a mean of 3 (0.7 to 5.5) fewer days alive; SU group (6.0) was not different. There was no difference in restricted mean survival time for nursing home admission. Compared with healthy group, SU group had 1.42-fold [95% confidence interval: (1.32 to 1.54)], PULM group had 1.71-fold (1.61 to 1.81), and CV group had 1.28-fold (1.20 to 1.37) higher rates of hospitalization.Identifying clinically distinct subgroups with latent profile analysis may be useful to identify targets for interventions and health care optimization in older PLWH.

Posterior reversible encephalopathy syndrome is a clinicoradiological syndrome characterized by a unique reversible pattern on imaging and total regression of clinical symptoms and signs. Hypertensive brainstem encephalopathy (HBE), a brainstem variant of posterior reversible encephalopathy syndrome, is rare. In addition, a concomitant occurrence of acute ischemic stroke and HBE is even more rare. We here report three patients with HBE accompanied by acute cerebral infarction detected by brain magnetic resonance imaging and the importance of initial blood pressure control.

The NP-Separate design methodology for very-large-scale integration (VLSI) design fine-controls the sizes of transistors, thereby achieving significant power, performance, and area improvement compared to the conventional standard-cell-based design methodology. NP-Separate uses NP cells formed by merging and routing N and P cells having only NFETs and PFETs, respectively. The NP cell formation, however, should be automated to design large circuits using the NP-Separate design methodology. In this paper, we propose design automation algorithms to create NP cells automatically. Simulation results show that the automated NP-Separate reduces the design time significantly, decreases the coupling capacitance by 13%, the critical path delay by 6%, and the power consumption by 10% on average compared to the manual NP-Separate designs. We also propose a detailed placement algorithm to generate more compact VLSI layouts with a little wirelength overhead. The combined effect reduces the coupling capacitance by 10%, the critical path delay by 5%, and the power consumption by 10% on average compared to the manual NP-Separate designs.

Stroke has become a significant threat to global public health, the ideal solution to which is primary prevention. Identification and management of determinants of stroke among various variables in different datasets are essential steps for its primary prevention. This study aimed to develop a flexible scoring model, which can easily modify different datasets. The public dataset containing 41,931 cases with 643 occurrences of stroke was randomly divided into training, validation, and test datasets comprising 25,158 (60%), 8,386 (20%), and 8,387 (20%) cases, respectively. Three continuous variables (age, body mass index, and average glucose level) and seven categorical variables (heart disease, hypertension, sex, married/smoking/work/residence status) in the dataset were converted using the weight of evidence method. The significant variables among 10 transformed variables were selected using multivariable logistic regression analyses. The scoring model for stroke occurrence was developed in the training and validation datasets, and performance was evaluated in the test dataset. Age, average glucose level, heart disease, and hypertension were significant variables of stroke occurrence. The scoring model was easily calculated using four determinants and indicates that the stroke occurrence ranged from 0.04–12.50%. The performance of the scoring model on the test dataset was similar to that on the validation dataset. This novel point scoring model is flexible enough to modify various datasets and can be used for determinant identification. Furthermore, its simplicity allows individuals to manage determinants by self-calculating stroke occurrence. Our model contributes to primary prevention using determinant identification and management.

Background and ObjectivesFemale patients tend to have greater disability and worse long-term outcomes after stroke than male patients. To date, the biological basis of sex difference in ischemic stroke remains unclear. We aimed to 1) assess sex differences in clinical manifestation and outcomes of acute ischemic stroke and 2) investigate whether the sex disparity is due to different infarct locations or different impacts of infarct in the same location.MethodsThis MRI-based multicenter study included 6,464 consecutive patients with acute ischemic stroke (ResultsMean (SD) age was 67.5 (12.6) years, and 2,641 (40.9%) were female patients. Percentage infarct volumes on diffusion-weighted MRI did not differ between female patients and male patients (median 0.14% vs. 0.14%, P=0.35). However, female patients showed higher stroke severity (NIHSS-score, median 4 vs. 3, P2) than male patients (adjusted-absolute-difference 4.5%; 95%-CI 2.0–7.0; PDiscussionFemale patients have more frequent middle cerebral artery disease and striatocapsular motor-pathway involvement with acute ischemic stroke, along with left parieto-occipital cortical infarcts showing greater severity for equivalent infarct volumes than in male patients. This leads to more severe initial neurological symptoms, higher susceptibility to neurological worsening, and less 3-month functional independence, when compared with male patients.

BackgroundThere is limited information on the delivery of acute stroke therapies and secondary preventive measures and clinical outcomes over time in young adults with acute ischemic stroke (AIS). This study investigated whether advances in these treatments improved outcomes in this population.MethodsUsing a prospective multicenter stroke registry in Korea, young adults (aged 18–50 years) with AIS hospitalized between 2008 and 2019 were identified. The observation period was divided into four epochs: 2008–2010, 2011–2013, 2014–2016, and 2017–2019. Secular trends for patient characteristics, treatments, and outcomes were analyzed.ResultsA total of 7,050 eligible patients (mean age 43.1; men 71.9%) were registered. The mean age decreased from 43.6 to 42.9 years (Ptrend=0.01). Current smoking decreased, whereas obesity increased. Other risk factors remained unchanged. Intravenous thrombolysis and mechanical thrombectomy rates increased over time from 2008–2010 to 2017–2019 (9.5% to 13.8% and 3.2% to 9.2%, respectively; Ptrend’strendtrend’strend=0.04), but was not significant after adjusting for warfarin use.ConclusionImprovements in the delivery of acute stroke treatments did not necessarily lead to better outcomes in young adults with AIS over the past decade, indicating a need for further improvement.

BACKGROUND Assessment of activities of daily living (ADLs) and instrumental activities of daily living (iADLs) is key to determining severity of dementia and care needs among older adults. However, such information is often only documented in free-text clinical notes within the electronic health record (EHR) and can be challenging to find. OBJECTIVE To develop and validate machine learning models to determine status of ADL and iADL impairments based on clinical notes. METHODS This cross-sectional study leveraged EHR clinical notes from Mass General Brigham’s Research Patient Data Repository linked with Medicare fee-for-service claims data from 2007-2017 to identify individuals aged 65 and older with at least one diagnosis of dementia. Notes for encounters both 180 days before and after the first date of dementia diagnosis were randomly sampled. Models were trained and validated using note sentences filtered by expert-curated keywords (filtered cohort) and further evaluated using unfiltered sentences (unfiltered cohort). Models’ performance was compared using area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). RESULTS The study included 10,000 key-term filtered sentences representing 441 subjects (283 [64.17%] women, mean [SD] age 82.7 [7.9] years), and 1,000 unfiltered sentences representing 80 subjects (56 [70%] women, mean [SD] age 82.8 [7.5] years). AUROC was high for the best-performing ADL and iADL models on both cohorts (>0.97). For ADL impairment identification, the random forest model achieved the best AUPRC (0.89; 95% CI, 0.86-0.91) on the filtered cohort; the SVM model achieved the highest AUPRC (0.82; 95% CI, 0.75-0.89) for the unfiltered cohort. For iADL impairment, the Bio+Clinical BERT model had the highest AUPRC (0.76 filtered; 95% CI, 0.68-0.82; 0.58 unfiltered; 95% CI, 0.001-1.0). Compared with a keyword-search approach on the unfiltered cohort, machine learning reduced false positive rates from 4.5% to 0.2% for ADL and 1.8% to 0.1% for iADL. CONCLUSIONS In this study, we demonstrated the ability of machine learning models to accurately identify ADL and iADL impairment based on free-text clinical notes, which could be useful in determining the severity of dementia.

The stemness of bone marrow mesenchymal stem cells (BMSCs) is maintained by hypoxia. The oxygen level increases from vessel-free cartilage to hypoxic bone marrow and, furthermore, to vascularized bone, which might direct the chondrogenesis to osteogenesis and regenerate the skeletal system. Hence, oxygen was diffused from relatively low to high levels throughout a three-dimensional chip. When we cultured BMSCs in the chip and implanted them into the rabbit defect models of low-oxygen cartilage and high-oxygen calvaria bone, (i) the low oxygen level (base) promoted stemness and chondrogenesis of BMSCs with robust antioxidative potential; (ii) the middle level (two times ≥ low) pushed BMSCs to quiescence; and (iii) the high level (four times ≥ low) promoted osteogenesis by disturbing the redox balance and stemness. Last, endochondral or intramembranous osteogenesis upon transition from low to high oxygen in vivo suggests a developmental mechanism–driven solution to promote chondrogenesis to osteogenesis in the skeletal system by regulating the oxygen environment.

Background Severe hypoglycemia is associated with adverse clinical outcomes. We evaluated the risk of severe hypoglycemia in older adults initiating newer glucose-lowering medications overall and across strata of known indicators of high hypoglycemia risk. Methods We conducted a comparative-effectiveness cohort study of older adults aged >65 years with type 2 diabetes initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) or SGLT2i versus glucagon-like peptide-1 receptor agonists (GLP-1RA) using Medicare claims (3/2013–12/2018) and Medicare-linked-electronic health records. We identified severe hypoglycemia requiring emergency or inpatient visits using validated algorithms. After 1:1 propensity score matching, we estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years. Analyses were stratified by baseline insulin, sulfonylurea, cardiovascular disease (CVD), chronic kidney disease (CKD), and frailty. Results Over a median follow-up of 7 (interquartile range: 4–16) months, SGLT2i was associated with a reduced risk of hypoglycemia versus DPP-4i (HR 0.75 [0.68, 0.83]; RD −3.21 [−4.29, −2.12]), and versus GLP-1RA (HR 0.90 [0.82, 0.98]; RD −1.33 [−2.44, −0.23]). RD for SGLT2i versus DPP-4i was larger in patients using baseline insulin than in those not, although HRs were similar. In patients using baseline sulfonylurea, the risk of hypoglycemia was lower in SGLT2i versus DPP-4i (HR 0.57 [0.49, 0.65], RD −6.80 [−8.43, −5.16]), while the association was near-null in those without baseline sulfonylurea. Results stratified by baseline CVD, CKD and frailty were similar to the overall cohort findings. Findings for the GLP-1RA comparison were similar. Conclusions SGLT2i was associated with a lower hypoglycemia risk versus incretin-based medications, with larger associations in patients using baseline insulin or sulfonylurea.