Lower risks of cirrhosis and hepatocellular carcinoma with GLP-1RAs in type 2 diabetes: A nationwide cohort study using target trial emulation framework.

BACKGROUND: To assess the association of cirrhosis and hepatocellular carcinoma (HCC) with the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs), which are the two commonly prescribed injectable glucose-lowering agents (GLAs) for patients with type 2 diabetes (T2D) after the failure of multiple oral GLAs. METHODS: We emulated a target trial using the nationwide data of a Taiwanese cohort with T2D. Incident new users of GLP-1RAs and LAIs during 2013-2018 were identified, and propensity score (PS) matching was applied to ensure between-group comparability in baseline patient characteristics. The primary outcome was the composite liver disease including cirrhosis or HCC. Each patient was followed until the occurrence of a study outcome, death, or the end of 2019, whichever came first. Subdistribution hazard models were employed to assess the treatment-outcome association. Sensitivity (e.g., stabilized inverse probability of treatment weighting analysis, time-dependent analysis), E-value, and negative control outcome analyses were performed to examine the robustness of study findings. RESULTS: We included 7171 PS-matched pairs of GLP-1RA and LAI users with no significant between-group differences at baseline. Compared with LAIs, the use of GLP-1RAs was associated with significantly reduced risks of composite liver disease (subdistribution hazard ratio [95% confidence interval]: 0.56 [0.42-0.76]), cirrhosis (0.59 [0.43-0.81]), and HCC (0.47 [0.24-0.93]). Results were consistent across sensitivity analyses and among patients with different baseline characteristics. CONCLUSION: Among T2D patients who require injectable GLAs, the use of GLP-1RAs versus LAIs was associated with lower risks of cirrhosis and HCC.

Assessing survival outcomes and complication profiles following surgical excision and radiotherapy as interventions for skull base chordoma: a systematic review of operative margins and surgical approaches.

INTRODUCTION: Despite their precarious behavioral classification (benign and low grade on histopathology yet behaviorally malignant), great strides have been taken to improve prognostication and treatment paradigms for patients with skull base chordoma. With respect to surgical techniques, lateral transcranial (TC) approaches have traditionally been used, however endoscopic endonasal approaches (EEA) have been advocated for midline lesions. Nonetheless, due to the rarity of this pathology (0.2% of all intracranial neoplasms), investigations within the literature remain limited to small retrospective series. Furthermore, radiotherapeutic treatments investigated to date have proven largely ineffective. METHODS: Accordingly, we performed a systematic review in order to profile surgical and survival outcomes for skull base chordoma. Fixed and random-effect meta-analyses were performed for categorical variables including GTR, STR, 5-year OS, 10-year OS, 5-year PFS, and 10-year PFS. Additionally, we pooled eligible studies for formal meta-analysis to compare outcomes by surgical approach (lateral versus midline). Statistical analyses were performed using R Studio 'metafor' package or Cochrane Review Manager. Furthermore, meta-analysis of pooled mortality rates and sub-analyses of operative margin and surgical complications were used to compare midline versus lateral approaches via the Mantel-Haenszel method. We considered all p-values < 0.05 to be statistically significant. RESULTS: Following the systematic search and screen, 55 studies published between 1993 and 2022 reporting data for 2453 patients remained eligible for analysis. Sex distribution was comparable between males and females, with a slight predominance of male-identifying patients (0.5625 [95% CI: 0.5418; 0.3909]). Average age at diagnosis was 42.4 ± 12.5 years, while average age of treatment initiation was 43.0 ± 10.6 years. Overall, I2 value indicated notable heterogeneity across the 55 studies [I2 = 56.3% (95%CI: 44.0%; 65.9%)]. With respect to operative margins, the rate of GTR was 0.3323 [95% CI: 0.2824; 0.3909], I2 = 91.9% [95% CI: 90.2%; 93.4%], while the rate of STR was significantly higher at 0.5167 [95% CI: 0.4596; 0.5808], I2 = 93.1% [95% CI: 91.6%; 94.4%]. The most common complication was CSF leak (5.4%). In terms of survival outcomes, 5-year OS rate was 0.7113 [95% CI: 0.6685; 0.7568], I2 = 91.9% [95% CI: 90.0%; 93.5%]. 10-year OS rate was 0.4957 [95% CI: 0.4230; 0.5809], I2 = 92.3% [95% CI: 89.2%; 94.4%], which was comparable to the 5-year PFS rate of 0.5054 [95% CI: 0.4394; 0.5813], I2 = 84.2% [95% CI: 77.6%; 88.8%] and 10-yr PFS rate of 0.4949 [95% CI: 0.4075; 0.6010], I2 = 14.9% [95% CI: 0.0%; 87.0%]. There were 55 reported deaths for a perioperative mortality rate of 2.5%. The relative risk for mortality in the midline group versus the lateral approach group did not indicate any substantial difference in survival according to laterality of approach (-0.93 [95% CI: -1.03, -0.97], I2 = 95%, (p < 0.001). CONCLUSION: Overall, these results indicate good 5-year survival outcomes for patients with skull base chordoma; however, 10-year prognosis for skull base chordoma remains poor due to its radiotherapeutic resistance and high recurrence rate. Furthermore, mortality rates among patients undergoing midline versus lateral skull base approaches appear to be equivocal.

Applications of supraorbital keyhole craniotomy in pediatric cranial trauma: illustrative series of two cases and systematic literature review.

Minimally invasive (MIS) approaches to neurosurgical diseases continue to increase in popularity due to their association with decreased infection risk, shorter recovery time, and improved cosmesis. Cosmesis and lower morbidity are especially important for pediatric patients. The supraorbital keyhole craniotomy (SOKC) is one MIS approach shown to be effective for both neoplastic and vascular pathologies in pediatric patients. However, it is limited data on its use in pediatric trauma patients. Two cases employing SOKC in pediatric trauma patients are presented here along with a systematic review of the literature. We queried PubMed, Scopus, and Web of Science databases from inception to August 2022 using the Boolean search term: (supraorbital OR eyebrow OR transeyebrow OR suprabrow OR superciliary OR supraciliary) AND (craniotomy OR approach OR keyhole OR procedure) AND (pediatric OR children OR child OR young) AND "trauma". Studies that discussed the use of an SOKC in a pediatric patient having sustained trauma to the frontal calvarium and/or anterior fossa/sellar region of the skull base were included. Details were extracted on patient demographics, trauma etiology, endoscope use, and surgical and cosmetic outcomes. We identified 89 unique studies, of which four met inclusion criteria. Thirteen total cases were represented. Age and sex were reported for 12 patients, 25% of whom were male; the mean age was 7.5 years (range: 3-16). Pathologies included acute epidural hematoma (9), orbital roof fracture with dural tear (1), blowout fracture of the medial wall of the frontal sinus with supraorbital rim fracture (1), and compound skull fracture (1). Twelve patients were treated with a conventional operating microscope, while one underwent endoscope-assisted surgery. Only one significant complication (recurrent epidural hematoma) was reported. There were no reported cosmetic complications. The MIS SOKC approach is a reasonable option for select anterior skull base trauma in the pediatric population. This approach has been used previously for successful frontal epidural hematoma evacuation, which is often treated by a large craniotomy. Further study is merited.

Schizophrenia and neurosurgery: systematic review and theories.

OBJECTIVE: Despite its relatively low prevalence, schizophrenia has a high burden of illness due to its lifelong effects and the fact that it is often refractory to psychotropic treatment. This review investigated how neurosurgical interventions, primarily neuromodulation through deep brain stimulation (DBS), can mitigate treatment-refractory schizophrenia. Pathophysiological data and ongoing clinical trials were reviewed to suggest which targets hold promise for neurosurgical efficacy. METHODS: A systematic review of the literature was conducted via an electronic search of the PubMed, Scopus, and Web of Science databases. Included papers were human or animal studies of neurosurgical interventions for schizophrenia conducted between 2012 and 2022. An electronic search of ClinicalTrials.gov and the International Clinical Trials Registry Platform was conducted to find ongoing clinical trials. The ROBINS-I (Risk of Bias in Nonrandomized Studies of Interventions) assessment tool was used to evaluate risk of bias in the study. RESULTS: Eight human and 2 rat studies were included in the review. Of the human studies, 5 used DBS targeting the nucleus accumbens, subgenual anterior cingulate cortex, habenula, and substantial nigra pars reticulata. The remaining 3 human studies reported the results of subcaudate tractotomies and anterior capsulotomies. The rat studies investigated DBS of the nucleus accumbens and medial prefrontal cortex. Overall, human studies demonstrated long-term reduction in Positive and Negative Syndrome Scale scores in many participants, with a low incidence of surgical and psychological side effects. The rat studies demonstrated improved prepulse and latent inhibition in the targeted areas after DBS. CONCLUSIONS: As identified in this review, recent studies have investigated the potential effects of therapeutic DBS for schizophrenia, with varying results. DBS targets that have been explored include the hippocampus, subgenual anterior cingulate cortex, habenula, substantia nigra pars reticulata, and medial prefrontal cortex. In addition to DBS, other neuromodulatory techniques such as neuroablation have been studied. Current evidence suggests that neuroablation in the subcaudate tract and anterior capsulotomy may be beneficial for some patients. The authors recommend further exploration of neuromodulation for treatment-refractory schizophrenia, under the condition that rigorous standards be upheld when considering surgical candidacy for these treatments, given that their safety and efficacy remain to be determined.

Staphylococcus Aureus Swabbing and Decolonization Before Neuromodulation Procedures: A Systematic Review and Meta-Analysis.

INTRODUCTION: Staphylococcus aureus (S aureus) is the foremost bacterial cause of surgical-site infection (SSI) and is a common source of neuromodulation SSI. Endogenous colonization is an independent risk factor for SSI; however, this risk has been shown to diminish with screening and decolonization. MATERIALS AND METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed, Cochrane Library, and Embase data bases from inception to January 1, 2022, for the purposes of identifying all studies reporting on the use of S aureus swabbing and/or decolonization before neuromodulation procedures. A random-effects meta-analysis was performed using the metaphor package in R to calculate odds ratios (OR). RESULTS: Five observational cohort studies were included after applying the inclusion and exclusion criteria. The average study duration was 6.6 ± 3.8 years. Three studies included nasal screening as a prerequisite for subsequent decolonization. Type of neuromodulation included spinal cord stimulation in two studies, deep brain stimulation in two studies, intrathecal baclofen in one study, and sacral neuromodulation in one study. Overall, 860 and 1054 patients were included in a control or intervention (ie, screening and/or decolonization) group, respectively. A combination of nasal mupirocin ointment and a body wash, most commonly chlorhexidine gluconate soap, was used to decolonize throughout. Overall infection rates were observed at 59 of 860 (6.86%) and ten of 1054 (0.95%) in the control and intervention groups, respectively. Four studies reported a significant difference. The OR for intervention (screen and/or decolonization) vs no intervention was 0.19 (95% CI, 0.09-0.37; p < 0.001). Heterogeneity between studies was nonsignificant (I2 = 0.43%, τ2 = 0.00). CONCLUSIONS: Preoperative S aureus swabbing and decolonization resulted in significantly decreased odds of infection in neuromodulation procedures. This measure may represent a worthwhile tool to reduce neuromodulation SSI, warranting further investigation.

Calcium Dynamics of the Ventrolateral Preoptic GABAergic Neurons during Spontaneous Sleep-Waking and in Response to Homeostatic Sleep Demands.

The ventrolateral preoptic area (VLPO) contains GABAergic sleep-active neurons. However, the extent to which these neurons are involved in expressing spontaneous sleep and homeostatic sleep regulatory demands is not fully understood. We used calcium (Ca2+) imaging to characterize the activity dynamics of VLPO neurons, especially those expressing the vesicular GABA transporter (VGAT) across spontaneous sleep-waking and in response to homeostatic sleep demands. The VLPOs of wild-type and VGAT-Cre mice were transfected with GCaMP6, and the Ca2+ fluorescence of unidentified (UNID) and VGAT cells was recorded during spontaneous sleep-waking and 3 h of sleep deprivation (SD) followed by 1 h of recovery sleep. Although both VGAT and UNID neurons exhibited heterogeneous Ca2+ fluorescence across sleep-waking, the majority of VLPO neurons displayed increased activity during nonREM/REM (VGAT, 120/303; UNID, 39/106) and REM sleep (VGAT, 32/303; UNID, 19/106). Compared to the baseline waking, VLPO sleep-active neurons (n = 91) exhibited higher activity with increasing SD that remained elevated during the recovery period. These neurons also exhibited increased Ca2+ fluorescence during nonREM sleep, marked by increased slow-wave activity and REM sleep during recovery after SD. These findings support the notion that VLPO sleep-active neurons, including GABAergic neurons, are components of neuronal circuitry that mediate spontaneous sleep and homeostatic responses to sustained wakefulness.

Unraveling the significance of soil organic carbon-gravel parameterization: Insights into soil water and heat transport on the Tibetan Plateau.

In the Tibetan Plateau (TP) soil water and heat transfer process, soil organic carbon (SOC) and gravel content are considered as the most influential soil texture factors. However, the issues of underestimating SOC and neglecting gravel effect affected the simulation performance of CLM5.0 on soil moisture (SM) and soil temperature (ST). This paper proposed a new parameterization scheme, the organic carbon-gravel (OC-G) scheme, to simulate ST and SM from 1990 to 2018. The results showed that correlation between the simulated and observed ST or SM was higher, and the error was smaller, after the modification of the parameterization scheme. This improvement justifies the applicability of the scheme for soil hydrothermal simulations on the TP. The experiment described that ST and SM were more sensitive to changes in SOC content. And changes in gravel or SOC content had the "Same-Frequency" effect in the northeast and southeast TP. When the SOC and gravel content changed at the same time, the effects on ST and SM were a "cumulative" effect. The change directly affected the memory time of ST and SM in summer. Specifically, when the SOC content was increased, the memory time of SM increased in the northwest and decreased in the southeast. When gravel content was increased, the memory time of SM decreased in the northwest but increased in the southeast, but the memory time of ST remained largely unchanged. Changes to the abnormal duration may alter summer weather and climate in Eastern China.

Roles of the ubiquitin ligase CUL4B and ADP-ribosyltransferase TiPARP in TCDD-induced nuclear export and proteasomal degradation of the transcription factor AHR.

The aryl hydrocarbon receptor (AHR) is a transcription factor activated by exogenous halogenated polycyclic aromatic hydrocarbon compounds, including the environmental toxin TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and naturally occurring dietary and endogenous compounds. The activated AHR enhances transcription of specific genes including phase I and phase II metabolism enzymes and other targets genes such as the TCDD-inducible poly(ADP-ribose) polymerase (TiPARP). The regulation of AHR activation is a dynamic process: immediately after transcriptional activation of the AHR by TCDD, the AHR is exported from the nucleus to the cytoplasm where it is subjected to proteasomal degradation. However, the mechanisms regulating AHR degradation are not well understood. Here, we studied the role of two enzymes reported to enhance AHR breakdown: the cullin 4B (CUL4B)AHR complex, an E3 ubiquitin ligase that targets the AHR and other proteins for ubiquitination, and TiPARP, which targets proteins for ADP-ribosylation, a posttranslational modification that can increase susceptibility to degradation. Using a WT mouse embryonic fibroblast (MEF) cell line and an MEF cell line in which CUL4B has been deleted (MEFCul4b-null), we discovered that loss of CUL4B partially prevented AHR degradation after TCDD exposure, while knocking down TiPARP in MEFCul4b-null cells completely abolished AHR degradation upon TCDD treatment. Increased TCDD-activated AHR protein levels in MEFCul4b-null and MEFCul4b-null cells in which TiPARP was knocked down led to enhanced AHR transcriptional activity, indicating that CUL4B and TiPARP restrain AHR action. This study reveals a novel function of TiPARP in controlling TCDD-activated AHR nuclear export and subsequent proteasomal degradation.

Self-adjusting inverse design method for nanophotonic devices.

Nanophotonic devices, which consist of multiple cell structures of the same size, are easy to manufacture. To avoid the optical proximity effect in the ultraviolet lithography process, the cell structures must be maintained at a distance from one another. In the inverse design process, the distance is maintained by limiting the optimized range of the location. However, this implementation can weaken the performance of the devices designed during transmission. To solve this problem, a self-adjusting inverse design method based on the adjoint variable method is developed. By introducing artificial potential field method, the location of one cell structure is modified only when the distances between this cell structure and other cell structures are smaller than a threshold. In this case, the range of the location can be expanded, and thus the performance of the designed devices can be improved. A wavelength demultiplexer with a channel spacing of 1.6 nm is designed to verify the performance of the proposed method. The experiment reveals that the transmission of the designed devices can be improved by 20%, and the self-adjusting inverse design process is 100 times faster than the inverse-design process based on the genetic algorithm.

Stimuli-Responsive Materials from Ferrocene-Based Organic Small Molecule for Wearable Sensors.

Stimuli-responsive crystals capable of energy conversion have emerged as promising materials for smart sensors, actuators, wearable devices, and robotics. Here, a novel ferrocene-based organic molecule crystal (Fc-Cz) that possesses anisotropic piezoelectric, optical, and mechanical properties is reported. It is demonstrated that the new crystal Fc-Cz can be used as an ultrasensitive piezoelectric material in fabricating strain sensors. The flexible sensor made of crystal Fc-Cz can detect small strains/deformations and motions with a fast response speed. Analysis based on density functional theory (DFT) indicates that an external pressure can affect the dipole moment by changing the molecular configuration of the asymmetric single crystal Fc-Cz in the crystalline state, leading to a change of polarity, and thereby an enhanced dielectric constant. This work demonstrates a new artificial organic small molecule for high-performance tactile sensors, indicating its great potential for developing low-cost flexible wearable sensors.

Cost-effectiveness of GLP-1 receptor agonists versus insulin for the treatment of type 2 diabetes: a real-world study and systematic review.

BACKGROUND: To conduct a real-word-study-based cost-effectiveness analysis of a GLP-1 receptor agonist (GLP-1RA) versus insulin among type 2 diabetes patients requiring intensified injection therapy and a systematic review of cost-effectiveness studies of GLP-1RAs versus insulin. METHODS: Individual-level analyses incorporating real-world effectiveness and cost data were conducted for a cohort of 1022 propensity-score-matched pairs of GLP-1RA and insulin users from Taiwan's National Health Insurance Research Database, 2007-2016. Study outcomes included the number needed to treat (NNT) to prevent one case of clinical events, healthcare costs, and cost per case of event prevented. Costs were in 2019 US dollars. Analyses were performed from a third-party payer and healthcare sector perspectives. Structured systematic review procedures were conducted to synthesize updated evidence on the cost-effectiveness of GLP-1RAs versus insulin. RESULTS: Over a mean follow-up of 2.3 years, the NNT using a GLP-1RA versus insulin to prevent one case of all-cause mortality and hospitalized hypoglycemia was 57 and 30, respectively. Using GLP-1RAs instead of insulin cost US$54,851 and US$29,115 per case of all-cause mortality and hospitalized hypoglycemia prevented, respectively, from the payer perspective, and saved US$19,391 and US$10,293, respectively, from the healthcare sector perspective. Sensitivity analyses showed that the probability of using GLP-1RAs versus insulin being cost-effective for preventing one case of all-cause mortality or hospitalized hypoglycemia ranged from 60 to 100%. The systematic review revealed a cost-effective profile of using GLP-1RAs versus insulin. CONCLUSIONS: Using GLP-1RAs versus insulin for type 2 diabetes patients requiring intensified injection therapy in clinical practice is cost-effective.

Renoprotective effect of SGLT-2 inhibitors among type 2 diabetes patients with different baseline kidney function: a multi-center study.

BACKGROUND: To assess the effect of sodium glucose cotransporter-2 inhibitors (SGLT-2is) for type 2 diabetes on kidney outcomes stratified by patient baseline estimated glomerular filtration rate (eGFR) levels (i.e., eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 mL/min/1.73 m2). METHODS: Patients from three large healthcare delivery systems in Taiwan who had initiated SGLT-2is or other glucose-lowering drugs (oGLDs) between May 2016 and December 2017 were included. Main outcomes were the times to 30%, 40%, and 50% eGFR reduction after treatment initiation. One-to-one propensity score matching in the overall study cohort and in each eGFR subgroup between SGLT-2i and oGLD users was applied to ensure between-group comparability in baseline characteristics. RESULTS: There were 13,666 matched pairs of SGLT-2is and oGLD users in the overall cohort. While a sustained eGFR decline was revealed in oGLD-treated patients (mean values [standard errors] from 85.61 [0.43] to 82.49 [0.44] mL/min/1.73 m2 during the 12 months after treatment initiation), the mean eGFR values of SGLT-2i users decreased in the first 3 months (85.68 [0.37] to 79.71 [0.41] mL/min/1.73 m2) but then improved and sustained until the end of follow-up. There were 2300, 5705, and 5509 matched SGLT-2i and oGLD users in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. Using SGLT-2is versus oGLDs was significantly associated with slower eGFR declines; hazard ratios (HRs) were 0.51 (95% CI 0.37-0.69), 0.51 (0.37-0.70), and 0.47 (0.31-0.71) for 40% eGFR reduction in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. The renoprotective effect of SGLT-2is versus oGLDs was confirmed in the outcomes of 30% and 50% eGFR reduction across the three eGFR subgroups. CONCLUSIONS: This study supports the renoprotective benefit of real-world SGLT-2i use irrespective of patient baseline kidney function.

Comparative cardiovascular safety of GLP-1 receptor agonists versus other glucose-lowering agents in real-world patients with type 2 diabetes: a nationwide population-based cohort study.

BACKGROUND: Current evidence about the cardiovascular safety of glucagon-like peptide-1 receptor agonist (GLP-1ra) possesses limited generalizability to real-world patients with type 2 diabetes (T2D) in usual practice. This study aimed to investigate the comparative cardiovascular safety of GLP-1ra in comparisons with dipeptidyl peptidase-4 inhibitor (DPP-4i), sulfonylurea (SU), and insulin in a real-world population with T2D. METHODS: Adults with newly-diagnosed T2D were identified from Taiwan's National Health Insurance Research Database in 2003-2014. A prevalent new-user cohort design was adopted to include a broad representation of real-world T2D patients being treated with GLP-1ra. The between-group comparability of baseline patient characteristics was achieved by matching on (1) initiation time of study drugs, (2) prior exposure to glucose-lowering agents, and (3) diabetes severity and complications, comorbidities, and concomitant cardiovascular medications using propensity scores. The primary outcome was a composite of cardiovascular disease (CVD) events and assessed up to the end of 2015. Cox modeling was employed to assess the association between study drugs and outcomes. RESULTS: A total of 3195 GLP-1ra stable users was identified in 2011-2014. 1893, 1829, and 1367 GLP-1ra stable users were 1:1 matched to DPP-4i, SU and insulin users, respectively. Compared to DPP-4i, SU and insulin, the use of GLP-1ra was associated with a lower risk of composite CVD events [hazard ratio (95% confidence interval) 0.73 (0.57-0.96), 0.76 (0.57-1.00), and 0.81 (0.62-1.07), respectively]. Subgroup analyses revealed that GLP-1ra versus DPP-4i yielded a greater cardiovascular benefit in those without established CVD versus those with established CVD. CONCLUSIONS: This comparison study extends the supporting evidence for the cardiovascular safety of GLP-1ra to a broad spectrum of real-world T2D patients using GLP-1ra.

Comparative predictive ability of visit-to-visit HbA1c variability measures for microvascular disease risk in type 2 diabetes.

BACKGROUND: To assess the associations of various HbA1c measures, including a single baseline HbA1c value, overall mean, yearly updated means, standard deviation (HbA1c-SD), coefficient of variation (HbA1c-CV), and HbA1c variability score (HVS), with microvascular disease (MVD) risk in patients with type 2 diabetes. METHODS: Linked data between National Cheng Kung University Hospital and Taiwan's National Health Insurance Research Database were utilized to identify the study cohort. The primary outcome was the composite MVD events (retinopathy, nephropathy, or neuropathy) occurring during the study follow-up. Cox model analyses were performed to assess the associations between HbA1c measures and MVD risk, with adjustment for patients' baseline HbA1c, demographics, comorbidities/complications, and treatments. RESULTS: In the models without adjustment for baseline HbA1c, all HbA1c variability and mean measures were significantly associated with MVD risk, except HVS. With adjustment for baseline HbA1c, HbA1c-CV had the strongest association with MVD risk. For every unit of increase in HbA1c-CV, the MVD risk significantly increased by 3.42- and 2.81-fold based on the models without and with adjustment for baseline HbA1c, respectively. The associations of HbA1c variability and mean measures with MVD risk in patients with baseline HbA1c < 7.5% (58 mmol/mol) were stronger compared with those in patients with baseline HbA1c ≥ 7.5% (58 mmol/mol). CONCLUSIONS: HbA1c variability, especially HbA1c-CV, can supplement conventional baseline HbA1c measure for explaining MVD risk. HbA1c variability may play a greater role in MVD outcomes among patients with relatively optimal baseline glycemic control compared to those with relatively poor baseline glycemic control.

Comparative effectiveness of dulaglutide versus liraglutide in Asian type 2 diabetes patients: a multi-institutional cohort study and meta-analysis.

BACKGROUND: Head-to-head comparison of clinical effectiveness between dulaglutide and liraglutide in Asia is limited. This study was aimed to assess the real-world comparative effectiveness of dulaglutide versus liraglutide. METHODS: We conducted a retrospective cohort study by utilizing multi-institutional electronic medical records to identify real-world type 2 diabetes patients treated with dulaglutide or liraglutide during 2016-2018 in Taiwan and followed up until 2019. Effectiveness outcomes were assessed at every 3 months in the 1-year follow-up. Propensity score techniques were applied to enhance between-group comparability. Significant differences in changes of effectiveness outcomes between treatment groups during the follow-up were examined and further analyzed using mixed-model repeated-measures approaches. RESULTS: A total of 1512 subjects receiving dulaglutide and 1513 subjects receiving liraglutide were identified. At 12 months, significant HbA1c changes from baseline were found in both treatments (dulaglutide: - 1.06%, p < 0.001; liraglutide: - 0.83%, p < 0.001), with a significant between-group difference (- 0.23%, 95% confidence interval - 0.38 to - 0.08%, p < 0.01). Both treatments yielded significant declines in weight, alanine aminotransferase level, and estimated glomerular filtration rate from baseline (dulaglutide: - 1.14 kg, - 3.08 U/L and - 2.08 mL/min/1.73 m2, p < 0.01; liraglutide: - 1.64 kg, - 3.65 U/L and - 2.33 mL/min/1.73 m2, p < 0.001), whereas only dulaglutide yielded a significant systolic blood pressure reduction (- 2.47 mmHg, p < 0.001). Between-group differences in changes of weight, blood pressure, and liver and renal functions at 12 months were not statistically significant. CONCLUSIONS: In real-world T2D patients, dulaglutide versus liraglutide was associated with better glycemic control and comparable effects on changes of weight, blood pressure, and liver and renal functions.

Cost-effectiveness of long-acting insulin analogues vs intermediate/long-acting human insulin for type 1 diabetes: A population-based cohort followed over 10 years.

AIMS: This study assessed the cost-effectiveness of long-acting insulin analogues (LAIAs) vs intermediate/long-acting human insulin (ILAHI) for patients with type 1 diabetes (T1D) in real-world clinical practice. METHODS: Individual-level analyses were conducted within a longitudinal population-based cohort of 540 propensity score-matched T1D patients (LAIAs, n = 270; ILAHI, n = 270) with over 10 years of follow-up using Taiwan's National Health Insurance Research Database, 2004-2013, from third-party payer and healthcare sector perspectives. The study outcomes included the number needed to treat (NNT) to prevent one case of clinical events (eg, hypoglycaemia, diabetes-related complications), medical costs, and cost per case of events prevented. Cost estimates are presented in 2013 British pounds (GBP, £). RESULTS: The NNTs using LAIAs vs ILAHI to avoid one case of hypoglycaemia requiring medical assistance, outpatient hypoglycaemia and any diabetes-related complications were 12, 9 and 10 for mean follow-up periods of 5.84, 6.02 and 3.62 years, respectively. From third-party payer and healthcare sector perspectives, using LAIAs instead of ILAHI saved GBP6924-GBP7116 per case of hypoglycaemia requiring medical assistance prevented, GBP5346-GBP5508 per case of outpatient hypoglycaemia prevented, and GBP3570-GBP3680 per case of any diabetes-related complications prevented. Sensitivity analyses considering sampling uncertainty showed that using LAIAs over ILAHI yields at least a 76% probability of cost-saving for avoiding one case of hypoglycaemia requiring medical assistance, outpatient hypoglycaemia or any diabetes-related complications. CONCLUSIONS: This real-world evidence reveals that compared with ILAHI, the greater pharmaceutical costs associated with LAIAs for patients with T1D could be substantially offset by savings from averted hypoglycaemia or diabetes-related complications.

Sensor Classification Using Convolutional Neural Network by Encoding Multivariate Time Series as Two-Dimensional Colored Images.

This paper proposes a framework to perform the sensor classification by using multivariate time series sensors data as inputs. The framework encodes multivariate time series data into two-dimensional colored images, and concatenate the images into one bigger image for classification through a Convolutional Neural Network (ConvNet). This study applied three transformation methods to encode time series into images: Gramian Angular Summation Field (GASF), Gramian Angular Difference Field (GADF), and Markov Transition Field (MTF). Two open multivariate datasets were used to evaluate the impact of using different transformation methods, the sequences of concatenating images, and the complexity of ConvNet architectures on classification accuracy. The results show that the selection of transformation methods and the sequence of concatenation do not affect the prediction outcome significantly. Surprisingly, the simple structure of ConvNet is sufficient enough for classification as it performed equally well with the complex structure of VGGNet. The results were also compared with other classification methods and found that the proposed framework outperformed other methods in terms of classification accuracy.

Lower risk of dementia with pioglitazone, compared with other second-line treatments, in metformin-based dual therapy: a population-based longitudinal study.

AIMS/HYPOTHESIS: The effect of pioglitazone was compared with that of other second-line glucose-lowering drugs on the risk of dementia among individuals with type 2 diabetes receiving metformin-based dual therapy. METHODS: A total of 204,323 individuals with type 2 diabetes aged ≥18 years who were stable metformin users and dementia-free before the initiation of second-line glucose-lowering medication were identified in the period 2000-2011 from Taiwan's National Health Insurance Research Database and followed to the end of 2013. Primary analyses included 51,415 individuals aged ≥65 years without dementia events in the first year of second-line glucose-lowering treatment. Study subjects were classified into mutually exclusive groups according to various second-line glucose-lowering drugs to metformin. Cox proportional hazards models were applied to assess the time-to-event between propensity score-matched glucose-lowering treatment groups. RESULTS: Individuals aged ≥65 years on metformin + pioglitazone had a significantly lower risk of dementia compared with those on metformin + sulfonylurea (HR 0.56; 95% CI 0.34, 0.93), and a lower, but insignificant, risk of dementia compared with those on other metformin-based dual regimens (i.e. metformin + acarbose, metformin + meglitinide, metformin + insulin or metformin + dipeptidyl peptidase 4 inhibitors). Among individuals aged ≥18 years, there was also a decreased risk of dementia in those taking pioglitazone compared with those taking other second-line glucose-lowering drugs. A lower incidence of dementia was found in users of metformin + pioglitazone compared with users of metformin + rosiglitazone. CONCLUSIONS/INTERPRETATION: Pioglitazone as a second-line treatment after metformin might provide a protective effect on dementia risk among individuals with type 2 diabetes.

Neuroprotection by Propofol Post-Conditioning: Focus on PKMζ/KCC2 Pathway Activity.

Critical and major operations are often accompanied by brain ischemic complications. Previous studies found that propofol post-conditioning provided neuroprotective functions through upregulating the expression of potassium chloride cotransporter 2 (KCC2) in gamma-aminobutyric acid (GABA) interneurons. Membrane expression and phosphorylation represents KCC2 activity, which were modulated by a protein kinase C (PKC)-dependent mechanism. However, the role of propofol in increasing KCC2 phosphorylation and the involvement of protein kinase Mζ (PKMζ), a major subtype of PKC, in the KCC2 pathway remained unclear. In this study, we established middle cerebral artery occlusion model in rats to evaluate the long-term recovery of brain functions using behavioral experiments. KCC2 and PKMζ were assessed via western blot. We used the selective inhibitor, zeta inhibitory peptide (ZIP), to investigate the relationship between KCC2 and PKMζ. Intracellular chloride concentration in the hippocampal CA1 area was measured to determine KCC2 activity. We found that propofol, infused at a speed of 20 mg kg-1 h-1 for 2 h at the onset of reperfusion, improved neurological deficits and cognitive dysfunction following ischemia/reperfusion injury. PKMζ expression was significantly upregulated, which improved KCC2 membrane expression and phosphorylation in the ischemic hippocampal CA1 area, and these effects could last up to 28 days. But ZIP inhibited this process. Ultimately, we showed that propofol increased KCC2 phosphorylation and PKMζ was the upstream of KCC2. Propofol led to long-term recovery of brain functions by upregulating the activity of the PKMζ/KCC2 pathway.

Cell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis.

CUL4B ubiquitin ligase belongs to the cullin-RING ubiquitin ligase family. Although sharing many sequence and structural similarities, CUL4B plays distinct roles in spermatogenesis from its homologous protein CUL4A. We previously reported that genetic ablation ofCul4ain mice led to male infertility because of aberrant meiotic progression. In the present study, we generated Cul4bgerm cell-specific conditional knock-out (Cul4b(Vasa)),as well asCul4bglobal knock-out (Cul4b(Sox2)) mouse, to investigate its roles in spermatogenesis. Germ cell-specific deletion of Cul4bled to male infertility, despite normal testicular morphology and comparable numbers of spermatozoa. Notably, significantly impaired sperm mobility caused by reduced mitochondrial activity and glycolysis level were observed in the majority of the mutant spermatozoa, manifested by low, if any, sperm ATP production. Furthermore,Cul4b(Vasa)spermatozoa exhibited defective arrangement of axonemal microtubules and flagella outer dense fibers. Our mass spectrometry analysis identified INSL6 as a novel CUL4B substrate in male germ cells, evidenced by its direct polyubiquination and degradation by CUL4B E3 ligase. Nevertheless,Cul4bglobal knock-out males lost their germ cells in an age-dependent manner, implying failure of maintaining the spermatogonial stem cell niche in somatic cells. Taken together, our results show that CUL4B is indispensable to spermatogenesis, and it functions cell autonomously in male germ cells to ensure spermatozoa motility, whereas it functions non-cell-autonomously in somatic cells to maintain spermatogonial stemness. Thus, CUL4B links two distinct spermatogenetic processes to a single E3 ligase, highlighting the significance of ubiquitin modification during spermatogenesis.