Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS: Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. CONCLUSIONS: Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).

Polatuzumab vedotin in previously untreated DLBCL: an Asia subpopulation analysis from the phase 3 POLARIX trial.

In the phase 3 POLARIX study in previously untreated diffuse large B-cell lymphoma, polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with similar safety. Patients were randomized 1:1 to 6 cycles of Pola-R-CHP or R-CHOP plus 2 cycles of rituximab alone. For registration of POLARIX in China, consistency of PFS in an Asia subpopulation (defined as ≥50% of the risk reduction in PFS expected in the global population) was evaluated. Overall, 281 patients were analyzed: 160 patients from Asia in the intention-to-treat (ITT) population of the global study and 121 from an ITT China extension cohort. Of these, 141 were randomized to Pola-R-CHP and 140 to R-CHOP. At data cutoff (28 June 2021; median follow-up 24.2 months), PFS met the consistency definition with the global population, and was superior with Pola-R-CHP vs R-CHOP (hazard ratio, 0.64; 95% confidence interval [CI], 0.40-1.03). Two-year PFS was 74.2% (95% CI, 65.7-82.7) and 66.5% (95% CI, 57.3-75.6) with Pola-R-CHP and R-CHOP, respectively. Safety was comparable between Pola-R-CHP and R-CHOP, including rates of grade 3 to 4 adverse events (AEs; 72.9% vs 66.2%, respectively), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to study treatment discontinuation (5.0% vs 7.2%), and any-grade peripheral neuropathy (44.3% vs 50.4%). These findings demonstrate consistent efficacy and safety of Pola-R-CHP vs R-CHOP in the Asia and global populations in POLARIX. This trial was registered at https://clinicaltrials.gov/ct2/home as # NCT03274492.

Resolution of tonic concentrations of highly similar neurotransmitters using voltammetry and deep learning.

With advances in our understanding regarding the neurochemical underpinnings of neurological and psychiatric diseases, there is an increased demand for advanced computational methods for neurochemical analysis. Despite having a variety of techniques for measuring tonic extracellular concentrations of neurotransmitters, including voltammetry, enzyme-based sensors, amperometry, and in vivo microdialysis, there is currently no means to resolve concentrations of structurally similar neurotransmitters from mixtures in the in vivo environment with high spatiotemporal resolution and limited tissue damage. Since a variety of research and clinical investigations involve brain regions containing electrochemically similar monoamines, such as dopamine and norepinephrine, developing a model to resolve the respective contributions of these neurotransmitters is of vital importance. Here we have developed a deep learning network, DiscrimNet, a convolutional autoencoder capable of accurately predicting individual tonic concentrations of dopamine, norepinephrine, and serotonin from both in vitro mixtures and the in vivo environment in anesthetized rats, measured using voltammetry. The architecture of DiscrimNet is described, and its ability to accurately predict in vitro and unseen in vivo concentrations is shown to vastly outperform a variety of shallow learning algorithms previously used for neurotransmitter discrimination. DiscrimNet is shown to generalize well to data captured from electrodes unseen during model training, eliminating the need to retrain the model for each new electrode. DiscrimNet is also shown to accurately predict the expected changes in dopamine and serotonin after cocaine and oxycodone administration in anesthetized rats in vivo. DiscrimNet therefore offers an exciting new method for real-time resolution of in vivo voltammetric signals into component neurotransmitters.

Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: Results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

Understanding the different effects of fouling mechanisms on working and reference electrodes in fast-scan cyclic voltammetry for neurotransmitter detection.

Fast-scan cyclic voltammetry (FSCV) is a widely used technique for detecting neurotransmitters. However, electrode fouling can negatively impact its accuracy and sensitivity. Fouling refers to the accumulation of unwanted materials on the electrode surface, which can alter its electrochemical properties and reduce its sensitivity and selectivity. Fouling mechanisms can be broad and may include biofouling, the accumulation of biomolecules on the electrode surface, and chemical fouling, the deposition of unwanted chemical species. Despite individual studies discussing fouling effects on either the working electrode or the reference electrode, no comprehensive study has been conducted to compare the overall fouling effects on both electrodes in the context of FSCV. Here, we examined the effects of biofouling and chemical fouling on the carbon fiber micro-electrode (CFME) as the working electrode and the Ag/AgCl reference electrode with FSCV. Both fouling mechanisms significantly decreased the sensitivity and caused peak voltage shifts in the FSCV signal with the CFME, but not with the Ag/AgCl reference electrode. Interestingly, previous studies have reported peak voltage shifts in FSCV signals due to the fouling of Ag/AgCl electrodes after implantation in the brain. We noticed in a previous study that energy-dispersive spectroscopy (EDS) spectra showed increased sulfide ion concentration after implantation. We hypothesized that sulfide ions may be responsible for the peak voltage shift. To test this hypothesis, we added sulfide ions to the buffer solution, which decreased the open circuit potential of the Ag/AgCl electrode and caused a peak voltage shift in the FSCV voltammograms. Also, EDS analysis showed that sulfide ion concentration increased on the surface of the Ag/AgCl electrodes after 3 weeks of chronic implantation, necessitating consideration of sulfide ions as the fouling agent for the reference electrodes. Overall, our study provides important insights into the mechanisms of electrode fouling and its impact on FSCV measurements. These findings could inform the design of FSCV experiments, with the development of new strategies for improving the accuracy and reliability of FSCV measurements in vivo.

Deep brain stimulation alleviates tics in Tourette syndrome via striatal dopamine transmission.

Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by intrusive motor and vocal tics that can lead to self-injury and deleterious mental health complications. While dysfunction in striatal dopamine neurotransmission has been proposed to underlie tic behaviour, evidence is scarce and inconclusive. Deep brain stimulation (DBS) of the thalamic centromedian parafascicular complex (CMPf), an approved surgical interventive treatment for medical refractory Tourette syndrome, may reduce tics by affecting striatal dopamine release. Here, we use electrophysiology, electrochemistry, optogenetics, pharmacological treatments and behavioural measurements to mechanistically examine how thalamic DBS modulates synaptic and tonic dopamine activity in the dorsomedial striatum. Previous studies demonstrated focal disruption of GABAergic transmission in the dorsolateral striatum of rats led to repetitive motor tics recapitulating the major symptom of Tourette syndrome. We employed this model under light anaesthesia and found CMPf DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons while concomitantly reducing motor tic behaviour. The improvement in tic behaviour was found to be mediated by D2 receptor activation as blocking this receptor prevented the therapeutic response. Our results demonstrate that release of striatal dopamine mediates the therapeutic effects of CMPf DBS and points to striatal dopamine dysfunction as a driver for motor tics in the pathoneurophysiology of Tourette syndrome.

The effect of types of sensory feedback on the acquisition and retention of squat performance: A randomized, double-blind, controlled trial.

Various sensory feedback methods are considered important for motor learning, but the effect of each sensory feedback method on effective squat learning still needs to be clarified. This study aimed to investigate the effect of sensory feedback types on the acquisition and retention of a squat. A double-blinded, randomized controlled trial was carried out. Thirty-healthy people were recruited and randomly assigned to the visual feedback group (VFG = 10), tactile feedback group (TFG = 10), and control group (CG = 10). VFG received visual feedback through video data of the participant performing squats, and TFG received tactile feedback through manual contact with a physical therapist. Both groups received feedback on the movements that needed correction after each set was completed. CG maintained rest without receiving any feedback. The retro-reflexive marker, force plate, and electromyography were used to measure body angle, foot center of pressure (COP), and muscle activity. All assessments were measured to confirm a squat acquisition. VFG and TFG showed significant differences in neutral knee position (NKP), trunk forward lean (TFL), anterior knee displacement (AKD), and anteroposterior (AP) foot COP (p < 0.050). In addition, the acquisition was retained until 3 days later for NKP and a week later for TFL, AKD, and AP foot COP in VFG (p < 0.050), while the acquisition was not retained in TFG (p > 0.050). There was no statistically significant change in CG (p > 0.050). This study demonstrated that visual feedback positively affects the acquisition and retention of squats. Therefore, we recommend the use of visual feedback for squat acquisition and retention in exercise novices.

A Prospective Study of Preemptive Tenofovir Disoproxil Fumarate Therapy in HBsAg-Positive Patients With Diffuse Large B-Cell Lymphoma Receiving Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.

INTRODUCTION: This prospective study aimed to investigate the efficacy and safety of preemptive antiviral therapy with tenofovir disoproxil fumarate (TDF) for HBsAg-positive patients with newly diagnosed diffuse large B-cell lymphoma receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. METHODS: We enrolled 73 patients from 20 institutions. The primary end point was the absolute risk of hepatitis B virus (HBV)-related hepatitis during preemptive TDF therapy and for 24 weeks after withdrawal from TDF. Hepatitis was defined as a more than 3-fold increase in serum alanine aminotransferase from baseline or an alanine aminotransferase level of ≥100 U/L. HBV-related hepatitis was defined as hepatitis with an increase in serum HBV-DNA to >10 times that of the pre-exacerbation baseline or an absolute increase of ≥20,000 IU/mL compared with the baseline. RESULTS: No patient developed HBV reactivation or HBV-related hepatitis during preemptive antiviral therapy (until 48 weeks after completion of R-CHOP chemotherapy) with TDF. All adverse events were grade 1 or 2. HBV reactivation was reported in 17 (23.3%) patients. All HBV reactivation was developed at a median of 90 days after withdrawal from TDF (range, 37-214 days). Six (8.2%) patients developed HBV-related hepatitis at a median of 88 days after withdrawal from TDF (range, 37-183 days). DISCUSSION: Preemptive TDF therapy in HBsAg-positive patients with diffuse large B-cell lymphoma receiving R-CHOP chemotherapy was safe and effective for preventing HBV-related hepatitis. However, a long-term maintenance strategy of preemptive TDF therapy should be recommended because of the relatively high rate of HBV-related hepatitis after withdrawal from TDF ( ClinicalTrials.gov ID: NCT02354846).

Daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with newly diagnosed AL amyloidosis: subgroup analysis of ANDROMEDA.

Subcutaneous daratumumab plus bortezomib/cyclophosphamide/dexamethasone (VCd; D-VCd) improved outcomes versus VCd for patients with newly diagnosed immunoglobulin light-chain (AL) amyloidosis in the phase 3 ANDROMEDA study. We report a subgroup analysis of Asian patients (Japan; Korea; China) from ANDROMEDA. Among 388 randomized patients, 60 were Asian (D-VCd, n = 29; VCd, n = 31). At a median follow-up of 11.4 months, the overall hematologic complete response rate was higher for D-VCd versus VCd (58.6% vs. 9.7%; odds ratio, 13.2; 95% confidence interval [CI], 3.3-53.7; P < 0.0001). Six-month cardiac and renal response rates were higher with D-VCd versus VCd (cardiac, 46.7% vs. 4.8%; P = 0.0036; renal, 57.1% vs. 37.5%; P = 0.4684). Major organ deterioration progression-free survival (MOD-PFS) and major organ deterioration event-free survival (MOD-EFS) were improved with D-VCd versus VCd (MOD-PFS: hazard ratio [HR], 0.21; 95% CI, 0.06-0.75; P = 0.0079; MOD-EFS: HR, 0.16; 95% CI, 0.05-0.54; P = 0.0007). Twelve deaths occurred (D-VCd, n = 3; VCd, n = 9). Twenty-two patients had baseline serologies indicating prior hepatitis B virus (HBV) exposure; no patient experienced HBV reactivation. Although grade 3/4 cytopenia rates were higher than in the global safety population, the safety profile of D-VCd in Asian patients was generally consistent with the global study population, regardless of body weight. These results support D-VCd use in Asian patients with newly diagnosed AL amyloidosis. ClinicalTrials.gov Identifier: NCT03201965.

Cardiovascular Outcomes in Patients Initiating First-Line Treatment of Type 2 Diabetes With Sodium-Glucose Cotransporter-2 Inhibitors Versus Metformin : A Cohort Study.

BACKGROUND: Evidence on the risk for cardiovascular events associated with use of first-line sodium-glucose cotransporter-2 inhibitors (SGLT-2i) compared with metformin is limited. OBJECTIVE: To assess cardiovascular outcomes among adults with type 2 diabetes (T2D) who initiated first-line treatment with SGLT-2i versus metformin. DESIGN: Population-based cohort study. SETTING: Claims data from 2 large U.S. commercial and Medicare databases (April 2013 to March 2020). PARTICIPANTS: Patients with T2D aged 18 years and older (>65 years in Medicare) initiating treatment with SGLT-2i or metformin during April 2013 to March 2020, without any use of antidiabetic medications before cohort entry, were identified. After 1:2 propensity score matching in each database, pooled hazard ratios (HRs) and 95% CIs were reported. INTERVENTION: First-line SGLT-2i (canagliflozin, empagliflozin, or dapagliflozin) or metformin. MEASUREMENTS: Primary outcomes were a composite of hospitalization for myocardial infarction (MI), hospitalization for ischemic or hemorrhagic stroke or all-cause mortality (MI/stroke/mortality), and a composite of hospitalization for heart failure (HHF) or all-cause mortality (HHF/mortality). Safety outcomes including genital infections were assessed. RESULTS: Among 8613 first-line SGLT-2i initiators matched to 17 226 metformin initiators, SGLT-2i initiators had a similar risk for MI/stroke/mortality (HR, 0.96; 95% CI, 0.77 to 1.19) and a lower risk for HHF/mortality (HR, 0.80; CI, 0.66 to 0.97) during a mean follow-up of 12 months. Initiators receiving SGLT-2i showed a lower risk for HHF (HR, 0.78; CI, 0.63 to 0.97), a numerically lower risk for MI (HR, 0.70; CI, 0.48 to 1.00), and similar risk for stroke, mortality, and MI/stroke/HHF/mortality compared with metformin. Initiators receiving SGLT-2i had a higher risk for genital infections (HR, 2.19; CI, 1.91 to 2.51) and otherwise similar safety as those receiving metformin. LIMITATION: Treatment selection was not randomized. CONCLUSION: As first-line T2D treatment, initiators receiving SGLT-2i showed a similar risk for MI/stroke/mortality, lower risk for HHF/mortality and HHF, and a similar safety profile except for an increased risk for genital infections compared with those receiving metformin. PRIMARY FUNDING SOURCE: Brigham and Women's Hospital and Harvard Medical School.

Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. METHODS: This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009-2020 were enrolled. RESULTS: At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. CONCLUSION: These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

Cocaine increases stimulation-evoked serotonin efflux in the nucleus accumbens.

Although dopamine is the most implicated neurotransmitter in the mediation of the pathophysiology of addiction, animal studies show serotonin also plays a vital role. Cocaine is one of the most common illicit drugs globally, but the role of serotonin in its mechanism of action is insufficiently characterized. Consequently, we investigated the acute effects of the psychomotor stimulant cocaine on electrical stimulation-evoked serotonin (phasic) release in the nucleus accumbens core (NAcc) of urethane-anesthetized (1.5 g/kg ip) male Sprague-Dawley rats using N-shaped fast-scan cyclic voltammetry (N-FSCV). A single carbon fiber microelectrode was first implanted in the NAcc. Stimulation was applied to the medial forebrain bundle using 60 Hz, 2 ms, 0.2 mA, 2-s biphasic pulses before and after cocaine (2 mg/kg iv) was administered. Stimulation-evoked serotonin release significantly increased 5 min after cocaine injection compared with baseline (153 ± 21 nM vs. 257 ± 12 nM; P = 0.0042; n = 5) but was unaffected by saline injection (1 mL/kg iv; n = 5). N-FSCV's selective measurement of serotonin release in vivo was confirmed pharmacologically via administration of the selective serotonin reuptake inhibitor escitalopram (10 mg/kg ip) that effectively increased the signal in a separate group of rats (n = 5). Selectivity to serotonin was further confirmed in vitro in which dopamine was minimally detected by N-FSCV with a serotonin to dopamine response ratio of 1:0.04 (200 nM of serotonin:1 µM dopamine ratio; P = 0.0048; n = 5 electrodes). This study demonstrates a noteworthy influence of cocaine on serotonin dynamics, and confirms that N-FSCV can effectively and selectively measure phasic serotonin release in the NAcc.NEW & NOTEWORTHY Serotonin plays a vital role in drug addiction. Here, using N-shaped fast-scan cyclic voltammetry, we demonstrated the effect of cocaine on the phasic release of serotonin at the nucleus accumbens core. To the best of our knowledge, this has not previously been elucidated. Our results not only reinforce the role of serotonin in the mechanism of action of cocaine but also help to fill a gap in our knowledge and provide a baseline for future studies in cocaine addiction.

Sequential eradication of Helicobacter pylori as a treatment for immune thrombocytopenia in patients with moderate thrombocytopenia: a multicenter prospective randomized phase 3 study.

Due to several issues, standard treatments are not recommended for asymptomatic patients with moderate immune thrombocytopenia (ITP). Since platelet responses are reported in some patients with Helicobacter pylori (H. pylori)-positive ITP after eradication, we conducted a multicenter, phase 3 study to evaluate the safety and efficacy of recently established sequential eradication for these patients having moderate thrombocytopenia. Persistent or chronic ITP patients with platelet count (30 × 103 ~ 80 × 103/µL) and confirmed active H. pylori infection were randomly assigned to a treatment and a control group. The former received 10-day sequential treatment. Eradication was assessed by urea breath test at 3 months after treatment. Primary endpoint was the overall platelet response rate at 3 months in successfully eradicated treatment group and control group. Secondary endpoints were platelet response time, H. pylori eradication success rate, etc. The patient enrollment terminated early because of the change of national insurance and treatment guideline for H. pylori-positive patients in Korea during the study. Of the 28 H. pylori-positive ITP patients, 17 were randomized to the treatment group, and eradication was achieved for 15 (88.2%) at 3 months, and seven in control group after withdrawal. Statistically, significant difference in platelet response rates between the two groups were observed (p = 0.017). Our study verifies that H. pylori eradication was an effective ITP treatment for patients with H. pylori-associated moderate ITP. This sequential eradication regimen showed not only a high H. pylori eradication rate, but also a remarkable platelet response for ITP patients. Trial registration number and date of registration for these prospectively registered trials is ClinicalTrials.gov number, NCT03177629 and June 6, 2017.

Evolving channeling in prescribing SGLT-2 inhibitors as first-line treatment for type 2 diabetes.

PURPOSE: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are increasingly being considered as first-line treatment for type 2 diabetes (T2D). The benefits of SGLT-2i from cardiovascular outcome trials may lead to preferential prescribing of SGLT-2i to patients at high cardiovascular risk, possibly causing confounding in non-randomized studies of SGLT-2i as first-line treatment. We assessed evolving imbalances in characteristics of patients starting SGLT-2i versus metformin as first-line monotherapy. METHODS: Using claims data from two US commercial health insurance and Medicare, we identified patients with T2D aged ≥18 years (>65 years in Medicare) initiating first-line SGLT-2i or metformin from 2013 through 2019. Standardized differences (SDs) for patient characteristics were assessed during four consecutive calendar time blocks (T1:4/2013-12/2014; T2:1/2015-6/2016; T3:7/2016-12/2017; and T4:1/2018-12/2019). We also estimated the propensity score of receiving SGLT-2i versus metformin within each time block and evaluated time trends in model discrimination with c-statistics. RESULTS: We identified 9113 initiators of first-line SGLT-2i and 810 348 initiators of first-line metformin. During T1, SGLT-2i initiators were younger (SD = -0.24) and less likely to have seen cardiologists (-0.07) with a similar prevalence of CVD (0.04) compared with metformin. During T4, patients were more balanced for age (-0.01). Cardiologist visits (0.08) and CVD (0.25) became more prevalent among SGLT-2i initiators. CONCLUSIONS: When comparing initiators of first-line SGLT-2i versus metformin, imbalances in patient characteristics evolved from 2013 through 2019, particularly channeling SGLT-2i to individuals at high cardiovascular risk. Evolving channeling in prescribing first-line SGLT-2i should be expected and accounted for in non-randomized comparative effectiveness research.

Biomarkers for Deep Brain Stimulation in Animal Models of Depression.

OBJECTIVES: Despite recent advances in depression treatment, many patients still do not respond to serial conventional therapies and are considered "treatment resistant." Deep brain stimulation (DBS) has therapeutic potential in this context. This comprehensive review of recent studies of DBS for depression in animal models identifies potential biomarkers for improving therapeutic efficacy and predictability of conventional DBS to aid future development of closed-loop control of DBS systems. MATERIALS AND METHODS: A systematic search was performed in Pubmed, EMBASE, and Cochrane Review using relevant keywords. Overall, 56 animal studies satisfied the inclusion criteria. RESULTS: Outcomes were divided into biochemical/physiological, electrophysiological, and behavioral categories. Promising biomarkers include biochemical assays (in particular, microdialysis and electrochemical measurements), which provide real-time results in awake animals. Electrophysiological tests, showing changes at both the target site and downstream structures, also revealed characteristic changes at several anatomic targets (such as the medial prefrontal cortex and locus coeruleus). However, the substantial range of models and DBS targets limits the ability to draw generalizable conclusions in animal behavioral models. CONCLUSIONS: Overall, DBS is a promising therapeutic modality for treatment-resistant depression. Different outcomes have been used to assess its efficacy in animal studies. From the review, electrophysiological and biochemical markers appear to offer the greatest potential as biomarkers for depression. However, to develop closed-loop DBS for depression, additional preclinical and clinical studies with a focus on identifying reliable, safe, and effective biomarkers are warranted.

Feasibility of Applying Fourier Transform Electrochemical Impedance Spectroscopy in Fast Cyclic Square Wave Voltammetry for the In Vivo Measurement of Neurotransmitters.

We previously reported on the use of fast cyclic square wave voltammetry (FCSWV) as a new voltammetric technique. Fourier transform electrochemical impedance spectroscopy (FTEIS) has recently been utilized to provide information that enables a detailed analytical description of an electrified interface. In this study, we report on attempts to combine FTEIS with FCSWV (FTEIS-FCSWV) and demonstrate the feasibility of FTEIS-FCSWV in the in vivo detection of neurotransmitters, thus giving a new type of electrochemical impedance information such as biofouling on the electrode surface. From FTEIS-FCSWV, three new equivalent circuit element voltammograms, consisting of charge-transfer resistance (Rct), solution-resistance (Rs), and double-layer capacitance (Cdl) voltammograms were constructed and investigated in the phasic changes in dopamine (DA) concentrations. As a result, all Rct, Rs, and Cdl voltammograms showed different DA redox patterns and linear trends for the DA concentration (R2 > 0.99). Furthermore, the Rct voltammogram in FTEIS-FCSWV showed lower limit of detection (21.6 ± 15.8 nM) than FSCV (35.8 ± 17.4 nM). FTEIS-FCSWV also showed significantly lower prediction errors than FSCV in selectivity evaluations of unknown mixtures of catecholamines. Finally, Cdl from FTEIS-FCSWV showed a significant relationship with fouling effect on the electrode surface by showing decreased DA sensitivity in both flow injection analysis experiment (r = 0.986) and in vivo experiments. Overall, this study demonstrates the feasibility of FTEIS-FCSWV, which could offer a new type of neurochemical spectroscopic information concerning electrochemical monitoring of neurotransmitters in the brain, and the ability to estimate the degree of sensitivity loss caused by biofouling on the electrode surface.

Tonic Serotonin Measurements In Vivo Using N-Shaped Multiple Cyclic Square Wave Voltammetry.

Here, we present the development of a novel voltammetric technique, N-shaped multiple cyclic square wave voltammetry (N-MCSWV) and its application in vivo. It allows quantitative measurements of tonic extracellular levels of serotonin in vivo with mitigated fouling effects. N-MCSWV enriches the electrochemical information by generating high dimensional voltammograms, which enables high sensitivity and selectivity against 5-hydroindoleacetic acid (5-HIAA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), histamine, ascorbic acid, norepinephrine, adenosine, and pH. Using N-MCSWV, in combination with PEDOT:Nafion-coated carbon fiber microelectrodes, a tonic serotonin concentration of 52 ± 5.8 nM (n = 20 rats, ±SEM) was determined in the substantia nigra pars reticulata of urethane-anesthetized rats. Pharmacological challenges with dopaminergic, noradrenergic, and serotonergic synaptic reuptake inhibitors supported the ability of N-MCSWV to selectively detect tonic serotonin levels in vivo. Overall, N-MCSWV is a novel voltammetric technique for analytical quantification of serotonin. It offers continuous monitoring of changes in tonic serotonin concentrations in the brain to further our understanding of the role of serotonin in normal behaviors and psychiatric disorders.

Clinical characteristics and prognostic factors of acquired haemophilia A in Korea.

INTRODUCTION: Acquired haemophilia A (AHA) treatment involves the haemostatic treatment for acute haemorrhage and immunosuppressive therapy (IST) to eradicate FVIII inhibitory antibodies. AIM: We assessed the clinical features of AHA and analysed treatment outcomes in Korea. We further identified prognostic factors affecting treatment outcomes. METHODS: Medical records of 55 patients with AHA from 18 institutions were reviewed retrospectively. Logistic and Cox regression analyses were performed to elucidate clinical factors affecting the achievement of complete remission (CR). The primary endpoint was time to CR after IST, and secondary endpoints were time to haemostasis, the achievement of CR, and overall survival (OS). RESULTS: Among the 55 patients, 50 (91%) had bleeding symptoms. Bleeding was severe in 74% of patients. Thirty-six (72%) patients received haemostatic therapy. Of the 42 patients who received IST, 23 (52%) received steroid alone, with a 52% response rate, and 10 (25%) received a combination of steroid and cyclophosphamide, with an 83% response rate. Five (16%) patients relapsed after a median duration of 220 days. There were eight deaths. In the Cox regression analysis, the FVIII inhibitor titre ≥ 20 BU/mL was the only significant prognostic factor affecting time to CR and haemostasis. No significant difference was observed in OS based on the inhibitor titre. CONCLUSION: The present study demonstrated the demographic data of AHA in Korea and showed that FVIII inhibitory antibody titre was a predictor of time to achieve CR after IST.

Prognostic Impact of Peripheral Blood T-Cell Subsets at the Time of Diagnosis on Survival in Patients with Diffuse Large B-Cell Lymphoma.

INTRODUCTION: The effects of lymphocyte subtypes, including helper (Th), natural killer (NK), and regulatory (Treg) cells, and other T-cell subtypes on treatment outcomes in diffuse large B-cell lymphoma (DLBCL) patients are not clearly established. METHODS: Among 151 consecutive patients diagnosed with DLBCL, we collected peripheral blood samples at diagnosis from 91 patients who received at least 1 cycle of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) chemotherapy and analyzed lymphocyte subsets by flow cytometry. RESULTS: DLBCL patients had a higher proportion of CD4+CD25+ Treg (p < 0.001) and lower absolute lymphocyte count than those of healthy controls. Lymphopenia at diagnosis was associated with advanced-stage disease (p = 0.001), a high-intermediate/high-risk International Prognostic Index (IPI) (p < 0.001), and older age (p = 0.060). High-intermediate/high-risk IPI, high proportion of CD3+CD4+ Th cells, and extranodal site ≥2 correlated with unfavorable prognostic factors for survival. High proportion of Th cells was associated with fewer cytotoxic T cells and NK cells at the time of diagnosis. CONCLUSION: This study showed an association between circulating lymphocyte subsets including Th cells, Tregs, and NK cells and clinical outcomes in DLBCL; however, further confirmation is needed via prospective trials.

Pegteograstim prophylaxis for chemotherapy-induced neutropenia and febrile neutropenia: a prospective, observational, postmarketing surveillance study in Korea.

PURPOSE: This observational study aimed to evaluate the safety and efficacy of pegteograstim prophylaxis in patients with lymphoma and solid malignancies. METHODS: This study was conducted at 18 sites in Korea between November 2015 and August 2018. RESULTS: In total, 611 patients (female, 61.2%) with a median age of 58 (range, 18-88) years were included. Most patients had lymphomas (n = 371, 60.7%) and breast cancer (n = 230, 37.6%) and were administered R-CHOP21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone per 21 days) (n = 284, 46.5%) and AC (doxorubicin and cyclophosphamide) (n = 177, 29.0%). The total pegteograstim dose in the 611 patients was 14,970 mg (2495 doses), with each patient receiving an average daily dose of 6.0 mg. Neutropenia grade 4 occurred in 97 patients (15.9%), and febrile neutropenia (FN) occurred in 31 patients (5.1%). Among the 611 patients, 267 patients (43.7%) developed 882 adverse events (AEs), and 11 patients (1.8%) experienced 18 adverse drug reactions (ADRs). There were 62 patients (10.2%) who experienced 81 cases of serious adverse events (SAEs), with FN and pneumonia being the most frequent at 14 and 13 episodes, respectively, in 13 patients (2.1%). Meanwhile, 1 patient (0.2%) developed 2 episodes of serious ADRs (grade 1 and grade 2 hypotension). No safety concerns in the elderly and patients with liver and/or renal disease were identified. CONCLUSION: The prophylactic use of pegteograstim might have good overall safety and efficacy in patients with lymphomas and solid malignancies in routine clinical practice, even in those who are elderly and have liver and renal diseases.