Effect of prior gestational diabetes on the risk of cardiovascular disease and death in women with type 2 diabetes: The Fremantle Diabetes Study Phase II.

BACKGROUND: To examine whether prior gestational diabetes mellitus (GDM) is associated with prevalent coronary heart disease (CHD), cerebrovascular disease (CeVD) and peripheral arterial disease (PAD), and all-cause mortality, in community-based women with type 2 diabetes. METHODS: Baseline prevalences of CHD/CeVD/PAD/prior GDM were determined in 718 females (mean ± SD age 65.5 ± 11.9 years) from the Fremantle Diabetes Study Phase II. Deaths between baseline (2008-2011) and end-2016 were ascertained. Cox regression identified predictors of mortality with GDM as a candidate variable. RESULTS: Compared to the 673 women without GDM, the 39 (5.4 %) with prior GDM were younger, more likely Aboriginal, smokers and obese, had longer diabetes duration and higher HbA1c levels, and were more dyslipidemic (P ≤ 0.046). Prevalences of CHD (24.6 versus 23.1 %), CeVD (7.5 % versus 2.6 %) and PAD (27.5 % versus 23.7 %) were not significantly different in those without versus with prior GDM (P ≥ 0.35). There were 116 deaths (16.2 %) during 6.8 ± 1.6 years of follow-up. Age, Aboriginal ethnicity, marital status, current smoking, heart rate, estimated glomerular filtration rate, CHD and PAD were independently associated with all-cause mortality (P ≤ 0.023); GDM status did not add to the most parsimonious model (P = 0.62). CONCLUSIONS: Prior GDM does not increase CVD risk or all-cause mortality in women with type 2 diabetes.

Allogeneic Disc Progenitor Cells Safely Increase Disc Volume and Improve Pain, Disability, and Quality of Life in Patients With Lumbar Disc Degeneration-Results of an FDA-Approved Biologic Therapy Randomized Clinical Trial.

BACKGROUND: Progenitor cells derived from intervertebral disc tissue demonstrated immunomodulatory and regenerative properties in preclinical studies. We report the safety and efficacy results of a US Food and Drug Administration-approved clinical trial of these cells for the treatment of symptomatic degenerative disc disease. METHODS: Sixty patients with symptomatic single-level lumbar degenerative disc disease (mean age 37.9 years, 60% men) were enrolled in a randomized, double-blinded, placebo-controlled Phase I/Phase II study at 13 clinical sites. They were randomized to receive single intradiscal injections of either low-dose cells (N = 20), high-dose cells (N = 20), vehicle alone (N = 10), or placebo (N = 10). The primary endpoint was mean visual analog scale (VAS) pain improvement >30% at 52 weeks. Disc volume was radiologically assessed. Adverse events (AEs), regardless of whether they were related to treatment, were reported. Patients were assessed at baseline and at 4, 12, 26, 52, 78, and 104 weeks posttreatment. RESULTS: At week 52, the high-dose group had a mean VAS percentage decrease from baseline (-62.8%, P = 0.0005), achieving the endpoint of back pain improvement >30%; the mean change was also significantly greater than the minimal clinically important difference of a 20-point decrease (-42.8, P = 0.001). This clinical improvement was maintained at week 104. The vehicle group had a smaller significant decrease in VAS (-52.8%, P = 0.044), while the low-dose and placebo groups showed nonsignificant improvements. Only the high-dose group had a significant change in disc volume, with mean increases of 249.0 mm3 (P = 0.028) at 52 weeks and 402.1 mm3 (P = 0.028) at 104 weeks. A minority of patients (18.3%) reported AEs that were severe. Overall, 6.7% of patients experienced serious AEs, all in the vehicle (n = 1) or placebo (n = 3) groups, none treatment related. CONCLUSIONS: High-dose allogeneic disc progenitor cells produced statistically significant, clinically meaningful improvements in back pain and disc volume at 1 year following a single intradiscal injection and were safe and well tolerated. These improvements were maintained at 2 years post-injection. CLINICAL TRIAL REGISTRATION: NCT03347708-Study to Evaluate the Safety and Preliminary Efficacy of Injectable Disc Cell Therapy, a Treatment for Symptomatic Lumbar Intervertebral Disc Degeneration.

Buried Autologous Breast Reconstruction: Outcomes and Technical Considerations.

The purpose of this study is to compare outcomes in patients undergoing buried and non-buried free flaps for breast reconstruction, in addition to evaluating the safety and reliability of venous flow couplers. A retrospective review was performed of all patients undergoing free flap breast reconstruction between 2013 and 2023. The primary outcomes were free flap failure, complications and the number of procedures required to complete the reconstructive journey. A total of 322 flaps were performed in 254 consecutive patients, with 47.5% (n = 153) being buried and 52.0% (n = 169) being non-buried reconstructions. The most common flap of choice being deep inferior epigastric artery perforator flaps (81.9%) followed by profunda artery perforator flaps (14.3%). There was no significant difference between the two groups in complications, including flap failure (buried 2.0% vs. non-buried 1.8% p = 0.902). There was a significant reduction in the number of procedures required to complete the reconstructive journey, with 52.2% (n = 59) of patients undergoing single-stage breast reconstruction in the buried group compared with only 25.5% (n = 36) in the non-buried group (p < 0.001). Two (0.6%) patients experienced a false negative in which the signal of the flow coupler was lost but the flap was perfused during re-exploration. No flap losses occurred without being identified in advance by a loss of audible venous flow signal. Buried free flap breast reconstruction is safe and requires fewer operations to complete patients' reconstructive journey. Flow couplers are a safe and effective method of monitoring buried free flaps in breast reconstruction.

Not enough known about fenofibrate's kidney effects in people with Type 2 diabetes.

Globally ≈10% of adults have diabetes, with 80% in disadvantaged regions, hence low-cost renoprotective agents are desirable. Fenofibrate demonstrated microvascular benefits in several cardiovascular end-point diabetes trials, but knowledge of effects in late-stage kidney disease is limited. We report new FIELD substudy data and call for further kidney outcomes data.

Prevalence and prognostic significance of cardiac autonomic neuropathy in community-based people with type 2 diabetes: the Fremantle Diabetes Study Phase II.

BACKGROUND: There is a paucity of contemporary data on the prevalence and prognostic significance of cardiac autonomic neuropathy (CAN) from community-based cohorts with type 2 diabetes assessed using gold standard methods. The aim of this study was to assess these aspects of CAN in the longitudinal observational Fremantle Diabetes Study Phase II (FDS2). METHODS: FDS2 participants were screened at baseline using standardised cardiovascular reflex tests (CARTs) of heart rate variation during deep breathing, Valsalva manoeuvre and standing. CAN (no/possible/definite) was assessed from the number of abnormal CARTs. Multinomial regression identified independent associates of CAN status. Cox proportional hazards modelling determined independent baseline predictors of incident heart failure (HF) and ischaemic heart disease (IHD), and all-cause mortality. RESULTS: Of 1254 participants assessed for CAN, 86 (6.9%) were outside CART age reference ranges and valid CART data were unavailable for 338 (27.0%). Of the remaining 830 (mean age 62.3 years, 55.3% males, median diabetes duration 7.3 years), 51.0%, 33.7% and 15.3% had no, possible or definite CAN, respectively. Independent associates of definite CAN (longer diabetes duration, higher body mass index and resting pulse rate, antidepressant and antihypertensive therapies, albuminuria, distal sensory polyneuropathy, prior HF) were consistent with those reported previously. In Kaplan-Meier analysis, definite CAN was associated with a lower likelihood of incident IHD and HF versus no/possible CAN (P < 0.001) and there was a graded increase in all-cause mortality risk from no CAN to possible and definite CAN (P < 0.001). When CAN category was added to the most parsimonious models, it was not a significant independent predictor of IHD (P ≥ 0.851) or HF (P ≥ 0.342). Possible CAN (hazard ratio (95% CI) 1.47 (1.01, 2.14), P = 0.046) and definite CAN (2.42 (1.60, 3.67), P < 0.001) increased the risk of all-cause mortality versus no CAN. CONCLUSIONS: Routine screening for CAN in type 2 diabetes has limited clinical but some prognostic value.

Pulmonary Function Trajectories Over 6 Years and Their Determinants in Type 2 Diabetes: The Fremantle Diabetes Study Phase II.

OBJECTIVE: To assess whether there are clusters of people with type 2 diabetes with distinct temporal profiles of lung function changes and characteristics. RESEARCH DESIGN AND METHODS: Group-based trajectory modeling (GBTM) identified groups of participants with type 2 diabetes from the community-based observational Fremantle Diabetes Study Phase II (FDS2) who had at least two biennial measurements of forced expiratory volume in 1 s as a percentage of predicted (FEV1%pred) over 6 years. Independent associates of group membership were assessed using multinomial regression. RESULTS: Of 1,482 potential FDS2 participants, 1,074 (72.5%; mean age, 65.2 years; 45.5% female; median diabetes duration, 8.0 years) were included in the modeling. The best fitting GBTM model identified four groups categorized by FEV1%pred trajectory: high (19.5%; baseline FEV1%pred, 106.5 ± 9.5%; slope 0%/year), medium (47.7%; FEV1%pred, 87.3 ± 8.7%; slope, -0.32%/year), low (25.0%; baseline FEV1%pred, 68.9 ± 9.8%; slope, -0.72%/year), and very low (7.9%; baseline FEV1%pred, 48.8 ± 9.6%; slope, -0.68%/year). Compared with the high group, the other groups were characterized by nonmodifiable and modifiable risk factors associated with lung function decline in the general population (including ethnicity, marital status, smoking, obesity, coronary heart disease, and chronic respiratory disease). The main, diabetes-specific, significant predictor of group membership was a higher HbA1c in the very low group. There was a graded increase in mortality from 6.7% in the high group to 22.4% in the very low group. CONCLUSIONS: Measurement of lung function in type 2 diabetes could help optimize clinical management and improve prognosis, including addressing glycemic control in those with a very low FEV1%pred.

Use of a type 1 genetic risk score for classification of diabetes type in young Australian adults: the Fremantle Diabetes Study Phase II.

The applicability of a UK-validated genetic risk score (GRS) was assessed in 158 participants in the Fremantle Diabetes Study Phase II diagnosed between 20 and <40 years of age with type 1 or type 2 diabetes or latent autoimmune diabetes of adults (LADA). For type 1 versus type 2/LADA, the area under the receiver operating characteristic curve (AUC) was highest for serum C-peptide (0.93) and lowest for the GRS (0.66). Adding age at diagnosis and body mass index to C-peptide increased the AUC minimally (0.96). The GRS appears of modest diabetes diagnostic value in young Australians.

Temporal Trends in Distal Symmetric Polyneuropathy in Type 2 Diabetes: The Fremantle Diabetes Study.

CONTEXT: Macrovascular outcomes in type 2 diabetes have improved over recent decades. There are scant equivalent distal symmetric polyneuropathy (DSPN) data. OBJECTIVE: This work aimed to characterize temporal changes in DSPN prevalence and incidence rates (IRs) in community-based Australians. METHODS: An observational study was conducted among an urban population. Participants included individuals with type 2 diabetes from the Fremantle Diabetes Study phases I (FDS1; n = 1296 recruited 1993-1996) and II (FDS2; n = 1509 recruited 2008-2011). Main outcome measures included Michigan Neuropathy Screening Instrument (MNSI) clinical grading. RESULTS: DSPN prevalence by 8-point MNSI was 30.8% (FDS1) and 58.9% (FDS2; P < .001), and by 6-point (excluding foot appearance) and 2-point (biothesiometry alone) MNSI was 37.5% and 35.7% (P = .336), and 33.8% and 38.7% (P = .011), respectively. Given between-phase changes in appearance assessment, 8-point MNSI data were not analyzed further. In multivariable analysis, FDS2 vs FDS1 participation was associated with 6-point (odds ratio (95% CI) 0.68 (0.56-0.83); P < .001) but not 2-point (0.90 (0.74-1.11); P = .326) MNSI DSPN prevalence. Four-year DSPN IRs (95% CI) for 6-point MNSI were 13.6 (12.0-15.4) and 17.6 (15.9-19.4)/100 person-years in FDS1 and FDS2, respectively (IR ratio [IRR] 1.31 [1.12-1.55]; P < .001), and for 2-point MNSI were 13.9 (12.3-15.8) and 7.4 (16.3-8.6/100 person-years; IRR 0.53 [0.43-0.64]; P < .001). FDS2 vs FDS1 independently predicted incident DSPN for 6-point (hazard ratio [95% CI] 1.25 [1.06-1.48]; P = .009) and 2-point (0.42 [0.33-0.55]; P < .001) MNSI. CONCLUSION: DSPN prevalence was lower or equivalent in FDS2 vs FDS1, and its incidence was greater or lower, in multivariable models depending on the MNSI features used.

Serum vitamin B12, distal symmetrical polyneuropathy and anaemia in type 2 diabetes: the Fremantle Diabetes Study Phase 2.

BACKGROUND: There are limited data relating to the effects of metformin-associated vitamin B12 deficiency on the risk of distal symmetrical polyneuropathy (DSPN) and megaloblastic anaemia in well-characterised community-based cohorts. AIMS: To assess inter-relationships between metformin therapy, vitamin B12 deficiency assessed using serum active B12 concentrations, and DSPN and anaemia in 1492 Fremantle Diabetes Study Phase 2 (FDS2) participants with type 2 diabetes. METHODS: Prevalence rates of vitamin B12 deficiency (total <80 pmol/L, active <23 pmol/L) and borderline deficiency (total ≥80 and ≤200 pmol/L, active ≥23 and ≤35 pmol/L) were determined using baseline sera. The relationship between vitamin B12 status and both DSPN and anaemia was assessed using multivariable analyses. RESULTS: Most FDS2 participants (94.4%) were vitamin B12 replete (total serum concentration >200 pmol/L, active >35 pmol/L), 2.0% were deficient (total <80 pmol/L, active <23 pmol/L) and the remainder (3.6%) borderline. Although metformin treatment increased the odds of deficiency (4.2%, 3.1% borderline) in a dose-dependent fashion (odds ratio (95% confidence interval) 39.4 (4.90-316) for >2000 mg daily compared with no treatment; P < 0.001), there was no significant association between vitamin B12 status and DSPN, anaemia (haemoglobin ≤130 g/L males, ≤120 g/L females), haemoglobin concentration or mean corpuscular volume (P ≥ 0.147). Metformin increased the likelihood of anaemia, especially at high doses, independent of vitamin B12 deficiency. CONCLUSIONS: Since nutritional sources likely attenuate metformin-associated vitamin B12 malabsorption and its clinical sequelae in developed countries such as Australia, there is no need for routine/opportunistic serum vitamin B12 screening in metformin-treated patients.

The relationship between glycated haemoglobin and blood glucose-lowering treatment trajectories in type 2 diabetes: The Fremantle Diabetes Study Phase II.

AIMS: To examine the relationships between glycaemia and treatment complexity over 6 years in well-characterized community-based people with type 2 diabetes. MATERIALS AND METHODS: Fremantle Diabetes Study Phase II participants who had type 2 diabetes with glycated haemoglobin (HbA1c) and blood glucose-lowering therapy (BGLT) data over 6 years were included. Group-based multi-trajectory modelling identified combined HbA1c/BGLT trajectory subgroups for diabetes durations of ≤1.0 year (Group 1; n = 160), >1.0 to 10.0 years (Group 2; n = 382;) and >10.0 years (Group 3; n = 357). Multinomial regression was used to identify baseline associates of subgroup membership. RESULTS: The optimum numbers of trajectory subgroups were three in Group 1 (low, medium, high) and four in Groups 2 and 3 (low, low/high medium, high). Each low trajectory subgroup maintained a mean HbA1c concentration of <53 mmol/mol (<7.0%) on lifestyle measures, or monotherapy (Group 3). All five medium subgroups had stable HbA1c trajectories at <58 mmol/mol (<7.5%) but required increasing oral BGLT, or insulin (Group 3, high medium). The Group 1 high subgroup showed a falling then increasing HbA1c with steady progression to insulin. The high subgroups in Groups 2 and 3 showed stable HbA1c profiles at means of approximately 64 mmol/mol (8.0%) and 86 mmol/L (10.0%), respectively, on insulin. Non-Anglo Celt ethnicity, central obesity and hypertriglyceridaemia were strongly associated with Group 1 high subgroup membership. Younger age at diagnosis and central obesity were independent associates of the most adverse HbA1c trajectories in Groups 2 and 3. CONCLUSIONS: These data demonstrate diabetes duration-dependent heterogeneity in glycaemic and treatment profiles and related clinical and laboratory variables, which have implications for management.

The Relationship between Pulmonary Artery Pressure and Mortality in Type 2 Diabetes: A Fremantle Diabetes Study Phase II and National Echocardiographic Database of Australia Data Linkage Study.

An elevated estimated right ventricular systolic pressure (eRVSP) identified on echocardiography is present in one-third of individuals with type 2 diabetes, but its prognostic significance is unknown. To assess the relationship between eRVSP and mortality, prospective data from 1732 participants in the Fremantle Diabetes Study Phase II were linked with the National Echocardiographic Database of Australia. Of this cohort, 416 (mean age 70.6 years, 47.4% males) had an eRVSP measured and 381 (91.4%) had previously confirmed type 2 diabetes. Receiver- operating characteristic analysis of the relationship between eRVSP and all-cause mortality was conducted. Survival analyses were performed for participants with type 2 diabetes diagnosed before first measured eRVSP (n = 349). Cox regression identified clinical and echocardiographic associates of all-cause mortality. There were 141 deaths (40.4%) during 2348 person-years (mean ± SD 6.7 ± 4.0 years) of follow-up. In unadjusted Kaplan-Meier analysis, mortality rose with higher eRVSP (log-rank test, p < 0.001). In unadjusted pairwise comparisons, eRVSP >30 to 35, >35 to 40, and >40 mmHg had significantly increased mortality compared with eRVSP ≤ 30 mmHg (p = 0.025, p = 0.001, p < 0.001, respectively). There were 50 deaths in 173 individuals (29.1%) with eRVSP ≤ 30 mmHg, and 91 in 177 (51.4%) with eRVSP > 30 mmHg (log-rank test, p < 0.001). In adjusted models including age, Aboriginal descent, Charlson Comorbidity Index ≥ 3 and left heart disease, eRVSP > 30 mmHg predicted a two-fold higher all-cause mortality versus ≤ 30 mmHg. An eRVSP > 30 mmHg predicts increased all-cause mortality in type 2 diabetes. Where available, eRVSP could inform type 2 diabetes outcome models.

The Clinical Relevance of Diabetes Distress versus Major Depression in Type 2 Diabetes: A Latent Class Analysis from the Fremantle Diabetes Study Phase II.

BACKGROUND: The nosological position and clinical relevance of the concept of diabetes distress (DD) are uncertain. The aim of this study was to use latent class analysis (LCA) to categorise classes of people with type 2 diabetes and to compare their characteristics. METHODS: Data from 662 participants in the longitudinal observational Fremantle Diabetes Study Phase II were analysed. LCA identified latent subgroups based on individual responses to the Patient Health Questionnaire-9, the Generalised Anxiety Disorder Scale, and the 5-item Problem Areas in Diabetes Scale. RESULTS: Four classes were identified: Class 1 (65.7%, no symptoms), Class 2 (14.0%, DD), Class 3 (12.6%, subsyndromal depression (SSD)), and Class 4 (7.6%, major depression (MD)). Multinomial regression analysis with Class 1 as reference showed significant associations between the DD class and Southern European and Asian ethnic background, HbA1c, and BMI. The SSD class was significantly associated with HbA1c, cerebrovascular disease, and coronary heart disease (CHD). The MD class had significant associations with age (inversely), Southern European ethnic background, HbA1c, BMI, and CHD. In conclusion, LCA identified a pure DD group comprising 14.0% of participants. The only variable uniquely associated with the DD class was Asian ethnic background. CONCLUSION: Although identification of DD may have some utility in assessing the psychological wellbeing of individuals with type 2 diabetes, it adds little to the assessment of depressive disorder and its significant clinical sequalae.

Ultrafast Time Dynamics of Plasmonic Fractional Orbital Angular Momentum.

The creation and manipulation of optical vortices, both in free space and in two-dimensional systems such as surface plasmon polaritons (SPPs), has attracted widespread attention in nano-optics due to their robust topological structure. Coupled with strong spatial confinement in the case of SPPs, these plasmonic vortices and their underlying orbital angular momentum (OAM) have promise in novel light-matter interactions on the nanoscale with applications ranging from on-chip particle manipulation to tailored control of plasmonic quasiparticles. Until now, predominantly integer OAM values have been investigated. Here, we measure and analyze the time evolution of fractional OAM SPPs using time-resolved two-photon photoemission electron microscopy and near-field optical microscopy. We experimentally show the field's complex rotational dynamics and observe the beating of integer OAM eigenmodes at fractional OAM excitations. With our ability to access the ultrafast time dynamics of the electric field, we can follow the buildup of the plasmonic fractional OAM during the interference of the converging surface plasmons. By adiabatically increasing the phase discontinuity at the excitation boundary, we track the total OAM, leading to plateaus around integer OAM values that arise from the interplay between intrinsic and extrinsic OAM.

Metal-on-Metal Hip Arthroplasty: A Comprehensive Review of the Current Literature.

Metal-on-metal (MoM) total hip arthroplasty has been widely used since the end of the 20th century, although rates have now decreased due to concerns regarding adverse reactions and failure rates. The MoM implant has been replaced with other materials, such as ceramic-on-ceramic (CoC) and metal-on-polyethylene (MoP). This literature review looks at the past and present use of MoM prostheses to assess whether the turn away from MoM use is justified. Online literature searches were performed on PubMed, Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science online databases using the search terms "MoM and (ARMD and ALVAL)" (ARMD: adverse reaction to metal debris; ALVAL: aseptic lymphocyte-dominant vasculitis-associated lesion). A total of 64 relevant titles were included in the review. Although risk factors for adverse reactions and the causes of ARMD are generally agreed upon, more work is required to further understand the specific thresholds of blood metal ion levels that can be used to consistently identify ARMD and excessive metal wear-debris in patients who have not had their MoM implants revised. Metal-on-metal devices are not an acceptable option for total hip arthroplasties (THAs) in their current formulation due to the high rate and risk of ARMD. Some MoM hip resurfacing operations are appropriate for very carefully selected patients who are fully aware of the risks posed by the implant. It is recommended that device-specific thresholds for metal ion levels be developed to identify patients at risk of ARMD locally and systemically while using auxiliary tools to assist diagnosis, such as metal artefact reduction sequences (MARS)-MRI and hip scoring tools. Further work should investigate device-specific blood metal ion levels, the systemic effects of raised metal ion concentrations secondary to MoM arthroprosthetic wear, and the potential risks of ARMD caused by wear from tapered stems (including the implications this has for patients with CoC and MoP prostheses).

Chimeric antigen receptor T cells to target CD79b in B-cell lymphomas.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent and durable effects in B-cell malignancies. However, antigen loss or downregulation is a frequent cause of resistance. Here, we report development of a novel CAR T-cell therapy product to target CD79b, a pan B-cell antigen, widely expressed in most B-cell lymphomas. METHODS: We generated a novel anti-CD79b monoclonal antibody by hybridoma method. The specificity of the antibody was determined by testing against isogenic cell lines with human CD79b knock-in or knock-out. A single-chain variable fragment derived from the monoclonal antibody was used to make a panel of CD79b-targeting CAR molecules containing various hinge, transmembrane, and co-stimulatory domains. These were lentivirally transduced into primary T cells and tested for antitumor activity in in vitro and in vivo B-cell lymphoma models. RESULTS: We found that the novel anti-CD79b monoclonal antibody was highly specific and bound only to human CD79b and no other cell surface protein. In testing the various CD79b-targeting CAR molecules, superior antitumor efficacy in vitro and in vivo was found for a CAR consisting CD8α hinge and transmembrane domains, an OX40 co-stimulatory domain, and a CD3ζ signaling domain. This CD79b CAR specifically recognized human CD79b-expressing lymphoma cell lines but not CD79b knock-out cell lines. CD79b CAR T cells, generated from T cells from either healthy donors or patients with lymphoma, proliferated, produced cytokines, degranulated, and exhibited robust cytotoxic activity in vitro against CD19+ and CD19- lymphoma cell lines and patient-derived lymphoma tumors relapsing after prior CD19 CAR T-cell therapy. Furthermore, CD79b CAR T cells were highly efficient at eradicating pre-established lymphoma tumors in vivo in three aggressive lymphoma xenograft models, including two cell line-derived xenografts and one patient-derived xenograft. Notably, these CAR T cells did not demonstrate any significant tonic signaling activity or markers of exhaustion. CONCLUSION: Our results indicated that this novel CD79b CAR T-cell therapy product has robust antitumor activity against B-cell lymphomas. These results supported initiation of a phase 1 clinical trial to evaluate this product in patients with relapsed or refractory B-cell lymphomas.

Mosquito surveillance on U.S military installations as part of a Japanese encephalitis virus detection program: 2016 to 2021.

Japanese encephalitis virus (JEV) continues to circulate throughout Southeast Asia and the Western Pacific where approximately 3 billion people in 24 countries are at risk of infection. Surveillance targeting the mosquito vectors of JEV was conducted at four military installations on Okinawa, Japan, between 2016 and 2021. Out of a total of 10,426 mosquitoes from 20 different species, zero were positive for JEV. The most abundant mosquito species collected were Aedes albopictus (36.4%) followed by Culex sitiens (24.3%) and Armigeres subalbatus (19%). Statistically significant differences in mosquito species populations according to location were observed. Changes in land use over time appear to be correlated with the species and number of mosquitoes trapped in each location. JEV appears to be absent from mosquito populations on Okinawa, but further research on domestic pigs and ardeid birds is warranted.

Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy.

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve fibers versus controls. Further, the severity of transmural innervation gradients was correlated with VAs. Transmural innervation gradients were also identified in human left ventricular free wall samples from DCM versus controls. We investigated mechanisms underlying this relationship by in silico studies in 1D, 2D, and 3D models of failing and normal human hearts, finding that arrhythmogenesis increased as heterogeneity in sympathetic innervation worsened. Specifically, both DCM-induced myocyte electrical remodeling and spatially inhomogeneous innervation gradients synergistically worsened arrhythmogenesis. Thus, heterogeneous innervation gradients in DCM promoted arrhythmogenesis. Restoration of homogeneous sympathetic innervation in the failing heart may reduce VAs.

Temporal trends in chronic complications of diabetes by sex in community-based people with type 2 diabetes: the Fremantle Diabetes Study.

BACKGROUND: Whether recent reductions in cardiovascular disease (CVD) events and mortality in type 2 diabetes apply equally to both sexes is largely unknown. The aim of this study was to characterize temporal changes in CVD events and related outcomes in community-based male and female Australian adults with type 2 diabetes or without known diabetes. METHODS: Participants from the longitudinal observational Fremantle Diabetes Study Phases I (FDS1; n = 1291 recruited 1993-1996) and II (FDS2; n = 1509 recruited 2008-2011) and four age-, sex- and postcode-matched individuals without diabetes (FDS1 n = 5159; FDS2 n = 6036) were followed for first myocardial infarction, stroke, heart failure hospitalization, lower extremity amputation, CVD death and all-cause mortality. Five-year incidence rates (IRs) for males versus females in FDS1 and FDS2 were calculated, and IR ratios (IRRs) derived. RESULTS: The FD1 and FDS2 participants were of mean age 64.0 and 65.4 years, respectively, and 48.7% and 51.8% were males. For type 2 diabetes, IRRs for all endpoints were 11-62% lower in FDS2 than FDS1 for both sexes. For participants without diabetes, IRRs were 8-56% lower in FDS2 versus FDS1 apart from stroke in females (non-significantly 41% higher). IRRs for males versus females across FDS phases were not significantly different for participants with type 2 diabetes or those without diabetes (P-values for male * FDS2 interaction ≥ 0.0.083 adjusted for age). For risk factors in participants with type 2 diabetes, greater improvements between FDS1 and FDS2 in smoking rates in males were offset by a greater reduction in systolic blood pressure in females. CONCLUSIONS: The incidence of chronic complications in Australians with type 2 diabetes and without diabetes has fallen similarly in both sexes over recent decades, consistent with comparably improved overall CVD risk factor management.