Low-Intensity Pulsed Ultrasound Versus Sham in the Treatment of Operatively Managed Scaphoid Nonunions: The SNAPU Randomized Controlled Trial.

BACKGROUND: The primary goal after open reduction and internal fixation of an established scaphoid nonunion is to achieve union. Low-intensity pulsed ultrasound (LIPUS) has been reported to increase the rate of union and to decrease the time to union for multiple fractures and nonunions in clinical and animal models. The evidence for LIPUS in the treatment of scaphoid nonunion, however, is sparse. The aim of this study was to assess whether active LIPUS (relative to sham LIPUS) accelerates the time to union following surgery for scaphoid nonunion. METHODS: Adults with a scaphoid nonunion indicated for surgery were recruited for a multicenter, prospective, double-blinded randomized controlled trial. After surgery, patients self-administered activated or sham LIPUS units beginning at their first postoperative visit. The primary outcome was the time to union on serial computed tomography (CT) scans starting 6 to 8 weeks postoperatively. Secondary outcomes included patient-reported outcome measures, range of motion, and grip strength. RESULTS: A total of 142 subjects completed the study (69 in the active LIPUS group and 73 in the sham group). The average age was 27 years, and the cohort was 88% male. There was no difference in time to union (p = 0.854; hazard ratio, 0.965; 95% confidence interval, 0.663 to 1.405). Likewise, there were no differences between the active LIPUS and sham groups with respect to any of the secondary outcomes, except for wrist flexion at baseline (p = 0.008) and at final follow-up (p = 0.043). CONCLUSIONS: Treatment with LIPUS had no effect on reducing time to union in patients who underwent surgical fixation of established scaphoid nonunions. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

The Impact of Behavior Change Counseling Delivered via a Digital Health Tool Versus Routine Care Among Adolescents With Obesity: Pilot Randomized Feasibility Study.

BACKGROUND: Youth overweight and obesity is a public health crisis and increases the risk of poor cardiovascular health (CVH) and chronic disease. Health care providers play a key role in weight management, yet few tools exist to support providers in delivering tailored evidence-based behavior change interventions to patients. OBJECTIVE: The goal of this pilot randomized feasibility study was to determine the feasibility of implementing the Patient-Centered Real-Time Intervention (PREVENT) tool in clinical settings, generate implementation data to inform scale-up, and gather preliminary effectiveness data. METHODS: A pilot randomized clinical trial was conducted to examine the feasibility, implementation, and preliminary impact of PREVENT on patient knowledge, motivation, behaviors, and CVH outcomes. The study took place in a multidisciplinary obesity management clinic at a children's hospital within an academic medical center. A total of 36 patients aged 12 to 18 years were randomized to use PREVENT during their routine visit (n=18, 50%) or usual care control (n=18, 50%). PREVENT is a digital health tool designed for use by providers to engage patients in behavior change education and goal setting and provides resources to support change. Patient electronic health record and self-report behavior data were collected at baseline and 3 months after the intervention. Implementation data were collected via PREVENT, direct observation, surveys, and interviews. We conducted quantitative, qualitative, and mixed methods analyses to evaluate pretest-posttest patient changes and implementation data. RESULTS: PREVENT was feasible, acceptable, easy to understand, and helpful to patients. Although not statistically significant, only PREVENT patients increased their motivation to change their behaviors as well as their knowledge of ways to improve heart health and of resources. Compared to the control group, PREVENT patients significantly improved their overall CVH and blood pressure (P<.05). CONCLUSIONS: Digital tools can support the delivery of behavior change counseling in clinical settings to increase knowledge and motivate patients to change their behaviors. An appropriately powered trial is necessary to determine the impact of PREVENT on CVH behaviors and outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT06121193; https://www.clinicaltrials.gov/study/NCT06121193.

Intensive Glycemic Management Is Associated With Reduced Retinal Structure Abnormalities on Ocular Coherence Tomography in the DCCT/EDIC Study.

OBJECTIVE: To investigate quantitative and qualitative changes in retinal structure using optical coherence tomography (OCT) and their associations with systemic or other risk factors in individuals with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, OCT images were obtained during study years 25-28 (2019-2022) in 937 participants; 54% and 46% were from the original intensive (INT) and conventional (CONV) glycemic management treatment groups, respectively. RESULTS: Average age for participants was 61 years old, diabetes duration 39 years, and HbA1c 7.6%. Participants originally in the CONV group were more likely to have disorganization of retinal inner layers (DRIL) (CONV 27.3% vs. INT 18.7%; P = 0.0003), intraretinal fluid (CONV 24.4% vs. INT 19.2%; P = 0.0222), and intraretinal cysts (CONV 20.8% vs. INT 16.6%; P = 0.0471). In multivariable models, sex, age, smoking, mean updated systolic blood pressure, and history of "clinically significant" macular edema (CSME) and of anti-VEGF treatment were independently associated with changes in central subfield thickness, while HbA1c, BMI, and history of CSME and of ocular surgery were associated with DRIL. Visual acuity (VA) decline was associated with significant thinning of all retinal subfields except for the central and inner nasal subfields. CONCLUSIONS: Early intensive glycemic management in T1D is associated with a decreased risk of DRIL. This important morphological abnormality was associated with a history of macular edema, a history of ocular surgery, and worse VA. This study reveals benefits of intensive glycemic management on the retina beyond features detected by fundus photographs and ophthalmoscopy.

Prevalence of Distal Symmetrical Polyneuropathy by Diabetes Prevention Program Treatment Group, Diabetes Status, Duration of Diabetes, and Cumulative Glycemic Exposure.

OBJECTIVE: To assess associations between distal symmetric polyneuropathy (DSPN) and Diabetes Prevention Program (DPP) treatment groups, diabetes status or duration, and cumulative glycemic exposure approximately 21 years after DPP randomization. RESEARCH DESIGN AND METHODS: In the DPP, 3,234 adults ≥25 years old at high risk for diabetes were randomized to an intensive lifestyle (ILS), metformin, or placebo intervention to prevent diabetes. After the DPP ended, 2,779 joined the Diabetes Prevention Program Outcomes Study (DPPOS). Open-label metformin was continued, placebo was discontinued, ILS was provided in the form of semiannual group-based classes, and all participants were offered quarterly lifestyle classes. Symptoms and signs of DSPN were assessed in 1,792 participants at DPPOS year 17. Multivariable logistic regression models were used to evaluate DSPN associations with treatment group, diabetes status/duration, and cumulative glycemic exposure. RESULTS: At 21 years after DPP randomization, 66% of subjects had diabetes. DSPN prevalence did not differ by initial DPP treatment assignment (ILS 21.5%, metformin 21.5%, and placebo 21.9%). There was a significant interaction between treatment assignment to ILS and age (P < 0.05) on DSPN. At DPPOS year 17, the odds ratio for DSPN in comparison with ILS with placebo was 17.4% (95% CI 3.0, 29.3) lower with increasing 5-year age intervals. DSPN prevalence was slightly lower for those at risk for diabetes (19.6%) versus those with diabetes (22.7%) and was associated with longer diabetes duration and time-weighted HbA1c (P values <0.001). CONCLUSIONS: The likelihood of DSPN was similar across DPP treatment groups but higher for those with diabetes, longer diabetes duration, and higher cumulative glycemic exposure. ILS may have long-term benefits on DSPN for older adults.

Major adverse events in youth-onset type 1 and type 2 diabetes: The SEARCH and TODAY studies.

AIMS: To determine contemporary incidence rates and risk factors for major adverse events in youth-onset T1D and T2D. METHODS: Participant interviews were conducted once during in-person visits from 2018 to 2019 in SEARCH (T1D: N = 564; T2D: N = 149) and semi-annually from 2014 to 2020 in TODAY (T2D: N = 495). Outcomes were adjudicated using harmonized, predetermined, standardized criteria. RESULTS: Incidence rates (events per 10,000 person-years) among T1D participants were: 10.9 ophthalmologic; 0 kidney; 11.1 nerve, 3.1 cardiac; 3.1 peripheral vascular; 1.6 cerebrovascular; and 15.6 gastrointestinal events. Among T2D participants, rates were: 40.0 ophthalmologic; 6.2 kidney; 21.2 nerve; 21.2 cardiac; 10.0 peripheral vascular; 5.0 cerebrovascular and 42.8 gastrointestinal events. Despite similar mean diabetes duration, complications were higher in youth with T2D than T1D: 2.5-fold higher for microvascular, 4.0-fold higher for macrovascular, and 2.7-fold higher for gastrointestinal disease. Univariate logistic regression analyses in T1D associated age at diagnosis, female sex, HbA1c and mean arterial pressure (MAP) with microvascular events. In youth-onset T2D, composite microvascular events associated positively with MAP and negatively with BMI, however composite macrovascular events associated solely with MAP. CONCLUSIONS: In youth-onset diabetes, end-organ events were infrequent but did occur before 15 years diabetes duration. Rates were higher and had different risk factors in T2D versus T1D.

Ligament Sparing Elbow Hemiarthroplasty: A Novel Technique for the Management of Distal Humeral Fractures.

Intra-articular distal humerus fractures present various challenges with a wide array of treatment options. Open reduction internal fixation remains the treatment of choice. In older patient populations with poor bone quality and short-end segment fractures with articular comminution, open reduction internal fixation, however, may bring on unsurmountable technical challenges. Total elbow arthroplasty and elbow hemiarthroplasty (EHA) may offer superior functional outcomes in these cases. During EHA for fractures, the medial and lateral columns are reconstructed with the collateral ligaments to restore elbow stability. We hypothesize that in coronal sheer fracture patterns where the columns are intact, maintaining the native collateral ligaments and columns will provide both an anatomic and stable elbow joint. We introduce the ligament sparing EHA technique for unreconstructible coronal shear fractures. We describe this novel technique and compare our postoperative outcomes in 2 patients who underwent this surgery to those described in the literature. The postoperative Disabilities of the Arm, Shoulder, and Hand scores for the 2 patients were 13.8 and 10.3, respectively. The Mayo Elbow Performance Score for the 2 patients were 80 and 85, respectively. The operative arm presented a grip strength of 82% and 89% when compared with the contralateral arm, for the patients respectively. The range of motion varied between 78% and 100% of the contralateral arm for both patients. Although our results are promising and the ligament sparing EHA technique may be a more anatomic option in certain fracture patterns, further research with larger cohorts and multiple surgeons is needed to reinforce our results.

Neuropathic Pain With and Without Diabetic Peripheral Neuropathy in Type 1 Diabetes.

OBJECTIVE: Diabetic peripheral neuropathy (DPN) is common; however, the features and burden of neuropathic pain (NP) in type 1 diabetes (T1D) are poorly understood. We evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for NP during long-term follow-up of participants with T1D. RESEARCH DESIGN AND METHODS: The Michigan Neuropathy Screening Instrument (MNSI) was administered annually (1994-2020) for 1,324 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. NP with clinical signs of DPN (NP DPN+) was defined according to self-reported NP plus an examination score >2, while NP without clinical signs of DPN (NP DPN-) was defined according to self-reported NP and an examination score ≤2. RESULTS: At EDIC year 1, median age for participants was 36 years (interquartile range 30, 41), diabetes duration 13 years (10, 18), and HbA1c 7.9% (7.2, 8.9). At year 26 (median diabetes duration 39 years), cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs. 46% NP DPN-). NP prevalence was 20% at 26 years (11% NP DPN+ and 9% NP DPN-), suggesting frequent remission. Annualized remission rates were similar regardless of pain medication use. In addition to HbA1c, female sex was associated with NP DPN-. CONCLUSIONS: NP incidence in T1D was high and frequently occurred in the absence of clinical signs of neuropathy, as assessed with the MNSI. Pain remission was not explained by pain medication use. Effective clinical strategies for identification and management are needed.

The Slip and Fall Index: Assessing the risk of slipping and falling on ice.

OBJECTIVES: Canadians are at an increased risk of outdoor slip and fall accidents during periods of ice and snow. The aim of this study was to create an index to alert the public of slippery outdoor conditions and promote pedestrian safety. METHODS: Emergency department (ED) presentations from the four adult hospitals in Calgary, Alberta, Canada, over an 11-year period (January 2008‒December 2018) were extracted and filtered using the ICD-10 code W00 (fall due to ice and snow). Multivariable dispersion-corrected Poisson regression models were used to determine the variables most predictive of these presentations. Month of year, the presence of ice, snow on ground (per 10 cm), and interactions between ice and snow, all up to 3 days prior, were used to create the Slip and Fall Index (SFI). RESULTS: The dataset included 14,977 slip and fall on ice/snow ED presentations. Females (57.36%, n = 8591) accounted for more presentations than males (42.64%, n = 6386). All months had a significant effect, either being predictive or protective of slip and falls on ice/snow. Current-day ice, snow on ground, and ice up to 3 days prior were predictive of increased presentations. Month and measurements of ice and snow can be input into the SFI, which generates the level of daily risk. CONCLUSION: The SFI is the first Canadian index with the purpose of measuring the risk of having a slip and fall accident on ice/snow.

RéSUMé: OBJECTIFS: Les Canadiennes et les Canadiens courent un risque accru de glissades et de chutes accidentelles à l'extérieur en période de glace et de neige. Notre étude visait à créer un indice pour avertir le public des conditions glissantes à l'extérieur et promouvoir la sécurité des piétons. MéTHODE: Les visites aux services des urgences (SU) des quatre hôpitaux pour adultes de Calgary (Alberta), au Canada, sur une période de 11 ans (janvier 2008‒décembre 2018) ont été extraites et filtrées à l'aide du code W00 (chute due à la glace et à la neige) de la CIM-10. Nous avons utilisé des modèles de régression de Poisson multivariés avec correction de la surdispersion pour déterminer les variables les plus susceptibles de prédire ces visites. Le mois de l'année, la présence de glace ou de neige au sol (par tranche de 10 cm) et les interactions entre la glace et la neige, tout cela au cours des trois jours précédents, ont servi à créer notre « indice des glissades et des chutes ¼ (IGC). RéSULTATS: Le jeu de données comprenait 14 977 visites aux SU en raison de glissades et de chutes sur la glace ou la neige. Les femmes (57,36%, n = 8 591) ont effectué plus de visites que les hommes (42,64%, n = 6 386). Tous les mois avaient un effet significatif, que ce soit comme variable prédictive ou préventive des glissades et des chutes sur la glace ou la neige. La présence de glace ou de neige au sol le jour même, et la présence de glace jusqu'à trois jours avant, ont permis de prédire les hausses des visites. Le mois et la hauteur de la glace et de la neige peuvent être saisis dans l'IGC, ce qui génère le niveau de risque quotidien. CONCLUSION: L'IGC est le premier indice canadien qui mesure le risque de glissades et de chutes accidentelles sur la glace ou la neige.

Risk Factors for the Development of Persistent Scaphoid Non-Union After Surgery for an Established Non-Union.

BACKGROUND: Between 2014 and 2020, candidates for scaphoid non-union (SNU) surgery were enrolled in a prospective randomized trial (Scaphoid Nonunion and Low Intensity Pulsed Ultrasound [SNAPU] trial) evaluating the effect of low-intensity pulsed ultrasound on postoperative scaphoid healing. At trial completion, 114/134 (85%) of these patients went on to union, and 20/134 (15%) went on to persistent SNU (PSNU). The purpose of this study was to use this prospectively gathered data to identify patient-, fracture-, and surgery-specific risk factors that may be predictive of PSNU in patients who undergo surgery for SNU. METHODS: Data were extracted from the SNAPU trial database. The inclusion and exclusion criteria of this study were the same as that of the SNAPU trial. Nineteen patient-, fracture-, and surgery-specific risk factors were determined a priori. A stepwise multivariable logistic regression model was used to identify independent risk factors for PSNU. RESULTS: Three risk factors were found to be independently significant predictors of PSNU: age at the time of surgery, dominant hand injury, and previous surgery on the affected scaphoid. With every decade of a patient's life, dominant hand injury, and previous scaphoid surgery, the odds of union are reduced by 1.72 times, 7.35 times, and 4.24 times, respectively. CONCLUSION: We identified three independent risk factors for PSNU: age at SNU surgery, dominant hand injury, and previous surgery on the affected scaphoid. The findings of this study are significant and may contribute to shared decision-making and prognostication between the patient, surgeon, and affiliated members of their care team.

FROST 2.0: Factors Predicting Orthopaedic Trauma Volumes - A Validation Study.

The anecdotal relationship between weather, season, and orthopaedic trauma volumes is understood by patients and healthcare providers: when the winter ground is icy, people fall. Previous research established that winter and summer months as well as ice and snow were significant predictors of orthopaedic trauma and surges in volumes. The current study validates the previously established predictive model in one Canadian city; the original methods were repeated using a new, yet geographically similar dataset. The effect of month and ice were consistent, which suggests the proposed model has sufficient external validity to guide resource allocation and primary prevention strategies.

Trends in implementation of evidence-based hip fracture management in a major Canadian city.

Aims: The importance of hip fracture care has resulted in an abundance of hip fracture management literature. The degree this evidence is incorporated into clinical practice is unknown. We examined 5 trends in hip fracture management: arthroplasty versus fixation, total hip arthroplasty (THA) versus hemiarthroplasty (HA), cemented versus uncemented femoral stem fixation, short versus long cephalomedullary nail (CMN) fixation, and time from admission to surgery. Our primary aim was to understand and assess hip fracture management trends in relation to pertinent literature. Methods: Data were collected from acute hip fractures in patients aged 50 years or older who presented from 2008 to 2018. ICD-10 diagnostic codes were assigned using preoperative radiographs. Surgical management was confirmed using intraoperative and postoperative radiographs and split into 6 categories: (1) short CMN, (2) long CMN, (3) cannulated screws, (4) dynamic hip screw, (5) HA, and (6) THA. Appropriate statistical tests were used to analyze trends. Results: In 4 assessed trends, hip fracture management aligned with high-level evidence. This was the case for a trend toward arthroplasty for displaced femoral neck fractures, increased use of THA relative to HA, increased use of short relative to long CMNs, and consistent decrease in surgical wait times. Despite the literature highlighting the disadvantages of uncemented femoral stems, our data demonstrated increased use of uncemented femoral stems. Conclusion: Evidence to guide orthopaedic practice is constantly emerging but may not be effectively used by clinicians. Our findings demonstrate the successes and failures of integrating evidence into hip fracture management and highlight that orthopaedic surgeons have an ongoing responsibility to strive for evidence-based practice.

Effects of metformin and intensive lifestyle interventions on the incidence of kidney disease in adults in the DPP/DPPOS.

AIMS: We analyzed the incidence of kidney disease in the Diabetes Prevention Program Outcomes Study (DPPOS) by originally randomized treatment group assignment: Intensive Lifestyle (ILS), Metformin (MET) or Placebo (PLB). METHODS: The current analyses used a time-to-event approach in which the primary outcome was kidney disease, ascertained as urine albumin-to-creatinine ratio (ACR) ≥ 3.39 mg/mmol (30 mg/g) or eGFR <45 mL/min/1.73m2, with confirmation required at the next visit, or adjudicated end-stage kidney disease (ESKD). RESULTS: At a median of 21 years following randomization in DPP, diabetes development was reduced in both the ILS (HR 0.73 [95%CI = 0.62, 0.85]) and MET groups (HR 0.85 [0.73, 0.99]) compared to the PLB group. Although risk for developing the primary kidney disease outcome was higher among those with incident diabetes compared to those without (HR 1.81 [1.43, 2.30]), it did not differ by intervention groups (ILS vs. PLB 1.02 (0.81, 1.29); MET vs. PLB 1.08 (0.86, 1.35). There was a non-significant metformin by age interaction (p = 0.057), with metformin being beneficial for kidney disease in the younger but potentially harmful in the older participants. CONCLUSIONS: Development of kidney disease was increased in participants who developed diabetes but did not differ by original treatment group assignment. CLINICAL TRIAL REGISTRATIONS: Diabetes Prevention Program (DPP) Clinical trial reg. no. NCT00004992 DPP Outcomes Study (DPPOS) Clinical trial reg. no. NCT0038727.

Risk Factors for Complications in Ulnar Shortening Osteotomies: A Multicenter Retrospective Review.

PURPOSE: Ulnar shortening osteotomy (USO) is commonly performed to alleviate pathologies causing ulnar-sided wrist pain. Surgical complications include nonunion and hardware removal, with rates up to 18% and 45%, respectively. The primary objective of the study was to report the overall complication rate of USO. The secondary objective was to identify risk factors for complications. METHODS: A retrospective multicenter cohort review was undertaken, including six Canadian cities over a 6-year period (January 2013-December 2018). Chart review was used to collect demographic data, surgical technique, implant used, and postoperative complications. Descriptive statistics of demographics and operative characteristics, including plate positioning, type of osteotomy, plate type, and ulnar variance (mm), were analyzed. Univariate analyses were used to select predictor variables for nonunion and hardware removal. These predictor variables were then entered into an adjusted multivariable logistic regression model. RESULTS: A total of 361 USOs were performed. Mean age was 46 ± 16 years (60.7% men). The overall complication rate was 37.1%, hardware removal rate was 29.6%, and nonunion rate was 9.4%. There was a workers' compensation claim associated with 21.6% of all complications, and it was a risk factor for both hardware removal (odds ratio [OR] = 3.81) and nonunion (OR = 2.88). Neither smoking nor diabetes was associated with complication rates. Seventy percent of plates were placed volarly, 25.5% dorsally, and 3.9% directly ulnar. Osteotomies were oblique in 83.7% of cases and transverse in 15.5%. Adjusted multivariate regression analysis revealed that younger age (OR = 0.98) was a risk factor for hardware removal and male sex (OR = 2.49) was a risk factor for nonunion. A surgical factor associated with hardware removal was direct ulnar plate placement (OR = 9.93). No surgical factors were associated with nonunions. CONCLUSIONS: There are substantial rates of complications with USOs. Direct ulnar plate placement should be avoided. Patients should be thoroughly counseled on the risks of complications prior to proceeding with USO. LEVEL OF EVIDENCE: Therapeutic IV.

Thermal Energy Harvesting from Slow Variations in Environmental Temperatures.

With the Internet of Things expanding to more locations across our planet, power becomes the main factor affecting device longevity. There is a need for more novel energy harvesting systems that are able to power remote devices for sustained periods. This publication presents one such device. Based on a novel actuator that utilises off-the-shelf gas mixtures to generate a variable force from temperature change, this publication presents a device capable of generating up to 150mJ per diurnal temperature cycle; this is enough electrical energy to send up to three LoRaWAN transmissions per day using slowly changing environmental temperatures.

Wirelessly Powered Drug-Free and Anti-Infective Smart Bandage for Chronic Wound Care.

We present a wirelessly powered ultraviolet-C (UVC) radiation-based disinfecting bandage for sterilization and treatment in chronic wound care and management. The bandage contains embedded low-power UV light-emitting diodes (LEDs) in the 265 to 285 nm range with the light emission controlled via a microcontroller. An inductive coil is seamlessly concealed in the fabric bandage and coupled with a rectifier circuit to enable 6.78 MHz wireless power transfer (WPT). The maximum WPT efficiency of the coils is 83% in free space and 75% on the body at a coupling distance of 4.5 cm. Measurements show that the UVC LEDs are emitting radiant power of about 0.6 mW and 6.8 mW with and without fabric bandage, respectively, when wirelessly powered. The ability of the bandage to inactivate microorganisms was examined in a laboratory which shows that the system can effectively eradicate Gram-negative bacteria, Pseudoalteromonas sp. D41 strain, on surfaces in six hours. The proposed smart bandage system is low-cost, battery-free, flexible and can be easily mounted on the human body and, therefore, shows great promise for the treatment of persistent infections in chronic wound care.

Retinopathy During the First 5 Years of Type 1 Diabetes and Subsequent Risk of Advanced Retinopathy.

OBJECTIVE: To determine whether individuals with type 1 diabetes (T1D) who develop any retinopathy at any time prior to 5 years of diabetes duration have an increased subsequent risk for further progression of retinopathy or onset of proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), diabetes-related retinal photocoagulation, or anti-vascular endothelial growth factor injections. Additionally, to determine the influence of HbA1c and other risk factors in these individuals. RESEARCH DESIGN AND METHODS: Diabetic retinopathy (DR) was assessed longitudinally using standardized stereoscopic seven-field fundus photography at time intervals of 6 months to 4 years. Early-onset DR (EDR) was defined as onset prior to 5 years of T1D duration. Cox models assessed the associations of EDR with subsequent risk of outcomes. RESULTS: In unadjusted models, individuals with EDR (n = 484) had an increased subsequent risk of PDR (hazard ratio [HR] 1.51 [95% CI 1.12, 2.02], P = 0.006), CSME (HR 1.44 [1.10, 1.88], P = 0.008), and diabetes-related retinal photocoagulation (HR 1.48 [1.12, 1.96], P = 0.006) compared with individuals without EDR (n = 369). These associations remained significant when adjusted for HbA1c, but only the association with PDR remained significant after adjustment for age, duration of T1D, HbA1c, sex, systolic/diastolic blood pressure, pulse, use of ACE inhibitors, albumin excretion rate, and estimated glomerular filtration rate (HR 1.47 [95% CI 1.04, 2.06], P = 0.028). CONCLUSIONS: These data suggest that individuals with any sign of retinopathy within the first 5 years of T1D onset may be at higher risk of long-term development of advanced DR, especially PDR. Identification of early-onset DR may influence prognosis and help guide therapeutic management to reduce the risk of future visual loss in these individuals.

Association of Metformin With the Development of Age-Related Macular Degeneration.

Importance: Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD. Objective: To investigate the association between metformin use and age-related macular degeneration (AMD). Design, Setting, and Participants: The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022. Interventions: Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo. Main Outcomes and Measures: Prevalence of AMD in the treatment arms. Results: Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02). Conclusions and Relevance: These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.

Initial Insights into the Genetic Variation Associated with Metformin Treatment Failure in Youth with Type 2 Diabetes.

Metformin is the first-line treatment for type 2 diabetes (T2D) in youth but with limited sustained glycemic response. To identify common variants associated with metformin response, we used a genome-wide approach in 506 youth from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study and examined the relationship between T2D partitioned polygenic scores (pPS), glycemic traits, and metformin response in these youth. Several variants met a suggestive threshold (P < 1 × 10-6), though none including published adult variants reached genome-wide significance. We pursued replication of top nine variants in three cohorts, and rs76195229 in ATRNL1 was associated with worse metformin response in the Metformin Genetics Consortium (n = 7,812), though statistically not being significant after Bonferroni correction (P = 0.06). A higher ß-cell pPS was associated with a lower insulinogenic index (P = 0.02) and C-peptide (P = 0.047) at baseline and higher pPS related to two insulin resistance processes were associated with increased C-peptide at baseline (P = 0.04,0.02). Although pPS were not associated with changes in glycemic traits or metformin response, our results indicate a trend in the association of the ß-cell pPS with reduced ß-cell function over time. Our data show initial evidence for genetic variation associated with metformin response in youth with T2D.

Retinal Thickness and Morphology Changes on OCT in Youth with Type 2 Diabetes: Findings from the TODAY Study.

Objective: To evaluate changes in retinal thickness and morphology using OCT in youth with type 2 diabetes (T2D) and to identify systemic biomarkers correlating with these changes. Design: Retrospective subgroup analysis of a prospective study. Participants: Participants who underwent OCT imaging in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) trial and its follow-up study TODAY2. Methods: In 2010-2011 (TODAY) and 2017-2018 (TODAY2), 6 × 6-mm macular volume OCT scans were acquired, segmented, and analyzed to generate total retinal thickness, inner retinal thickness, and outer retinal thickness. The main retinal morphologies graded were intraretinal cystoid spaces, subretinal fluid, and posterior vitreous detachment (PVD). Main Outcome Measures: Changes in total and individual retinal layer thickness and development of abnormal vitreomacular morphology between TODAY and TODAY2. Results: Participants had a mean age of 17.9 ± 2.4 years and glycated hemoglobin (HbA1c) of 8.2 ± 2.8% in TODAY and a mean age of 25.0 ± 2.4 years and mean HbA1c of 9.5 ± 2.8% in TODAY2. Longitudinally between assessments, there were overall decreases in outer retinal thickness from 167.2 ± 11.5 microns to 158.4 ± 12.8 microns (P < 0.001) and in photoreceptor thickness from 30.3 ± 2.9 microns to 29.8 ± 4.1 microns (P = 0.04) in the central subfield, while in the inner subfield, we noted a decrease in outer retinal thickness from 150.5 ± 10.1 microns to 144.9 ± 10.5 microns (P < 0.001) and an increase in inner retinal thickness from 136.9 ± 11.5 microns to 137.4 ± 12.6 microns (P = 0.01). Multivariate analysis showed that in the center subfield, HbA1c increases were associated with increases in total retinal thickness (r: 0.67, P = 0.001), whereas fasting glucose was positively correlated with inner retinal thickness (r: 0.02, P = 0.02). In the inner subfield, both systolic (r: -0.22, P < 0.001) and diastolic (r: -0.22, P = 0.003) blood pressures were negatively correlated with total retinal thickness. There was an increase in PVD (18.9%) and cystoid spaces (4.2%). Conclusions: Youth with T2D develop retinal thickness changes on OCT, including increases in total retinal and inner retinal thickness in the center subfield that correlate with HbA1c and fasting glucose, respectively. Taken together with the increased prevalence of abnormal vitreomacular morphology in this cohort at risk, these findings emphasize the importance of controlling risk factors to prevent the development of sight-threatening retinal complications.

Lithium-sensing riboswitch classes regulate expression of bacterial cation transporter genes.

Lithium is rare in Earth's crust compared to the biologically relevant alkali metal cations sodium and potassium but can accumulate to toxic levels in some environments. We report the experimental validation of two distinct bacterial riboswitch classes that selectively activate gene expression in response to elevated Li+ concentrations. These RNAs commonly regulate the expression of nhaA genes coding for ion transporters that weakly discriminate between Na+ and Li+. Our findings demonstrated that the primary function of Li+ riboswitches and associated NhaA transporters is to prevent Li+ toxicity, particularly when bacteria are living at high pH. Additional riboswitch-associated genes revealed how some cells defend against the deleterious effects of Li+ in the biosphere, which might become more problematic as its industrial applications increase.