Offloading Devices For Neuropathic Foot Ulcers In Adult Persons With T1D Or T2D
There is limited evidence from RCTs to suggest that F-TCC has a shorter ulcer healing time compared with RCW among adults with diabetic NPFUs.
Summary
A Rapid Review With Meta-Analysis And Trial Sequential Analysis Of Randomized Controlled Trials
[Posted 13/May/2022]
AUDIENCE: Endocrinology
KEY FINDINGS: There is limited evidence from RCTs to suggest that F-TCC has a shorter ulcer healing time compared with RCW among adults with diabetic NPFUs. Properly designed and conducted RCTs are still required for a stronger evidence base.
BACKGROUND: Healing time for neuropathic planter foot ulcers (NPFUs) in persons with diabetes may be reduced through use of non-removable fiberglass total contact casting (F-TCC) compared with removable cast walkers (RCWs), although the evidence base is still growing.
DETAILS: A rapid review was conducted and systematically searched for, and critically assessed, randomized controlled trials (RCTs) that compared the efficacy of F-TCC versus RCW, focusing on the time to ulcer healing in adult persons (18+ years) with NPFUs and type 1 or type 2 diabetes. We meta-analysed the mean differences and associated 95% CIs using an inverse variance, random-effects model. Also conducted a trial sequential analysis (TSA) to assess if the available evidence is up to the required information size for a robust conclusion. Assessed and quantified statistical heterogeneity between the included studies using the I2 statistic. Out of 102 retrieved citations, five RCTs met the eligibility criteria. Participants' inclusion in relation to stage of ulcer was highly variable as was peripheral neuropathy complicating comparisons. F-TCC appeared to present a shorter ulcer healing time (-5.42 days, 95% CI -9.66 days to -1.17 days; I2 9.9%; 5 RCTs; 169 participants) compared with RCW. This finding was supported by the TSA.
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Copyright © BMJ Publishing Group Ltd. All rights reserved.
Source: Okoli GN, Rabbani R, Lam OLT, et al. (2022). Offloading Devices For Neuropathic Foot Ulcers In Adult Persons With Type 1 Or Type 2 Diabetes: A Rapid Review With Meta-Analysis And Trial Sequential Analysis Of Randomized Controlled Trials. BMJ DRC. 2022; 10(3): e002822. Published: May 12, 2022. DOI: 10.1136/bmjdrc-2022-002822.
Fluocinolone Acetonide Implant as Baseline Therapy for Diabetic Macular Edema
This randomized Phase 4 study found that a fluocinolone acetonide implant-based treatment strategy maintained visual and retinal anatomical outcomes comparable with aflibercept monotherapy while significantly reducing overall injection burden. Although the primary endpoint was not met, the findings suggest that sustained corticosteroid therapy may offer a treatment-burden advantage in appropriately selected patients, with careful monitoring for cataract formation and intraocular pressure elevation.
Summary
Results from the Phase 4 NEW DAY Study
[Posted 16/Jul/2026]
AUDIENCE: Ophthalmology, Internal Medicine
KEY FINDINGS: This randomized Phase 4 study demonstrated that baseline treatment with the fluocinolone acetonide implant achieved visual and anatomic outcomes comparable to aflibercept monotherapy while reducing the total number of intravitreal injections by more than half over 18 months. Although steroid-associated cataract and IOP events occurred more frequently, the overall safety profile was consistent with previous studies, supporting the FAc implant as a potential early treatment strategy for selected patients with DME.
BACKGROUND: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy remains the standard treatment for diabetic macular edema (DME), but the need for frequent injections and clinic visits can create a substantial treatment burden. The fluocinolone acetonide (FAc) 0.19-mg intravitreal implant provides sustained corticosteroid delivery and has demonstrated efficacy in persistent DME. The Phase 4 NEW DAY study evaluated whether using the FAc implant as baseline therapy, supplemented with aflibercept only when needed, could reduce injection burden while maintaining visual and anatomic outcomes comparable with aflibercept monotherapy.
DETAILS: NEW DAY was a prospective, randomized, single-masked, active-controlled, multicenter, 18-month Phase 4 trial conducted at 42 sites in the United States. A total of 517 participants were screened, and 306 adults with type 1 or type 2 diabetes and center-involving DME were randomized to receive either a 0.19-mg FAc implant (n = 154) followed by rescue aflibercept injections as needed or aflibercept (n = 152) administered as five loading doses every four weeks followed by rescue treatment when required. The primary endpoint was the mean number of rescue supplemental aflibercept injections during the study. Secondary outcomes included total intravitreal injections, time to first rescue injection, best-corrected visual acuity (BCVA), central subfield thickness (CST), cataract procedures, and intraocular pressure (IOP)-related safety outcomes. The primary endpoint was not met, with a similar mean number of rescue aflibercept injections in the FAc and aflibercept groups (2.4 ± 3.2 vs. 2.5 ± 3.1; P = 0.76). However, the FAc strategy substantially reduced overall treatment burden, requiring fewer total injections than aflibercept monotherapy (3.4 ± 3.2 vs. 7.2 ± 3.4; nominal P < 0.001). Time to first rescue injection was significantly longer with the FAc implant (185.4 ± 97.9 days vs. 132.8 ± 94.0 days; nominal P < 0.001). Approximately one-third of participants in both groups required no rescue injections throughout the study (32.5% vs. 30.3%; nominal P = 0.68). Improvements in visual acuity and retinal anatomy were comparable between groups, with mean BCVA changes of 1.8 letters and 5.5 letters (nominal P = 0.08) and mean CST reductions of -119 ± 112 µm and -114 ± 103 µm (nominal P = 0.71) in the FAc and aflibercept groups, respectively. Cataract procedures occurred more frequently with the FAc implant (27.9% vs. 6.6%), and increased IOP was reported in 15.6% of FAc-treated participants compared with 3.3% receiving aflibercept. Despite these steroid-related adverse events, incisional IOP procedures were uncommon, and no new safety signals were identified.
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Source: Singer, M. A., Wykoff, C. C., Riemann, C. D., et al. Fluocinolone Acetonide Implant as a Baseline Therapy for Diabetic Macular Edema. American Academy of Ophthalmology. 2026; 133(7): 837-851. Published: June 22, 2026. DOI: 10.1016/j.ophtha.2026.03.019.
Gadolinium-Based Contrast Agents: Reassessing Safety Beyond Nephrogenic Systemic Fibrosis
This review highlights that gadolinium-based contrast agents continue to play a critical role in diagnostic MRI, but their use should be guided by careful patient selection and individualized risk assessment. Although the risk of nephrogenic systemic fibrosis has declined considerably, further research is needed to clarify the clinical significance of gadolinium retention and its long-term safety.
KEY FINDINGS: This review emphasizes that GBCAs remain indispensable for diagnostic MRI but should be used following an individualized benefit-risk assessment, particularly in patients with chronic kidney disease or acute kidney injury. Although modern practice has substantially reduced the incidence of NSF, uncertainties remain regarding gadolinium retention, long-term toxicity, and persistent symptoms after exposure. Continued research into the mechanisms of gadolinium-associated injury, along with transparent patient counseling and evidence-based imaging policies, will be essential to optimize both patient safety and diagnostic care.
BACKGROUND: Gadolinium-based contrast agents (GBCAs) have been widely used to enhance magnetic resonance imaging (MRI) since the 1980s because of their favorable diagnostic performance and generally low incidence of acute adverse reactions. However, concerns regarding nephrogenic systemic fibrosis (NSF), gadolinium retention, and potential long-term toxicity have prompted ongoing debate about their safety, particularly in patients with kidney disease. This review examines current evidence on GBCA-associated complications, mechanisms of toxicity, and considerations for balancing diagnostic benefits with potential risks.
DETAILS: This narrative review synthesizes published evidence on the clinical safety of GBCAs, including acute hypersensitivity reactions, nephrotoxicity, NSF, gadolinium retention, and emerging concepts such as gadolinium-associated symptoms. The authors discuss differences between linear and macrocyclic GBCAs, proposed mechanisms of tissue deposition and fibrosis, the role of kidney dysfunction in gadolinium elimination, current American College of Radiology (ACR) recommendations, and unresolved questions regarding long-term toxicity. Experimental and clinical data addressing tissue retention, dialysis, and mechanistic pathways underlying gadolinium-induced injury are also reviewed. The review highlights that the incidence of NSF has declined substantially following the adoption of risk-based prescribing practices and updated clinical guidelines. Nevertheless, available evidence indicates that gadolinium retention can occur in multiple tissues, including the brain, even in individuals without severe renal impairment. The authors emphasize that tissue retention and toxicity are not fully explained by current GBCA classifications and that macrocyclic agents, although generally considered more stable, do not completely eliminate potential risk. Evidence reviewed also suggests that gadolinium may contribute to acute kidney injury, persistent tissue deposition, rare cases of encephalopathy, and symptoms associated with gadolinium exposure. Current data do not establish a definitive exposure threshold for toxicity, and the benefit of prophylactic hemodialysis after GBCA administration remains uncertain. While observational studies have estimated the risk of NSF with group II agents to be below 0.07%, the review notes that the true absolute risk remains difficult to define because of limitations in available evidence and confounding factors.
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Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts
Early initiation of a 5-day oral ensitrelvir regimen within 72 hours after symptom onset in an index patient significantly reduced the risk of developing Covid-19 among household contacts while maintaining a safety profile comparable to placebo. Clinical benefit was observed across major patient subgroups, including individuals at increased risk for severe disease, and treatment was associated with reduced household transmission. These findings support ensitrelvir as an effective postexposure prophylactic option for household contacts and suggest potential utility in other high-risk exposure settings where rapid outbreak control is needed.
KEY FINDINGS: Early initiation of a 5-day oral ensitrelvir regimen within 72 hours after symptom onset in an index patient significantly reduced the risk of developing Covid-19 among household contacts while maintaining a safety profile comparable to placebo. Clinical benefit was observed across major patient subgroups, including individuals at increased risk for severe disease, and treatment was associated with reduced household transmission. These findings support ensitrelvir as an effective postexposure prophylactic option for household contacts and suggest potential utility in other high-risk exposure settings where rapid outbreak control is needed.
BACKGROUND: Household transmission remains a major contributor to the spread of SARS-CoV-2, particularly among individuals at increased risk for severe Covid-19. Although vaccination and prior infection have reduced disease severity, waning immunity and emerging variants continue to sustain transmission. Previous trials evaluating oral antiviral agents for postexposure prophylaxis in household contacts have not demonstrated significant protection, highlighting the need for effective preventive therapies. This phase 3 trial evaluated whether oral ensitrelvir, a SARS-CoV-2 3C-like protease inhibitor, could prevent Covid-19 among household contacts exposed to an infected index patient.
DETAILS: This phase 3, double-blind, randomized, placebo-controlled trial was conducted between June 2023 and mid-September 2024 across the United States, Argentina, Japan, South Africa, and Vietnam. Eligible household contacts were 12 years of age or older, had a negative SARS-CoV-2 test at enrollment, and were randomized within 72 hours after symptom onset in the index patient. Participants received either ensitrelvir 375 mg on day 1 followed by 125 mg once daily on days 2-5 or matching placebo. The primary endpoint was laboratory-confirmed Covid-19 by day 10 in the modified intention-to-treat population, defined as RT-PCR positivity accompanied by at least one prespecified Covid-19 symptom lasting 48 hours or longer. Secondary endpoints included laboratory-confirmed SARS-CoV-2 infection regardless of symptoms, subgroup analyses, and safety outcomes. Overall, 2,387 household contacts were randomized, including 1,030 participants in the ensitrelvir group and 1,011 in the placebo group within the modified intention-to-treat population. The mean participant age was 42.4 years, 71.1% were enrolled within 48 hours after symptom onset in the index patient, and 37.0% had at least one risk factor for severe Covid-19. By day 10, laboratory-confirmed Covid-19 occurred in 2.9% of participants receiving ensitrelvir compared with 9.0% receiving placebo, corresponding to a risk ratio of 0.33 (95% CI, 0.22-0.49; P<0.001) and an approximate 67% relative risk reduction in the modified intention-to-treat population. In the intention-to-treat population, Covid-19 developed in 4.4% and 10.2% of participants, respectively (risk ratio, 0.43; 95% CI, 0.32-0.59; P<0.001). Laboratory-confirmed SARS-CoV-2 infection irrespective of symptoms was also lower with ensitrelvir (14.0% vs. 21.5%; risk ratio, 0.66; 95% CI, 0.55-0.79). Subgroup analyses demonstrated generally consistent efficacy across age groups and participants with risk factors for severe disease. Among participants with risk factors, Covid-19 developed in 2.4% of the ensitrelvir group compared with 9.9% of the placebo group. Ensitrelvir was also associated with a 34% relative reduction in household SARS-CoV-2 transmission. Adverse events occurred at similar frequencies in the ensitrelvir and placebo groups (15.1% vs. 15.5%), with serious adverse events reported in 0.2% of participants in each group. No Covid-19-related hospitalizations or deaths occurred. Transient reductions in high-density lipoprotein concentrations were observed with ensitrelvir but returned toward baseline by day 15 and were not associated with clinical events.
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Pharmacogenomic-Informed Antidepressant Prescribing in Australian Primary Care
In this pragmatic double-blind randomized controlled trial conducted in Australian primary care, pharmacogenomic-informed antidepressant prescribing did not improve depressive symptoms compared with prescribing guided by national therapeutic guidelines. Clinical outcomes, medication tolerability, adherence, and quality of life were similar between groups, while cost-effectiveness analyses did not support routine implementation of pharmacogenomic testing in this setting. These findings suggest that broad pharmacogenomic-guided antidepressant prescribing in general practice does not provide additional clinical benefit over guideline-based management, although targeted evaluation in carefully selected patient populations may warrant further investigation.
Summary
Findings from the PRESIDE Double-Blind Randomized Controlled Trial
[Posted 7/Jul/2026]
AUDIENCE: Family Medicine, Psychiatry
KEY FINDINGS: In this pragmatic double-blind randomized controlled trial conducted in Australian primary care, pharmacogenomic-informed antidepressant prescribing did not improve depressive symptoms compared with prescribing guided by national therapeutic guidelines. Clinical outcomes, medication tolerability, adherence, and quality of life were similar between groups, while cost-effectiveness analyses did not support routine implementation of pharmacogenomic testing in this setting. These findings suggest that broad pharmacogenomic-guided antidepressant prescribing in general practice does not provide additional clinical benefit over guideline-based management, although targeted evaluation in carefully selected patient populations may warrant further investigation.
BACKGROUND: Pharmacogenomic testing has been proposed as a strategy to individualize antidepressant selection by identifying CYP2D6 and CYP2C19 variants that influence drug metabolism. Although previous studies have suggested potential clinical benefits, evidence from pragmatic primary care settings remains limited. The Pharmacogenomic-Informed Antidepressant Prescribing for Moderate-to-Severe Depressive Symptoms in Australian General Practice (PRESIDE) trial evaluated whether pharmacogenomic-guided prescribing improves depression outcomes compared with guideline-based prescribing in routine general practice.
DETAILS: PRESIDE was a multicenter, double-blind, randomized controlled trial conducted in Australian general practice between May 26, 2021, and September 28, 2023. Of 5185 patients approached, 552 were randomized, and 550 participants (275 per group) were included in the intention-to-treat analysis. Participants with moderate-to-severe depressive symptoms were assigned in a 1:1 ratio to receive antidepressant prescribing recommendations based either on pharmacogenomic testing combined with Australian Therapeutic Guidelines or on Australian Therapeutic Guidelines alone. Pharmacogenomic reports incorporated CYP2D6 and CYP2C19 metabolizer phenotypes derived from saliva-based genotyping. The primary endpoint was change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 12 weeks after the prescribing report was received. Secondary outcomes included remission, treatment response, antidepressant-related adverse effects, medication adherence, prescribing congruence, quality of life, and cost-effectiveness. A total of 479 participants (87%) completed the primary 12-week outcome assessment. Depressive symptoms improved over time in both groups. At 12 weeks, the adjusted between-group difference in PHQ-9 change was 0.90 (95% CI, 0.06-1.75; standardized mean difference 0.23 [95% CI, 0.02-0.45]; p=0.036), indicating a small but greater improvement in depressive symptoms in the guideline-based control group. No significant between-group differences were observed at 4, 8, or 26 weeks. Remission at 12 weeks occurred in 11% of participants receiving pharmacogenomic-guided prescribing compared with 18% in the control group, corresponding to an adjusted difference of -7.22% (95% CI, -13.25 to -1.19) and an odds ratio of 0.530 (95% CI, 0.311-0.903; p=0.020). Treatment response rates did not differ significantly between groups (29% vs 32%; OR 0.874; 95% CI, 0.581-1.315; p=0.518). Approximately two-thirds of participants had an actionable CYP2D6 or CYP2C19 phenotype, yet subgroup analyses demonstrated no differential treatment benefit based on genotype. Antidepressant adherence, side-effect burden, health-related quality of life, and health-care utilization were comparable between groups. Economic analyses indicated that pharmacogenomic-guided prescribing was more costly and less effective than standard guideline-based care, although differences in costs and quality-adjusted life years were not statistically significant. No grade 2-5 adverse events occurred, and only one grade 1 adverse event related to an administrative reporting error was documented.
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Source: Saya, S., Chondros, P., Abela, A., et al. Pharmacogenomic-informed antidepressant prescribing for moderate-to-severe depressive symptoms in Australian general practice (PRESIDE): a double-blind, randomised controlled trial. The Lancet Primary Care. 2026; Published: June 25, 2026. DOI: 10.1016/j.lanprc.2026.100158
Relationships Between Regional and Ectopic Adiposity and Insulin Sensitivity in Early and Late Pregnancy
Insulin resistance in early pregnancy is strongly associated with total, regional, and ectopic adiposity. However, in late pregnancy, factors other than regional and ectopic adiposity predominately influence insulin sensitivity. Prepregnancy weight categories proportionately alter gestational weight gain, adiposity distribution, and glucometabolic responses.
KEY FINDINGS: Insulin resistance in early pregnancy is strongly associated with total, regional, and ectopic adiposity. However, in late pregnancy, factors other than regional and ectopic adiposity predominately influence insulin sensitivity. Prepregnancy weight categories proportionately alter gestational weight gain, adiposity distribution, and glucometabolic responses.
BACKGROUND: Purpose of this study is to determine relationships between measurements of total body, visceral, and ectopic (liver, skeletal muscle) fat with insulin sensitivity in pregnancy.
DETAILS: Pregnant women of varying prepregnancy weights were prospectively studied in early (n = 59) and late (n = 47) gestation. At each visit, participants underwent body composition measurements including fat mass (FM), fat-free mass (FFM), abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), ectopic lipid amounts in liver (intrahepatic lipid [IHL]) and calf skeletal muscle (intramyocellular lipid [IMCL] and extramyocellular lipid), and hyperinsulinemia-euglycemic clamp to determine insulin sensitivity (Rd), endogenous glucose production (EGP), hepatic insulin sensitivity index (HISI), and free fatty acid (FFA) levels. In early pregnancy, Rd ([mg/kg FFM/min]/µIU/mL) inversely correlated (P values <0.05) with BMI, FM, SAT, VAT, IHL, IMCL, and FFA. HISI inversely correlated (P values <0.05) with BMI, FM, SAT, VAT, IMCL, and FFA but not with IHL. In late pregnancy, however, neither EGP ([mg/kg FFM/min]/µIU/mL) nor Rd correlated with regional or ectopic fat measures, but HISI remained inversely correlated with BMI, FM, SAT, VAT, and IMCL. Early-pregnancy IHL levels did not predict late-pregnancy insulin sensitivity. Pregnant women with prepregnancy obesity were more insulin resistant but gained less gestational weight, VAT, and SAT, and experienced less decline in insulin sensitivity, than normal prepregnancy weight women.
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Copyright © American Diabetes Association. All rights reserved.
Source: Purnell, J. Q., Marshall, N., Francisco, M., et al. Relationships Between Regional and Ectopic Adiposity and Insulin Sensitivity in Early and Late Pregnancy. Diabetes Care. 2026; 49(7)): 1175-1184. Published: July 22, 2026. DOI: 10.2337/dc25-2081
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