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BACKGROUND: Nonadherence and nonpersistence to antidepressants in major depressive disorder (MDD) are common and associated with poor clinical and functional outcomes and increased health care reso...

The Australian Fairy Tern Sternula nereis nereis is a seabird that breeds along the coast and whose small populations are dispersed over vast stretches of the Australian seaboard and nearshore islands. In recent years, citizen science programs have been developed to bolster monitoring efforts to better understand breeding success and identify site threat profiles. The development of protocols that facilitate the collection of consistent measurements is important for long-term monitoring of this threatened (Vulnerable) species. This study describes plumage development and age-related behaviour in juvenile Australian Fairy Terns using direct observations and photographic recapture of individually marked birds. This information may be used as the basis for the development of a field ageing guide, enabling the collection of standardised information on colony demographics and juvenile development. A temporary colour-banding study was trialled by painting nail varnish onto 15 Australian Bird and Bat Banding Scheme (ABBBS) incoloy bands, avoiding the need to band nestlings with additional readable or PVC colour-bands. The varnish remained intact, albeit chipped, on four surviving birds that were resighted ≤80 days after banding, enabling the identification of individuals away from the colony site, without the need for recapture. The temporary marking of ABBBS bands using nail varnish offered an effective short-term solution for identifying individual juvenile Fairy Terns in the field and for describing plumage changes over a period of c. 3 months.

To assess from a US payer perspective the relative cost-effectiveness of the catechol-A Markov model was created to estimate cost-effectiveness of adjunctive opicapone treatment compared with adjunctive entacapone treatment in a synthetic cohort of 1,000 patients with PD taking LD/CD. Clinical inputs were derived from clinical trials, published literature, and expert opinion. Cost data (in 2018 US dollars) were obtained from the Centers for MedicareMedicaid Services, the Kaiser Family Foundation, and Analy$ource. Cost-effectiveness outcomes included incremental cost per OFF-time hours avoided, cost per life year gained, and cost per quality-adjusted life year (QALY) gained. Outcomes were projected over a 25-year lifetime horizon and discounted at 3% annually.Opicapone treatment was associated with an average of 1,187 fewer OFF-time hours per patient and an increase of 0.07 QALYs compared with entacapone. Total lifetime costs for opicapone were $3,100 higher than entacapone, resulting in an incremental cost-effectiveness ratio of $46,900 per QALY. One-way sensitivity analyses showed the model was most sensitive to mean OFF-time hours associated with opicapone and entacapone. Probabilistic sensitivity analysis suggested a 60-65% probability that opicapone was cost-effective relative to entacapone at any willingness-to-pay threshold ≥$5,000.There exists a single head-to-head clinical trial comparing the effectiveness of opicapone with entacapone, thus the clinical inputs regarding relative treatment effect of the drugs to reduce OFF-time hours in PD patients receiving LD/CD were derived from that single non-inferiority trial.Add-on treatment with opicapone in PD patients receiving LD/CD appeared to be cost-effective compared with entacapone.

Aims To compare the safety and efficacy of insulin glargine 300 U/mL (Gla-300) versus first-generation standard-of-care basal insulin analogues (SOC-BI; insulin glargine 100 U/mL or insulin detemir) at 6 months. Methods In the 12-month, open-label, multicentre, randomized, pragmatic ACHIEVE Control trial, insulin-naive adults with type 2 diabetes (T2D) and glycated haemoglobin A1c (HbA1c) 64-97 mmol/mol (8.0%-11.0%) after ≥1 year of treatment with ≥2 diabetes medications were randomized to Gla-300 or SOC-BI. The composite primary endpoint, evaluated at 6 months, was the proportion of participants achieving individualized HbA1c targets per HEDIS criteria without documented symptomatic (blood glucose ≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia at any time of the day at 6 months. Results Of 1651 and 1653 participants randomized to Gla-300 and SOC-BI, respectively, 31.3% and 27.9% achieved the composite primary endpoint at 6 months (odds ratio [OR] 1.19; 95% CI 1.01-1.39; P = 0.03 for superiority); 78.4% and 75.3% had no documented symptomatic or severe hypoglycaemia (OR 1.19; 95% CI 1.01-1.41). Changes from baseline to month 6 in HbA1c, fasting plasma glucose, weight, and BI analogue dose were similar between groups. Conclusions Among insulin-naive adults with poorly controlled T2D, Gla-300 was associated with a statistically significant higher proportion of participants achieving individualized HEDIS HbA1c targets without documented symptomatic or severe hypoglycaemia (versus SOC-BI) in a real-life population managed in a usual-care setting. The ACHIEVE Control study results add value to treatment decisions and options for patients, healthcare providers, payers, and decision makers. ClinicalTrials.gov identifier: NCT02451137 This article is protected by copyright. All rights reserved.

The current International Association for the Study of Pain (IASP) definition of pain as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" was recommended by the Subcommittee on Taxonomy and adopted by the IASP Council in 1979. This definition has become accepted widely by health care professionals and researchers in the pain field and adopted by several professional, governmental, and nongovernmental organizations, including the World Health Organization. In recent years, some in the field have reasoned that advances in our understanding of pain warrant a reevaluation of the definition and have proposed modifications. Therefore, in 2018, the IASP formed a 14-member, multinational Presidential Task Force comprising individuals with broad expertise in clinical and basic science related to pain, to evaluate the current definition and accompanying note and recommend whether they should be retained or changed. This review provides a synopsis of the critical concepts, the analysis of comments from the IASP membership and public, and the committee's final recommendations for revisions to the definition and notes, which were discussed over a 2-year period. The task force ultimately recommended that the definition of pain be revised to "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage," and that the accompanying notes be updated to a bulleted list that included the etymology. The revised definition and notes were unanimously accepted by the IASP Council early this year.

Purpose Hemoglobin A1c (HbA1c) is the accepted measure of effectiveness for type 1 diabetes therapies. We investigated preferences for measures of diabetes control in addition to HbA1c among adults with type 1 diabetes and caregivers of children with type 1 diabetes. Methods Using discrete-choice experiment methodology, surveys for adults with type 1 diabetes and caregivers presented choices between hypothetical treatments described by six attributes with varying levels: HbA1c, time in optimal glucose range, weekly number and severity of hypoglycemic and hyperglycemic events, additional disease management time, and additional treatment cost. Choice data were analyzed using random-parameters logit. Results A total of 300 adults with type 1 diabetes and 400 caregivers completed the survey. Adults and caregivers placed the most importance on reducing hypoglycemic and hyperglycemic events. For adults, avoiding 1-5 mild-to-moderate hypoglycemic events (glucose 54-69 mg/dL)/week was five times more important than being a half-point above target HbA1c. Avoiding 1-5 hyperglycemic events (glucose >180 mg/dL)/week was seven times more important than being a half-point above target HbA1c. Additional time in optimal glucose range was as important as a reduction greater than a half-point in HbA1c. Avoiding hyperglycemic and hypoglycemic events was more important than all other outcomes for caregivers of younger children. Caregivers of children >12 years placed relatively more weight on avoiding hypoglycemic events

BACKGROUND: Larotrectinib and entrectinib are FDA-approved therapies for patients with non-small cell lung cancer (NSCLC) with neurotrophic receptor tyrosine kinase gene fusion (TRK fusion-positive...

The transport of Ca2+ across membranes precedes the fusion and fission of various lipid bilayers. Yeast vacuoles under hyperosmotic stress become fragmented through fission events that requires the release of Ca2+ stores through the TRP channel Yvc1. This requires the phosphorylation of phosphatidylinositol-3-phosphate (PI3P) by the PI3P-5-kinase Fab1 to produce transient PI(3,5)P2 pools. Ca2+ is also released during vacuole fusion upon trans-SNARE complex assembly, however, its role remains unclear. The effect of PI(3,5)P2 on Ca2+ flux during fusion was independent of Yvc1. Here, we show that while low levels of PI(3,5)P2 were required for Ca2+ uptake into the vacuole, increased concentrations abolished Ca2+ efflux. This was as shown by the addition of exogenous dioctanoyl PI(3,5)P2 or increased endogenous production of by the hyperactive fab1T2250A mutant. In contrast, the lack of PI(3,5)P2 on vacuoles from the kinase dead fab1EEE mutant showed delayed and decreased Ca2+ uptake. The effects of PI(3,5)P2 were linked to the Ca2+ pump Pmc1, as its deletion rendered vacuoles resistant to the effects of excess PI(3,5)P2 . Experiments with Verapamil inhibited Ca2+ uptake when added at the start of the assay, while adding it after Ca2+ had been taken up resulted in the rapid expulsion of Ca2+ . Vacuoles lacking both Pmc1 and the H+ /Ca2+ exchanger Vcx1 lacked the ability to take up Ca2+ and instead expelled it upon the addition of ATP. Together these data suggest that a balance of efflux and uptake compete during the fusion pathway and that the levels of PI(3,5)P2 can modulate which path predominates.

DISCLOSURES: No funding was required for this project. The authors are or have been members of the Format Executive Committee.

To propose a set of guidelines for use by health care organizations in the United States that seek useful, comparative clinical information and economic analysis on pharmaceutical products to make sound drug purchasing decisions.Based on a therapy intervention approach, the guidelines provide a structured framework to help managed care purchasers become more consistent in how they evaluate drug products for inclusion in the formulary. The guidelines factor in the need to examine the impact of new drug products on overall costs within the entire health system.Intended for use by managed care organizations in the U.S. that purchase prescription drugs.Not applicable.Not applicable.The guidelines provide MCOs with a new systematic approach for identifying the overall cost and clinical outcomes impact of drug therapies. The guidelines are designed to take into account the characteristics of the patient population being treated and the fact that patients generally are redistributed among different treatment categories once a new drug product is introduced, thus offering MCOs an analysis model that extends beyond the traditional partial cost-outcomes approach. Emphasis is placed on looking at the cost-outomes impact of a new drug or therapy within a systems or disease area framework in which the redistribution of patients between therapy options is explicitly modelled. The guidelines specify that the following information elements be used in pharmacoeonomic analysis: product description, place in therapy, comparator products, therapy intervention framework, supporting clinical data, supporting pharmacoeconomic data, system impact assessments-costs-outcomes, overall assessment, and bibliography and supporting materials.

Despite the recognized role of wild waterfowl in the potential dispersal and transmission of highly pathogenic avian influenza (HPAI) virus, little is known about how infection affects these birds. This lack of information limits our ability to estimate viral spread in the event of an HPAI outbreak, thereby limiting our abilities to estimate and communicate risk. Here, we present telemetry data from a wild Lesser Scaup (Aythya affinis), captured during a separate ecology study in the Chesapeake Bay, Maryland. This bird tested positive for infection with clade 2.3.4.4 HPAI virus of the A/goose/Guangdong/1/1996 (Gs/GD) H5N1 lineage (results received post-release) during the 2021-2022 ongoing outbreaks in North America. While the infected bird was somewhat lighter than other adult males surgically implanted with transmitters (790 g, x̅ = 868 g, n = 11), it showed no clinical signs of infection at capture, during surgery, nor upon release. The bird died 3 days later-pathology undetermined as the specimen was not able to be recovered. Analysis of movement data within the 3-day window showed that the infected individual's maximum and average hourly movements (3894.3 and 428.8 m, respectively) were noticeably lower than noninfected conspecifics tagged and released the same day (x̅ = 21,594.5 and 1097.9 m, respectively; n = 4). We identified four instances where the infected bird had close contact (fixes located within 25 m and 15 min) with another marked bird during this time. Collectively, these data suggest that the HPAI-positive bird observed in this study may have been shedding virus for some period prior to death, with opportunities for direct bird-to-bird or environmental transmission. Although limited by low sample size and proximity to the time of tagging, we hope that these data will provide useful information as managers continue to respond to this ongoing outbreak event.

Reward-based motivation is associated with transient and sustained dopaminergic activity and with modulatory effects on attention and cognitive control. Age-related changes in the dopamine system are well documented, but little is known about age differences in the temporal dynamics of motivational influences on cognitive functions. The current study examined the effects of financial incentives on visual attention using event-related potentials (ERPs). Participants (26 younger, aged 18-33; 24 older, aged 65-95) completed an incentivized flanker task in which trial-level incentive cues signaled the availability of performance-contingent reward, and subsequent alerting cues signaled the onset of the flanker target. ERP components of interest included incentive-cue P2 and CNV, alerting-cue N1, target N1, and target P3. Transient effects of incentives were assessed by comparing ERP amplitudes across incentive and non-incentive trials from mixed-incentive blocks. Younger adults showed transient effects of incentives on all components, whereas older adults showed effects for incentive-cue P2 and alerting-cue N1 only. Sustained effects of incentives were assessed by comparing ERP amplitudes across non-incentive trials from mixed-incentive blocks and non-incentive trials from pure non-incentive blocks. Both age groups showed sustained effects of incentives on cue-locked ERPs, but only younger adults showed sustained effects on target-locked ERPs. Reaction-time patterns mirrored the ERP findings, in that younger adults showed greater incentive-based modulation than older adults. Overall, these findings suggest that both transient and sustained effects of incentives on visual attention are more fleeting for older than younger adults, consistent with widespread alterations in dopaminergic neuromodulation in aging.

Despite the recognized role of wild waterfowl in the potential dispersal and transmission of highly pathogenic avian influenza (HPAI) virus, little is known about how infection affects these birds. This lack of information limits our ability to estimate viral spread in the event of an HPAI outbreak, thereby limiting our abilities to estimate and communicate risk. Here we present telemetry data from a wild Lesser Scaup ( Aythya affinis), captured during a separate ecology study in the Chesapeake Bay, Maryland. This bird tested positive for infection with clade 2.3.4.4 HPAI virus of the A/goose/Guangdong/1/1996 (Gs/GD) H5N1 lineage (results received post-release) during the 2021-22 ongoing outbreaks in North America. While the infected bird was somewhat lighter than other adult males surgically implanted with transmitters (790g, mean=868g, n=11), it showed no clinical signs of infection at capture, during surgery, nor upon release. The bird died 3d later, pathology undetermined as the specimen was not able to be recovered. Analysis of movement data within the 3d window showed that the infected individual’s maximum and average hourly movements (3894.3m, 428.8m respectively) were noticeably lower than noninfected conspecifics tagged and released the same day (mean =21594.5m, mean =1097.9m, respectively; n=4). We identified four instances where the infected bird had direct contact (fixes located within 25m and 15 min) with another marked bird during this time. Collectively, these data suggest that the HPAI positive bird observed in this study may have been shedding virus for some period prior to death, with opportunities for direct bird to bird or environmental transmission. Although limited by low sample size and proximity to the time of tagging, we hope that these data will provide useful information as managers continue to respond to this ongoing outbreak event.

We present a new combinatorial model for identifying regulatory modules in gene co-expression data using a decomposition into weighted cliques. To capture complex interaction effects, we generalize the previously-studied weighted edge clique partition problem. As a first step, we restrict ourselves to the noise-free setting, and show that the problem is fixed parameter tractable when parameterized by the number of modules (cliques). We present two new algorithms for finding these decompositions, using linear programming and integer partitioning to determine the clique weights. Further, we implement these algorithms in Python and test them on a biologically-inspired synthetic corpus generated using real-world data from transcription factors and a latent variable analysis of co-expression in varying cell types.

The biopsychosocial model (BPS) of chronic pain aspires to be comprehensive, incorporating psychological and social factors omitted from biomedical models. Although psychosocial factors are viewed as highly influential in understanding behavioral and psychological responses to pain, these factors are usually viewed as modifiers of biological causes of the experience of pain itself, rather than as equal contributors to pain. To further advance the BPS model, we re-examine a classic 1994 article by Wilbert "Bill" Fordyce, "Pain and suffering: what is the unit?" In this article, Fordyce suggested that pain-related disability and suffering should be viewed as "transdermal," as having causes both inside and outside the body. We consider Fordyce's article theoretically important because this concept allows us to more fully break free of the medical model of chronic pain than customary formulations of the BPS model. It makes it possible to place psychological and social factors on an equal footing with biological ones in explaining pain itself and to remove distinctions between pain mechanisms and pain meanings. The brain's salience network now offers a platform on which diverse influences on pain experience-from nociception to multisensory indicators of safety or danger-can be integrated, bridging the gap between impersonal nociceptive mechanisms and personal meanings. We also argue that Fordyce's article is practically important because this concept expands the BPS model beyond the bounds of the clinical encounter, opening the door to the full range of social, psychological, and biological interventions, empowering patients and nonmedical providers to tackle chronic pain.

Pathological sodium-water retention or edema/congestion is a primary cause of heart failure (HF) decompensation, clinical symptoms, hospitalization, reduced quality of life, and premature mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) based therapies reduce hospitalization due to HF, improve functional status, quality, and duration of life in patients with HF with reduced ejection fraction (HFrEF) independently of their glycemic status. The pathophysiologic mechanisms and molecular pathways responsible for the benefits of SGLT-2i in HFrEF remain inconclusive, but SGLT-2i may help HFrEF by normalizing salt-water homeostasis to prevent clinical edema/congestion. In HFrEF, edema and congestion are related to compromised cardiac function. Edema and congestion are further aggravated by renal and pulmonary abnormalities. Treatment of HFrEF patients with SGLT-2i enhances natriuresis/diuresis, improves cardiac function, and reduces natriuretic peptide plasma levels. In this review, we summarize current clinical research studies related to outcomes of SGLT-2i treatment in HFrEF with a specific focus on their contribution to relieving or preventing edema and congestion, slowing HF progression, and decreasing the rate of rehospitalization and cardiovascular mortality.

The impacts of interferon (IFN) signaling on COVID-19 pathology are multiple, with both protective and harmful effects being documented. We report here a multiomics investigation of systemic IFN signaling in hospitalized COVID-19 patients, defining the multiomics biosignatures associated with varying levels of 12 different type I, II, and III IFNs. The antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of IFNs, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage and platelet activation associate with high levels of IFNB1 and IFNA6. Seroconversion and time since hospitalization associate with a significant decrease in a specific subset of IFNs. Additionally, differential IFN subtype production is linked to distinct constellations of circulating myeloid and lymphoid immune cell types. Each IFN has a unique metabolic signature, with IFNG being the most associated with activation of the kynurenine pathway. IFNs also show differential relationships with clinical markers of poor prognosis and disease severity. For example, whereas IFNG has the strongest association with C-reactive protein and other immune markers of poor prognosis, IFNB1 associates with increased neutrophil to lymphocyte ratio, a marker of late severe disease. Altogether, these results reveal specialized IFN action in COVID-19, with potential diagnostic and therapeutic implications.

Larotrectinib and entrectinib are tumor-agnostic tropomyosin receptor kinase (TRK) inhibitors that are indicated for the treatment of advanced or metastatic solid tumor cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Regulatory approval of both agents was based on data from single-arm phase 1/2 studies, including tumor-agnostic basket trials. In the absence of randomized controlled trials, there remains a paucity of data to demonstrate the comparative effectiveness of larotrectinib and entrectinib vs established standard-of-care treatments in cancers with NTRK gene fusions. Furthermore, no studies have directly compared the 2 agents. This article reviews what is known about the comparative effectiveness of larotrectinib and entrectinib vs standard therapies in TRK fusion cancer and examines the comparative effectiveness of the 2 TRK inhibitors. Historical and intrapatient comparisons suggest that TRK inhibitors improve disease response compared with preexisting treatments across most tumor histologies; indirect and limited comparisons of phase 1/2 data and preliminary simulation modeling suggest a potential advantage for larotrectinib over entrectinib in terms of clinical response and survival. Although limited, these data provide some insight into the position of these treatments in established treatment paradigms for TRK fusion cancer, a setting where real-world evidence will be slow to accrue due to the rare nature of these tumors but may be the only way in the future to answer the outstanding questions regarding these 2 agents. Meanwhile, we need to try to obtain the maximum benefit that can be achieved for our patients using the currently available knowledge.

The tropomyosin receptor kinase (TRK) family of proteins is encoded by neurotrophic tyrosine receptor kinase (NTRK) genes and has a role in the development and normal functioning of the nervous system. NTRK gene fusions have been identified as oncogenic drivers in a wide range of tumors in both adult and pediatric patients. There has recently been a paradigm shift in cancer treatment toward biomarker-based targeted therapies, as an increasing number of actionable targets are being identified across different tumors and/or tumor histologies. These targeted agents offer greater comparative effectiveness and safety vs historical nontargeted standard therapies. The development of drugs that specifically target oncogenic drivers of cancer has led to the emergence of screening technologies to identify the patients most likely to benefit from targeted therapy. This review describes the role of NTRK gene fusions in cancer and outlines the epidemiology of NTRK gene fusions, the therapeutic benefits of targeting TRK fusions with small molecule inhibitors, and recommendations for NTRK gene fusion testing in adult and pediatric patients with cancer, in order to guide treatment decisions.

Preventing depression in cancer patients on long-term opioid therapy should begin with depression screening before opioid initiation and repeated screening during treatment. In weighing the high morbidity of depression and opioid use disorder in patients with chronic cancer pain against a dearth of evidence-based therapies studied in this population, patients and clinicians are left to choose among imperfect but necessary treatment options. When possible, we advise engaging psychiatric and pain/palliative specialists through collaborative care models and recommending mindfulness and psychotherapy to all patients with significant depression alongside cancer pain. Medications for depression should be reserved for moderate to severe symptoms. We recommend escitalopram/citalopram or sertraline among selective serotonin reuptake inhibitors (SSRIs), or the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine, venlafaxine, or desvenlafaxine if patients have a significant component of neuropathic pain or fibromyalgia. Tricyclic antidepressants (TCAs) (consider nortriptyline or desipramine, which have better anticholinergic profiles) should be considered for patients who do not respond to or tolerate SSRI/SNRIs. Existing evidence is inadequate to definitively recommend methylphenidate or novel agents, such as ketamine or psilocybin, as adjunctive treatments for cancer-related depression and pain. Physicians who treat patients with cancer pain should utilize universal precautions to limit the risk of non-medical opioid use (non-medical opioid use). Patients should be screened for non-medical opioid use behaviors at initial consultation and at regular intervals during treatment using a non-judgmental approach that reduces stigma. Co-management with an addiction specialist may be indicated for patients at high risk of non-medical opioid use and opioid use disorder. Buprenorphine and methadone are indicated for the treatment of opioid use disorder, and while they have not been systematically studied for treatment of opioid use disorder in patients with cancer pain, they do provide analgesia for cancer pain. While an interdisciplinary team approach to manage psychological stress may be beneficial, this may not be possible for patients treated outside of comprehensive cancer centers.

Trisomy 21 causes Down syndrome, a condition characterized by cognitive impairments, immune dysregulation, and atypical morphogenesis. Using whole blood transcriptome analysis, we demonstrate that specific overexpression of four interferon receptors encoded on chromosome 21 associates with chronic interferon hyperactivity and systemic inflammation in Down syndrome. To define the contribution of interferon receptor overexpression to Down syndrome phenotypes, we used genome editing to correct interferon receptor gene dosage in mice carrying triplication of a large genomic region orthologous to human chromosome 21. Normalization of interferon receptor copy number attenuated lethal antiviral responses, prevented heart malformations, decreased developmental delays, improved cognition and normalized craniofacial anomalies. Therefore, interferon receptor gene dosage determines major hallmarks of Down syndrome, indicating that trisomy 21 elicits an interferonopathy amenable to therapeutic intervention.One-Sentence SummaryCorrection of interferon receptor gene dosage rescues multiple key phenotypes in a mouse model of trisomy 21.

It was not until the twentieth century that pain was considered a disease. Before that it was managed medically as a symptom. The motivations for declaring chronic pain a disease, whether of the body or of the brain, include increasing its legitimacy as clinical problem and research focus worthy of attention from healthcare and research organizations alike. But 1 problem with disease concepts is that having a disease favors medical solutions and tends to reduce patient participation. We argue that chronic pain, particularly chronic primary pain (recently designated a first tier pain diagnosis in International Diagnostic Codes 11), is a learned state that is not intransigent even if it has biological correlates. Chronic pain is sometimes a symptom, and may sometimes be its own disease. But here we question the value of a disease focus for much of chronic pain for which patient involvement is essential, and which may need a much broader societal approach than is suggested by the disease designation. PERSPECTIVE: This article examines whether designating chronic pain a disease of the body or brain is helpful or harmful to patients. Can the disease designation help advance treatment, and is it needed to achieve future therapeutic breakthrough? Or does it make patients over-reliant on medical intervention and reduce their engagement in the process of recovery?

Aims To compare 12‐month clinical effectiveness of insulin glargine 300 units/mL (Gla‐300) versus first‐generation basal insulin analogues (BIAs) (insulin glargine 100 units/mL [Gla‐100] or insulin detemir [IDet]) in patients with type 2 diabetes (T2D) who were at high risk of hypoglycaemia and switched from one BIA to a different one (Gla‐300 or Gla‐100/IDet) in a real‐world setting. Methods DELIVER High Risk was a retrospective observational cohort study of 2550 patients with T2D who switched BIA to Gla‐300 (Gla‐300 switchers) and were propensity score‐matched (1:1) to patients who switched to Gla‐100 or IDet (Gla‐100/IDet switchers). Outcomes were change in glycated haemoglobin A1c (HbA1c), attainment of HbA1c goals (, In patients with type 2 diabetes at high risk of hypoglycaemia, risk of inpatient/emergency department‐related hypoglycaemia was significantly lower during 12 months after switching to insulin glargine 300 units/mL, compared with switching to insulin glargine 100 units/mL or insulin detemir.

Objectives Publication bias has the potential to adversely impact clinical decision making and patient health if alternative decisions would have been made had there been complete publication of evidence. Methods The objective of our analysis was to determine if earlier publication of the complete evidence on rosiglitazone’s risk of myocardial infarction (MI) would have changed clinical decision making at an earlier point in time. We tested several methods for adjustment of publication bias to assess the impact of potential time delays to identifying the MI effect. We then performed a cumulative meta-analysis (CMA) for both published studies (published-only data set) and all studies performed (comprehensive data set). We then created an adjusted data set using existing methods of adjustment for publication bias (Harbord regression, Peter’s regression, and the nonparametric trim and fill method) applied to the limited data set. Finally, we compared the time to the decision threshold for each data set using CMA. Results Although published-only and comprehensive data sets did not provide notably different final summary estimates [OR = 1.4 (95 percent confidence interval [CI]: .95–2.05) and 1.42 (95 percent CI: 1.03–1.97)], the comprehensive data set reached the decision threshold 36 months earlier than the published-only data set. All three adjustment methods tested did not show a differential time to decision threshold versus the published-only data set. Conclusions Complete access to studies capturing MI risk for rosiglitazone would have led to the evidence reaching a clinically meaningful decision threshold 3 years earlier.

Chronic kidney disease (CKD) is a progressive and irreversible disease often associated with type 2 diabetes (T2D). CKD is associated with an elevated risk of cardiovascular (CV) events, increased mortality, and diminished quality of life. Finerenone is a new treatment for patients with CKD and T2D that delays CKD progression and reduces CV complications.To describe the approach and structure of a costeffectiveness model for finerenone for patients with CKD and T2D and compare it with existing economic models in CKD.A de novo cost-effectiveness model (FINE-CKD model), reflective of FIDELIO-DKD results, was developed for finerenone. The FINE-CKD model was designed and implemented in accordance with published guidance on modeling and was developed with input from economic and clinical experts. The final model approach was evaluated against existing modeling structures in CKD identified through a systematic literature review.The FINE-CKD model structure follows recommended modeling guidelines and has been designed in accordance with the best practices of modeling in CKD, while also incorporating important features of the FIDELIO-DKD design and results. The approach is consistent with the published literature, ensuring transparency and minimizing uncertainty that can arise from unnecessary complexity. The FINE-CKD model allows for reliable assessment of benefits and costs related to the use of finerenone in patients with CKD and T2D, and it is a reliable assessment of cost-effectiveness.