A loss-of-function mutation in KCNJ11 causing sulfonylurea-sensitive diabetes in early adult life.

AIMS/HYPOTHESIS: The ATP-sensitive potassium (KATP) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) or regulatory (sulfonylurea receptor 1, encoded by ABCC8) subunits result in congenital hyperinsulinism, whereas gain-of-function mutations cause neonatal diabetes. Here, we report a novel loss-of-function mutation (Ser118Leu) in the pore helix of Kir6.2 paradoxically associated with sulfonylurea-sensitive diabetes that presents in early adult life. METHODS: A 31-year-old woman was diagnosed with mild hyperglycaemia during an employee screen. After three pregnancies, during which she was diagnosed with gestational diabetes, the patient continued to show elevated blood glucose and was treated with glibenclamide (known as glyburide in the USA and Canada) and metformin. Genetic testing identified a heterozygous mutation (S118L) in the KCNJ11 gene. Neither parent was known to have diabetes. We investigated the functional properties and membrane trafficking of mutant and wild-type KATP channels in Xenopus oocytes and in HEK-293T cells, using patch-clamp, two-electrode voltage-clamp and surface expression assays. RESULTS: Functional analysis showed no changes in the ATP sensitivity or metabolic regulation of the mutant channel. However, the Kir6.2-S118L mutation impaired surface expression of the KATP channel by 40%, categorising this as a loss-of-function mutation. CONCLUSIONS/INTERPRETATION: Our data support the increasing evidence that individuals with mild loss-of-function KATP channel mutations may develop insulin deficiency in early adulthood and even frank diabetes in middle age. In this case, the patient may have had hyperinsulinism that escaped detection in early life. Our results support the importance of functional analysis of KATP channel mutations in cases of atypical diabetes.

A qualitative study on opportunities to improve research engagement and inclusion of Black adults with systemic lupus erythematosus.

In response to racial inequities in systemic lupus erythematosus (SLE), we aimed to identify practical recommendations for increasing engagement and inclusion of Black adults in SLE research. We used a qualitative, interpretive description approach and recruited 30 Black adults diagnosed with SLE in Michigan to participate in semi-structured interviews. Theme development focused on what factors influenced research perceptions and how research did not meet participant needs and expectations. We developed five main themes: (1) Ethical and equitable research. Participants shared how the impacts of past and present-day racism impacted their willingness to participate in research. (2) Trusting researchers to conduct studies and translate findings to health care. Participants had concerns related to researcher intentions and expressed the importance of communicating research outcomes to participants and translating findings to health care. (3) Drug trial beneficence. When considering drug trials, several people did not consider the potential benefits worth the risk of side effects, and some said they would need to consult with their doctor before agreeing to participate. (4) Altruism. Participants explained how the desire to help others was a motivating factor for participating in research and donating biological samples. (5) Research priorities. Participants described a need for better treatments that value their overall health and well-being. Findings indicate that researchers can center the perspectives of Black people with SLE across the research life cycle-beyond a focus on adequate racial diversity among study participants.

Perforation of the Heart During Elective Removal of an Inferior Vena Cava Filter.

ABSTRACT: A common treatment for venous thromboembolic disease in patients with contraindications to anticoagulation includes placement of an inferior vena cava (IVC) filter. Temporary filters are available to avoid the risk of long-term permanent placement. A woman in her 60s with a history of uterine serous carcinoma presented to the emergency department with cardiac arrest following elective attempted IVC filter removal. Three months prior, a temporary filter was placed because anticoagulation medication was stopped in preparation for a hysterectomy. During the IVC retrieval procedure, which was performed using an intravascular approach from the right jugular vein, the filter was tilted, requiring the use of a different retrieval sheath. During catheter reentry, the patient complained of discomfort in the chest and neck, after which she became hypotensive, lost consciousness, and died. Autopsy revealed 2 cardiac perforations, one in each ventricle. Approximately 600 mL of liquid and clotted blood was within the tense pericardial sac. An IVC filter was found in place, with no adjacent hemorrhage.To our knowledge, this is the first reported fatality due to cardiac perforation by an access sheath during intravascular removal of an IVC filter. This instance also documents the time course of the cardiac perforations to the resultant loss of consciousness.

'I'm still here, I'm alive and breathing': The experience of Black Americans with long COVID.

AIMS AND OBJECTIVES: In this study, we aimed to characterize the impact of long COVID on quality of life and approaches to symptom management among Black American adults. BACKGROUND: As a novel condition, qualitative evidence concerning long COVID symptoms and their impact on quality of life can inform the refinement of diagnostic criteria and care plans. However, the underrepresentation of Black Americans in long COVID research is a barrier to achieving equitable care for all long COVID patients. DESIGN: We employed an interpretive description study design. METHODS: We recruited a convenience sample of 15 Black American adults with long COVID. We analysed the anonymized transcripts from race-concordant, semi-structured interviews using an inductive, thematic analysis approach. We followed the SRQR reporting guidelines. RESULTS: We identified four themes: (1) The impact of long COVID symptoms on personal identity and pre-existing conditions; (2) Self-management strategies for long COVID symptoms; (3) Social determinants of health and symptom management; and (4) Effects on interpersonal relationships. CONCLUSION: Findings demonstrate the comprehensive ramifications of long COVID on the lives of Black American adults. Results also articulate how pre-existing conditions, social risk factors, distrust due to systemic racism, and the nature of interpersonal relationships can complicate symptom management. RELEVANCE TO CLINICAL PRACTICE: Care approaches that support access to and implementation of integrative therapies may be best suited to meet the needs of long COVID patients. Clinicians should also prioritize eliminating patient exposure to discrimination, implicit bias, and microaggressions. This is of particular concern for long COVID patients who have symptoms that are difficult to objectively quantify, such as pain and fatigue. NO PATIENT OR PUBLIC CONTRIBUTION: While patient perspectives and experiences were the focus of this study, patients were not involved with the design or conduct of the study, data analysis or interpretation, or writing the manuscript.

Preclinical development of ZED8, an 89Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy.

BACKGROUND: ZED8 is a novel monovalent antibody labeled with zirconium-89 for the molecular imaging of CD8. This work describes nonclinical studies performed in part to provide rationale for and to inform expectations in the early clinical development of ZED8, such as in the studies outlined in clinical trial registry NCT04029181 [1]. METHODS: Surface plasmon resonance, X-ray crystallography, and flow cytometry were used to characterize the ZED8-CD8 binding interaction, its specificity, and its impact on T cell function. Immuno-PET with ZED8 was assessed in huCD8+ tumor-bearing mice and in non-human primates. Plasma antibody levels were measured by ELISA to determine pharmacokinetic parameters, and OLINDA 1.0 was used to estimate radiation dosimetry from image-derived biodistribution data. RESULTS: ZED8 selectively binds to human CD8α at a binding site approximately 9 Å from that of MHCI making mutual interference unlikely. The equilibrium dissociation constant (KD) is 5 nM. ZED8 binds to cynomolgus CD8 with reduced affinity (66 nM) but it has no measurable affinity for rat or mouse CD8. In a series of lymphoma xenografts, ZED8 imaging was able to identify different CD8 levels concordant with flow cytometry. In cynomolgus monkeys with tool compound 89Zr-aCD8v17, lymph nodes were conspicuous by imaging 24 h post-injection, and the pharmacokinetics suggested a flat-fixed first-in-human dose of 4 mg per subject. The whole-body effective dose for an adult human was estimated to be 0.48 mSv/MBq, comparable to existing 89Zr immuno-PET reagents. CONCLUSION: 89Zr immuno-PET with ZED8 appears to be a promising biomarker of tissue CD8 levels suitable for clinical evaluation in cancer patients eligible for immunotherapy.

Social determinants of depression in systemic lupus erythematosus: A systematic scoping review.

Social determinants of health (SDOH) influence inequities in systemic lupus erythematosus (SLE). While these inequities contribute to overall disease experience, there is little consensus guiding our understanding of the psychological implications of SDOH in SLE. Given the paucity of evidence in this area, the aim of this scoping review was to systematically assess the volume and features of available research literature on associations of SDOH with depression in SLE over the past 20 years, from 1 January 2000 to 16 November 2021. We developed a search strategy for PubMed and EMBASE that included keywords for depression and lupus. After screening 2188 articles, we identified 22 original articles that met our inclusion criteria. At least one SDOH was associated with depression in two of the six studies with unadjusted estimates and 13 of the 16 studies with adjusted estimates. Results provide consistent but sparse evidence that SDOH are associated with depression in SLE. Additionally, depression epidemiology in SLE may differ from the general population such that depression risk is more similar across genders and racial/ethnic groups. More work is needed to identify the SDOH that have the greatest impact on depression and mental health among SLE patients, as well as how and when to intervene.

Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies.

Posttranslational modification of proteins with polyubiquitin occurs in diverse signaling pathways and is tightly regulated to ensure cellular homeostasis. Studies employing ubiquitin mutants suggest that the fate of polyubiquitinated proteins is determined by which lysine within ubiquitin is linked to the C terminus of an adjacent ubiquitin. We have developed linkage-specific antibodies that recognize polyubiquitin chains joined through lysine 63 (K63) or 48 (K48). A cocrystal structure of an anti-K63 linkage Fab bound to K63-linked diubiquitin provides insight into the molecular basis for specificity. We use these antibodies to demonstrate that RIP1, which is essential for tumor necrosis factor-induced NF-kappaB activation, and IRAK1, which participates in signaling by interleukin-1beta and Toll-like receptors, both undergo polyubiquitin editing in stimulated cells. Both kinase adaptors initially acquire K63-linked polyubiquitin, while at later times K48-linked polyubiquitin targets them for proteasomal degradation. Polyubiquitin editing may therefore be a general mechanism for attenuating innate immune signaling.

Comparing the structures and photophysical properties of two charge transfer co-crystals.

Organic co-crystals have emerged as a promising class of semiconductors for next-generation optoelectronic devices due to their unique photophysical properties. This paper presents a joint experimental-theoretical study comparing the crystal structure, spectroscopy, and electronic structure of two charge transfer co-crystals. Reported herein is a novel co-crystal Npe:TCNQ, formed from 4-(1-naphthylvinyl)pyridine (Npe) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) via molecular self-assembly. This work also presents a revised study of the co-crystal composed of Npe and 1,2,4,5-tetracyanobenzene (TCNB) molecules, Npe:TCNB, herein reported with a higher-symmetry (monoclinic) crystal structure than previously published. Npe:TCNB and Npe:TCNQ dimer clusters are used as theoretical model systems for the co-crystals; the geometries of the dimers are compared to geometries of the extended solids, which are computed with periodic boundary conditions density functional theory. UV-Vis absorption spectra of the dimers are computed with time-dependent density functional theory and compared to experimental UV-Vis diffuse reflectance spectra. Both Npe:TCNB and Npe:TCNQ are found to exhibit neutral character in the S0 state and ionic character in the S1 state. The high degree of charge transfer in the S1 state of both Npe:TCNB and Npe:TCNQ is rationalized by analyzing the changes in orbital localization associated with the S1 transitions.

Incentives for Uptake of and Adherence to Outpatient Stroke Rehabilitation Services: A 3-Arm Randomized Controlled Trial.

OBJECTIVE: To determine if rehabilitation uptake and adherence can be increased by providing coordinated transportation (increased convenience) and eliminating out-of-pocket costs (reduced expense). DESIGN: Three-arm randomized controlled trial. SETTING: Stroke units of 2 Singapore tertiary hospitals. PARTICIPANTS: Singaporeans or permanent residents 21 years or older who were diagnosed as having stroke and were discharged home with physician's recommendation to continue outpatient rehabilitation (N=266). INTERVENTIONS: A Transportation Incentives arm (T), which provides free transportation services, a Transportation & Sessions Incentives arm (T&S), offering free transportation and prescribed stroke rehabilitation sessions, and a control arm, Education (E), consisting of a stroke rehabilitation educational program. MAIN OUTCOME MEASURES: The primary study outcome was uptake of outpatient rehabilitation services (ORS) among patients poststroke and key predefined secondary outcomes being number of sessions attended and adherence to prescribed sessions. RESULTS: Uptake rate of ORS was 73.0% for E (confidence interval [CI], 63.8%-82.3%), 81.8% for T (CI, 73.8%-89.8%), and 84.3% for T&S (CI, 76.7%-91.8%). Differences of T and T&S vs E were not statistically significant (P=.22 and P=.10, respectively). However, average number of rehabilitation sessions attended were significantly higher in both intervention arms: 5.50±7.65 for T and 7.51±9.52 for T&S vs 3.26±4.22 for control arm (E) (T vs E: P=.017; T&S vs E: P<.001). Kaplan-Meier analysis indicated that persistence was higher for T&S compared with E (P=.029). CONCLUSIONS: This study has demonstrated a possibility in increasing the uptake of and persistence to stroke ORS with free transportation and sessions. Incentivizing survivors of stroke to take up ORS is a new strategy worthy of further exploration for future policy change in financing ORS or other long-term care services.

Evidence of intrauterine growth restriction and growth hormone deficiency in 49,XXXXY syndrome.

49,XXXXY is an X and Y chromosome variation that occurs in 1:85,000 to 1:100,000 live male births. Previous case studies have described boys with this disorder to be shorter than average when compared with boys with only one extra chromosome and with the mean stature in a small cohort reported to range from the seventh to 33rd percentile. The origin behind the possible differences in height between boys with 47,XXY and 49,XXXXY is currently unknown, however one study hypothesized that it was due to a difference in the expression of the SHOX gene. This study reports on the anthropometric measurements of 84 boys with 49,XXXXY. Forty-five percent of children with 49,XXXXY were found to be below the third percentile in height at the time of evaluation. In addition, 7.14% of the cohort were diagnosed and given treatment for growth hormone deficiency (GHD). The analysis of this cohort demonstrates that the below average heights seen throughout childhood in this population potentially begins prenatally and suggests that boys with 49,XXXXY may be at a higher risk for intrauterine growth restriction (IUGR) and GHD. Future research is needed to investigate the etiology of the poor growth in boys with 49,XXXXY and evaluate the incidence of GHD and IUGR in this population.

Patients without colonoscopic follow-up after abnormal fecal immunochemical tests are often unaware of the abnormal result and report several barriers to colonoscopy.

BACKGROUND: The fecal immunochemical test (FIT) is the second most commonly used colorectal cancer (CRC) screening modality in the United States; yet, follow-up of abnormal FIT results with diagnostic colonoscopy is underutilized. Our objective was to determine patient-reported barriers to diagnostic colonoscopy following abnormal FIT in an academic healthcare setting. METHODS: We included patients age 50-75 with an abnormal FIT result between 1/1/2015 and 10/31/2017 and no documented follow-up diagnostic colonoscopy. We abstracted demographic data from the electronic health record (EHR). Study personnel conducted telephone surveys with patients to confirm colonoscopy completion and elicit data on notification of FIT results and barriers to colonoscopy. We also provided brief verbal education about diagnostic colonoscopy. We calculated frequencies of demographic data and survey responses and compared survey responses by interest in colonoscopy after education. RESULTS: We surveyed 67 patients. Fifty-one were aware of the abnormal FIT result, and a majority learned of the abnormal FIT result by direct communication with providers (19, 37.3%) or EHR messaging (11, 21.6%). Overall, fifty-three patients (79.1%) confirmed lack of colonoscopy, citing provider-related (19, 35.8%), patient-related (16, 30.2%), system-related (1, 1.9%), or multifactorial (17, 32.1%) reasons. Lack of knowledge of FIT result (14, 26.4%) was most common. After brief education, 20 (37.7%) patients requested colonoscopy. CONCLUSION: Patients with an abnormal FIT reported various multi-level barriers to diagnostic colonoscopy after abnormal FIT, including knowledge of FIT results. When provided with brief education, participants expressed interest in diagnostic colonoscopy. Future efforts will evaluate interventions to improve colonoscopy follow-up.

A review of the intriguing interaction between testosterone and neurocognitive development in males with 47,XXY.

PURPOSE OF REVIEW: Although 47,XXY (Klinefelter syndrome) was first discovered more than 50 years ago, there have been limited comprehensive studies on this disorder. The present review explains the study of neurodevelopmental dysfunction and the impact of testosterone replacement at specific junctions in the life of males with 47,XXY. The intricate relationship between testosterone, neurodevelopment, health, and well being warrants an in-depth investigation in order to achieve optimal outcomes. RECENT FINDINGS: Current literature suggests that the implementation of biological treatment has a positive impact on numerous areas of neurodevelopment. Further research is needed to determine ideal dosage, timing, and frequency of biological treatment for efficacy and safety of the child with 47,XXY. SUMMARY: As noninvasive prenatal screening has detected increasing numbers of fetuses with 47,XXY, parents may benefit from both prenatal and postnatal counseling, including the latest innovative biological treatment, that may further optimize the child's outcome, especially when coupled with targeted early intervention services.

Barriers to Follow-up Colonoscopies for Patients With Positive Results From Fecal Immunochemical Tests During Colorectal Cancer Screening.

BACKGROUND & AIMS: Colorectal cancer is common yet largely preventable. The fecal immunochemical test (FIT) is a highly recommended screening method, but patients with positive results must receive a follow-up colonoscopy to determine if they have precancerous or cancerous lesions. We characterized colonoscopic follow-up evaluations and reasons for lack of follow-up in a Veterans Affairs (VA) cohort. METHODS: We conducted a retrospective cross-sectional analysis of patients 50 to 75 years old with a positive FIT result from January 1, 2014, through May 31, 2016, in a network of 12 VAs sites in southern California. We determined the proportion of patients who received a follow-up colonoscopy, median time to colonoscopy, and colonoscopy findings. For patients who did not undergo colonoscopy, we determined the documented reason for lack of colonoscopy and factors associated with declining the colonoscopy examination. RESULTS: Of the 10,635 FITs performed, 916 (8.6%) produced positive results; 569 of these (62.1%) were followed by colonoscopy. The median time to colonoscopy after a positive FIT result was 83 days (interquartile range, 54-145 d), which did not vary between veterans who received a colonoscopy at a VA facility (81 d; interquartile range, 52-143 d) vs a non-VA site (87 d; interquartile range, 60-154 d) (P = .2). For the 347 veterans (37.9%) who did not undergo follow-up colonoscopy, the reasons were patient-related (49.3%), provider-related (16.4%), system-related (12.1%), or multifactorial (22.2%). Overall, patient decline of colonoscopy (35.2%) was the most common reason. CONCLUSIONS: In a cohort of veterans with positive results from FITs during CRC screening, reasons for lack of follow-up colonoscopy varied and included patient, provider, and system factors. These findings can be used to reduce barriers to follow-up colonoscopy and to address system-level challenges in scheduling and attrition for colonoscopy.

Water molecules in protein-ligand interfaces. Evaluation of software tools and SAR comparison.

Targeting the interaction with or displacement of the 'right' water molecule can significantly increase inhibitor potency in structure-guided drug design. Multiple computational approaches exist to predict which waters should be targeted for displacement to achieve the largest gain in potency. However, the relative success of different methods remains underexplored. Here, we present a comparison of the ability of five water prediction programs (3D-RISM, SZMAP, WaterFLAP, WaterRank, and WaterMap) to predict crystallographic water locations, calculate their binding free energies, and to relate differences in these energies to observed changes in potency. The structural cohort included nine Bruton's Tyrosine Kinase (BTK) structures, and nine bromodomain structures. Each program accurately predicted the locations of most crystallographic water molecules. However, the predicted binding free energies correlated poorly with the observed changes in inhibitor potency when solvent atoms were displaced by chemical changes in closely related compounds.

K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specific antibody.

Polyubiquitination is a posttranslational modification where ubiquitin chains containing isopeptide bonds linking one of seven ubiquitin lysines with the C terminus of an adjoining ubiquitin are covalently attached to proteins. While functions of K48- and K63-linked polyubiquitin are understood, the role(s) of noncanonical K11-linked chains is less clear. A crystal structure of K11-linked diubiquitin demonstrates a distinct conformation from K48- or K63-linked diubiquitin. We engineered a K11 linkage-specific antibody and use it to demonstrate that K11 chains are highly upregulated in mitotic human cells precisely when substrates of the ubiquitin ligase anaphase-promoting complex (APC/C) are degraded. These chains increased with proteasomal inhibition, suggesting they act as degradation signals in vivo. Inhibition of the APC/C strongly impeded the formation of K11-linked chains, suggesting that a single ubiquitin ligase is the major source of mitotic K11-linked chains. Our results underscore the importance of K11-linked ubiquitin chains as critical regulators of mitotic protein degradation.

Ubiquitin binding to A20 ZnF4 is required for modulation of NF-κB signaling.

Inactivating mutations in the ubiquitin (Ub) editing protein A20 promote persistent nuclear factor (NF)-κB signaling and are genetically linked to inflammatory diseases and hematologic cancers. A20 tightly regulates NF-κB signaling by acting as an Ub editor, removing K63-linked Ub chains and mediating addition of Ub chains that target substrates for degradation. However, a precise molecular understanding of how A20 modulates this pathway remains elusive. Here, using structural analysis, domain mapping, and functional assays, we show that A20 zinc finger 4 (ZnF4) does not directly interact with E2 enzymes but instead can bind mono-Ub and K63-linked poly-Ub. Mutations to the A20 ZnF4 Ub-binding surface result in decreased A20-mediated ubiquitination and impaired regulation of NF-κB signaling. Collectively, our studies illuminate the mechanistically distinct but biologically interdependent activities of the A20 ZnF and ovarian tumor (OTU) domains that are inherent to the Ub editing process and, ultimately, to regulation of NF-κB signaling.

Impact of baseline glycated haemoglobin, diabetes duration and body mass index on clinical outcomes in the LixiLan-O trial testing a titratable fixed-ratio combination of insulin glargine/lixisenatide (iGlarLixi) vs insulin glargine and lixisenatide monocomponents.

To determine whether baseline characteristics had an impact on clinical outcomes in the LixiLan-O trial (N = 1170), we compared the efficacy and safety of iGlarLixi, a titratable fixed-ratio combination of insulin glargine 100 U (iGlar) and lixisenatide (Lixi) with iGlar or Lixi alone in patients with uncontrolled type 2 diabetes mellitus (T2DM) on oral therapy. Subgroups according to baseline glycated haemoglobin (HbA1c; <8% or ≥8% [<64 or ≥64 mmol/mol]), T2DM disease duration (<7 or ≥7 years) and body mass index (BMI; <30 or ≥30 kg/m2 ) were investigated. In all subpopulations, iGlarLixi was consistently statistically superior to iGlar and Lixi alone in reducing HbA1c from baseline to week 30; higher proportions of patients achieved HbA1c <7% (<53 mmol/mol) with iGlarLixi vs iGlar and Lixi alone. Compared with iGlar, iGlarLixi resulted in a substantial decrease in 2-hour postprandial plasma glucose levels, and mitigation of weight gain, with no differences among subpopulations in incidence of symptomatic hypoglycaemia. iGlarLixi consistently improved glycaemic control compared with iGlar and Lixi alone, without weight gain or increase in hypoglycaemic risk compared with iGlar in the subpopulations tested, regardless of baseline HbA1c, disease duration and BMI.

Consistent findings in glycaemic control, body weight and hypoglycaemia with iGlarLixi (insulin glargine/lixisenatide titratable fixed-ratio combination) vs insulin glargine across baseline HbA1c, BMI and diabetes duration categories in the LixiLan-L trial.

AIMS: To assess the impact of baseline characteristics on clinical outcomes in the LixiLan-L trial, a randomized open-label trial designed to evaluate the efficacy and safety of iGlarLixi, a novel fixed-ratio combination of insulin glargine 100 U (iGlar) plus lixisenatide, in comparison with iGlar over 30 weeks in a population of patients with type 2 diabetes mellitus (T2DM) inadequately controlled on a previous regimen of basal insulin alone or in combination with 1 or 2 oral glucose-lowering drugs. MATERIALS AND METHODS: In this exploratory analysis of LixiLan-L (N = 736), efficacy outcomes were assessed within population subgroups derived from the following baseline characteristics: glycated haemoglobin [HbA1c; <8%, ≥8% (<64, ≥64 mmol/mol)]; duration of T2DM (<10, ≥10 years); body mass index (<30, ≥30 kg/m2 ). Furthermore, the incidence of symptomatic hypoglycaemia with plasma glucose ≤3.9 mmol/L (≤70 mg/dL) was also analysed according to the same subgroups. RESULTS: Compared with the iGlar treatment group, patients treated with iGlarLixi showed consistently greater reductions in HbA1c during the treatment period, with higher percentages of patients achieving the HbA1c target level of <7% (<53 mmol/mol) in all of the subpopulations tested (P < .0001 for all), having consistent mitigation of body weight gain and with no major differences in the incidence of hypoglycaemia. CONCLUSIONS: iGlarLixi consistently improved glycaemic control compared with iGlar in all baseline characteristic subgroups of patients with T2DM inadequately controlled with insulin, including difficult-to-treat subgroups of patients with long duration of diabetes, obesity and high HbA1c. Clinical trial number: NCT02058160 (clinicaltrials.gov).