Divergent transcriptional regulation of astrocyte reactivity across disorders.

Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder1-4. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.

Standardizing feeding strategies for preterm infants born greater than 1500 grams.

BACKGROUND: Use of standardized feeding protocols and donor breast milk (DBM) have been studied primarily in infants born <1500 g and not examined exclusively in infants born >1500 g. METHODS: In this retrospective pre-post-implementation cohort study, we evaluated a protocol for preterm infants born >1500 g that was implemented clinically to standardize feeding advancements at 30 mL/kg/day, with infants born <33 weeks eligible to receive DBM. We compared placement of peripherally inserted central catheters for parenteral nutrition, feeding tolerance, growth, and maternal milk provision in the 18 months before/after implementation. The association between DBM intake and growth was evaluated using multivariable linear regression. RESULTS: We identified 133 and 148 eligible infants pre/post-implementation. Frequency of peripherally inserted central catheters and rate of maternal milk provision was not statistically different. While there was no difference in median days to full enteral volume, there was a narrower distribution post-implementation (p < 0.001). Growth was similar between eras, but each 10% increase in DBM was associated with 1.0 g/d decrease in weight velocity (p < 0.001). CONCLUSIONS: A feeding protocol for preterm infants >1500 g is associated with more consistent time to full enteral volume. Further investigation is needed to clarify DBM's impact on growth in this population. IMPACT: Despite practice creep, no study has examined the use of standardized feeding protocols or pasteurized donor breast milk exclusively in infants >1500 g. A feeding protocol in this population may achieve full enteral feedings more consistently. With appropriate fortification, donor breast milk can support adequate growth in infants born >1500 g but warrants further study.

Required growth facilitators propel axon regeneration across complete spinal cord injury.

Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury1-3, but efficient reversal of this regrowth failure remains elusive4. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity2,5-9, (ii) growth-supportive substrate10,11 and (iii) chemoattraction12,13-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI14,15; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor16,17 delivered via spatially and temporally controlled release from biomaterial depots18,19, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.

Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder.

Importance: Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results. Objective: To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test. Design, Setting, and Participants: The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021. Exposure: Enrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient's phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform. Main Outcomes and Measures: Primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care). Results: A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis. Conclusions and Relevance: The molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.

Parent Readiness for Their Preterm Infant's Neonatal Intensive Care Unit Discharge.

This study aims to examine the influence of hospital experience factors on parental discharge readiness, accounting for key background characteristics. Parents/guardians of infants 33 weeks of gestation or less at birth receiving neonatal intensive care at 6 sites were enrolled from April 2017 to August 2018. Participants completed surveys at enrollment, 3 weeks later, and at discharge. Multiple regression analysis assessed relationships between parental experience, well-being, and perceived readiness for infant discharge, adjusting for socioenvironmental, infant clinical, and parent demographic characteristics. Most (77%) of the 139 parents reported high levels of readiness for their infant's discharge and 92% reported high self-efficacy at discharge. The multiple regression model accounted for 40% of the variance in discharge readiness. Perceptions of family-centered care accounted for 12% of the variance; measures of parent well-being, anxiety, and parenting self-efficacy accounted for an additional 16% of the variance; parent characteristics accounted for an additional 9%; and infant characteristics accounted for less than 3% of the variance. Parental perceptions of the family-centeredness of the hospital experience, anxiety, and parenting self-efficacy accounted for a substantial proportion of the variance in readiness for discharge scores among parents of preterm infant. These influential perceptions are potentially modifiable by nursing-led interventions.

Relationship between social support and post-discharge mental health symptoms in mothers of preterm infants.

BACKGROUND: Social support is associated with decreased symptoms of postpartum mood and anxiety disorders (PMAD) in mothers of healthy infants, but less is known about social support and PMADs in mothers with preterm infants. The purpose of this study was to examine the relationship between social support and symptoms of PMADs reported by mothers in the months following hospital discharge of their preterm infant. METHODS: Mothers of infants less than 33 weeks gestational age were enrolled from neonatal intensive care units (NICU) at 6 sites. Mothers completed PMAD measures of depression, anxiety and post-traumatic stress approximately 3 months following their infant's discharge. Multivariable regression was used to evaluate relationships between social support and PMAD measures. RESULTS: Of 129 mothers, 1 in 5 reported clinically significant PMAD symptoms of: depression (24%), anxiety (19%), and post-traumatic stress (20%). Social support was strongly inversely associated with all 3 PMADs. Social support explained between 21% and 26% of the variance in depression, anxiety and post-traumatic stress symptoms. CONCLUSION: Increased social support may buffer PMAD symptoms in mothers of preterm infants after discharge. Research is needed to determine effective screening and interventions aimed at promoting social support for all parents during and following their infant's hospitalisation.

Remote ischemic conditioning in necrotizing enterocolitis: study protocol of a multi-center phase II feasibility randomized controlled trial.

PURPOSE: Remote ischemic conditioning (RIC) is a maneuver involving brief cycles of ischemia reperfusion in an individual's limb. In the early stage of experimental NEC, RIC decreased intestinal injury and prolonged survival by counteracting the derangements in intestinal microcirculation. A single-center phase I study demonstrated that the performance of RIC was safe in neonates with NEC. The aim of this phase II RCT was to evaluate the safety and feasibility of RIC, to identify challenges in recruitment, retainment, and to inform a phase III RCT to evaluate efficacy. METHODS: RIC will be performed by trained research personnel and will consist of four cycles of limb ischemia (4-min via cuff inflation) followed by reperfusion (4-min via cuff deflation), repeated on two consecutive days post randomization. The primary endpoint of this RCT is feasibility and acceptability of recruiting and randomizing neonates within 24 h from NEC diagnosis as well as masking and completing the RIC intervention. RESULTS: We created a novel international consortium for this trial and created a consensus on the diagnostic criteria for NEC and protocol for the trial. The phase II multicenter-masked feasibility RCT will be conducted at 12 centers in Canada, USA, Sweden, The Netherlands, UK, and Spain. The inclusion criteria are: gestational age < 33 weeks, weight ≥ 750 g, NEC receiving medical treatment, and diagnosis established within previous 24 h. Neonates will be randomized to RIC (intervention) or no-RIC (control) and will continue to receive standard management of NEC. We expect to recruit and randomize 40% of eligible patients in the collaborating centers (78 patients; 39/arm) in 30 months. Bayesian methods will be used to combine uninformative prior distributions with the corresponding observed proportions from this trial to determine posterior distributions for parameters of feasibility. CONCLUSIONS: The newly established NEC consortium has generated novel data on NEC diagnosis and defined the feasibility parameters for the introduction of a novel treatment in NEC. This phase II RCT will inform a future phase III RCT to evaluate the efficacy and safety of RIC in early-stage NEC.

Growth Failure Prevalence in Neonates with Gastroschisis : A Statewide Cohort Study.

OBJECTIVES: To perform a multicenter study to assess growth failure in hospitalized infants with gastroschisis. STUDY DESIGN: This study included neonates with gastroschisis within sites in the University of California Fetal Consortium. The study's primary outcome was growth failure at hospital discharge, defined as a weight or length z score decrease >0.8 from birth. Regression analysis was performed to assess changes in z scores over time. RESULTS: Among 125 infants with gastroschisis, the median gestational age was 37 weeks (IQR 35-37). Length of stay was 32 days (23-60); 55% developed weight or length growth failure at discharge (28% had weight growth failure, 42% had length growth failure, and 15% had both weight and length growth failure). Weight and length z scores at 14 days, 30 days, and discharge were less than birth (P < .01 for all). Weight and length z scores declined from birth to 30 days (-0.10 and -0.11 z score units/week, respectively, P < .001). Length growth failure at discharge was associated with weight and length z score changes over time (P < .05 for both). Lower gestational age was associated with weight growth failure (OR 0.70 for each gestational age week, 95% CI 0.55-0.89, P = .004). CONCLUSIONS: Growth failure, in particular linear growth failure, is common in infants with gastroschisis. These data suggest the need to improve nutritional management in these infants.

The effects of green tea on acne vulgaris: A systematic review and meta-analysis of randomized clinical trials.

Green tea extract (GTE) has been studied for the treatment of acne based on its anti-inflammatory/antioxidant properties. This systematic review and meta-analysis aimed to examine the effects of GTE on acne. Electronic databases, including PubMed, Embase, and the Cochrane Library were systematically searched up to August 2019. The effect size of acne lesion counts is presented as mean differences and 95% confidence intervals (CIs). Five randomized-controlled studies were included in the meta-analysis (N; experimental = 125, control = 122). GTE significantly reduced the number of inflammatory lesions (-9.38; 95% CI: -14.13 to -4.63). In subgroup analysis, topical GTE application significantly reduced the inflammatory lesion counts (-11.39; 95% CI: -15.91 to -6.86) whereas oral GTE intake showed minimal effect (-1.40; 95% CI: -2.50 to -0.30). Although GTE did not significantly reduce the number of non-inflammatory lesions (-21.65; 95% CI: -47.52 to 4.22), when stratified by the route of admission, non-inflammatory acne lesions were significantly reduced by topical GTE application (-32.44; 95% CI: -39.27 to -25.62) but not with oral GTE administration (0.20; 95% CI: 0.00 to 0.40). This systematic review and meta-analysis suggest that topical GTE application is beneficial for the treatment of acne without causing significant adverse events while oral GTE intake has limited effects. Further high-quality clinical trials are warranted.

Challenges in diagnosing necrotizing enterocolitis.

One of the many challenges with necrotizing enterocolitis (NEC) remains our inability to make an accurate diagnosis of NEC. The lack of a unifying cause and multiple variations in presentations lead to great uncertainty with NEC. Separating out the needs of the researcher wanting to define NEC from the clinician and patient family's perspectives who want an accurate diagnosis for NEC is important. The need to augment and/or replace the outdated modified Bell staging criteria is crucial to improving NEC management. Emerging literature suggests that genetic susceptibility and stool microbiota signatures may help identify preterm infants at increased risk of the disease. Ongoing studies using single or multi-omic approaches may help to characterize biomarkers that will aid in the prediction or early diagnosis of NEC, as well as differentiate other causes of severe bowel injury. Bowel ultrasound shows promise in improving our diagnostic accuracy for NEC but has been slow in adoption. Patient family perspectives are key in accelerating our efforts to integrate newer diagnostic methods into practice.

Human milk fortification: the clinician and parent perspectives.

This study reports on the human milk fortification session at the 2019 NEC Society Symposium, which included clinicians and parents discussing the evidence comparing fortification options such as efficacy, safety, cost effectiveness, and the need for parents to be informed about fortifier choice. With the current literature available and the varying standard of care practices for human milk fortification, further studies are needed to determine the most complete diet for preterm infants. The optimal diet would not only provide key nutrients and energy for growth and development, but also improve short- and long-term outcomes. Parents, as advocates and providers for their infant, should be informed, educated, and included in the discussion and decisions regarding fortification of human milk for their infant.

Grading the evidence to identify strategies to modify risk for necrotizing enterocolitis.

Although risk for necrotizing enterocolitis (NEC) is often presented from the perspective of a premature infant's vulnerability to nonmodifiable risk factors, in this paper we describe the evidence and present recommendations to manage modifiable risks that are amenable to clinical actions. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, we present recommendations in the context of their supporting evidence in a way that balances risks (e.g. potential harm, cost) and benefits. Across the prenatal, intrapartum, early and late clinical course, strategies to limit NEC risk in premature infants are presented. Our goal is to summarize modifiable NEC risk factors, grade the evidence to offer quality improvement (QI) targets for healthcare teams and offer a patient-family advocate's perspective on how to engage parents to recognize and reduce NEC risk.

Team Stress and Adverse Events during Neonatal Tracheal Intubations: A Report from NEAR4NEOS.

OBJECTIVE: This study aimed to examine the association between team stress level and adverse tracheal intubation (TI)-associated events during neonatal intubations. STUDY DESIGN: TIs from 10 academic neonatal intensive care units were analyzed. Team stress level was rated immediately after TI using a 7-point Likert scale (1 = high stress). Associations among team stress, adverse TI-associated events, and TI characteristics were evaluated. RESULT: In this study, 208 of 2,009 TIs (10%) had high stress levels (score < 4). Oxygenation failure, hemodynamic instability, and family presence were associated with high stress level. Video laryngoscopy and premedication were associated with lower stress levels. High stress level TIs were associated with adverse TI-associated event rates (31 vs. 16%, p < 0.001), which remained significant after adjusting for potential confounders including patient, provider, and practice factors associated with high stress (odds ratio: 1.90, 96% confidence interval: 1.36-2.67, p < 0.001). CONCLUSION: High team stress levels during TI were more frequently reported among TIs with adverse events.

Through Thick and Thin: The In Vitro Effects of Thickeners on Infant Feed Viscosity.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common problem in neonates, and current modalities for thickening human milk produce inconsistent outcomes. The objective of this in vitro study is to measure the viscosity effect of different thickening strategies. METHODS: We thickened donor human milk (DHM) and formula using various thickeners: starch-based thickeners (SBT; Thick It, rice cereal), and gum-based thickeners (GBT; xanthan gum: Simply Thick, Thicken Up Clear; carob gum: GelMix). We also assessed formula with added starches marketed for reflux, including Similac Spit Up (SSU) and Enfamil AR (EAR). The viscosity of each sample was measured over time using a rotary viscometer. Additional variables, including acidity, temperature, and the addition of human milk fortifier, were tested. RESULTS: Formula can be effectively thickened with all tested thickeners, but the viscosities of thickened formula increase over time. On the other hand, DHM does not effectively thicken with SBT. Autoclaving DHM inactivates digestive enzymes, thus allowing SBT to successfully thicken autoclaved DHM. GBT effectively thickened both DHM and formula but reached higher viscosities than intended based on manufacturer recommendations. Adding acid to xanthan-gum thickened DHM resulted in phase separation and formation of solid precipitant. CONCLUSIONS: Current thickening strategies of preterm infant feeding produces highly variable results in final feed viscosity. The unpredictable properties of gum-based thickeners raise questions about their safety profile. Objective measures of liquid viscosity and careful consideration of acidity and time are recommended for adequate comparisons of thickening regimens. Human milk continues to be the most challenging feed type to thicken.

Comparison of family centered care with family integrated care and mobile technology (mFICare) on preterm infant and family outcomes: a multi-site quasi-experimental clinical trial protocol.

BACKGROUND: Family Centered Care (FCC) has been widely adopted as the framework for caring for infants in the Neonatal Intensive Care Unit (NICU) but it is not uniformly defined or practiced, making it difficult to determine impact. Previous studies have shown that implementing the Family Integrated Care (FICare) intervention program for preterm infants in the NICU setting leads to significant improvements in infant and family outcomes. Further research is warranted to determine feasibility, acceptability and differential impact of FICare in the US context. The addition of a mobile application (app) may be effective in providing supplemental support for parent participation in the FICare program and provide detailed data on program component uptake and outcomes. METHODS: This exploratory multi-site quasi-experimental study will compare usual FCC with mobile enhanced FICare (mFICare) on growth and clinical outcomes of preterm infants born at or before 33 weeks gestational age, as well as the stress, competence and self-efficacy of their parents. The feasibility and acceptability of using mobile technology to gather data about parent involvement in the care of preterm infants receiving FCC or mFICare as well as of the mFICare intervention will be evaluated (Aim 1). The effect sizes for infant growth (primary outcome) and for secondary infant and parent outcomes at NICU discharge and three months after discharge will be estimated (Aim 2). DISCUSSION: This study will provide new data about the implementation of FICare in the US context within various hospital settings and identify important barriers, facilitators and key processes that may contribute to the effectiveness of FICare. It will also offer insights to clinicians on the feasibility of a new mobile application to support parent-focused research and promote integration of parents into the NICU care team in US hospital settings. TRIAL REGISTRATION: ClinicalTrials.gov, ID NCT03418870. Retrospectively registered on December 18, 2017.

The Use of Telemedicine to Address Disparities in Access to Specialist Care for Neonates.

Introduction: Outcomes for premature and critically ill neonates are improved with care provided by neonatologists in a neonatal intensive care unit (NICU). For smaller hospitals, maintaining the personnel and equipment necessary for the delivery and care of unexpectedly high-risk neonates is a significant challenge. To address this disparity in access, telemedicine has been increasingly used to support providers, patients, and their families in community newborn nurseries and NICUs. The purpose of this review is to present the current state of the use of telemedicine by regional NICUs to support community newborn nurseries, NICUs, and families. Methods: A literature review was conducted by two independent reviewers. Articles were selected for inclusion if they described the use of telemedicine with neonates or in the NICU. Two reviewers assessed the quality of the articles using the National Heart, Lung, and Blood Institute Study Quality Assessment Tools. Results: Fourteen articles were identified. After consensus discussion, eight of the articles were rated good and six were rated fair by the two reviewers. Many of the articles suggested improvements in quality of care, family satisfaction, and reductions in the cost of care. Unfortunately, a majority of the studies to date have had small sample sizes or were performed in a single institution and lacked robust evaluations of patient- and family-centered outcomes and provider decision making. Conclusions: While these early studies are promising, more robust studies involving more patients and more institutions are needed to identify opportunities where telemedicine can impact health outcomes, patient-centeredness, or costs of care of neonates.

Human milk oligosaccharide composition predicts risk of necrotising enterocolitis in preterm infants.

OBJECTIVE: Necrotising enterocolitis (NEC) is one of the most common and often fatal intestinal disorders in preterm infants. Markers to identify at-risk infants as well as therapies to prevent and treat NEC are limited and urgently needed. NEC incidence is significantly lower in breast-fed compared with formula-fed infants. Infant formula lacks human milk oligosaccharides (HMO), such as disialyllacto-N-tetraose (DSLNT), which prevents NEC in neonatal rats. However, it is unknown if DSLNT also protects human preterm infants. DESIGN: We conducted a multicentre clinical cohort study and recruited 200 mothers and their very low birthweight infants that were predominantly human milk-fed. We analysed HMO composition in breast milk fed to infants over the first 28 days post partum, matched each NEC case with five controls and used logistic regression and generalised estimating equation to test the hypothesis that infants who develop NEC receive milk with less DSLNT than infants who do not develop NEC. RESULTS: Eight infants in the cohort developed NEC (Bell stage 2 or 3). DSLNT concentrations were significantly lower in almost all milk samples in NEC cases compared with controls, and its abundance could identify NEC cases prior to onset. Aggregate assessment of DSLNT over multiple days enhanced the separation of NEC cases and control subjects. CONCLUSIONS: DSLNT content in breast milk is a potential non-invasive marker to identify infants at risk of developing NEC, and screen high-risk donor milk. In addition, DSLNT could serve as a natural template to develop novel therapeutics against this devastating disorder.

Effect of gemigliptin on glycaemic variability in patients with type 2 diabetes (STABLE study).

The aim of this study was to evaluate the effect of gemigliptin vs sitagliptin or glimepiride as initial combination therapy with metformin on glycaemic variability and to assess the correlation between glycaemic variability reduction and the dipeptidyl peptidase-4 (DPP-4) inhibition in patients with type 2 diabetes. This multicentre, randomized, active-controlled, open-label exploratory study included 69 patients with HbA1c > 7.5%. Subjects were randomized to receive gemigliptin 50 mg (n = 24), sitagliptin 100 mg (n = 23) or glimepiride 2 mg (n = 22) for 12 weeks. After 12 weeks, the change in mean amplitude of glycaemic excursion (MAGE) compared with baseline was significantly lower in the DPP-4 inhibitor groups compared with that in patients who received glimepiride. Furthermore, the standard deviation (SD) of glucose was significantly lower in patients who received gemigliptin than that in patients who received sitagliptin or glimepiride. The DPP-4 inhibition was significantly correlated with changes in MAGE and SD of glucose. In conclusion, gemigliptin and sitagliptin were more effective than glimepiride in reducing glycaemic variability as initial combination therapy with metformin in patients with type 2 diabetes, and the DPP-4 inhibition was associated with a reduction in glycaemic variability.