Publications

Background: Human milk diet, preferably mother's own milk (MOM) over donor milk (DM), is recommended for preterm infants. Expression of MOM in proximity to preterm infants, especially during or immediately after skin-to-skin contact (SSC), is associated with greater milk production. However, the correlation between SSC and MOM production during hospital admission in preterm infants has not yet been studied. Our study investigated the relationship between SSC and MOM production and consumption in preterm infants during the first postnatal month of life. Materials and Methods: This was a prospective cohort study. Mothers and their preterm infants born at <35 weeks by gestational age (GA) and eligible for SSC within the first 5 postnatal days were eligible for the study. Mothers were given a binder to document pumped breast milk volumes and SSC sessions. Pumped breast milk volumes, enteral feeding type and volume, and SSC duration and frequency were collected daily over the first 28 days of life, along with demographic, perinatal, and feeding data from electronic medical records (EMR). Results: Mean birth GA and weight were 30 ± 3 weeks and 1,443 ± 576 g, respectively. SSC duration was inversely correlated with GA and weight. The SSC duration was positively correlated with ingested MOM volume after correcting for birth GA. The SSC duration was predictive of increased volumes of pumped MOM. Conclusion: Our findings suggest that SSC duration is associated with improved MOM production and consumption. SSC can be a useful tool to increase MOM exposure and improve long-term health outcomes in preterm infants.

MOTIVATION: Allostery enables changes to the dynamic behavior of a protein at distant positions induced by binding. Here, we present APOP, a new allosteric pocket prediction method, which perturbs the pockets formed in the structure by stiffening pairwise interactions in the elastic network across the pocket, to emulate ligand binding. Ranking the pockets based on the shifts in the global mode frequencies, as well as their mean local hydrophobicities, leads to high prediction success when tested on a dataset of allosteric proteins, composed of both monomers and multimeric assemblages.

RESULTS: Out of the 104 test cases, APOP predicts known allosteric pockets for 92 within the top 3 rank out of multiple pockets available in the protein. In addition, we demonstrate that APOP can also find new alternative allosteric pockets in proteins. Particularly interesting findings are the discovery of previously overlooked large pockets located in the centers of many protein biological assemblages; binding of ligands at these sites would likely be particularly effective in changing the protein's global dynamics.

AVAILABILITY AND IMPLEMENTATION: APOP is freely available as an open-source code (https://github.com/Ambuj-UF/APOP) and as a web server at https://apop.bb.iastate.edu/.

Autologous hematopoietic cell transplantation (auto-HCT) has long been the standard approach for patients with relapsed/refractory (R/R) chemosensitive diffuse large B cell lymphoma (DLBCL). However, the advent of chimeric antigen receptor (CAR) T cell therapy has caused a paradigm shift in the management of R/R DLBCL patients, especially with the recent approval of CD19-directed CAR-T therapy in the second-line setting in high-risk groups (primary refractory and early relapse [≤12 months]). Consensus on the contemporary role, optimal timing, and sequencing of HCT and cellular therapies in DLBCL is lacking; therefore, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines undertook this project to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 20 consensus statements with a few key statements as follows: (1) in the first-line setting, there is no role for auto-HCT consolidation for patients achieving complete remission (CR) following R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) or similar therapy in non-double-hit/triple-hit cases (DHL/THL) and in DHL/THL cases receiving intensive induction therapies, but auto-HCT may be considered in eligible patients receiving R-CHOP or similar therapies in DHL/THL cases; (2) auto-HCT consolidation with thiotepa-based conditioning is standard of care for eligible patients with primary central nervous system lymphoma achieving CR with first-line therapy; and (3) in the primary refractory and early relapse setting, the preferred option is CAR-T therapy, whereas in late relapse (>12 months), consolidation with auto-HCT is recommended for patients achieving chemosensitivity to salvage therapy (complete or partial response), and CAR-T therapy is recommended for those not achieving remission. These clinical practice recommendations will serve as a tool to guide clinicians managing patients with newly diagnosed and R/R DLBCL.

OBJECTIVE: Ample evidence exists for the role of abnormal gut microbiota composition and increased gut permeability ('leaky gut') in chronic inflammation that commonly co-occurs in the gut in both obesity and diabetes, yet the detailed mechanisms involved in this process have remained elusive.

DESIGN: In this study, we substantiate the causal role of the gut microbiota by use of faecal conditioned media along with faecal microbiota transplantation. Using untargeted and comprehensive approaches, we discovered the mechanism by which the obese microbiota instigates gut permeability, inflammation and abnormalities in glucose metabolism.

RESULTS: We demonstrated that the reduced capacity of the microbiota from both obese mice and humans to metabolise ethanolamine results in ethanolamine accumulation in the gut, accounting for induction of intestinal permeability. Elevated ethanolamine increased the expression of microRNA-miR-101a-3p by enhancing ARID3a binding on the miR promoter. Increased miR-101a-3p decreased the stability of zona occludens-1 (Zo1) mRNA, which in turn, weakened intestinal barriers and induced gut permeability, inflammation and abnormalities in glucose metabolism. Importantly, restoring ethanolamine-metabolising activity in gut microbiota using a novel probiotic therapy reduced elevated gut permeability, inflammation and abnormalities in glucose metabolism by correcting the ARID3a/miR-101a/Zo1 axis.

CONCLUSION: Overall, we discovered that the reduced capacity of obese microbiota to metabolise ethanolamine instigates gut permeability, inflammation and glucose metabolic dysfunctions, and restoring ethanolamine-metabolising capacity by a novel probiotic therapy reverses these abnormalities.

TRIAL REGISTRATION NUMBER: NCT02869659 and NCT03269032.

BACKGROUND: Lifestyle changes and dietary intervention, including the use of probiotics, can modulate dysbiosis of gut microbiome and contribute to the management of type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aim to assess the efficacy of metformin plus probiotics versus metformin alone on outcomes in patients with T2DM.

METHODS: We searched MEDLINE and EMBASE from inception to February 2023 to identify all randomized controlled trials (RCTs), which compared the use of metformin plus probiotics versus metformin alone in adult patients with T2DM. Data were summarized as mean differences (MD) with 95 % confidence interval (CI) and pooled under the random effects model.

FINDINGS: Fourteen RCTs (17 comparisons, 1009 patients) were included in this systematic review. Pooled results show a significant decrease in fasting glucose (FG) (MD = -0.64, 95 % CI = -1.06, -0.22) and HbA1c (MD = -0.29, 95 % CI = -0.47, -0.10) levels in patients with T2DM treated with metformin plus probiotics versus metformin alone. The addition of probiotics to metformin resulted in lower odds of gastrointestinal adverse events (Odds ratio = 0.18, 95 % CI = 0.09, 0.3.8; I2 = 0 %).

CONCLUSIONS: The addition of probiotics to metformin therapy is associated with improvement in T2DM outcomes. However, high-quality and adequately reported RCTs are needed in the future to confirm our findings.

BACKGROUND: Opioids are routinely prescribed to patients postoperatively after cesarean delivery. With rates of cesarean deliveries increasing globally and the opioid epidemic continuing to have deleterious effects, finding methods to achieve effective pain control without opioids is of increasing importance. The ERAS (Enhanced Recovery After Surgery) protocol applied following cesarean delivery engages multimodal perioperative management techniques to encourage early recovery. In the obstetrical surgery setting, these interventions include increasing scheduled nonsteroidal anti-inflammatory drug administration and laxative use to improve postoperative gastrointestinal motility and pain scores. Postcesarean patients are also encouraged to use abdominal binders, incentive spirometry, and early movement as pain modulators.

OBJECTIVE: This quality improvement study aimed to measure whether the introduction of an ERAS protocol following cesarean delivery at a United States-based health network would improve outcomes such as the use of opioid medications for pain and pain control.

STUDY DESIGN: This single-center retrospective cohort study compared patients who gave birth via cesarean delivery before (n=1425) and after (n=3478) the implementation of the postsurgical recovery protocol. Outcomes of interest included total postoperative opioid medications used, discharge opioid prescription, average pain score, pain scores by postoperative day, and highest pain score. Patients with a history of opioid use disorder, those who underwent a cesarean hysterectomy, and those who experienced a major surgical complication at delivery were excluded. Data were collected from the electronic medical record.

RESULTS: Patients in the postimplementation period used significantly fewer opioid medications than those who gave birth before the protocol was introduced at the institution. The total median opioid use before implementation was 75 morphine milligram equivalents (interquartile range, 45-112.5) vs 30 (interquartile range, 15-52.5) after implementation (P<.001). The median discharge prescription was 225 (interquartile range, 150-225) before implementation vs 112.5 (interquartile range, 75-150) after implementation (P<.001). Pain scores were also significantly lower after implementation. The median highest pain score was 8 (interquartile range, 6-8) on a 10-point pain scale before implementation vs 7 (interquartile range, 6-8) after implementation (P<.001). The average pain score before implementation was 3.4 (interquartile range, 2.4-4.5) vs 2.9 (interquartile range, 1.9-3.9) after implementation (P<.001). Results of paired-sample analyses of 177 patients who gave birth by cesarean delivery in both time periods showed statistically significant outcomes similar to those of the larger cohort groups.

CONCLUSION: Implementation of multimodal pain regimens following cesarean delivery, such as the ERAS protocol, which incorporate both pharmacologic (nonsteroidal anti-inflammatory drugs, laxatives) and nonpharmacologic methods (abdominal binders, deep breathing, movement) can be effective for pain control and may decrease postoperative opioid prescribing needs, thus mitigating the potential for opioid misuse and dependence.

OBJECTIVE: To explore the factor structure of the Rehabilitation Needs Survey (RNS).

DESIGN: Secondary analysis of observational cohort study who were 5-years post-traumatic brain injury (TBI).

SETTING: Five Inpatient Rehabilitation Facilities.

PARTICIPANTS: Veterans enrolled in the TBI Model Systems longitudinal study who completed the RNS at 5-year follow-up (N=378).

MAIN OUTCOME MEASURE(S): RNS.

RESULTS: RNS factor structure was examined with exploratory factor analysis (EFA) with oblique rotation. Analyses returned 2- and 3-factor solutions with Cronbach alphas ranging from 0.715 to 0.905 and corrected item-total correlations that ranged from 0.279 to 0.732. The 2-factor solution accounted for 61.7% of the variance with ≥3 exclusively loading items on each factor with acceptable internal consistency metrics and was selected as the most parsimonious and clinically applicable model. Ad hoc analysis found the RNS structure per the EFA corresponded with elements of the International Classification of Functioning, Disability and Health (ICF) conceptual framework. All factors had adequate internal consistency (α≥0.70) and 20 of the 21 demonstrated good discrimination (corrected item-total correlations≥0.40).

CONCLUSIONS: The 2-factor solution of the RNS appears to be a useful model for enhancing its clinical interpretability. Although there were cross-loading items, they refer to complex rehabilitation needs that are likely influenced by multiple factors. Alternatively, there are items that may require alteration and redundant items that should be considered for elimination.

OBJECTIVE(S): To assess the association between pharmacist intervention counseling with medication adherence and quality of life. Also, to assess if these associations vary by the focus, structure, training, or robustness of the counseling.

METHODS: The initial search identified 1805 references, of which 62 randomized trials (RCTs) met inclusion criteria for the systematic review. Of the 62 RCTs, 60 (with 62 results) had extractable data for the meta-analysis. Data were pooled using a random-effects model.

RESULTS: Most study patients were older and taking multiple prescription drugs. The pooled results showed a statistically significant increase in the odds of medication adherence with the pharmacist counseling intervention versus no counseling (pooled odds ratio [OR] = 4.41; 95% confidence interval [CI] 2.46-7.91; P < 0.01). The results of a subgroup analysis suggest the primary disease, counseling focus, location, and robustness may modify the effect of pharmacist counseling on medication adherence. There was a statistically significant improvement in the quality of life with pharmacist counseling versus no pharmacist counseling (pooled standardized mean difference [SMD] = 0.69; 95% CI 0.41-0.96; P < 0.01). The results of a subgroup analysis suggest that counseling focus, location, training, robustness, and the measurement method, but not the disease category, may modify the effect of pharmacist counseling on quality of life.

CONCLUSION: The evidence supports pharmacist intervention counseling to increase mediation adherence and quality of life. The counseling location and structure may be significant factors in improving medication adherence. The overall methodological quality of evidence was very low.

The management of newly diagnosed primary central nervous system lymphoma (PCNSL) includes administration of high-dose methotrexate based regimens followed by consolidation therapy to minimize the risk of relapse. However, the best consolidation strategy (autologous hematopoietic cell transplant [auto-HCT] vs. whole-brain radiotherapy [WBRT]) is controversial. Hence, we performed a systematic review and meta-analysis of all randomized controlled trials that compared auto-HCT versus WBRT consolidation for patients with PCNSL after first-line treatment.The primary outcome was overall survival (OS), while the secondary outcomes included progression-free survival (PFS), response rates (overall response rate [ORR] and complete remission [CR]), relapse rate, treatment-related mortality (TRM), and neuropsychological adverse events. We performed a pooled analysis of the single-arm studies that incorporated auto-HCT or WBRT consolidation and evaluated neurocognitive outcomes. Only two studies met the inclusion criteria (n = 240). There was no significant difference in OS (HR = 1.50; 95% CI = 0.95-2.36), PFS (HR = 0.99; 95% CI = 0.44-2.22), ORR (RR = 1.48; 95% CI = 0.90-2.44), CR rate (RR = 1.21; 95% CI = 0.90-1.63), relapse rate (RR = 0.46; 95% CI = 0.05-4.28), and TRM (RR = 5.67; 95% CI = 1.01-31.91). The neuropsychological tests to assess neurocognitive domains were different and inconsistently reported in the two studies and therefore we were unable to perform a meta-analysis but provide a descriptive assessment. Both the studies showed a significant decline in the attention/executive function (based on the trail making test A and trail making test B) in those receiving WBRT compared to auto-HCT. We found 9 single-arm phase II studies that reported data on outcomes associated with either auto-HCT (5 studies) or WBRT (4 studies) consolidation. Of these, two studies (n = 43) reported data on neurocognitive decline following auto-HCT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 6% (95% CI, 0%-17%) for those receiving auto-HCT and there was no heterogeneity between studies (I2  = 0%). Three studies (n = 122) reported data on neurocognitive decline following WBRT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 43% (95% CI, 11%-78%) for those receiving WBRT and there was high heterogeneity between studies (I2  = 94%). There was significant heterogeneity between subgroups (p = 0.035). The outcomes were not significantly different in patients with PCNSL receiving auto-HCT or WBRT consolidation therapies, however, there is a higher degree of neurocognitive decline associated with WBRT compared to auto-HCT consolidation. The decision to choose a consolidation strategy needs to be individualized based on age, frailty, and co-morbidities.

INTRODUCTION: Veterans and service members (V/SM) may have more risk factors for arrest and felony incarceration (e.g., posttraumatic stress disorder and at-risk substance use) but also more protective factors (e.g., access to health care) to mitigate behaviors that may lead to arrest. As such, understanding which factors are associated with criminal justice involvement among V/SM could inform prevention and treatment efforts. The current study examined relationships between lifetime history of arrests and felony incarceration and sociodemographic, psychological, and brain injury characteristics factors among combat V/SM.

MATERIALS AND METHODS: The current study was a secondary data analysis from the Chronic Effects of Neurotrauma Consortium multicenter cohort study, approved by local institutional review boards at each study site. Participants were V/SM (N = 1,540) with combat exposure (19% active duty at time of enrollment) who were recruited from eight Department of Veterans Affairs and DoD medical centers and completed a baseline assessment. Participants were predominantly male (87%) and white (72%), with a mean age of 40 years (SD = 9.7). Most (81%) reported a history of at least one mild traumatic brain injury, with one-third of those experiencing three or more mild traumatic brain injuries (33%). Participants completed a self-report measure of lifetime arrest and felony incarceration history, a structured interview for all potential concussive events, the post-traumatic stress disorder checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and the Alcohol Use Disorders Identification Test-Consumption. Three groups were compared on self-reported level of lifetime history of criminal justice system involvement: (1) no history of arrest or incarceration (65%); (2) history of arrest but no felony incarceration (32%); and (3) history of felony incarceration (3%).

RESULTS: Ordinal regression analyses revealed that hazardous alcohol consumption (β = .44, P < .001; odds ratio = 1.56) was positively associated with increased criminal justice involvement after adjusting for all other variables. Being married or partnered (β = -.44, P < .001; odds ratio = 0.64) was negatively associated with decreased criminal justice involvement.

CONCLUSIONS: The rate of lifetime arrest (35%) in this V/SM sample was consistent with rates of arrests in the U.S. general population. One modifiable characteristic associated with lifetime arrest and felony incarceration was hazardous alcohol consumption. Alcohol use should be a top treatment target for V/SM at risk for arrest and those with history of criminal justice involvement.