Faculty Bibliography
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department:Medicine. General Internal Medicine
recentyears:2
school:SOM
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14543
Die Pulsatile Insulin Infusionstherapie: Behandlungsoption zur Verzogerung der Dialyse bei Patienten mit Typ-2-Diabetes und Niereninsuffizienz im Stadium III
Introduction: Mimicking physiological pan-creatic pulsatile insulin secretion has led to the concept of pulsatile insulin infusion therapy (PIT).
Method(s): This exploratory pilot study investigated the effect of PIT for three months once weekly on kidney function in patients with type 2 diabetes and chronic renal failure (glomerular filtration rate (GFR) < 60 ml/min or GFR < 75 ml/min with mac-roproteinurea).
Result(s): Seventeen type 2 patients com-pleted the trial per protocol (7 women, 10 men, age: 69 +/- 7 yrs., HbA1c : 7.9 +/- 1.0 %). After three months, mean GFR improved by 12 % (from 47.6 +/- 10.0 ml/ min to 53.3 +/- 11.9 ml/min, p < 0.01) while mean serum creatinine decreased by 7 % (1.4 +/- 0.3 mg/dl/1.3 +/- 0.3 mg/dl, p < 0.05). Blood pressure medication was kept constant during the study; systolic blood pressure improved by 6 % (p < 0.05) while HbA1c and body weight remained stable. Treatment satisfaction scores improved from 3.7 +/- 2.7 to 2.7 +/- 2.1 (p < 0.005). The PIT procedures were well tolerated; only few cases of muscle cramps were consid-ered related to the treatments.
Conclusion(s): Improvements in kidney func-tion, systolic blood pressure and treatmensatisfaction were observed. These results will now be used to plan for appropriately designed controlled confirmatory studies.
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Method(s): This exploratory pilot study investigated the effect of PIT for three months once weekly on kidney function in patients with type 2 diabetes and chronic renal failure (glomerular filtration rate (GFR) < 60 ml/min or GFR < 75 ml/min with mac-roproteinurea).
Result(s): Seventeen type 2 patients com-pleted the trial per protocol (7 women, 10 men, age: 69 +/- 7 yrs., HbA
Conclusion(s): Improvements in kidney func-tion, systolic blood pressure and treatmensatisfaction were observed. These results will now be used to plan for appropriately designed controlled confirmatory studies.
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EMBASE:2022851580
ISSN: 1861-7603
CID: 5513822
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
PMCID:9005347
PMID: 35379992
ISSN: 1546-1718
CID: 5213092
Burnout of the US midwifery workforce and the role of practice environment
OBJECTIVES/OBJECTIVE:To determine the prevalence of burnout among the midwifery workforce and the association between fixed personal and practice characteristics and modifiable organizational factors, specifically practice environment, to burnout among midwives in the United States. DATA SOURCE/METHODS:Primary data collection was conducted via online survey of the full national roster of certified nurse-midwives and certified midwives over three weeks in April 2017. STUDY DESIGN/METHODS:The study was a cross-sectional observational survey consisting of 95 items about personal and practice characteristics, respondents' practice environments, and professional burnout. DATA COLLECTION METHODS/METHODS:The inclusion criteria was actively practicing midwifery in the US. Data were analyzed with bivariate analyses to determine the association between personal and practice characteristics and burnout. A hierarchal multilinear regression evaluated to the inter-relationship between personal and practice characteristics, practice environment, and burnout. PRINCIPAL FINDINGS/RESULTS:Of the almost one third (30.9%) of certified nurse-midwives and certified midwives who responded to the survey, 40.6% met criteria for burnout. Weak negative correlations existed between burnout and indicators of career longevity: age (r(2256)=-0.09, p<0.01), years as a midwife (r(2267)=-0.07, p=0.01), and years with employer (r(2271)=-0.05, p=0.02). There were significant relationships between burnout score and patient workload indicators: patients per day in out-patient setting [F(5,2292)=13.995, p<0.01], birth volume [F(3,1864)=8.35, p<0.01], and patient acuity [F(2,2295)=20.21, p<0.01]. When the practice environment was entered into the model with personal and practice characteristics, the explained variance increased from 6.4% to 26.5% (F(20,1478)=27.98, p<0.01). CONCLUSIONS:Our findings suggested that a key driver of burnout among US midwives was practice environment, specifically practice leadership and participation and support for the midwifery model of care. Structural and personal characteristics contributed less to burnout score than the practice environment, implying that prevention of burnout may be achieved through organizational support and does not require structural changes to the provision of perinatal health.
PMID: 34893977
ISSN: 1475-6773
CID: 5079802
Grouping people by language exacerbates health inequities-The case of Latinx/Hispanic populations in the US [Editorial]
PMID: 35247219
ISSN: 1098-240x
CID: 5174812
Ketamine Cystitis: An Underrecognized Cause of Dysuria
PMCID:8722656
PMID: 34981355
ISSN: 1525-1497
CID: 5106952
Distinct Neoadjuvant Chemotherapy Response and 5-Year Outcome in Patients With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Tumors That Reclassify as Basal-Type by the 80-Gene Signature
PURPOSE/OBJECTIVE:The 80-gene molecular subtyping signature (80-GS) reclassifies a proportion of immunohistochemistry (IHC)-defined luminal breast cancers (estrogen receptor-positive [ER+], human epidermal growth factor receptor 2-negative [HER2-]) as Basal-Type. We report the association of 80-GS reclassification with neoadjuvant treatment response and 5-year outcome in patients with breast cancer. METHODS:Neoadjuvant Breast Registry Symphony Trial (NBRST; NCT01479101) is an observational, prospective study that included 1,069 patients with early-stage breast cancer age 18-90 years who received neoadjuvant therapy. Pathologic complete response (pCR) and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed in 477 patients with IHC-defined ER+, HER2- tumors and in a reference group of 229 patients with IHC-defined triple-negative breast cancer (TNBC). RESULTS:< .001) tumors. The 5-year DMFS (%, [95% CI]) was significantly lower for patients with ER+/Basal tumors (66% [52.6 to 77.3]), compared with those with ER+/Luminal A tumors (92.3% [85.2 to 96.1]) and ER+/Luminal B tumors (73.5% [44.5 to 79.3]). Importantly, patients with ER+/Basal or TNBC/Basal tumors that had a pCR exhibited significantly improved DMFS and OS compared with those with residual disease. By contrast, patients with ER+/Luminal B tumors had comparable 5-year DMFS and OS whether or not they achieved pCR. CONCLUSION/CONCLUSIONS:Significant differences in chemosensitivity and 5-year outcome suggest patients with ER+/Basal molecular subtype may benefit from neoadjuvant regimens optimized for patients with TNBC/Basal tumors compared with patients with ER+/Luminal subtype. These data highlight the importance of identifying this subset of patients to improve treatment planning and long-term survival.
PMID: 35476550
ISSN: 2473-4284
CID: 5210342
GENOME-SCALE SCREEN FOR SYNTHETIC DRIVERS OF T-CELL PROLIFERATION [Meeting Abstract]
The engineering of patient T-cells for adoptive cell therapies has revolutionized the treatment of several cancer types. However, further improvements are needed to increase durability and response rate. While CRISPR-based loss-of-function screens have shown promise for high-throughput identification of genes that modulate T-cell response, these methods have been limited thus far to negative regulators of T-cell functions, and raise safety concerns due to the permanent nature of genome modification. Here we identify positive T-cell regulators via overexpression of ~12,000 barcoded human open reading frames (ORFs). Using this genome-scale ORF screen, we find modulator genes that may not normally be expressed by T-cells. The top-ranked genes increased primary human T-cell proliferation, activation, and secretion of key cytokines. In addition, we developed a single-cell genomics method for high-throughput quantification of the transcriptome and surface proteome in ORF-engineered T-cells. The top-ranked ORF, lymphotoxin beta receptor (LTBR), is typically expressed by myeloid cells but absent in lymphocytes. When expressed in T-cells, LTBR induced profound transcriptional and epigenomic remodeling, resulting in an increase in T-cell stemness and effector functions, as well as resistance to apoptosis and exhaustion in chronic stimulation settings. Using mutagenesis and epistasis approaches, we demonstrated that LTBR constitutive activates the canonical NFkB pathway via ligand shortcircuiting and tonic signaling. Expression of several top-ranked genes, including LTBR, improved antigen-specific chimeric antigen receptor (CAR) T-cell responses in healthy donors and diffuse large B-cell lymphoma patients. Finally, the top-ranked genes discovered in alphabeta T-cells also improved antigen-specific responses of gammadelta T-cells, highlighting the potential for cancer-agnostic therapies. Our results provide several strategies for improving next generation T-cell therapies via induction of new synthetic cell programs
EMBASE:638055202
ISSN: 1557-7422
CID: 5251822
Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals
We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57.
PMCID:9005349
PMID: 35361970
ISSN: 1546-1718
CID: 5210182
Effects of Reduced Sodium Consumption on Interdialytic Weight Gain and Blood Pressure in Maintenance Hemodialysis Patients [Meeting Abstract]
Dietary sodium (Na) restriction is universally prescribedfor hemodialysis patients to decrease adverse outcomes.1 However, few studies have investigated the impact of Na restriction on volume status and blood pressure (BP), and none in American community-dwelling populations in prospective, randomized controlled trial (RCT). The purpose of this feasibility RCT was to assess the effects of three levels of Na intake (unrestricted [control group; CG], 1.5G, 2.4G) on interdialytic weight gain (IDWG) and BP in patients undergoing hemodialysis. We conducted a three-group, double-blinded, RCT of 42 individuals living with end stage kidney disease in a domiciled feeding study. We examined the effects of 5 days of unrestricted Na in the control group (CG, n=14) and Na restriction to 1.5G (n=11) or 2.4G (n=14) per day on IDWG and BP. Our sample was overwhelmingly African American (85%), male (52.2%), with hypertension as the primary etiology of kidney disease (45%). The mean IDWG on Day 1 was 2.62kg (SD=1.54) and BP was 143/75.44 (SD=29.77/17.74). There were no significant differences in the change in IDWG regardless of group membership, although the trend demonstrated a decrease by Day 5. Decreases in BP were also not statistically significant across the groups, but there were potentially meaningful differences in systolic BP of 7mmHg and 11mmHg in the 1.5G and 2.4G groups respectfully, and diastolic BP in the 2.4G group of 7.31mmHg Our small pilot study suggests that Na restriction can reduce IDWG and systolic and diastolic BP in potentially clinically meaningful amounts. The optimal Na intake prescription and the long-term impact on hemodialysis-specific variables and cardiovascular disease remains unclear. A prospective, longitudinal study, with a sample sufficient to achieve adequate power is needed to gain a better understanding of the interplay between dietary sodium and outcomes.
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EMBASE:2017310594
ISSN: 1523-6838
CID: 5378032
Antihypertensive drugs reduced risk for new-onset type 2 diabetes; effect varies by antihypertensive class [Comment]
SOURCE CITATION:Lancet. 2021;398:1803-10. 34774144.
PMID: 35377716
ISSN: 1539-3704
CID: 5216822
