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Article: Dynamic neuroinflammatory profiles predict Alzheimer's disease pathology in microglia-containing cerebral organoids.

Kuhn, Madison K / Kang, Rachel Y / Kim, ChaeMin / Tagay, Yerbol / Morris, Nathan / Tabdanov, Erdem D / Elcheva, Irina A / Proctor, Elizabeth A

bioRxiv : the preprint server for biology

2024

Abstract: Neuroinflammation and the underlying dysregulated immune responses of microglia actively contribute to the progression and, likely, the initiation of Alzheimer's disease (AD). Fine-tuned therapeutic modulation of immune dysfunction to ameliorate disease ... ...

Abstract	Neuroinflammation and the underlying dysregulated immune responses of microglia actively contribute to the progression and, likely, the initiation of Alzheimer's disease (AD). Fine-tuned therapeutic modulation of immune dysfunction to ameliorate disease cannot be achieved without the characterization of diverse microglial states that initiate unique, and sometimes contradictory, immune responses that evolve over time in chronic inflammatory environments. Because of the functional differences between human and murine microglia, untangling distinct, disease-relevant reactive states and their corresponding effects on pathology or neuronal health may not be possible without the use of human cells. In order to profile shifting microglial states in early AD and identify microglia-specific drivers of disease, we differentiated human induced pluripotent stem cells (iPSCs) carrying a familial AD PSEN2 mutation or its isogenic control into cerebral organoids and quantified the changes in cytokine concentrations over time with Luminex XMAP technology. We used partial least squares (PLS) modeling to build cytokine signatures predictive of disease and age to identify key differential patterns of cytokine expression that inform the overall organoid immune milieu and quantified the corresponding changes in protein pathology. AD organoids exhibited an overall reduction in cytokine secretion after an initial amplified immune response. We demonstrate that reduced synapse density observed in the AD organoids is prevented with microglial depletion. Crucially, these differential effects of dysregulated immune signaling occurred without the accumulation of pathological proteins. In this study, we used microglia-containing AD organoids to quantitatively characterize an evolving immune milieu, made up of a diverse of collection of activation patterns and immune responses, to identify how a dynamic, overall neuroinflammatory state negatively impacts neuronal health and the cell-specific contribution of microglia.
Language	English
Publishing date	2024-04-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.16.567220
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Article ; Online: Non-English Primary Language: A Growing Population's Access to Cholecystectomy.

Bakillah, Emna / Sharpe, James / Tong, Jason K / Goldshore, Matthew / Morris, Jon B / Kelz, Rachel R

Annals of surgery

2023 Volume 278, Issue 6, Page(s) e1175–e1179

Abstract: Objective: To examine access to cholecystectomy and postoperative outcomes among non-English primary-speaking patients.: Background: The population of U.S. residents with limited English proficiency is growing. Language affects health literacy and is ...

Abstract	Objective: To examine access to cholecystectomy and postoperative outcomes among non-English primary-speaking patients. Background: The population of U.S. residents with limited English proficiency is growing. Language affects health literacy and is a well-recognized barrier to health care in the United States of America. Historically marginalized communities are at greater risk of requiring emergent gallbladder operations. However, little is known about how primary language affects surgical access and outcomes of common surgical procedures, such as cholecystectomy. Methods: We conducted a retrospective cohort study of adult patients after receipt of cholecystectomy in Michigan, Maryland, and New Jersey utilizing the Healthcare Cost and Utilization Project State Inpatient Database and State Ambulatory Surgery and Services Database (2016-2018). Patients were classified by primary spoken language: English or non-English. The primary outcome was admission type. Secondary outcomes included operative setting, operative approach, in-hospital mortality, postoperative complications, and length of stay. Multivariable logistics and Poisson regression were used to examine outcomes. Results: Among 122,013 patients who underwent cholecystectomy, 91.6% were primarily English speaking and 8.4% were non-English primary language speaking. Primary non-English speaking patients had a higher likelihood of emergent/urgent admissions (odds ratio: 1.22, 95% CI: 1.04-1.44, P = 0.015) and a lower likelihood of having an outpatient operation (odds ratio: 0.80, 95% CI: 0.70-0.91, P = 0.0008). There was no difference in the use of a minimally invasive approach or postoperative outcomes based on the primary language spoken. Conclusions: Non-English primary language speakers were more likely to access cholecystectomy through the emergency department and less likely to receive outpatient cholecystectomy. Barriers to elective surgical presentation for this growing patient population need to be further studied.
MeSH term(s)	Adult ; Humans ; United States ; Retrospective Studies ; Language ; Hospitalization ; Elective Surgical Procedures ; Cholecystectomy
Language	English
Publishing date	2023-05-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	340-2
ISSN	1528-1140 ; 0003-4932
ISSN (online)	1528-1140
ISSN	0003-4932
DOI	10.1097/SLA.0000000000005919
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Article ; Online: Impact of intrapartum antibiotics on the infant gastrointestinal microbiome: a narrative review.

Diamond, Laura / Wine, Rachel / Morris, Shaun K

Archives of disease in childhood

2021 Volume 107, Issue 7, Page(s) 627–634

Abstract: Background: The composition of the infant gastrointestinal (GI) microbiome has been linked to adverse long-term health outcomes and neonatal sepsis. Several factors are known to impact the composition of the microbiome, including mode of delivery, ... ...

Abstract	Background: The composition of the infant gastrointestinal (GI) microbiome has been linked to adverse long-term health outcomes and neonatal sepsis. Several factors are known to impact the composition of the microbiome, including mode of delivery, gestational age, feeding method and exposure to antibiotics. The impact of intrapartum antibiotics (IPAs) on the infant microbiome requires further research. Objective: We aimed to evaluate the impact of IPAs on the infant GI microbiome. Methods: We searched Ovid MEDLINE and Embase Classic+Embase for articles in English reporting on the microbiome of infants exposed to IPAs from the date of inception to 3 January 2021. Primary outcomes included abundance and colonisation of Results: 30 papers were included in this review. In the first year of life, following exposure to IPAs, 30% (6/20) of infant cohorts displayed significantly reduced Conclusions: IPAs impact the composition of the infant GI microbiome, resulting in possible reductions
MeSH term(s)	Anti-Bacterial Agents/adverse effects ; Gastrointestinal Microbiome ; Gestational Age ; Humans ; Infant ; Infant, Newborn ; Probiotics
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2021-10-29
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	524-1
ISSN	1468-2044 ; 0003-9888 ; 1359-2998
ISSN (online)	1468-2044
ISSN	0003-9888 ; 1359-2998
DOI	10.1136/archdischild-2021-322590
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Article ; Online: Artificial intelligence-powered discovery of small molecules inhibiting CTLA-4 in cancer.

Sobhani, Navid / Tardiel-Cyril, Dana Rae / Chai, Dafei / Generali, Daniele / Li, Jian-Rong / Vazquez-Perez, Jonathan / Lim, Jing Ming / Morris, Rachel / Bullock, Zaniqua N / Davtyan, Aram / Cheng, Chao / Decker, William K / Li, Yong

BJC reports

2024 Volume 2

Abstract: Background/objectives: Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially ... ...

Abstract	Background/objectives: Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4. Subjects/methods: In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the hits molecules with biochemical, biophysical, immunological, and experimental animal assays. Results: The primary hits obtained from the virtual screening were successfully validated in vitro and in vivo. We then optimized lead compounds and obtained inhibitors (inhibitory concentration, 1 micromole) that disrupted the CTLA-4/CD80 interaction without degrading CTLA-4. Conclusions: Several compounds inhibited tumor development prophylactically and therapeutically in syngeneic and CTLA-4-humanized mice. Our findings support using AI-based frameworks to design small molecules targeting immune checkpoints for cancer therapy.
Language	English
Publishing date	2024-01-23
Publishing country	England
Document type	Journal Article
ISSN	2731-9377
ISSN (online)	2731-9377
DOI	10.1038/s44276-023-00035-5
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Article ; Online: Impact of a coaching program on resident perceptions of communication confidence and feedback quality.

Gold, Carl A / Jensen, Rachel / Sasnal, Marzena / Day, Heather S / Miller-Kuhlmann, Rebecca K / Blankenburg, Rebecca L / Rassbach, Caroline E / Morris, Arden M / Korndorffer, James R / Nassar, Aussama K

BMC medical education

2024 Volume 24, Issue 1, Page(s) 435

Abstract: Background: While communication is an essential skill for providing effective medical care, it is infrequently taught or directly assessed, limiting targeted feedback and behavior change. We sought to evaluate the impact of a multi-departmental ... ...

Abstract	Background: While communication is an essential skill for providing effective medical care, it is infrequently taught or directly assessed, limiting targeted feedback and behavior change. We sought to evaluate the impact of a multi-departmental longitudinal residency communication coaching program. We hypothesized that program implementation would result in improved confidence in residents' communication skills and higher-quality faculty feedback. Methods: The program was implemented over a 3-year period (2019-2022) for surgery and neurology residents at a single institution. Trained faculty coaches met with assigned residents for coaching sessions. Each session included an observed clinical encounter, self-reflection, feedback, and goal setting. Eligible residents completed baseline and follow-up surveys regarding their perceptions of feedback and communication. Quantitative responses were analyzed using paired t-tests; qualitative responses were analyzed using content analysis. Results: The baseline and follow-up survey response rates were 90.0% (126/140) and 50.5% (46/91), respectively. In a paired analysis of 40 respondents, residents reported greater confidence in their ability to communicate with patients (inpatient: 3.7 vs. 4.3, p < 0.001; outpatient: 3.5 vs. 4.2, p < 0.001), self-reflect (3.3 vs. 4.3, p < 0.001), and set goals (3.6 vs. 4.3, p < 0.001), as measured on a 5-point scale. Residents also reported greater usefulness of faculty feedback (3.3 vs. 4.2, p = 0.001). The content analysis revealed helpful elements of the program, challenges, and opportunities for improvement. Receiving mentorship, among others, was indicated as a core program strength, whereas solving session coordination and scheduling issues, as well as lowering the coach-resident ratio, were suggested as some of the improvement areas. Conclusions: These findings suggest that direct observation of communication in clinical encounters by trained faculty coaches can facilitate long-term trainee growth across multiple core competencies. Future studies should evaluate the impact on patient outcomes and workplace-based assessments.
Language	English
Publishing date	2024-04-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2044473-4
ISSN	1472-6920 ; 1472-6920
ISSN (online)	1472-6920
ISSN	1472-6920
DOI	10.1186/s12909-024-05383-5
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Article ; Online: Are prophylactic adjunctive macrolides efficacious against caesarean section surgical site infection: A systematic review and meta-analysis.

Farmer, Nicola / Hodgetts-Morton, Victoria / Morris, Rachel K

European journal of obstetrics, gynecology, and reproductive biology

2019 Volume 244, Page(s) 163–171

Abstract: Surgical site infection (SSI) post- caesarean section (CS) remains high, prophylactic adjunctive macrolides may reduce this. This systematic review and meta-analysis evaluated whether adjunctive prophylactic macrolides administered at CS reduce the risk ... ...

Abstract	Surgical site infection (SSI) post- caesarean section (CS) remains high, prophylactic adjunctive macrolides may reduce this. This systematic review and meta-analysis evaluated whether adjunctive prophylactic macrolides administered at CS reduce the risk of endometritis and wound infection. MEDLINE, EMBASE, CINHAL and the Cochrane library were searched from inception to July-2018. Observational and randomised studies investigating women undergoing a CS receiving standard prophylactic antibiotics, adjunctive prophylactic macrolides and assessed any SSI outcome was included. Data was double-extracted. Studies were included in a meta-analysis if the same study design and SSI outcome was used. Risk ratios were calculated and heterogeneity was assessed using the I
MeSH term(s)	Antibiotic Prophylaxis ; Cesarean Section/adverse effects ; Endometritis/prevention & control ; Female ; Humans ; Macrolides/therapeutic use ; Pregnancy ; Surgical Wound Infection/etiology ; Surgical Wound Infection/prevention & control
Chemical Substances	Macrolides
Language	English
Publishing date	2019-11-22
Publishing country	Ireland
Document type	Journal Article ; Meta-Analysis ; Systematic Review
ZDB-ID	190605-7
ISSN	1872-7654 ; 0301-2115 ; 0028-2243
ISSN (online)	1872-7654
ISSN	0301-2115 ; 0028-2243
DOI	10.1016/j.ejogrb.2019.11.026
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Article ; Online: Vitamin D and miscarriage: a systematic review and meta-analysis.

Tamblyn, Jennifer A / Pilarski, Nicole S P / Markland, Alexandra D / Marson, Ella J / Devall, Adam / Hewison, Martin / Morris, Rachel K / Coomarasamy, Arri

Fertility and sterility

2022 Volume 118, Issue 1, Page(s) 111–122

Abstract: Objective: To investigate whether a significant association between vitamin D status and the risk of miscarriage or recurrent miscarriage (RM) exists.: Design: Systematic review and meta-analysis.: Setting: Not applicable.: Patient(s): Women ... ...

Abstract	Objective: To investigate whether a significant association between vitamin D status and the risk of miscarriage or recurrent miscarriage (RM) exists. Design: Systematic review and meta-analysis. Setting: Not applicable. Patient(s): Women with miscarriage and RM. Intervention(s): We searched the Ovid MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials from database inception to May 2021. Randomized and observational studies investigating the association between maternal vitamin D status and miscarriage and/or vitamin D treatment and miscarriage were included. Main outcome measure(s): The primary outcome was miscarriage or RM, with vitamin D status used as the predictor of risk. Whether vitamin D treatment reduces the risk of miscarriage and RM was also assessed. Result(s): Of 902 studies identified, 10 (n = 7,663 women) were included: 4 randomized controlled trials (n = 666 women) and 6 observational studies (n = 6,997 women). Women diagnosed with vitamin D deficiency (<50 nmol/L) had an increased risk of miscarriage compared with women who were vitamin D replete (>75 nmol/L) (odds ratio, 1.94; 95% confidence interval, 1.25-3.02; 4 studies; n = 3,674; I Conclusion(s): Vitamin D deficiency and insufficiency are associated with miscarriage. Whether preconception treatment of vitamin D deficiency protects against pregnancy loss in women at risk of miscarriage remains unknown. Registration number: CRD42021259899.
MeSH term(s)	Abortion, Habitual/diagnosis ; Abortion, Habitual/epidemiology ; Abortion, Habitual/prevention & control ; Female ; Humans ; Pregnancy ; Vitamin D/therapeutic use ; Vitamin D Deficiency/complications ; Vitamin D Deficiency/diagnosis ; Vitamin D Deficiency/drug therapy ; Vitamins/therapeutic use
Chemical Substances	Vitamins ; Vitamin D (1406-16-2)
Language	English
Publishing date	2022-05-28
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Review ; Systematic Review
ZDB-ID	80133-1
ISSN	1556-5653 ; 0015-0282
ISSN (online)	1556-5653
ISSN	0015-0282
DOI	10.1016/j.fertnstert.2022.04.017
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Article ; Online: Variations in Incidence of Trigger Finger and Response to Corticosteroid Injection after Aromatase Inhibitor Therapy for Breast Cancer.

Hollins, Andrew W / Hein, Rachel E / Atia, Andrew N / Zhang, Gloria X / Sergesketter, Amanda R / Darner, Grant / Morris, Miranda / Mithani, Suhail K

Plastic and reconstructive surgery

2022 Volume 151, Issue 5, Page(s) 1043–1050

Abstract: Background: Aromatase inhibitors (AIs), such as letrozole and anastrozole, have been demonstrated to have significant musculoskeletal symptoms in patients. The purpose of this study was to evaluate the effect of specific AI medications on the incidence ... ...

Abstract	Background: Aromatase inhibitors (AIs), such as letrozole and anastrozole, have been demonstrated to have significant musculoskeletal symptoms in patients. The purpose of this study was to evaluate the effect of specific AI medications on the incidence of trigger finger and independent factors affecting treatment outcomes within this population. Methods: A retrospective chart review was performed at the authors' institution between the years 2014 and 2018 in patients with the diagnosis of breast cancer. This cohort was then sorted based on receiving medication regimens, trigger finger diagnosis, steroid injections, and need for surgical release of trigger finger. Results: A total of 15,144 patients were included for initial review. The overall rate of trigger finger diagnosis was 2.75% in the entire breast cancer population and 4.5% for patients receiving AI therapy. Patients taking letrozole and anastrozole had an increased odds ratio of 2.0 and 1.7, respectively, for developing trigger finger. Patients who switched between letrozole and anastrozole during treatment had a higher rate of failed steroid injection treatment (45.2% versus 23.5%; P = 0.021). Among patients receiving AI treatment diagnosed with trigger finger, diabetes and hemoglobin A1c level greater than 6.5 were associated with significantly increased rates of failed steroid therapy. Conclusions: Patients receiving AI therapy have an increased incidence of trigger finger. The outcomes of treatment are equivalent between AI and non-AI trigger finger populations. However, steroid therapy is more likely to fail in patients who require switching of regimens because of significant musculoskeletal symptoms. Poorly controlled diabetes was also an independent factor for compromised steroid treatment of trigger finger. Clinical question/level of evidence: Therapeutic, III.
MeSH term(s)	Humans ; Female ; Aromatase Inhibitors/adverse effects ; Breast Neoplasms/drug therapy ; Breast Neoplasms/surgery ; Anastrozole/adverse effects ; Letrozole/adverse effects ; Trigger Finger Disorder/drug therapy ; Incidence ; Retrospective Studies ; Steroids ; Adrenal Cortex Hormones/therapeutic use
Chemical Substances	Aromatase Inhibitors ; Anastrozole (2Z07MYW1AZ) ; Letrozole (7LKK855W8I) ; Steroids ; Adrenal Cortex Hormones
Language	English
Publishing date	2022-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	208012-6
ISSN	1529-4242 ; 0032-1052 ; 0096-8501
ISSN (online)	1529-4242
ISSN	0032-1052 ; 0096-8501
DOI	10.1097/PRS.0000000000010087
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Article ; Online: Re: Reducing health inequality in Black, Asian and other minority ethnic pregnant women: Impact of first-trimester combined screening for placental dysfunction on perinatal mortality.

Allotey, John / Bewley, Susan / Kenny, Louise C / Magee, Laura Ann / Morris, Rachel K / O'Donoghue, Keelin / Paul, Ash / van Smeden, Maarten / Thangaratinam, Shakila / Thornton, James G / Von Dadelszen, Peter / Zamora, Javier

BJOG : an international journal of obstetrics and gynaecology

2022 Volume 129, Issue 9, Page(s) 1614–1615

MeSH term(s)	Female ; Humans ; Pregnancy ; Health Status Disparities ; Minority Groups ; Perinatal Mortality ; Placenta ; Placenta Diseases ; Pregnancy Trimester, First ; Pregnant Women ; Infant, Newborn
Language	English
Publishing date	2022-04-21
Publishing country	England
Document type	Letter
ZDB-ID	2000931-8
ISSN	1471-0528 ; 0306-5456 ; 1470-0328
ISSN (online)	1471-0528
ISSN	0306-5456 ; 1470-0328
DOI	10.1111/1471-0528.17161
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Article ; Online: Association of maternal, obstetric, fetal, and neonatal mortality outcomes with Lady Health Worker coverage from a cross-sectional survey of >10,000 households in Gilgit-Baltistan, Pakistan.

Farrar, Daniel S / Pell, Lisa G / Muhammad, Yasin / Khan, Sher Hafiz / Tanner, Zachary / Bassani, Diego G / Ahmed, Imran / Karim, Muhammad / Madhani, Falak / Paracha, Shariq / Khan, Masood Ali / Soofi, Sajid B / Taljaard, Monica / Spitzer, Rachel F / Abu Fadaleh, Sarah M / Bhutta, Zulfiqar A / Morris, Shaun K

PLOS global public health

2024 Volume 4, Issue 2, Page(s) e0002693

Abstract: Pakistan has among the highest rates of maternal, perinatal, and neonatal mortality globally. Many of these deaths are potentially preventable with low-cost, scalable interventions delivered through community-based health worker programs to the most ... ...

Abstract	Pakistan has among the highest rates of maternal, perinatal, and neonatal mortality globally. Many of these deaths are potentially preventable with low-cost, scalable interventions delivered through community-based health worker programs to the most remote communities. We conducted a cross-sectional survey of 10,264 households during the baseline phase of a cluster randomized controlled trial (cRCT) in Gilgit-Baltistan, Pakistan from June-August 2021. The survey was conducted through a stratified, two-stage sampling design with the objective of estimating the neonatal mortality rate (NMR) within the study catchment area, and informing implementation of the cRCT. Study outcomes were self-reported and included neonatal death, stillbirth, health facility delivery, maternal death, postpartum hemorrhage (PPH), and Lady Health Worker (LHW) coverage. Summary statistics (proportions and rates) were weighted according to the sampling design, and mixed-effects Poisson regression was conducted to explore the relationship between LHW coverage and maternal/newborn outcomes. We identified 7,600 women who gave birth in the past five years, among whom 13% reported experiencing PPH. The maternal mortality ratio was 225 maternal deaths per 100,000 live births (95% confidence interval [CI] 137-369). Among 12,376 total births, the stillbirth rate was 41.4 per 1,000 births (95% CI 36.8-46.7) and the perinatal mortality rate was 53.0 per 1,000 births (95% CI 47.6-59.0). Among 11,863 live births, NMR was 16.2 per 1,000 live births (95% CI 13.6-19.3) and 65% were delivered at a health facility. LHW home visits were associated with declines in PPH (risk ratio [RR] 0.89 per each additional visit, 95% CI 0.83-0.96) and late neonatal mortality (RR 0.80, 95% CI 0.67-0.97). Intracluster correlation coefficients were also estimated to inform the planning of future trials. The high rates of maternal, perinatal, and neonatal death in Gilgit-Baltistan continue to fall behind targets of the 2030 Sustainable Development Goals.
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ISSN	2767-3375
ISSN (online)	2767-3375
DOI	10.1371/journal.pgph.0002693
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