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Moving from genome-scale to community-scale metabolic models for the human gut microbiome.
No full textMetabolic models of individual microorganisms or small microbial consortia have become standard research tools in the bioengineering and systems biology fields. However, extending metabolic modelling to diverse microbial communities, such as those in the human gut, remains a practical challenge from both modelling and experimental validation perspectives. In complex communities, metabolic models accounting for community dynamics, or those that consider multiple objectives, may provide optimal predictions over simpler steady-state models, but require a much higher computational cost. Here we describe some of the strengths and limitations of microbial community-scale metabolic models and argue for a robust validation framework for developing personalized, mechanistic and accurate predictions of microbial community metabolic behaviours across environmental contexts. Ultimately, quantitatively accurate microbial community-scale metabolic models could aid in the design and testing of personalized prebiotic, probiotic and dietary interventions that optimize for translationally relevant outcomes
Inclusive Care Starts with Inclusive Language in Breast Health Care for LGBTQIA+ Patients
No full textA New Method Using the Four-Chamber View to Identify Fetuses With Subsequently Confirmed Postnatal Aortic Coarctation.
No full textOBJECTIVE: To determine the sensitivity, specificity, and false-positive rate among fetuses suspected prenatally to have coarctation of the aorta (CoA) using size and shape measurements of the fetal heart from the four-chamber view (4CV).
METHODS: This was a retrospective study of 108 fetuses identified by pediatric cardiologists to be at risk for CoA. 4CV s from the last antenatal ultrasound performed by the cardiologists were analyzed. The end-diastolic area was computed using the point-to-point trace method around the epicardial border of the 4CV, and the largest end-diastolic length and width were measured from the epicardium to the epicardium to compute the global sphericity index (GSI) (length/width). Using speckle tracking analysis, the ventricular end-diastolic area, length, basal and mid-chamber widths were measured. The sphericity index of the base and mid-chamber of the ventricles was computed (length/width). In addition, the end-diastolic area ratios were computed as follows: right ventricular area/4CV area and the left ventricular area/4CV area. The z-scores for the above measurements were computed. Using logistic regression analysis, coefficients for predicting the probability of CoA from a test group of 27 fetuses with CoA and 27 without CoA was done. The logistic regression equation derived from the test group was applied to a validation group of 27 fetuses with CoA and 27 fetuses without CoA.
RESULTS: The regression equation from the test group identified the following end-diastolic measurements: 4CV GSI, RV area/heart area, LV base SI, and the RV Base SI. The test group consisted of 14 of 27 fetuses with an isolated CoA (52%) and 13 of 27 (48%) with additional heart abnormalities. For the validation group, 10 of 27 (37%) had an isolated CoA, and 17 (63%) had additional cardiac abnormalities. Using the logistic regression equation derived from the test group (54 fetuses: 27 with CoA and 27 without CoA), the validation group (54 fetuses: 27 with CoA and 27 without CoA) demonstrated the following: sensitivity for detecting CoA of 98.15%, specificity 98.15%, and a false-positive rate of 1.85%. When the logistic regression was applied to the test group of fetuses with isolated CoA, 100% (14/14) were identified with logistic regression analysis. For the validation group, 9 of 10 (90%) of fetuses with isolated CoA were identified using the logistic regression equation.
CONCLUSIONS: Using length, width, and area measurements of the 4CV and ventricles from which ratios are computed detects 98.15% of high-risk fetuses who will demonstrate CoA following birth, with a specificity of 98.15%, or a false-positive rate of 1.85%
Adjuvant chemotherapy for stage IA-IIA non-squamous, non-small-cell lung cancer identified as molecular high-risk by a 14-gene expression profile (AIM-HIGH): an international, randomised, phase 3 trial.
No full textBACKGROUND: Survival for non-small-cell lung cancer (NSCLC) remains unacceptably low, even in stage IA-IIA. Current guidelines recommend adjuvant treatment for patients considered to be at high risk in stages IB and IIA, but suggest criteria that have not been validated to predict benefit. A previously validated, CLIA-certified 14-gene expression profile has identified patients with high-risk non-squamous NSCLC tumours in stages IA-IIA who benefitted from adjuvant chemotherapy in a non-randomised prospective study. In this prespecified interim analysis, we aimed to assess the efficacy and safety of platinum-based adjuvant chemotherapy in patients with stage IA-IIA molecular high-risk non-squamous NSCLC in a randomised trial.
METHODS: AIM-HIGH, a randomised, phase 3 trial, was done at 45 centres in France, Germany, and the USA. Patients aged 18 years or older with stage IA-IIA non-squamous NSCLC, an adequate tumour sample, and an Eastern Cooperative Oncology Group performance status of 0-1 underwent risk stratification with the 14-gene assay. Patients with a molecular high risk, defined as those receiving a high-risk or an intermediate-risk score, were randomly assigned (1:1) to four cycles of platinum-based adjuvant chemotherapy (using local institutional standard of care regimens) or observation. Randomisation was stratified according to age, sex, and tumour size of 4 cm or more. The primary outcomes for the study and for this prespecified interim analysis were 48-month and 24-month disease-free survival, respectively, in the modified intention-to-treat (mITT) population, which was defined as randomly assigned patients who continued to meet eligibility criteria either at chemotherapy initiation or at random assignment to observation; an early interim analysis was prespecified to detect a large difference between groups. This trial is registered at ClinicalTrials.gov, NCT01817192, and is closed to enrolment.
FINDINGS: Between Sept 11, 2020, and Feb 7, 2025, 449 patients were enrolled and underwent risk stratification. 236 patients with molecular high risk were randomly assigned to chemotherapy (n=124) or observation (n=112). At the time of the prespecified interim analysis, 87 patients were evaluable in the mITT population (47 [54%] males and 40 [46%] females; median age 63 years [IQR 52-74]) in the chemotherapy group and 107 (58 [54%] males and 49 [46%] females; 66 years [56-76]) in the observation group. 48 (55%) patients in the chemotherapy group and 58 (54%) patients in the observation group had stage IA disease; 34 (39%) and 44 (41%), respectively, had stage IB disease, and five (6%) and five (5%), respectively, had stage IIA disease. Six (3%) of 200 patients in the mITT population had died at the time of the interim analysis. 24-month disease-free survival was 96% (95% CI 92-100) with adjuvant chemotherapy versus 79% (70-90) with observation (hazard ratio 0·22 [0·06-0·76]; p=0·0087).
INTERPRETATION: The 14-gene assay identified patients with molecular high risk who benefitted from adjuvant chemotherapy. Use of the assay to determine eligibility for adjuvant therapy in stage IA-IIA non-squamous NSCLC has the potential to substantially improve otherwise persistently poor outcomes.
FUNDING: Razor Genomics
Nonconsensual Condom Removal or Stealthing: A Case Study.
No full textBACKGROUND: NCCR is a form of sexual violence that complicates the traumatic physical and emotional experience of sexual assault. Correlates to victimization include being a racial or sexual minority and being in nonexclusive, noncommitted relationships, or transactional relationships. Decreased confidence, guilt and worry, fear, depression, or a history of sexual abuse are correlates to being a victim.
AIM: To present a case of nonconsensual condom removal (NCCR), also known as stealthing, in a 25-year-old transexual male sexual assault patient.
CASE SUMMARY: A 25-year-old transexual male, hereafter known as AK, presented to the emergency department (ED) requesting to be seen by a sexual assault nurse examiner (SANE). The partner put the condom on; during sex, AK could see that the condom was no longer in place. He asked the man to stop but was ignored. Thoughtful care was given during the exam, with attention to patient preference about use of a speculum. Prophylactic treatment for sexually transmitted infections, human immunodeficiency virus, and pregnancy were indicated and given. Follow-up care with an advocacy agency was provided. Research, policy, and practice must be developed to address this increasingly common practice
Outcomes following planned two-stage exchange arthroplasty for periprosthetic joint infections in the United States: a systematic review of the literature.
No full textINTRODUCTION: While two-stage exchange arthroplasty is the gold standard for treating periprosthetic joint infections (PJIs), it results in a prolonged treatment period with the potential for complications and non-planned additional procedures, limited joint function during the interstage period, and emotional stress for patients. The primary objective of this systematic literature review was to evaluate outcomes associated with two-stage exchange arthroplasty for treating total hip arthroplasty (THA) and total knee arthroplasty (TKA) PJIs. This literature review analyzed U.S. data on the timing and health consequences associated with the interstage period and outcomes following reimplantation in patients undergoing two-stage exchange arthroplasty.
MATERIALS AND METHODS: A search of U.S. studies published between January 2014 and January 2024 was conducted using PubMed and Embase databases.
RESULTS: Sixty-five studies reporting data on 26,354 patients undergoing two-stage exchange arthroplasty were included. There were 29.0% and 68.6% of patients who underwent THA and TKA respectively, with 2.4% patients not having the affecting joint identified. The mean interstage period was 141.4 ± 74.2 days with 16.9 ± 12.2% patients not re-implanted. The mean infection eradication was 74.2 ± 10.5% and the average reinfection rate was 15.7 ± 7.1%. Complications and additional procedures were common during the interstage and post-implant periods. Only four studies utilized Musculoskeletal Infection Society (MSIS) Outcomes Reporting Tool. Patients undergoing treatment for TKA PJIs had less successful MSIS outcomes compared to those being treated for THA PJIs. This includes a lower rate of infection control (46.0% vs. 65.5%), a higher rate of reoperation, revision, and/or spacer retention (40.6% vs. 25.2%) and a higher death rate (13.4% vs. 9.4%), respectively.
CONCLUSION: Two-stage exchange arthroplasty treatment of PJIs is associated with major morbidity and often requires additional surgical procedures to address complications. The prolonged duration of the interstage period contributes to morbidity and negatively impacts patients\u27 quality of life and increases the risk of mortality
Radiographic Evaluation of Unruptured Cerebral Aneurysms.
No full textIntracranial vascular imaging plays an important role in the diagnosis, risk assessment and treatment planning of unruptured intracranial aneurysms (UIAs). In this review article, we will discuss the various imaging modalities commonly employed in the imaging of UIAs including computed tomography and MR Angiography highlighting the technological advancements, strengths and drawbacks for each modality. The different techniques of 3-dimensional digital subtraction angiography, high resolution cone beam computed technology (HR-CBCT), the different clinical scenarios in which HR-CBCT can prove useful, and the pathology that enables the neurointerventionalist to make better informed decisions ultimately leading to better patient outcomes, are also discussed
When Is Intensive Care Warranted for the Most Immature Infants?
No full textWithholding or starting, withdrawing or continuing, high-technology interventions available to extremely premature newborns is a fundamental challenge in obstetrics and neonatology. Attempting to save an infant\u27s life is a judgment fraught with uncertainty and risk because suffering can be prolonged, long-term outcomes are frequently unfavorable, and socio-economic inequities are burdensome to families. Survival rates of 22-23-24-week infants are increasing in hospitals that promote active care, yet morbidity rates and long-term neurodevelopmental impairments remain substantial and not improving. Outcomes acceptable to some pregnant women and families are not to others. Delivery of premature infants, particularly by cesarean section, is associated with maternal health risks. Intensive care of extremely premature infants is expensive, and lost opportunity costs are under-appreciated. Autonomy of pregnant women contrasted with the rights of the fetus and infant are culture and religion-affected, technology-influenced, and powerfully persuaded by physicians and institutions who possess a conflict of interest related to career goals, research, and income, all factors not necessarily shared by pregnant women.Physicians should resist dogmatic positions tethered to unproven technologies and nonrigorous evidence. Some hospitals promote near-universal intensive care of 22-23-24-week infants while others recommend palliative care, differences curiously seen between and within countries, even cities. The legitimate zone of parental discretion is characterized by the value pluralistic shared decision-making of informed consent and is endorsed by the American Academy of Pediatrics, the Canadian Paediatric Society, and the American College of Obstetricians and Gynecologists. Physicians should objectively provide clinical outcomes, compassionately listen to pregnant women\u27s concerns and preferences, and resist presenting care options as a restrictive protocol, or a wide-open menu. Because there is no unifying cultural or bioethical ethos, we should embrace shared decision-making recognizing inherent contingencies and tensions, with humble circumspection of possible nihilism (which might influence palliative care), and therapeutic fury (which might promote unreasonable zeal for interventional care). · Extreme prematurity requires knowing outcomes.. · Parental discretion may broaden with uncertainty.. · Shared decision-making assumes informed consent.. · Parental values differ from the values of physicians.. · Asymmetry of responsibility supports parental values.
OVATION-2: A randomized phase I/II study evaluating the safety and efficacy of IMNN-001 (IL-12 gene therapy) with neo/adjuvant chemotherapy in patients newly-diagnosed with advanced epithelial ovarian cancer.
No full textOBJECTIVE: OVATION-2, a randomized, controlled, open label phase 1/2 study, evaluated the safety and efficacy of IMNN-001, an IL-12 immune gene therapy, with neo/adjuvant chemotherapy (N/ACT) compared to N/ACT in newly-diagnosed advanced epithelial ovarian cancer (EOC).
METHODS: IMNN-001 is an immunotherapeutic nanoparticle comprising a DNA plasmid encoding the IL-12 gene encased in a lipopolymer. High-grade EOC patients were randomized 1:1 to carboplatin/paclitaxel IV every 21 days for 3 cycles, before and after interval debulking surgery (IDS) or to intraperitoneal (IP) IMNN-001, given weekly concurrently with chemotherapy for 8 weeks before and 9 weeks after IDS.
RESULTS: 54 and 58 patients with predominantly Stage IIIC/IV EOC were evaluated in the control and experimental arm, respectively. Primary endpoints were safety and PFS. Overall, the experimental arm was well tolerated with gastrointestinal and cytopenias as the most common TEAEs with no CRS or elevated risk of immune events. PFS was 14.9 months (mo) for the experimental arm vs 11.9 mo; HR 0.79 (95 % CI: 0.51-1.23). Secondary endpoints included OS (46.0 mo for experimental arm vs 33.0 mo; HR 0.69 (CI: 0.40-1.19)) and surgical response R0 rate (64.6 % experimental arm vs 52.1 %). For patients who received PARPi maintenance, PFS was 33.8 mo vs 22.1 mo; HR 0.80 (CI: 0.31-2.12) and OS was NE vs 37.1 mo with a HR of 0.38 (CI: 0.13-1.06) both favoring the experimental arm.
CONCLUSION: The addition of IMNN-001 to N/ACT shows a promising numerical 13-mo benefit on survival with an acceptable safety profile in patients with newly-diagnosed advanced EOC
Clinical characteristics and CKD care delivery in African American and American Indian or Alaska Native patients: A real-world cohort study.
No full textBACKGROUND: Racially minoritized populations in the United States (US), notably African American (AA) and American Indian/Alaska Native (AI/AN), experience disproportionately higher rates of chronic kidney disease (CKD), diabetes, and hypertension compared to their White peers but are understudied. This real-world cohort study examines the standards of CKD care provided to these groups in two US health systems.
METHODS: Using electronic health record data from the Center for Kidney Disease Research, Education, and Hope (CURE-CKD) Registry (N = 381,011) collected between 2015 and 2020, adjusted binary logistic regression models were used to identify predictors of two CKD care outcomes: 1) prescriptions for CKD-related guideline-directed medical therapy (CKD-GDMT) in the form of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and 2) testing for urine albumin-creatinine/urine protein-creatinine ratio (UACR/UPCR) among adult patients of AA and AI/AN race compared to the reference group (White, non-Hispanic).
RESULTS: AA (62 ± 17 years) and AI/AN (57 ± 18 years) patients with CKD were younger compared to the White, non-Hispanic reference group (68 ± 17 years). Diabetes and hypertension were the most important predictors for increased odds of CKD-GDMT and UACR/UPCR testing. Prevalence of CKD-GDMT was only 46%, 40% and 38% in AA, White, and AI/AN patients, respectively. AA patients were more likely to receive CKD-GDMT prescriptions (OR = 1.20, 95% CI: 1.17-1.23, p \u3c 0.001) and UACR/UPCR testing (OR = 1.34, 95% CI: 1.29-1.38, p \u3c 0.001) compared to White patients. AI/AN were also more likely to receive GDMT (OR = 1.07, 95% CI: 1.00-1.15, p = 0.046) compared to White patients but had lower odds of UACR/UPCR testing (OR = 0.73, 95% CI: 0.67-0.81, p \u3c 0.001). However, the frequency or prescribing of CKD-GDMT and UACR/UPCR testing were suboptimal across all examined racial identity groups. Exploratory machine learning approaches, including logistic regression, lasso regression, and random forest found similar findings.
CONCLUSIONS: While there were modest racial differences in the prescription of CKD-GDMT and frequency of UACR/UPCR testing, rates were lower than expected in this high-risk population. Our findings suggest the disproportionate burden of CKD on AA and AI/AN individuals is not solely attributable to the current standards of care delivery. The relatively higher rates of CKD-GDMT for AA patients may be due to clinician recognition of their increased risk for progressing to kidney failure.
CLINICAL TRIAL NUMBER: Not applicable