This study of the effect of a microbiota-directed supplement on the growth of young children with moderate acute malnutrition included tests of association between changes in growth and changes in ...the plasma proteome and fecal microbiota.
Undernutrition in children is a pressing global health problem, manifested in part by impaired linear growth (stunting). Current nutritional interventions have been largely ineffective in over-coming ...stunting, emphasizing the need to obtain better understanding of its underlying causes. Treating Bangladeshi children with severe acute malnutrition with therapeutic foods reduced plasma levels of a biomarker of osteoclastic activity without affecting biomarkers of osteoblastic activity or improving their severe stunting. To characterize interactions among the gut microbiota, human milk oligosaccharides (HMOs), and osteoclast and osteoblast biology, young germ-free mice were colonized with cultured bacterial strains from a 6-mo-old stunted infant and fed a diet mimicking that consumed by the donor population. Adding purified bovine sialylated milk oligosaccharides (S-BMO) with structures similar to those in human milk to this diet increased femoral trabecular bone volume and cortical thickness, reduced osteoclasts and their bone marrow progenitors, and altered regulators of osteoclastogenesis and mediators of Th2 responses. Comparisons of germ-free and colonized mice revealed S-BMO-dependent and microbiota-dependent increases in cecal levels of succinate, increased numbers of small intestinal tuft cells, and evidence for activation of a succinate-induced tuft cell signaling pathway linked to Th2 immune responses. A prominent fucosylated HMO, 2′-fucosyllactose, failed to elicit these changes in bone biology, highlighting the structural specificity of the S-BMO effects. These results underscore the need to further characterize the balance between, and determinants of, osteoclastic and osteoblastic activity in stunted infants/children, and suggest that certain milk oligosaccharides may have therapeutic utility in this setting.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Multiparametric Magnetic Resonance Imaging (mpMRI) has been rapidly incorporated into the prostate cancer (PCa) diagnosis pathway. The Prostate Imaging Reporting & Data System (PI-RADS) scoring ...guidelines were developed to address the substantial variation in interpretation and reporting of mpMRI results, and subsequent updates have sought to further improve inter-reader reliability. Nonetheless, the variability of PI-RADS scoring in real-world settings may represent a continuing challenge to the widespread standardization of prostate mpMRI and limit its overall clinical benefit. In this study, we aimed to evaluate the discrepancies in PI-RADS scoring between community practices and a tertiary academic care center.
In this retrospective cohort study, 262 patients with mpMRI studies originally performed at an outside non-academic facility that were interpreted by a radiologist at our institution between January 2016 and July 2022 were identified. Results of targeted MRI fusion biopsy were identified for 193 patients and represented a total of 302 lesions. For each lesion, PI-RADS scoring from both community and academic interpreters were recorded in addition to presence of clinically significant PCa (csPCa; International Society of Urological Pathology grade group 2 or higher) on pathological analysis of targeted cores. We assessed inter-reader reliability via intraclass correlation (ICC) and the kappa statistic. We assessed the diagnostic accuracy of PI-RADS scoring for detecting csPCa for both cohorts via receiver operator characteristics (ROC) analysis and compared these findings using;paired-sample area difference under curve analysis.
Inter-reader agreement and reliability of PI-RADS scoring per lesion was generally poor (absolute agreement ICC=0.393, 95%CI: 0.288-0.488;;consistency ICC=0.407, 95%CI: 0.308-0.497;;kappa=0.336, 95%CI:0.267-0.406). Reliability results from studies obtained after the publication of PI-RADSv2.1 were similar to those of the overall analysis. No agreement was observed in the subgroup of lesions scored as PIRADS 3 by community interpreters. No statistically significant difference in diagnostic accuracy was observed between cohorts (ROC area under curve AUC: 0.759 vs 0.785, respectively; p=0.337). PI-RADS 3 was determined to be the optimal cutoff for detecting clinically significant disease in both cohorts.
The PI-RADS scoring system is widely employed for the detection and evaluation of PCa using mpMRI. Our results suggest that diagnostic accuracy of mpMRI for detecting csPCa is not significantly different between academic and community practices. However, significantly poor reliability of mpMRI was observed between cohorts, suggesting the risk of introducing practice variation for prostate cancer management in the community. Future PI-RADS guideline updates should seek to further improve interobserver reliability, and further investigation of the current performance and limitations of mpMRI in more diverse clinical settings is warranted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Most Prostate Imaging Reporting and Data System (PI-RADS) 5 lesions on prostate MRI are found to harbor Gleason grade group ≥2 prostate cancer on initial biopsy. As a result, the optimal management ...of patients found to have Gleason grade group 1 (GG1) prostate cancer despite PI-RADS 5 lesions on prostate MRI remains unclear. To estimate risks of grade misclassification, we evaluated the occurrence of Gleason upgrade on subsequent active surveillance (AS) prostate biopsy or radical prostatectomy among patients diagnosed with GG1 prostate cancer with PI-RADS 5 lesions on MRI.
We conducted a retrospective analysis at a single institution to identify patients diagnosed with GG1 prostate cancer whose MRI nearest to diagnosis demonstrated ≥1 lesion classified as PI-RADS 5. The primary study outcome was the presence of Gleason reclassification to GG≥2 prostate cancer on subsequent prostate biopsy or radical prostatectomy. The secondary outcomes included rates of grade reclassification on prostate biopsy, or conversion to active treatment among patients managed with initial active surveillance. We used multivariable logistic regression to identify factors associated with Gleason reclassification on subsequent biopsy or radical prostatectomy.
Among 3,042 patients undergoing prostate biopsy between 01/2013-12/2022, we identified 110 with GG1 prostate cancer and PI-RADS 5 lesions on;MRI who received a total of 216 biopsies. The median age was 69 years and median PSA at diagnosis was 6.4 ng/mL. There were 104 patients (94.6%) who elected initial AS and six (5.5%) were treated. Sixty-one patients managed with AS underwent ≥1 additional biopsy. Among this group, 43 (70.5%) experienced Gleason upgrade including 32 (74.4%) on second, 9 (20.9%) on third, and one (2.3%) each on fourth and fifth biopsy. A total of 44 (40%) patients received definitive treatment including prostatectomy in 15 (13.6%) and radiation in 25 (22.73%). Two patients (1.8%) developed metastatic disease, of whom one patient later demonstrated higher grade disease on biopsy, and one died of disease. In multivariable logistic regression, no clinical or pathological factors were significantly associated with odds of Gleason upgrade.
The majority of patients diagnosed with GG1 prostate cancer in the setting of a PI-RADS 5 lesion will be found to have GG2 or higher disease in the short term during active surveillance or during treatment, suggesting substantial initial misclassification. These findings reinforce the need for confirmatory testing in these patients due to risks of disease under-sampling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The relationship between patient and meningioma characteristics and hormone receptors (HRs) of progesterone, estrogen, and androgen remains poorly defined despite literature suggesting that ...meningiomas are sensitive to gonadal steroid hormones. Therefore, the authors sought to collect and compare data on this topic by performing a systematic review and meta-analysis of reported studies of HR status in meningiomas.
A MEDLINE PubMed literature review conducted for articles published between January 1, 1951, and December 31, 2020, resulted in 634 unduplicated articles concerning meningiomas and HRs. There were 114 articles that met the criteria of detailed detection protocols for progesterone receptor (PR), estrogen receptor (ER), and/or androgen receptor (AR) using immunohistochemistry (IHC) or ligand-binding (LB) assays and simultaneous reporting of HR status with at least one variable among age, sex, histology, location, grade, or recurrence. Between-study heterogeneity and risk of bias were evaluated using graphical and statistical methods. The authors performed a multilevel meta-analysis using random-effects modeling on aggregated data (n = 4447) and individual participant data (n = 1363) with subgroup results summarized as pooled effects. A mixed-effects meta-regression using individual participant data was performed to analyze independently associated variables.
The 114 selected articles included data for 5810 patients with 6092 tumors analyzed to determine the expression of three HRs in human meningiomas: PRs, ARs, and ERs. The proportions of HR+ meningiomas were estimated to be 0.76 (95% CI 0.72-0.80) for PR+ and 0.50 (95% CI 0.33-0.66) for AR+ meningiomas. ER+ meningioma detection varied depending on the measurement method used and was 0.06 (95% CI 0.03-0.10) with IHC and 0.11 (95% CI 0.06-0.20) with LB assays. There were associations between age and PR and ER expression that varied between male and female patients. PR+ and AR+ were more common in female patients (OR 1.84, 95% CI 1.47-2.29 for PR and OR 4.16, 95% CI 1.62-10.68 for AR). Additionally, PR+ meningiomas were enriched in skull base locations (OR 1.89, 95% CI 1.03-3.48) and meningothelial histology (OR 1.86, 95% CI 1.23-2.81). A meta-regression showed that PR+ was independently associated with age (OR 1.11 95% CI 1.09-1.13; p < 0.0001) and WHO grade I tumors (OR 8.09, 95% CI 3.55-18.44; p < 0.0001). ER+ was negatively associated with meningothelial histology (OR 0.94, 95% CI 0.86-0.98; p = 0.044) and positively associated with convexity location (OR 1.12, 95% CI 1.05-1.18; p = 0.0003).
The association between HRs and meningioma features has been investigated but unexplained for decades. In this study the authors demonstrated that HR status has a strong association with known meningioma features, including WHO grade, age, female sex, histology, and anatomical location. Identifying these independent associations allows for a better understanding of meningioma heterogeneity and provides a foundation for revisiting targeted hormonal therapy in meningioma on the basis of proper patient stratification according to HR status.
Disrupted development of the gut microbiota is a contributing cause of childhood malnutrition.
subspecies
is a prominent early colonizer of the infant gut that consumes human milk oligosaccharides ...(HMOs). We found that the absolute abundance of
is lower in 3- to 24-month-old Bangladeshi infants with severe acute malnutrition (SAM) compared to their healthy age-matched counterparts. A single-blind, placebo-controlled trial (SYNERGIE) was conducted in 2- to 6-month-old Bangladeshi infants with SAM. A commercial U.S. donor-derived
strain (EVC001) was administered daily with or without the HMO lacto-
-neotetraose for 28 days. This intervention increased fecal
abundance in infants with SAM, although to levels still 10- to 100-fold lower than in untreated healthy controls. EVC001 treatment promoted weight gain that was associated with reduced intestinal inflammation markers in infants with SAM. We cultured fecal
strains from Bangladeshi infants and colonized gnotobiotic mice with these cultured strains. The gnotobiotic mice were fed a diet representative of that consumed by 6-month-old Bangladeshi infants, with or without HMO supplementation. One
strain, Bg_2D9, expressing two gene clusters involved in uptake and utilization of
-glycans and plant-derived polysaccharides, exhibited superior fitness over EVC001. The fitness advantage of Bg_2D9 was confirmed in a gnotobiotic mouse model of mother-to-infant gut microbiota transmission where dams received a pretreatment fecal community from a SAM infant in the SYNERGIE trial. Whether Bg_2D9 is superior to EVC001 for treating malnourished infants who consume a diet with limited breastmilk requires further clinical testing.
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