Tracking Drugs and Lipids: Quantitative Mass Spectrometry Imaging of Liposomal Doxorubicin Delivery and Bilayer Fate in Three-Dimensional Tumor Models.

Targeted therapy to the tumor would greatly advance precision medicine. Many drug delivery vehicles have emerged, but liposomes are cited as the most successful to date. Recent efforts to develop liposomal drug delivery systems focus on drug distribution in tissues and ignore liposomal fate. In this study, we developed a novel method to elucidate both drug and liposomal bilayer distribution in a three-dimensional cell culture model using quantitative matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI qMSI) alongside fluorescence microscopy. Imaging liposomal distribution in a cell culture model is challenging, as lipids forming the bilayer are endogenous to the model system. To resolve this issue, we functionalized the bilayer by chemically cross-linking a fluorescent tag to the alkyne-containing lipid hexynoyl phosphoethanolamine (HPE). We synthesized liposomes incorporating the tagged HPE lipid and encapsulated within them doxorubicin, yielding a theranostic liposome capable of both drug delivery and monitoring liposomal uptake. We employed an "in-tissue" MALDI qMSI approach to generate a calibration curve with R2 = 0.9687, allowing for quantification of doxorubicin within spheroid sections at multiple time points. After 72 h of treatment with the theranostic liposomes, full doxorubicin penetration was observed. The metabolites doxorubicinone and 7-deoxydoxorubicinone were also detected after 48 h. Modification of the bilayer allowed for fluorescence microscopy tracking of liposomes, while MALDI MSI simultaneously permitted the imaging of drugs and metabolites. While we demonstrated the utility of our method with doxorubicin, this system could be applied to examine the uptake, release, and metabolism of many other liposome-encapsulated drugs.

Reevaluating Associations between Prenatal Care Utilization and Current Trends in Preterm Birth.

OBJECTIVE: Studies have suggested an association between prenatal care (PNC) and preterm birth (PTB). We evaluated trends in PTB and association of PNC and PTB. STUDY DESIGN: This was a retrospective cohort study of singleton, viable nonanomalous deliveries from 1991 to 2018. PNC utilization was defined by World Health Organization using number of visits: adequate (≥8), suboptimal (5-7), and inadequate (<5). Primary outcome was PTB. Tests of trend were used to assess changes in PTB over time. Baseline characteristics and outcomes were compared. Logistic regression estimated the association of PNC and PTB. We evaluated for effect modification by year of birth. RESULTS: Of 92,294 patients, 14,057 (15%) had PTB. Inadequate and suboptimal PNC were associated with higher odds of PTB compared to adequate PNC (adjusted odds ratios [aOR 6.21], 95% confidence interval [CI] 5.84-6.60; aOR 3.57, 95% CI 3.36-3.79). Inadequate PNC was associated with higher odds of PTB over time (effect modification p < 0.0001). Inadequate PNC was associated with 5.4 times higher odds of PTB in 1998, 7.0 times in 2008, and 9.1 times in 2018. CONCLUSION: Despite an increase in adequate PNC, there was a rise in PTB associated with inadequate and suboptimal PNC. PNC utilization was a stronger risk factor in recent years with higher PTB in patients who attended more than five PNC visits. KEY POINTS: · PNC utilization is associated with the risk of PTB.. · Despite an increase in PNC utilization, PTB rates have increased.. · There is an even stronger association between PNC utilization and PTB over time..

Antibiotic treatment of bacterial vaginosis to prevent preterm delivery: Systematic review and individual participant data meta-analysis.

BACKGROUND: Bacterial vaginosis (BV) increases preterm delivery (PTD) risk, but treatment trials showed mixed results in preventing PTD. OBJECTIVES: Determine, using individual participant data (IPD), whether BV treatment during pregnancy reduced PTD or prolonged time-to-delivery. DATA SOURCES: Cochrane Systematic Review (2013), MEDLINE, EMBASE, journal searches, and searches (January 2013-September 2022) ("bacterial vaginosis AND pregnancy") of (i) clinicaltrials.gov; (ii) Cochrane Central Register of Controlled Trials; (iii) World Health Organization International Clinical Trials Registry Platform Portal; and (iv) Web of Science ("bacterial vaginosis"). STUDY SELECTION AND DATA EXTRACTION: Studies randomising asymptomatic pregnant individuals with BV to antibiotics or control, measuring delivery gestation. Extraction was from original data files. Bias risk was assessed using the Cochrane tool. Analysis used "one-step" logistic and Cox random effect models, adjusting gestation at randomisation and PTD history; heterogeneity by I2 . Subgroup analysis tested interactions with treatment. In sensitivity analyses, studies not providing IPD were incorporated by "multiple random-donor hot-deck" imputation, using IPD studies as donors. RESULTS: There were 121 references (96 studies) with 23 eligible trials (11,979 participants); 13 studies (6915 participants) provided IPD; 12 (6115) were incorporated. Results from 9 (4887 participants) not providing IPD were imputed. Odds ratios for PTD for metronidazole and clindamycin versus placebo were 1.00 (95% CI 0.84, 1.17), I2  = 62%, and 0.59 (95% CI 0.42, 0.82), I2  = 0 before; and 0.95 (95% CI 0.81, 1.11), I2  = 59%, and 0.90 (95% CI: 0.72, 1.12), I2  = 0, after imputation. Time-to-delivery did not differ from null with either treatment. Including imputed IPD, there was no evidence that either drug was more effective when administered earlier, or among those with a PTD history. CONCLUSIONS: Clindamycin, but not metronidazole, was beneficial in studies providing IPD, but after imputing data from missing IPD studies, treatment of BV during pregnancy did not reduce PTD, nor prolong pregnancy, in any subgroup or when started earlier in gestation.

Commensal microbiome promotes hair follicle regeneration by inducing keratinocyte HIF-1α signaling and glutamine metabolism.

Tissue injury induces metabolic changes in stem cells, which likely modulate regeneration. Using a model of organ regeneration called wound-induced hair follicle neogenesis (WIHN), we identified skin-resident bacteria as key modulators of keratinocyte metabolism, demonstrating a positive correlation between bacterial load, glutamine metabolism, and regeneration. Specifically, through comprehensive multiomic analysis and single-cell RNA sequencing in murine skin, we show that bacterially induced hypoxia drives increased glutamine metabolism in keratinocytes with attendant enhancement of skin and hair follicle regeneration. In human skin wounds, topical broad-spectrum antibiotics inhibit glutamine production and are partially responsible for reduced healing. These findings reveal a conserved and coherent physiologic context in which bacterially induced metabolic changes improve the tolerance of stem cells to damage and enhance regenerative capacity. This unexpected proregenerative modulation of metabolism by the skin microbiome in both mice and humans suggests important methods for enhancing regeneration after injury.

Socio-demographic factors associated with medication adherence among People Living with HIV in the Kumasi Metropolis, Ghana.

BACKGROUND: Medication adherence is important to the survival of People Living with HIV (PLHIV) globally. Although, HIV viral load is reduced by antiretroviral therapy (ART), the number of people on ART continues to rise in Ghana. In the Kumasi Metropolis, Ghana, we looked at the socio-demographic factors associated with medication adherence among PLHIV. METHODS: A quantitative study involving 420 PLHIV who sought healthcare at the Kumasi South Regional Hospital was conducted utilizing a cross-sectional study design. We employed a structured questionnaire to collect data on medication adherence using the eight-item Morisky Medication Adherence Scale (MMAS) and socio-demographic factors that influence medication adherence. The data were analysed using Stata 14.2. Frequencies and percentages were used to present the descriptive data. The association between socio-demographic factors and medication adherence among PLHIV was investigated using both univariate and multivariate analyses. RESULTS: More than half (53.10%) of PLHIV adhered to ART. Place of residence was significantly established to be influencing medication adherence among PLHIV. PLHIV who were residing in urban centers (aOR = 3.61; CI = 2.24-5.82) were more likely to adhere to medication as compared to those who resided in rural areas. CONCLUSION: Slightly more than half of PLHIV took their medicines as prescribed. Government and Policymakers such as the Ghana AIDS Commission, Ministry of Health, and Ghana Health Service should incorporate socio-demographic factors such as place of residence while creating and executing medication adherence initiatives to evaluate HIV management regimen for PLHIV.

Progression to Severe Chronic Hypertension 5-7 Years After a Pregnancy With Mild Chronic Hypertension.

OBJECTIVE: To estimate the incidence of severe chronic hypertension (cHTN) within 5-7 years after a pregnancy complicated by mild cHTN. METHODS: This was a retrospective cohort study of women with mild cHTN during an index pregnancy between 2012 and 2014. Women were included if they received prenatal care at a single academic center and had mild cHTN during their pregnancy. Women with severe cHTN, type 1 diabetes, systemic lupus erythematosus, cardiomyopathy, proteinuria, or creatinine level greater than 1.1 mg/dL before 23 weeks of gestation at baseline were excluded. The primary outcome was a composite of severe cHTN (defined as new-onset of two or more severe blood pressures) or new-onset cardiovascular disease complications more than 12 weeks after the index delivery. RESULTS: A total of 647 women with mild cHTN met inclusion criteria. Of these, 236 (36.5%, 95% CI 32.8-40.2%) women experienced the primary composite outcome of severe cHTN within 5-7 years of the index pregnancy. Black women progressed more rapidly than White women (adjusted hazard ratio [aHR] 1.99, 95% CI 1.43-2.76). Smoking tobacco was also associated with more rapid progression to severe cHTN (aHR 1.47, 95% CI 1.13-1.90). CONCLUSION: In this cohort, one in three women with mild cHTN in an index pregnancy progressed to severe cHTN within 5-7 years. Prospective studies to validate this finding are needed.

Treatment for Mild Chronic Hypertension during Pregnancy.

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth. METHODS: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth. RESULTS: A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<0.001). The percentage of small-for-gestational-age birth weights below the 10th percentile was 11.2% in the active-treatment group and 10.4% in the control group (adjusted risk ratio, 1.04; 95% CI, 0.82 to 1.31; P = 0.76). The incidence of serious maternal complications was 2.1% and 2.8%, respectively (risk ratio, 0.75; 95% CI, 0.45 to 1.26), and the incidence of severe neonatal complications was 2.0% and 2.6% (risk ratio, 0.77; 95% CI, 0.45 to 1.30). The incidence of any preeclampsia in the two groups was 24.4% and 31.1%, respectively (risk ratio, 0.79; 95% CI, 0.69 to 0.89), and the incidence of preterm birth was 27.5% and 31.4% (risk ratio, 0.87; 95% CI, 0.77 to 0.99). CONCLUSIONS: In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight. (Funded by the National Heart, Lung, and Blood Institute; CHAP ClinicalTrials.gov number, NCT02299414.).

The Association of Cesarean Skin Incision Length and Postoperative Wound Complications.

OBJECTIVE: This study was aimed to evaluate the relationship between cesarean skin incision length and wound complications. STUDY DESIGN: Planned secondary analysis of a multicenter double-blind randomized trial of adjunctive azithromycin versus placebo (in addition to standard cefazolin) in women ≥24 weeks undergoing cesarean delivery during labor or ≥4 hours after membrane rupture. Skin incision length (cm) was measured just prior to skin closure. The primary outcome was a composite of wound complications (wound infection, separation, seroma, hematoma, or dehiscence) up to 6 weeks of postpartum. Individual components of the composite were examined as secondary outcomes. Outcomes were compared between groups defined by the lowest (≤25th), middle (25-75th) and highest (>75th) incision length quartiles. Logistic regression was used to adjust for potential confounding variables. RESULTS: Of the 2,013 women enrolled in the primary trial, 1,916 had recorded incision lengths and were included in this secondary analysis. The overall rate of composite wound complications was 7.8%. Median incision length was 15.0 cm (interquartile range: 14.0-16.5) with the lowest quartile defined as ≤14, middle as >14 to ≤16.5, and highest as >16.5 cm. Mean BMI, parity, use of staples, and duration of surgery differed significantly between the three incision length groups. In unadjusted analysis, the longest incision lengths were associated with an increased risk of the wound composite and wound infections (odds ratio [OR] = 2.27, 95% confidence interval [CI]: 1.43-3.60 and OR = 2.30, 95% CI: 1.27-4.15, respectively) compared with the shortest incision lengths. However, after multivariable adjustments, these associations were nullified. Additional analyses considering incision length as a continuous variable and using 10th/90th percentile cut-offs still did not suggest any associations with outcomes. CONCLUSION: Increasing skin incision length is not independently associated with an increased risk of postoperative wound complications. KEY POINTS: · After multivariable adjustments, skin incision length was not independently associated with an increased risk of postoperative wound complications.. · A reasonable incision length needed to safely perform the procedure should be used..

Skin preparation type and post-cesarean infection with use of adjunctive azithromycin prophylaxis.

OBJECTIVE: To compare the frequency of postoperative surgical site infection (SSI) by type of skin preparation used for unscheduled cesarean in the setting of adjunctive azithromycin prophylaxis. METHODS: Secondary analysis of a multi-center randomized controlled trial of adjunctive azithromycin (500 mg intravenous) versus placebo in women who were ≥24 weeks gestation and undergoing unscheduled cesarean (i.e. during labor or ≥4 h after membrane rupture). Type of skin preparation used was identified based on the protocol at the hospital at the time of delivery: iodine-alcohol, chlorhexidine, chlorhexidine-alcohol, or the combination of chlorhexidine-alcohol and iodine. The primary outcome of this analysis was incidence of post-operative SSI, as defined by CDC criteria. Multivariable logistic regression was applied for adjustments. RESULTS: All 2013 women in the primary trial were included in this analysis. Women were grouped according to type of skin preparation received: iodine-alcohol (n = 193), chlorhexidine (n = 733), chlorhexidine-alcohol (n = 656), and chlorhexidine-alcohol and iodine combined sequentially (n = 431). The unadjusted rates of wound infection ranged from 2.9% to 5.7%. Using iodine-alcohol as the referent, the adjusted odds ratios for wound SSI were 0.71 (95% CI 0.30-1.66) for chlorhexidine, 0.97 (95% CI 0.41-2.28) for chlorhexidine-alcohol, and 0.88 (95% CI 0.36-2.20) for chlorhexidine-alcohol with iodine combination. CONCLUSION: In women undergoing unscheduled cesarean delivery in a trial of adjunctive azithromycin, the type of skin preparation used did not appear to be associated with the frequency of wound SSI.

A systematic review of biomarkers associated with maternal infection in pregnant and postpartum women.

BACKGROUND: Serum biomarkers are commonly used to support the diagnosis of infection in non-pregnant patients whose clinical presentation suggests infection. The utility of serum biomarkers for infection in pregnant and postpartum women is uncertain. SEARCH STRATEGY: PubMed, CINAHL, EMBASE, ClinicalTrials.gov, Cochrane Library, CINAHL, and SCOPUS were searched from inception to February 2020. SELECTION CRITERIA: Full-text manuscripts in English were included if they reported the measurement of maternal serum biomarkers-and included a control group-to identify infection in pregnant and postpartum women. DATA COLLECTION AND ANALYSIS: two authors independently screened manuscripts, extracted data, and assessed methodologic quality. MAIN RESULTS: Interleukin-6 (IL-6), C-reactive protein, procalcitonin, insulin-like growth factor binding protein 1, tumor necrosis factor-α, calgranulin B, neopterin, and interferon-γ inducible protein 10 reliably indicated infection. Intercellular adhesion molecule 1, monocyte chemotactic and activating factor, soluble IL-6 receptor, and IL-8 were not useful markers in pregnant and postpartum women. CONCLUSIONS: Findings suggest that certain biomarkers have diagnostic value when maternal infection is suspected, but also confirms limitations in this population.

Constitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation.

Mutations of the mitochondrial genome (mtDNA) cause a range of profoundly debilitating clinical conditions for which treatment options are very limited. Most mtDNA diseases show heteroplasmy - tissues express both wild-type and mutant mtDNA. While the level of heteroplasmy broadly correlates with disease severity, the relationships between specific mtDNA mutations, heteroplasmy, disease phenotype and severity are poorly understood. We have carried out extensive bioenergetic, metabolomic and RNAseq studies on heteroplasmic patient-derived cells carrying the most prevalent disease related mtDNA mutation, the m.3243 A > G. These studies reveal that the mutation promotes changes in metabolites which are associated with the upregulation of the PI3K-Akt-mTORC1 axis in patient-derived cells and tissues. Remarkably, pharmacological inhibition of PI3K, Akt, or mTORC1 reduced mtDNA mutant load and partially rescued cellular bioenergetic function. The PI3K-Akt-mTORC1 axis thus represents a potential therapeutic target that may benefit people suffering from the consequences of the m.3243 A > G mutation.

DNA Intercalators Inhibit Eukaryotic Ribosomal RNA Synthesis by Impairing the Initiation of Transcription.

In eukaryotes, ribosome biogenesis is driven by the synthesis of the ribosomal RNA (rRNA) by RNA polymerase I (Pol-I) and is tightly linked to cell growth and proliferation. The 3D-structure of the rDNA promoter plays an important, yet not fully understood role in regulating rRNA synthesis. We hypothesized that DNA intercalators/groove binders could affect this structure and disrupt rRNA transcription. To test this hypothesis, we investigated the effect of a number of compounds on Pol-I transcription in vitro and in cells. We find that intercalators/groove binders are potent inhibitors of Pol-I specific transcription both in vitro and in cells, regardless of their specificity and the strength of its interaction with DNA. Importantly, the synthetic ability of Pol-I is unaffected, suggesting that these compounds are not targeting post-initiating events. Notably, the tested compounds have limited effect on transcription by Pol-II and III, demonstrating the hypersensitivity of Pol-I transcription. We propose that stability of pre-initiation complex and initiation are affected as result of altered 3D architecture of the rDNA promoter, which is well in line with the recently reported importance of biophysical rDNA promoter properties on initiation complex formation in the yeast system.

Electroblotting through Enzymatic Membranes to Enhance Molecular Tissue Imaging.

MALDI-TOF mass spectrometry imaging (MSI) is a powerful tool for studying biomolecule localization in tissue. Protein distributions in tissue provide important histological information; however, large proteins exhibit a high limit of detection in MALDI-MS when compared to their corresponding smaller proteolytic peptides. As a result, several techniques have emerged to digest proteins into more detectable peptides for imaging. Digestion is typically accomplished through trypsin deposition on the tissue, but this technique increases the complexity of the tissue microenvironment, which can limit the number of detectable species. This proof-of-principle study explores tryptic tissue digestion during electroblotting through a trypsin-containing membrane. This approach actively extracts and enzymatically digests proteins from mouse brain tissue sections while simultaneously reducing the complexity of the tissue microenvironment (compared to trypsin deposition on the surface) to obtain an increased number of detectable peptide fragments. The method does not greatly compromise spatial location or require expensive devices to uniformly deposit trypsin on tissue. Using electrodigestion through membranes, we detected and tentatively identified several tryptic peptides that were not observed after on-tissue digestion. Moreover, the use of pepsin rather than trypsin in digestion membranes allows extraction and digestion at low pH to detect peptides from a complementary subset of tissue proteins. Future studies will aim to further improve the method, including changing the substrate membrane to increase spatial resolution and the number of detected peptides.

Value improvement at the point of care: engaging and empowering front-line teams with a new quality improvement methodology.

BACKGROUND: Healthcare organisations require systems to consistently meet the needs of their patients while providing excellent quality of care. The value improvement (VI) approach was developed by the Institute for healthcare improvement and successfully piloted at Raigmore Hospital, Scotland. It showed positive results in improving outcomes and reducing costs. Our multidisciplinary team from a tertiary care cardiac hospital in Doha, Qatar wanted to see if we could improve value in a clinically and geographically distinct context. We sought to understand the effectiveness of this approach as an integrative management philosophy that aims for continuous improvement in the quality of services by increasing efficiency and reducing waste. METHODS: This study evaluates the outcomes achieved from applying the VI methodology. The method is rooted in a framework that emphasises standardisation, continuous process improvement and rightsizing capacity to demand. The main tools include a data box score, a visual management board and weekly communication huddles. RESULTS: As a result of the VI methodology, our team achieved improvements across performance, staff capacity and cost domains. Compared with the 4-8 weeks baseline data collection period, these improvements included an increase in discharges before 13:00 hour by 61%, a reduction in the number of blood samples per patient per day by 20%, an increase in nursing time spent in direct patient care by 18%, and an increase in staff satisfaction to 40%. CONCLUSIONS: We found that the VI approach offered a systematic method for continuously improving the quality of care by focusing attention each week on safety, efficiency and patient experience. The team improved numerous processes and outcomes resulting in a positive impact on patients and families and increased the engagement of staff in continuous improvement. In this way, we improved our capacity to undertake and complete quality projects.

Bacteria induce skin regeneration via IL-1ß signaling.

Environmental factors that enhance regeneration are largely unknown. The immune system and microbiome are attributed roles in repairing and regenerating structure but their precise interplay is unclear. Here, we assessed the function of skin bacteria in wound healing and wound-induced hair follicle neogenesis (WIHN), a rare adult organogenesis model. WIHN levels and stem cell markers correlate with bacterial counts, being lowest in germ-free (GF), intermediate in conventional specific pathogen-free (SPF), and highest in wild-type mice, even those infected with pathogenic Staphylococcus aureus. Reducing skin microbiota via cage changes or topical antibiotics decreased WIHN. Inflammatory cytokine IL-1ß and keratinocyte-dependent IL-1R-MyD88 signaling are necessary and sufficient for bacteria to promote regeneration. Finally, in a small trial, a topical broad-spectrum antibiotic also slowed skin wound healing in adult volunteers. These results demonstrate a role for IL-1ß to control morphogenesis and support the need to reconsider routine applications of topical prophylactic antibiotics.

Predicting long-term neurodevelopmental outcomes in very preterm neonates by umbilical cord gas parameters.

BACKGROUND: The predictive value of acidemia at birth on long-term neurodevelopmental outcomes remains poorly understood, especially in preterm neonates. OBJECTIVE: This study aimed to assess the relationship between the umbilical artery acid-base status and major neurodevelopmental disability at an age of between 5 and 8 years among children born very prematurely. STUDY DESIGN: We performed a secondary analysis of the data from a follow-up study of a prospective cohort of 457 children aged between 23 weeks and 31 weeks and 6 days from 1996 to 2001. Arterial cord gas parameters that were <10th percentile in the original cohort of 457 neonates (ie, pH of <7.1, base deficit of <-8.6 mEq/L, and a partial pressure of CO2 of >77 mm Hg) were considered abnormal. Sensitivity analyses considered alternative definitions for abnormal cord gases including a pH of <7.0 or base deficit of <-12 mEq/L. The primary outcome was a composite of major neurodevelopmental disability, including an intelligence quotient score of <70, cerebral palsy, blindness, deafness, abnormal balance, impaired cognition, dystonia, and seizure disorder. A logistic regression analysis was used to adjust for race and caregiver intelligence quotient score and, in an additional analysis, for gestational age. RESULTS: A total of 259 of 261 maternal-infant dyads were evaluated at a mean child age of 6.8 years, with complete umbilical cord gas data for 228 of those. Infants with an abnormal pH and a base deficit (defined above) were over 4-fold more likely to have the composite disability and an intelligence quotient score of <70. These increased odds persisted after adjusting for age and caregiver intelligence quotient score, but when considering gestational age as well, none of the umbilical cord gas parameters significantly predicted the presence of the composite disability or an intelligence quotient score of <70. However, when using the stricter umbilical cord gas criteria (ie, pH of <7.0 and a base deficit of <-12 mEq/L), a base deficit of <-12 mEq/L was independently associated with both neurodevelopmental disability and an intelligence quotient score of <70. CONCLUSION: When defined more strictly, abnormal umbilical cord gases, specifically a base deficit of <-12 mEq/L, are associated with an increased risk for major long-term neurodevelopmental disability and an intelligence quotient score of <70 in children born very prematurely.

Epidemiology of readmissions in early infancy following nonelective cesarean delivery.

OBJECTIVE: Determine incidence and risk factors for readmissions in early infancy. STUDY DESIGN: Secondary analysis of data from the Cesarean Section Optimal Antibiotic Prophylaxis trial. All unplanned revisits (unplanned clinic, ER visits, and hospital readmissions) and hospital readmissions (initial discharge to 3-month follow-up) were analyzed. RESULTS: 295 (15.9%) of 1850 infants had revisits with risk factors being ethnicity (adjusted odds ratio (aOR): 0.6 for Hispanic), maternal postpartum antibiotics (1.89), azithromycin treatment (1.22), small for gestational age (1.68), apnea (3.82), and hospital stay after birth >90th percentile (0.49). 71 (3.8%) of 1850 infants were readmitted with risk factors being antenatal steroids (aOR 2.49), elective repeat C/section (0.72), postpartum maternal antibiotics (2.22), O2 requirement after delivery room (2.82), and suspected/proven neonatal sepsis (0.55). CONCLUSION(S): Multiple risk factors were identified, suggesting potential impact on the neonatal microbiome (maternal postpartum antibiotics) or issues related to access/cost of care (Hispanic ethnicity associated with fewer revisits).

A Geologically Based Indoor-Radon Potential Map of Kentucky.

We combined 71,930 short-term (median duration 4 days) home radon test results with 1:24,000-scale bedrock geologic map coverage of Kentucky to produce a statewide geologically based indoor-radon potential map. The test results were positively skewed with a mean of 266 Bq/m3, median of 122 Bq/m3, and 75th percentile of 289 Bq/m3. We identified 106 formations with ≥10 test results. Analysis of results from 20 predominantly monolithologic formations showed indoor-radon concentrations to be positively skewed on a formation-by-formation basis, with a proportional relationship between sample means and standard deviations. Limestone (median 170 Bq/m3) and dolostone (median 130 Bq/m3) tended to have higher indoor-radon concentrations than siltstones and sandstones (median 67 Bq/m3) or unlithified surficial deposits (median 63 Bq/m3). Individual shales had median values ranging from 67 to 189 Bq/m3; the median value for all shale values was 85 Bq/m3. Percentages of values falling above the U.S. Environmental Protection Agency (EPA) action level of 148 Bq/m3 were sandstone and siltstone: 24%, unlithified clastic: 21%, dolostone: 46%, limestone: 55%, and shale: 34%. Mississippian limestones, Ordovician limestones, and Devonian black shales had the highest indoor-radon potential values in Kentucky. Indoor-radon test mean values for the selected formations were also weakly, but statistically significantly, correlated with mean aeroradiometric uranium concentrations. To produce a map useful to nonspecialists, we classified each of the 106 formations into five radon-geologic classes on the basis of their 75th percentile radon concentrations. The statewide map is freely available through an interactive internet map service.

Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions.

Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer's disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H AD risk variant. The prevailing phenotype of Trem2 R47H knock-in mice was decreased expression levels of Trem2 in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reduced Trem2 expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreased Trem2 expression under conditions of lipopolysaccharide (LPS) pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a program of genes including Arg1 and Ap1b1 in microglia, which showed an attenuated response to IL-4 when Trem2 expression was decreased. Genes showing a similar expression profile to Arg1 were enriched for STAT6 transcription factor recognition elements in their promoter, and Trem2 knockdown decreased levels of STAT6. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2's anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream of Trem2 in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease.