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Abstract Background The promoters of housekeeping genes are well-bound by RNA polymerase II (RNAP) in different tissues. Although the promoters of these genes are known to contain CpG islands, the specific DNA sequences that are associated with high RNAP binding to housekeeping promoters has not been described. Results ChIP-chip experiments from three mouse tissues, liver, heart ventricles, and primary keratinocytes, indicate that 94% of promoters have similar RNAP binding, ranging from well-bound to poorly-bound in all tissues. Using all 8-base pair long sequences as a test set, we have identified the DNA sequences that are enriched in promoters of housekeeping genes, focusing on those DNA sequences which are preferentially localized in the proximal promoter. We observe a bimodal distribution. Virtually all sequences enriched in promoters with high RNAP binding values contain a CpG dinucleotide. These results suggest that only transcription factor binding sites (TFBS) that contain the CpG dinucleotide are involved in RNAP binding to housekeeping promoters while TFBS that do not contain a CpG are involved in regulated promoter activity. Abundant 8-mers that are preferentially localized in the proximal promoters and exhibit the best enrichment in RNAP bound promoters are all variants of six known CpG-containing TFBS: ETS, NRF-1, BoxA, SP1, CRE, and E-Box. The frequency of these six DNA motifs can predict housekeeping promoters as accurately as the presence of a CpG island, suggesting that they are the structural elements critical for CpG island function. Experimental EMSA results demonstrate that methylation of the CpG in the ETS, NRF-1, and SP1 motifs prevent DNA binding in nuclear extracts in both keratinocytes and liver. Conclusion In general, TFBS that do not contain a CpG are involved in regulated gene expression while TFBS that contain a CpG are involved in constitutive gene expression with some CpG containing sequences also involved in inducible and tissue specific gene regulation. These TFBS are not bound when the CpG is methylated. Unmethylated CpG dinucleotides in the TFBS in CpG islands allow the transcription factors to find their binding sites which occur only in promoters, in turn localizing RNAP to promoters.

Objectives: The use of secondary databases has become popular for evaluating the effectiveness and safety of interventions in real-life settings. However, the absence of important confounders in these databases is challenging. To address this issue, the high-dimensional propensity score (hdPS) algorithm was developed in 2009. This algorithm uses proxy variables for mitigating confounding by combining information available across several healthcare dimensions. This study assessed the methodology and reporting of the hdPS in comparative effectiveness and safety research., Study Design and Setting: In this methodological review, we searched PubMed and Google Scholar from July 2009 to May 2022 for studies that used the hdPS for evaluating the effectiveness or safety of healthcare interventions. Two reviewers independently extracted study characteristics and assessed how the hdPS was applied and reported. Risk of bias was evaluated with the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool., Results: In total, 136 studies met the inclusion criteria; the median publication year was 2018 (Q1-Q3 2016-2020). The studies included 192 datasets, mostly North American databases (n = 132, 69%). The hdPS was used in primary analysis in 120 studies (88%). Dimensions were defined in 101 studies (74%), with a median of 5 (Q1-Q3 4-6) dimensions included. A median of 500 (Q1-Q3 200-500) empirically identified covariates were selected. Regarding hdPS reporting, only 11 studies (8%) reported all recommended items. Most studies (n = 81, 60%) had a moderate overall risk of bias., Conclusion: There is room for improvement in the reporting of hdPS studies, especially regarding the transparency of methodological choices that underpin the construction of the hdPS., Competing Interests: Declaration of competing interest G.L.M. reports a relationship with Synapse Medicine that includes employment. C.P. reports a relationship with Parexel International that includes employment. L.L. reports a relationship with Synapse Medicine that includes board membership and employment. There are no competing interests for any other author., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Determine whether use of reflective questions asked on a twice monthly basis is a useful addition to our intern wellness curriculum, with a goal of longitudinal development. Prior studies have demonstrated the use of reflection in processing educational experiences toward professional growth at both the medical student and resident level., Design: During the first year, every 2 weeks, the 13 interns were asked and answered 2 reflective prompts by email. Their responses went to a single faculty member and were then blinded for analysis. The second year of the program, prompts were discussed by participants in a closed group setting. Participation was voluntary. The questions fell into 6 major categories: role expectations, role assessment, role affirmation, role reflection, emotional self-assessment, work-life integration, and boundaries. Thematic analysis of the responses was performed using an inductive approach by 2 independent expert reviewers., Setting: Brown General Surgery Residency Program, academic years 2021 to 2022 and 2022 to 2023., Conclusions: Use of reflective questions is a valuable tool as part of an intern wellness curriculum and can be easily implemented. It is inexpensive, does not require a huge time commitment, and is easily adaptable to a program's specific needs. It encourages developing surgeons to recognize and share in their emotions as they encounter the new and stressful experiences inherent in residency and may help to prevent burnout. Sustained participation through the year and robust responses suggest good resident engagement and acceptance of the program., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

This study analyzes the weather-related health damage of present and future extreme temperatures in Argentina. Focusing on mortality, short-term impacts of temperature are obtained by regressing monthly mortality rates on inter-annual monthly weather variability. For this purpose, a countrywide panel dataset at the municipal level was constructed from the universe of deaths between 2010 and 2019, and daily meteorological records from the ERA5 weather dataset. Then, NASA Earth Exchange Global Daily Downscaled Projections (NEX-GDDP) are used to project future mortality by 2085 under two climate scenarios. Finally, present and future mortality-related economic damages are assessed using the Value of a Statistical Life. The results show that one additional day of extreme temperatures increase all-cause mortality rates relative to mild weather and that the impact of hotter-than-average temperatures is greater in magnitude than that of colder ones. Substantial heterogeneity exists between causes of death and age groups, with older people facing greater risks, while the results for gender are inconclusive. All days of extreme cold in a year generate damage equivalent to 0.64% of GDP, while heat damage is 0.11% of GDP. The total damage by extreme temperatures adds up to 0.75% of the 2019 GDP. When future temperatures are valued, the total damage increases by an additional 1.45% under scenario RCP8.5 because the lower mortality occurring on cold days only partially offsets the increase in the number of hot days. On the contrary, if temperature changes were to be mild (i.e., under scenario RCP4.5), overall mortality would be lower at the national level and the corresponding damages would decrease by 0.02%., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A cluster of three confirmed autochthonous dengue cases was detected in October 2023 in the Val-de-Marne department neighbouring Paris, France. This marks the northernmost transmission of dengue in Europe reported to date. The epidemiological and microbiological investigations and the vector control measures are described. This event confirms the need for early case detection and response to contain dengue in Europe, especially given the 2024 Summer Olympic and Paralympic Games, when millions of visitors will visit the Greater Paris area.

People experiencing homelessness are particularly vulnerable when diagnosed with pancreatic cancer. Patients with lower socioeconomic status have worse outcomes from pancreatic cancer as the result of disparities in access to treatment and barriers to navigation of the health care system. Patients with lower socioeconomic status, or who are vulnerably housed, are less likely to receive surgical treatment even when it is recommended by National Comprehensive Cancer Network guidelines. This disparity in access to surgical care explains much of the gap in pancreatic cancer outcomes. There are many factors that contribute to this disparity in surgical management of pancreatic cancer in people experiencing homelessness. These include a lack of reliable transportation, feeling unwelcome in the medical setting, a lack of primary care and health insurance, and implicit biases of health care providers, including racial bias. Solutions that focus on rectifying these problems include utilizing patient navigators, addressing implicit biases of all health care providers and staff, creating an environment that caters to the needs of patients experiencing homelessness, and improving their access to insurance and regional support networks. Implementing these potential solutions all the way from the individual provider to national safety nets could improve outcomes for patients with pancreatic cancer who are experiencing homelessness.

Background: The Beck Depression Inventory (BDI-II) may be used to evaluate individuals for symptoms of depression., Methods: In a 1-year prospective study, 52 adult Lyme disease patients with erythema migrans and 104 matched control subjects were clinically assessed and completed the BDI-II at study entry and approximately 6 and 12 months later following antibiotic treatment., Results: The mean BDI-II score was significantly higher at the baseline visit among Lyme disease patients compared with controls (P = .002), but no significant differences between the groups were observed at either the 6- or 12-month study visits. Over the course of the study, the mean BDI-II scores decreased an average of approximately 0.22 points per month (P < .0005) for Lyme disease patients, whereas the mean scores changed very little for controls (mean change = -0.02 per month, P = .50). The total number of somatic symptoms, of the 12 symptoms evaluated, strongly and directly correlated with the BDI-II scores at the baseline visit for the Lyme disease patients., Conclusions: The mean BDI-II scores of patients with early Lyme disease significantly exceeded that of matched controls at study entry, but by 6 months the values did not differ significantly. There was a good-to-excellent direct correlation between the BDI-II score and the total number of symptoms, suggesting that the BDI-II scores were reflecting somatic rather than affective depressive symptoms. When using the BDI-II as an assessment tool of patients with Lyme disease, infection-related somatic symptoms per se need to be considered in the interpretation of the results., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: In 2016, 23% of children (155 million) aged [Formula: see text] were stunted. Global-level modeling has consistently found climate change impacts on food production are likely to impair progress on reducing undernutrition., Objectives: We adopt a new perspective, assessing how climate change may affect child stunting via its impacts on two interacting socioeconomic drivers: incomes of the poorest 20% of populations (due to climate impacts on crop production, health, labor productivity, and disasters) and food prices., Methods: We developed a statistical model to project moderate and severe stunting in children aged [Formula: see text] at the national level in 2030 under low and high climate change scenarios combined with poverty and prosperity scenarios in 44 countries., Results: We estimated that in the absence of climate change, 110 million children aged [Formula: see text] would be stunted in 2030 under the poverty scenario in comparison with 83 million under the prosperity scenario. Estimates of climate change-attributable stunting ranged from 570,000 under the prosperity/low climate change scenario to [Formula: see text] under the poverty/high climate change scenario. The projected impact of climate change on stunting was greater in rural vs. urban areas under both socioeconomic scenarios. In countries with lower incomes and relatively high food prices, we projected that rising prices would tend to increase stunting, whereas in countries with higher incomes and relatively low food prices, rising prices would tend to decrease stunting. These findings suggest that food prices that provide decent incomes to farmers alongside high employment with living wages will reduce undernutrition and vulnerability to climate change., Conclusions: Shifting the focus from food production to interactions between incomes and food price provides new insights. Futures that protect health should consider not just availability, accessibility, and quality of food, but also the incomes generated by those producing the food. https://doi.org/10.1289/EHP2916.

Study Objectives: The aims of the present study were to evaluate acupuncture as an alternative treatment to an indwelling catheter for women with postpartum urinary retention, and to evaluate the accuracy of sonographic estimation of bladder volume by portable bedside equipment in women postpartum., Study Background: Post-partum urinary retention is a common obstetric complication. The accepted method for diagnosing post void residual bladder volume is by ultrasound or catheterization. However, the accuracy of bedside sonographic evaluation of bladder volume in women postpartum is controversial due to anatomical and technical issues. The traditional treatment of urinary retention is catheterization for variable lengths of time. Acupuncture, while an accepted treatment method for urinary retention in traditional societies in the Far East, has not been proven scientifically to resolve the problem. Therefore, the aims of our study were to evaluate acupuncture as an alternative treatment to catheterization for urinary retention, and to evaluate the accuracy of sonographic estimation of bladder volume by portable bedside ultrasound in women postpartum., Materials and Methods: The study was a prospective randomized case-controlled trial conducted in 55 women post-partum with urinary retention. All patients underwent a pre and post treatment sonographic evaluation of bladder volume. Women with urinary retention were given the choice of treatment by acupuncture or catheterization. Acupuncture was performed by an experienced acupuncturist licensed in Traditional Chinese Medicine and point selection was based on Meridian theory and clinical experience., Results: In the acupuncture group, 23 women (92%) achieved spontaneous micturition within one hour following treatment. Bedside sonographic evaluation of bladder volume showed excellent correlation to actual volume as measured by catheterization (r 2  = 0.988)., Conclusion: Acupuncture proved to be an excellent alternative to catheterization in treatment of women with postpartum urinary retention., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A multifunctional chlorin platform appended with four short polyethylene glycols and a carboxylate-linker allows rapid conjugation to biotargeting motifs such as proteins and oligonucleotides. The stability and photophysical properties of the chlorin enable development of diagnostics, imaging, molecular tracking, and theranostics.

The Self-reference effect (SRE) on long-term episodic memory and autonoetic consciousness has been investigated in young adults, scarcely in older adults, but never in Alzheimer's patients. Is the functional influence of Selfreference still present when the individual's memory and identity are impaired? We investigated this issue in 60 young subjects, 41 elderly subjects, and 28 patients with Alzheimer's disease, by using 1) an incidental learning task of personality traits in three encoding conditions, inducing variable degrees of depth of processing and personal involvement, 2) a 2- minute retention interval free recall task, and 3) a 20-minute delayed recognition task, combined with a remember-know paradigm. Each recorded score was corrected for errors (intrusions in free recall, false alarms in recognition, and false source memory in remember responses). Compared with alternative encodings, the Self-reference significantly enhanced performance on the free recall task in the young group, and on the recognition task both in the young and older groups but not in the Alzheimer group. The most important finding in the Alzheimer group is that the Self-reference led the most often to a subjective sense of remembering (especially for the positive words) with the retrieval of the correct encoding source. This Self-reference recollection effect in patients was related to independent subjective measures of a positive and definite sense of Self (measured by the Tennessee Self Concept Scale), and to memory complaints in daily life. In conclusion, these results demonstrated the power and robustness of the Self-reference effect on recollection in long-term episodic memory in Alzheimer's disease, albeit the retrieval is considerably reduced. These results should open new perspectives for the development of rehabilitation programs for memory deficits.

Objective: During hypotension induced by tilt-table testing, low presyncopal blood pressure (BP) usually recovers within 1 min after tilt back. However, in some patients prolonged post faint hypotension (PPFH) is observed. We assessed the hemodynamics underlying PPFH in a retrospective study., Methods: Seven patients (2 females, aged 31-72 years) experiencing PPFH were studied. PPFH was defined as a systolic BP below 85 mmHg for at least 2 min after tilt back. In 6 out of 7 presyncope was provoked by 0.4 mg sublingual NTG, administered in the 60° head-up tilt position following head-up tilt for 20 min. Continuous BP was monitored and stroke volume (SV) was computed from pressure pulsations. Cardiac output (CO) was calculated from SV × heart rate (HR); and total peripheral resistance (TPR) from mean BP/CO. Left ventricular contractility was estimated by dP/dt (max) of finger pressure pulse., Results: Systolic BP (SYS), diastolic BP (DIAS) and HR during PPFH were lower compared to baseline: SYS 75 ± 14 versus 121 ± 18 mmHg, DIAS 49 ± 9 versus 71 ± 9 mmHg and HR 52 ± 14 versus 67 ± 12 beats/min (p < 0.05). Marked hypotension was associated with a 47% fall in CO 3.1 ± 0.6 versus 5.9 ± 1.3 L/min (p < 0.05) and decreases in dP/dt, 277 ± 77 versus 759 ± 160 mmHg/s (p < 0.05). The difference in TPR was not significant 1.1 ± 0.3 versus 1.0 ± 0.3 MU (p = 0.229). In four patients, we attempted to treat PPFH by 30° head-down tilt. This intervention increased SYS only slightly (to 89 ± 12 mmHg)., Interpretation: PPFH seems to be mediated by severe cardiac depression.

Activation of Ras signaling in cardiomyocytes has been linked to pathogenic myocardial hypertrophy progression and subsequent heart failure. Whether cardiomyopathy can regress once initiated needs to be established more fully. A 'tet-off' system was used to regulate expression of H-Ras-G12V in myocardium to examine whether Ras-induced pathogenic myocardial hypertrophy could resolve after removal of Ras signaling in vivo. Ras activation at weaning for 2 wk caused hypertrophy, whereas activation for 4 to 8 wk led to cardiomyopathy and heart failure. Discontinuing H-Ras-G12V transgene expression after cardiomyopathy onset led to improved survival and cardiomyopathy lesion scores, with reduced heart:body weight ratios, demonstrating the reversibility of early pathogenic hypertrophy. Activation of Ras and downstream ERK 1/2 was associated with elevated expression of proliferating cell nuclear antigen and cyclins B1 and D1, indicating cell-cycle activation and reentry. Coordinate elevation of broad-spectrum cyclin-dependent kinase inhibitors (p21, p27, and p57) and Tyr15 phosphorylation of cdc2 signified the activation of cell-cycle checkpoints; absence of cell-cycle completion and cardiomyocyte replication were documented by using immunohistochemistry for mitosis and cytokinesis markers. After resolution of cardiomyopathy, cell-cycle activators and inhibitors examined returned to basal levels, a change that we interpreted as exit from the cell cycle. Cardiac cell-cycle regulation plays a role in recovery from pathogenic hypertrophy. The model we present provides a means to further explore the underlying mechanisms governing cell-cycle capacity in cardiomyocytes, as well as progression and regression of pathogenic cardiomyocyte hypertrophy.

DNA methylation of the cytosine in the CpG dinucleotide is typically associated with gene silencing. Genomic analyses have identified low CpG promoters that are both methylated and transcriptionally active, but the mechanism underlying the activation of these methylated promoters remains unclear. Here we show that CpG methylation of the CRE sequence (TGACGTCA) enhances the DNA binding of the C/EBPα transcription factor, a protein critical for activation of differentiation in various cell types. Transfection assays also show that C/EBPα activates the CRE sequence only when it is methylated. The biological significance of this observation was seen in differentiating primary keratinocyte cultures from newborn mice where certain methylated promoters are both bound by C/EBPα and activated upon differentiation. Experimental demethylation by either 5-azacytidine treatment or DNMT1 depletion diminished both C/EBPα binding and activation of the same methylated promoters upon differentiation suggesting that CpG methylation can localize C/EBPα. Transfection studies in cell cultures using methylated tissue-specific proximal promoters identified half-CRE (CGTCA) and half-C/EBP (CGCAA) sequences that need to be methylated for C/EBPα mediated activation. In primary dermal fibroblasts, C/EBPα activates a different set of methylated tissue-specific promoters upon differentiation into adipocytes. These data identify a new function for methyl CpGs: producing DNA binding sites at half-CRE and half-C/EBP sequences for C/EBPα that are needed to activate tissue-specific genes.