bluuebunny/crossref_metadata_2025 huggingface dataset:
Trajectory of Cognitive Decline After Sepsis
Authors: Wang Henry E. , Kabeto Mohammed M. , Gray Marquita , Wadley Virginia G. , Muntner Paul , Judd Suzanne E. , Safford Monika M. , Kempker Jordan , Levine Deborah A.
Published: February 2021

OBJECTIVES:

Cognitive impairment is an important consequence of sepsis. We sought to determine long-term trajectories of cognitive function after sepsis.

DESIGN:

Prospective study of the Reasons for Geographic and Racial Differences in Stroke cohort.

SETTING:

United States.

PATIENTS:

Twenty-one thousand eight-hundred twenty-three participants greater than or equal to 45 years, mean (sd) age 64.3 (9.2) years at first cognitive assessment, 30.9% men, and 27.1% Black.

MEASUREMENTS AND MAIN RESULTS:

The main exposure was time-dependent sepsis hospitalization. The primary outcome was global cognitive function (Six-Item Screener range, 0–6). Secondary outcomes were incident cognitive impairment (Six-Item Screener score ≤ 4 [impaired] vs ≥5 [unimpaired]), new learning (Consortium to Establish a Registry for Alzheimer Disease Word List Learning range, 0–30), verbal memory (word list delayed recall range, 0–10), and executive function/semantic fluency (animal fluency test range, ≥ 30). Over a median follow-up of 10 years (interquartile range, 6–12 yr), 840 (3.8%) experienced sepsis (incidence 282 per 1,000 person-years). Sepsis was associated with faster long-term declines in Six-Item Screener (–0.02 points per year faster [95% CI, –0.01 to –0.03]; p < 0.001) and faster long-term rates of incident cognitive impairment (odds ratio 1.08 per year [95% CI, 1.02–1.15]; p = 0.008) compared with presepsis slopes. Although cognitive function acutely changed after sepsis (0.05 points [95% CI, 0.01–0.09]; p = 0.01), the odds of acute cognitive impairment (Six-Item Screener ≤ 4) immediately after sepsis was not significant (odds ratio, 0.81 [95% CI, 0.63–1.06]; p = 0.12). Sepsis hospitalization was not associated with acute changes or faster declines in word list learning, word list delayed recall, or animal fluency test.

CONCLUSIONS:

Sepsis is associated with accelerated long-term decline in global cognitive function.
Epidemiology of Sepsis Among Children and Neonates in Germany: Results From an Observational Study Based on Nationwide Diagnosis-Related Groups Data Between 2010 and 2016*
Authors: Born Sebastian , Dame Christof , Matthäus-Krämer Claudia , Schlapbach Luregn J. , Reichert Felix , Schettler Anna , Schwarzkopf Daniel , Thomas-Rüddel Daniel , Proquitté Hans , Reinhart Konrad , Fleischmann-Struzek Carolin
Published: February 2021

OBJECTIVES:

Worldwide, more than half of all sepsis cases occur in pediatric and adolescent patients, particularly in neonates. Previous population-based studies in these age groups often were limited to either neonatal or pediatric patients admitted to ICUs. We aimed to investigate the overall and age-specific incidence and case fatality of sepsis in children in Germany, a high-income country with a total population of 82 million.

DESIGN:

Retrospective observational study based on the German Diagnosis-related Groups statistics of the years 2010–2016.

SETTING:

All acute care hospitals in Germany except for prison and psychiatric hospitals.

PATIENTS:

Pediatric patients less than or equal to 19 years with International Classification of Diseases, 10th Revision-coded sepsis, neonates with International Classification of Diseases, 10th Revision-coded neonatal sepsis.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We analyzed pediatric sepsis incidence in patients aged birth to less than or equal to 19 years old, case fatality, and underlying comorbidities, and neonatal sepsis incidence and case fatality within the neonatal period. We identified 14,635 pediatric sepsis cases among 15.4 million pediatric hospitalizations between 2010 and 2016 (= 0.1% of pediatric hospitalizations). The incidence of pediatric sepsis was 14 cases per 100,000 children between 0 and 19 years. Case fatality was 16.6% and decreased from 17.8% (2010) to 15.0% (2016). A total of 11.5% of hospital deaths in the age group 0–19 years were associated with pediatric sepsis. Sepsis incidence and case fatality were highest in children less than 1 year old and declined in older children and adolescents. Admissions with pediatric sepsis were more common in children with preexisting comorbidities compared with those without (0.52% vs 0.03% of pediatric admissions). In neonates, the incidence of neonatal sepsis was 1,006 cases per 100,000 live births. Case fatality was 3.9%. While 17.7% of very low birth weight infants had neonatal sepsis, only 2.1% of low birth weight and 0.6% of normal birth weight neonates were affected, respectively.

CONCLUSIONS:

Sepsis is also in Germany a common and frequently fatal condition in pediatric patients, particularly among neonates and children with comorbidities.
Use of Corticosteroids in Cardiac Arrest—A Systematic Review and Meta-Analysis
Authors: Shah Kieran , Mitra Anish R.
Published: February 2021

OBJECTIVES:

The objective of this systematic review was to evaluate the impact of intraarrest corticosteroids on neurologic outcomes and mortality in patients with cardiac arrest.

DATA SOURCES:

We conducted a systematic search using the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE databases.

STUDY SELECTION:

We included all randomized controlled trials and comparative observational studies. We excluded single arm studies, case reports/series, narrative reviews, and studies irrelevant to the focus of this article.

DATA EXTRACTION:

Two reviewers independently assessed trial eligibility. Data were collected for the following outcomes: primary outcomes included good neurologic outcome, survival to hospital discharge, and survival at greater than or equal to 1 year. Secondary outcomes included incidence of return of spontaneous circulation, ICU and hospital length of stay, duration of vasopressor and inotropic treatment, and blood pressure during cardiopulmonary resuscitation and after return of spontaneous circulation.

DATA SYNTHESIS:

The pooled estimates from randomized controlled trials for the following subgroups were analyzed using random-effects models: 1) patients with in-hospital cardiac arrest who received vasopressin, steroids, and epinephrine; 2) patients with in-hospital cardiac arrest who used corticosteroids only (i.e., no vasopressin); and 3) patients with out-of-hospital cardiac arrest who used corticosteroids only. Results included an increase in good neurologic outcomes (relative risk, 2.84; 95% CI, 1.36–5.94) and survival to hospital discharge (relative risk, 2.58; 95% CI, 1.36–4.91) in in-hospital cardiac arrest patients receiving vasopressin, steroids, and epinephrine followed by corticosteroids for postresuscitation shock. This was further supported by an increase in return of spontaneous circulation (relative risk, 1.35; 95% CI, 1.12–1.64) and hemodynamics in this population. There was no benefit observed in in-hospital cardiac arrest or out-of-hospital cardiac arrest patients receiving corticosteroids alone.

CONCLUSIONS:

Our study found that there are limited high-quality data to analyze the association between corticosteroids and reducing mortality in cardiac arrest, but the available data do support future randomized controlled trials. We did find that corticosteroids given as part of a vasopressin, steroids, and epinephrine regimen in in-hospital cardiac arrest patients and for postresuscitation shock did improve neurologic outcomes, survival to hospital discharge, and surrogate outcomes that include return of spontaneous circulation and hemodynamics. We found no benefit in in-hospital cardiac arrest or out-of-hospital cardiac arrest patients receiving corticosteroids only; however, a difference cannot be ruled out due to imprecision and lack of available data.
Evaluation of the chemopreventive effect of selected medicinal plants extracts via induction of the Nrf2 in a modified model of breast cancer cells: identification of bioactive lead compounds
Authors: Guetchueng Stephanie T. , Nahar Lutfun , Ritchie Kenneth J. , Sarker Satyajit D.
Published: February 2021

The cancer chemopreventive potential of various solvent extracts from six medicinal plants was evaluated by their ability to activate the transcription factor Nrf2 using AREc32 cells, which contain a luciferase gene under the control of antioxidant responsive element promoters. Nrf2 regulates the expression of many detoxification enzymes, making it an ideal target for cancer prevention. The present research revealed Zanthoxylum zanthoxyloides extracts as promising sources of cancer chemopreventive compounds. Bioassay-guided isolation of the Z. Zanthoxyloides methanol extract resulted in the isolation of N-methylatanine, N-methylplatydesminecation, sesamin and skimmianine. Among these compounds, skimmianine was identified as the most active compound, causing a 2.8-fold increase in luciferase activity. Skimmianine and other related quinolone alkaloids could represent an appropriate starting scaffold for the development of new chemopreventive cancer drugs.
Bone marrow-derived mesenchymal stem cells modulate autophagy in RAW264.7 macrophages via the phosphoinositide 3-kinase/protein kinase B/heme oxygenase-1 signaling pathway under oxygen-glucose deprivation/restoration conditions
Authors: Wang Ning-Fang , Bai Chun-Xue
Published: February 2021

Background

Autophagy of alveolar macrophages is a crucial process in ischemia/reperfusion injury-induced acute lung injury (ALI). Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent cells with the potential for repairing injured sites and regulating autophagy. This study was to investigate the influence of BM-MSCs on autophagy of macrophages in the oxygen-glucose deprivation/restoration (OGD/R) microenvironment and to explore the potential mechanism.

Methods

We established a co-culture system of macrophages (RAW264.7) with BM-MSCs under OGD/R conditions in vitro. RAW264.7 cells were transfected with recombinant adenovirus (Ad-mCherry-GFP-LC3B) and autophagic status of RAW264.7 cells was observed under a fluorescence microscope. Autophagy-related proteins light chain 3 (LC3)-I, LC3-II, and p62 in RAW264.7 cells were detected by Western blotting. We used microarray expression analysis to identify the differently expressed genes between OGD/R treated macrophages and macrophages co-culture with BM-MSCs. We investigated the gene heme oxygenase-1 (HO-1), which is downstream of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway.

Results

The ratio of LC3-II/LC3-I of OGD/R treated RAW264.7 cells was increased (1.27 ± 0.20 vs. 0.44 ± 0.08, t = 6.67, P 
< 0.05), while the expression of p62 was decreased (0.77 ± 0.04 vs. 0.95 ± 0.10, t = 2.90, P 
< 0.05), and PI3K (0.40 ± 0.06 vs. 0.63 ± 0.10, t = 3.42, P 
< 0.05) and p-Akt/Akt ratio was also decreased (0.39 ± 0.02 vs. 0.58 ± 0.03, t = 9.13, P 
< 0.05). BM-MSCs reduced the LC3-II/LC3-I ratio of OGD/R treated RAW264.7 cells (0.68 ± 0.14 vs. 1.27 ± 0.20, t = 4.12, P 
< 0.05), up-regulated p62 expression (1.10 ± 0.20 vs. 0.77 ± 0.04, t = 2.80, P 
< 0.05), and up-regulated PI3K (0.54 ± 0.05 vs. 0.40 ± 0.06, t = 3.11, P 
< 0.05) and p-Akt/Akt ratios (0.52 ± 0.05 vs. 0.39 ± 0.02, t = 9.13, P 
< 0.05). A whole-genome microarray assay screened the differentially expressed gene HO-1, which is downstream of the PI3K/Akt signaling pathway, and the alteration of HO-1 mRNA and protein expression was consistent with the data on PI3K/Akt pathway.

Conclusions

Our results suggest the existence of the PI3K/Akt/HO-1 signaling pathway in RAW264.7 cells under OGD/R circumstances in vitro, revealing the mechanism underlying BM-MSC-mediated regulation of autophagy and enriching the understanding of potential therapeutic targets for the treatment of ALI.
Neem leaf glycoprotein salvages T cell functions from Myeloid-derived suppressor cells-suppression by altering IL-10/STAT3 axis in melanoma tumor microenvironment
Authors: Sarkar Madhurima , Bhuniya Avishek , Ghosh Sarbari , Sarkar Anirban , Saha Akata , Dasgupta Shayani , Bera Saurav , Chakravarti Mohona , Dhar Sukanya , Guha Ipsita , Ganguly Nilanjan , Das Tapasi , Banerjee Saptak , Pal Smarajit , Ghosh Swapan Kr , Bose Anamika , Baral Rathindranath
Published: February 2021

Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune functions. We have observed that an immunomodulator, neem leaf glycoprotein (NLGP), inhibits tumor-resident MDSCs and enhances antitumor CD8+ T cell immunity. NLGP inhibits the number as well as functions of tumor-resident MDSCs (Gr1±CD11b±) and enhances antitumor CD8± T cell immunity by downregulating arginase 1 and inducible nitric oxide synthase production in MDSCs. Accordingly, decreased T cell anergy and helper to regulatory T cell conversion have been observed in the presence of NLGP, which ultimately augments T cell functions. Mechanistically, NLGP-mediated rectification of T cell suppressive functions of MDSCs was primarily associated with downregulation of the interleukin (IL)-10/signal transducer and activator of transcription 3 (STAT3) signaling axis within the tumor microenvironment, as confirmed by knockdown of STAT3 (by STAT3-siRNA) and using IL-10−/− mice. Thus, NLGP-mediated suppression of MDSC functions in tumor hosts is appeared to be another associated effective mechanism for the eradication of murine melanoma by NLGP.
Metabolomic characterisation of progression and spontaneous regression of melanoma in the melanoma-bearing Libechov minipig model
Authors: Kertys Martin , Grendar Marian , Horak Vratislav , Zidekova Nela , Kupcova Skalnikova Helena , Mokry Juraj , Halasova Erika , Strnadel Jan
Published: February 2021

Melanoma-bearing Libechov minipig (MeLiM) represents a large animal model for melanoma research. This model shows a high incidence of complete spontaneous regression of melanoma – a phenomenon uncommon in humans. Here, we present the first metabolomic characterisation of the MeLiM model comparing animals with progressing and spontaneously regressing melanomas. Plasma samples of 19 minipigs with progression and 27 minipigs with evidence of regression were analysed by a targeted metabolomic assay based on mass spectrometry detection. Differences in plasma metabolomics patterns were investigated by univariate and multivariate statistical analyses. Overall, 185 metabolites were quantified in each plasma sample. Significantly altered metabolomic profile was found, and 42 features were differentially regulated in plasma. Besides, the machine learning approach was used to create a predictive model utilising Arg/Orn and Arg/ADMA ratios to discriminate minipigs with progressive disease development from minipigs with regression evidence. Our results suggest that progression of melanoma in the MeLiM model is associated with alteration of arginine, glycerophospholipid and acylcarnitines metabolism. Moreover, this study provides targeted metabolomics characterisation of an animal model of melanoma with progression and spontaneous regression of tumours.
Advances in cell and gene therapy for HIV disease: it is good to be specific
Authors: Pauza C. David , Huang Kelly , Bordon Jose
Published: February 2021

Purpose of review

Tremendous advances in cell and gene therapy may soon realize the goal of treating and possibly curing HIV disease. These advances rely on new technologies for cell engineering and new strategies for product manufacturing that are targeting the most important immune deficits in HIV and promising to reconstitute protective, antiviral immunity and achieve natural suppression of HIV disease.

Recent findings

We summarize important advances in vectored passive immunity, e.g., directing in vivo expression of protective antibodies or antiviral proteins, B cell engineering to overcome the inadequate humoral immune response to HIV, and T cell engineering that is breaking new ground using viral vector modification of HIV specific T cells. These innovative approaches build on a substantial history of gene and cell therapy research in HIV disease.

Cell and gene therapy for HIV disease has been an area of tremendous innovation during the nearly two decades since early reports showed evidence for modulating disease. Recent efforts are building on the early experiences, closing gaps in previous approaches, and moving closer to effective treatment. Products approaching or already in clinical trials hold great promise for achieving durable suppression of HIV that will revolutionize therapy and offering hope to infected individuals that disease may be controlled without lifelong dependence on antiretroviral medications.

Video abstract

http://links.lww.com/COHA/A15.
Ciliated and Mucinous Adenomatous Syringometaplasia: The Missing Link of the “Ciliated Eccrine Metaplasia” Theory in the Histogenesis of Cutaneous Eccrine Ciliated Cyst?
Authors: Tran Tien Anh N.
Published: February 2021

A variety of metaplastic changes has been reported in eccrine ducts and glands with squamous and mucinous syringometaplasia representing the most common histopathologic patterns. In the current case, a previously unreported variant of syringometaplasia was described in a female newborn with a 2-cm occipital cutaneous defect consistent with cutis aplasia. Over a more than 1-year period of local treatment, an enlarging plaque associated with local alopecia developed at the site of the original ulcerated area. A local excision demonstrated a superficial hypertrophic scar associated with a complete loss of hair follicles. In addition, there was a proliferation of eccrine glands and ducts lined by cuboidal epithelial cells arranged in a linear distribution beneath the scar area. Focal anastomosing of the proliferative ducts was identified. In few dilated ducts, the epithelial lining was composed of an inner layer of columnar cells with well-formed apical cilia and intracytoplasmic mucin and an outer layer of myoepithelial cells. The mucinous and ciliated cells were positive for epithelial membranous antigen and carcinoembryonic antigen, but negative for estrogen receptors, progesterone receptors, and thyroid transcription factor-1. Because this variant of eccrine metaplasia has not hitherto been reported in the literature, the term ciliated and mucinous adenomatous syringometaplasia was proposed for this unusual histologic finding. Mucinous and ciliated adenomatous syringometaplasia not only expands the spectrum of metaplastic changes in sweat gland units, but also might represent the missing link in the histogenesis of a subset of cutaneous ciliated cysts.
Lesson to Learn From Cellular infiltrate in Scalp Biopsy of Alopecia Areata
Authors: Genedy Rasha Mahmoud , Badran Fairouz Khalil , Tayae Eman Mohamed , Sabra Heba Nasrallah
Published: February 2021

Background:

Alopecia areata (AA) is a common cause of hair loss. It is mediated by T lymphocytes. Scalp biopsy findings in AA differ according to the disease phase and activity.

Objectives:

To study the cellular infiltrate in the transverse section of scalp biopsy of AA at different disease stages and in relation to disease activity.

Methods:

The study was performed on 40 subjects with AA. A 4-mm punch biopsy was obtained from an AA scalp lesion. Biopsies were sectioned horizontally; 2 anatomical levels were studied (mid dermal and deep dermal levels).

Results:

Ninety-five percent of AA showed noncicatrical alopecia. A significant relation was found between the course of AA and the terminal:vellus ratio. Peribulbar lymphocytic infiltration was seen in 70% of cases. Mast cells were observed in 87.5% of cases, including fibrous tract and around the arrector pili muscles. Eosinophils were detected in the scalp biopsy of 22.5% of cases. Course and activity of AA were significantly related to the peribulbar lymphocytic cell infiltration but not to mast cells and eosinophils.

Conclusion:

Although a peribulbar lymphocytic infiltrate is the classical finding of AA, it is absent in the chronic phase. Mast cells are commonly found in the scalp biopsy of AA and could explain the potential therapeutic effect of antihistamines.
What Happens After a Positive Primary Care Autism Screen Among Historically Underserved Families? Predictors of Evaluation and Autism Diagnosis
Authors: Kuhn Jocelyn , Levinson Julia , Udhnani Manisha D. , Wallis Kate , Hickey Emily , Bennett Amanda , Fenick Ada M. , Feinberg Emily , Broder-Fingert Sarabeth
Published: February 2021

Objective:

Families, pediatric providers, and service systems would benefit from expanded knowledge regarding (1) who is most likely to receive a recommended diagnostic evaluation after a positive primary care–administered autism screen and (2) of those who screen positive, who is most likely to be diagnosed with autism?

Method:

Participants included 309 predominantly low-income, racial/ethnic minority parents and their child, aged 15 to 27 months, who screened positive on the Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F). Generalized estimating equations were used to fit models of predictors for each binary outcome: receiving a diagnostic evaluation and receiving an autism diagnosis on evaluation.

Results:

Significant predictors of diagnostic evaluation receipt included the parent being older or non-Hispanic and the child having private insurance, lower child communication functioning, or receiving Early Intervention services. Significant predictors of an autism diagnosis on evaluation included male child, lower child communication functioning, screening directly in the parent's preferred language, White/non-Hispanic parent, and no parent history of mood disorder.

Conclusion:

Children with younger parents, Hispanic ethnicity, relatively higher communication skills, public insurance, and no Early Intervention services were less likely to receive recommended diagnostic care. Reduced likelihood of autism diagnosis after a positive screen in non-White/non-Hispanic subgroups supports previous research indicating issues with M-CHAT-R/F positive predictive power for racial/ethnic minorities. The use of telephonic interpreters to administer screens, as opposed to directly screening in families' preferred languages, may lead to identification of fewer true autism cases. Thus, multilingual clinical staff capacity may improve positive predictive power of autism screening.
Treatment of Extramammary Paget Disease and the Role of Reflectance Confocal Microscopy: A Prospective Study
Authors: Navarrete-Dechent Cristian , Aleissa Saud , Cordova Miguel , Hibler Brian P. , Erlendsson Andres M. , Polansky Max , Cordova Frank , Lee Erica H. , Busam Klaus J. , Hollmann Travis , Lezcano Cecilia , Moy Andrea , Pulitzer Melissa , Leitao Mario M. , Rossi Anthony M.
Published: February 2021

BACKGROUND

Extramammary Paget disease (EMPD) poses treatment challenges. Invasive and noninvasive treatment modalities exist with variable success reported. Reflectance confocal microscopy (RCM) is emerging as an adjuvant diagnostic tool.

OBJECTIVE

To evaluate the treatment of EMPD patients and the role of RCM.

METHODS

Prospective study. Demographic and tumor characteristics were recorded. Handheld-RCM was performed and correlated with histology. Treatment, clearance, pathology, and follow-up were all recorded.

RESULTS

Thirty-six EMPD lesions in 33 patients were included. Mean age was 71.7 years, and 23 were men. Mean number of surgical stages needed to clear margins was 1.9 (SD, 0.9; 1.0–3.0 stages), and mean margin needed to clear was 1.8 cm. Reflectance confocal microscopy correlated well with scouting punch biopsies (kappa, 0.93; p < .001). Disruption of the dermoepidermal junction was associated with invasive EMPD versus in situ (83.3% vs 25.9%) on histology (p = .01).

Limitations

Relatively small sample size.

CONCLUSION

Extramammary Paget disease is challenging, and lesion demarcation is of the utmost importance. Using a staged surgical excision approach, the mean margins needed were 1.8 cm, less than previously reported. Nonsurgical modalities, including radiation therapy, imiquimod, or photodynamic therapy can be considered if surgery is not pursued. Reflectance confocal microscopy is a valuable noninvasive imaging modality for the management of EMPD.
Narcotic Use for Acute Postoperative Pain Management in Mohs Micrographic Surgery Patients With End Stage Renal Disease: A Review of the Literature
Authors: Gruber Paul J. , Scholtz Jaclyn M. , Donnelly Heidi B.
Published: February 2021

BACKGROUND

Uncontrolled acute postoperative pain presents a significant management challenge when opioids are used in patients with end-stage renal disease (ESRD). Currently, there is a lack of quality pharmacokinetic and pharmacodynamic data regarding opioid medication use in ESRD patients to optimize safe and effective management.

OBJECTIVE

To review the published literature on pharmacologic evidence for and against the use of opioid medications for acute postoperative pain following Mohs micrographic surgery in ESRD patients.

METHODS

A search of PubMed was conducted to identify articles on the pharmacokinetic and pharmacodynamic properties of opioid pain medications in ESRD patients through March 1, 2020.

RESULTS

Seventy-five articles were reviewed. Limited data exist on opioids safe for use in ESRD and are mostly confined to small case series. Studies suggest tramadol and hydromorphone could be considered when indicated. Methadone may be a safe option, but should be reserved for treatment coordinated by a trained pain subspecialist.

CONCLUSION

Randomized clinical trials are lacking. Studies that are available are not sufficient to perform a quantitative methodologic approach. Evidence supports the judicious use of postoperative opioid medications in ESRD patients at the lowest possible dose to achieve clinically meaningful improvement in pain and function.
Sex- and Type-specific Genital Human Papillomavirus Transmission Rates Between Heterosexual Partners: A Bayesian Reanalysis of the HITCH Cohort
Authors: Malagón Talía , MacCosham Aaron , Burchell Ann N. , El-Zein Mariam , Tellier Pierre-Paul , Coutlée François , Franco Eduardo L. ,   for the HITCH Study Group
Published: February 2021

Background:

It is unclear whether sexual transmission rates of human papillomaviruses (HPV) differ between sexes and HPV types. We estimate updated transmission rates from the final HITCH cohort study and propose an estimation method that accounts for interval-censored data and infection clearance.

Methods:

We enrolled young women 18–24 years old and their male sex partners ≥18 years old in Montréal, Canada, between 2005 and 2011. We followed women over 24 months and men over 4 months. We tested genital samples with Linear Array for HPV DNA detection and genotyping. We calculated infection transmission rates between partners using a multistate Markov model via a Bayesian approach. We report the posterior median and 2.5%–97.5% percentile intervals (95% PI).

Results:

We observed 166 type-specific incident HPV transmission events in 447 women and 402 men. The estimated median transmission rate from an HPV-positive to a negative partner was 4.2 (95% PI = 3.1 to 5.3) per 100 person-months. The transmission rate from men-to-women was 3.5 (95% PI = 2.5 to 4.7) and from women-to-men was 5.6 (95% PI = 3.8 to 7.0) per 100 person-months, corresponding to a rate ratio of 1.6 (95% PI = 1.0 to 2.5). Partners reporting always using condoms had a 0.22 (95% PI = 0.05 to 0.61) times lower HPV transmission rate than those reporting never using condoms. HPV16/18 did not have particularly high transmission rates relative to other HPV types.

Conclusion:

Our updated analysis supports previous research suggesting higher women-to-men than men-to-women HPV transmission rates and a protective effect of condoms in heterosexual partnerships. Our results also suggest that crude incidence rates underestimate HPV transmission rates due to interval-censoring. See video abstract at http://links.lww.com/EDE/B794.
Exposure to household air pollutants and endothelial dysfunction in rural Bangladesh
Authors: Shahriar Mohammad Hasan , Chowdhury Muhammad Ashique Haider , Ahmed Shyfuddin , Eunus Mahbubul , Kader Shirmin Bintay , Begum Bilkis A. , Islam Tariqul , Sarwar Golam , Al Shams Rabab , Raqib Rubhana , Alam Dewan S. , Parvez Faruque , Ahsan Habibul , Yunus Md
Published: February 2021

Background:

More than one third of world’s population use biomass fuel for cooking that has been linked to an array of adverse health hazards including cardiovascular mortality and morbidity. As part of Bangladesh Global Environmental and Occupational Health (GEO Health) project, we assessed whether household air pollution (HAP) was associated with dysfunction in microvascular circulation (measured by reactive hyperemia index [RHI]).

Methods:

We measured exposure to HAP (particulate matter [PM2.5], carbon monoxide [CO], and black carbon [BC]) for 48 hours of 200 healthy nonsmoker adult females who used biomass fuel for cooking. Exposure to PM2.5 and BC were measured using personal monitor, RTI MicroPEM (RTI International, NC) with an internal filter that had been both pre- and post-weighed to capture the deposited pollutants concentration. Lascar CO logger was used to measure CO. Endothelial function was measured by forearm blood flow dilatation response to brachial artery occlusion using RHI based on peripheral artery tonometry. A low RHI score (<1.67) indicates impaired endothelial function.

Results:

Average 48 hours personal exposure to PM2.5 and BC were 144.15 μg/m3 (SD 61.26) and 6.35 μg/m3 (SD 2.18), respectively. Interquartile range for CO was 0.73 ppm (0.62–1.35 ppm). Mean logarithm of RHI (LnRHI) was 0.57 in current data. No statistically significant association was observed for LnRHI with PM2.5 (odds ratio [OR] = 0.97; 95% confidence interval [CI] = 0.92, 1.01; P = 0.16), BC (OR = 0.85; 95% CI = 0.72, 1.01; P = 0.07), and CO (OR = 0.89; 95% CI = 0.64, 1.25; P = 0.53) after adjusting for potential covariates.

Conclusions:

In conclusion, HAP was not associated with endothelial dysfunction among nonsmoking females in rural Bangladesh who used biomass fuel for cooking for years.
Infectious disease, the climate, and the future
Authors: Tong Shilu , Ebi Kristie , Olsen Jorn
Published: February 2021

Emergence and resurgence of infectious diseases are serious threats to population health. The ongoing COVID-19 pandemic has caused an enormous human toll and health crisis. Responses to the pandemic are significantly affecting the global economy. What is most concerning about COVID-19 is not the virus itself, but rather that it may compound with other and more serious crises. Climate change will likely affect human health, economy, and the society more than disease outbreaks. Governments at all levels, from local to international, can chart a greener, healthier, and equitable course for the future, investing in strategies and technologies that minimize and prevent risks, including those posed by climate change and the pandemic, promoting obligations to drastically reduce emissions, enhancing societal equality, improving community resilience, and achieving sustainable development goals.
Spatial and intraseasonal variation in changing susceptibility to extreme heat in the United States
Authors: Spangler Keith R. , Wellenius Gregory A.
Published: February 2021

Background:

Exposure to excessive heat is associated with a higher risk of death. Although the relative risk of death on extreme-heat days has decreased over the past several decades in the United States, the drivers of this decline have not been fully characterized. In particular, while extreme heat earlier in the warm season has been shown to confer greater risk of mortality than exposure later in the season, it is unknown whether this within-season variability in susceptibility has changed over time and whether it is modified by region, climatic changes, or social vulnerability.

Methods:

We used distributed-lag nonlinear models and meta-regression to estimate the association between ambient maximum daily temperature during the early, late, and overall warm seasons and the relative risk of mortality for two decades, 1973–1982 and 1997–2006, in 186 metropolitan areas in the United States. We assessed changes in relative risk nationally, regionally, and between places with differential changes in early-season relative extreme heat and indicators of social vulnerability.

Results:

Most of the reduction in heat-related mortality nationally between the two decades is driven by decreases in late-season mortality, while substantial early-season risk remains. This difference is most apparent in the Northeast, in cities with greater increases in early-season relative extreme heat, and in places that have become more socially vulnerable.

Conclusions:

Early-season heat mortality risks have persisted despite overall adaptations, particularly in places with greater warming and increasing social vulnerability. Interventions to reduce heat mortality may need to consider greater applicability to the early warm season.
Ultrasound assessment of gastric volumes of thick fluids
Authors: Tacken Marijn C.T. , van Leest Tristan A.J. , van de Putte Peter , Keijzer Christiaan , Perlas Anahi
Published: February 2021

BACKGROUND

Enteral nutrition is essential in the treatment of critically ill patients. Current methods to monitor enteral nutrition such as aspiration of residual volume may be inaccurate. Gastric ultrasonography estimates total gastric fluid volume using the Perlas model, but this model is validated for clear fluids only, and its accuracy for measuring thick fluids is unknown.

OBJECTIVES

The primary aim of this study was to evaluate the Perlas model for gastric volume estimation of enteral nutrition, a thick fluid product.

DESIGN

A single-centre, single blinded, randomised controlled study.

SETTING

Single university hospital, from May to July 2019.

PARTICIPANTS

Seventy-two healthy fasted volunteers were randomly allocated to different fluid volume groups.

INTERVENTION

Participants randomly ingested predetermined volumes between 50 and 400 ml of a feeding-drink (Nutricia Nutridrink). Following a standardised gastric ultrasound scanning protocol, a blinded sonographer measured the antral cross-sectional area in the supine and right-lateral decubitus positions.

MAIN OUTCOME MEASURES

Measurements were performed at baseline, 5 min postingestion and 20 min postingestion. Gastric volumes were predicted using the previously established Perlas model and compared with total gastric fluid volumes after ingestion of the study drink.

RESULTS

The Perlas model underestimated the volume of thick gastric fluid and yielded a suboptimal fit for our data. However, antral cross-sectional area and total gastric thick fluid volumes were significantly correlated (Pearson's correlation coefficient 0.73, P < 0.01). A new model was fitted to predict gastric volumes of thick fluids, using the antral cross-sectional area (cm2) in the right-lateral decubitus position: Volume (ml) = 79.38 + 13.32 x right-lateral cross-sectional area.

CONCLUSION

The Perlas model for clear gastric fluid volume estimation is suboptimal for thick fluid volume assessment and an alternative model is presented.

CLINICAL TRIAL REGISTRATION

Netherlands Trial Register Trial NL7677, Registration date: 16 April 2019; https://www.trialregister.nl/trial/7677.
Reducing the time to successful intravenous cannulation in anaesthetised children with poor vein visibility using a near-infrared device
Authors: Gras Severine , Roy-Gash Fabian , Bruneau Béatrice , Salvi Nadège , Colas Anne-Emmanuelle , Skhiri Alia , Orliaguet Gilles , Dahmani Souhayl , Devys Jean-Michel
Published: February 2021

BACKGROUND

During inhalational induction of anaesthesia for children, severe respiratory events can occur but can be rapidly treated once intravenous access is in place. Reducing the time to successful cannulation during inhalational induction for children with poor vein visibility would improve safety.

OBJECTIVE

To study the effectiveness of a near-infrared (NIR) vascular imaging device (Veinviewer) to facilitate intravenous cannulation.

DESIGN

A prospective, multicentre, randomised, open clinical trial.

SETTING

The operating rooms of three paediatric hospitals in Paris, France, from 1 October 2012 to 31 March 2016.

PATIENTS

Children up to the age of 7 years, with poor vein visibility requiring general anaesthesia.

INTERVENTION

Inhalational anaesthesia was initiated and intravenous cannulation was performed with the standard approach or with the Veinviewer Vision.

MAIN OUTCOME MEASURES

The primary outcome was the time to successful intravenous cannulation. A secondary outcome was the proportion of successful first attempts.

RESULTS

The mean time to successful intravenous cannulation was 200 (95% CI, 143 to 295) seconds in the Veinviewer and 252 (95% CI, 194 to 328) seconds for the control group: hazard ratio 1.28 (1.02 to 1.60) (P = 0.03). The adjusted hazard ratio for known predictive factors was 1.25 (0.99 to 1.56) (P = 0.06). Success at the first attempt was 64.6% (102/158) in the ‘Veinviewer’ group vs. 55.6% (85/153) in the ‘control’ group (P = 0.10).

CONCLUSION

The Veinviewer has limited value in reducing the time to successful intravenous cannulation during inhalational anaesthesia for young children with poor vein visibility. However, there is a strong trend to reducing the delay in some cases and, given its absence of side effects, it could be part of a rescue option for a difficult venous-access strategy.

CLINICAL TRIAL REGISTRATION

NCT01685866 (http://www.clinicaltrials.gov).
Sex difference and intra-operative tidal volume
Authors: Nijbroek Sunny G. , Hol Liselotte , Swart Pien , Hemmes Sabrine N.T. , Serpa Neto Ary , Binnekade Jan M. , Hedenstierna Goran , Jaber Samir , Hiesmayr Michael , Hollmann Markus W. , Mills Gary H. , Vidal Melo Marcos F. , Putensen Christian , Schmid Werner , Severgnini Paolo , Wrigge Hermann , Gama de Abreu Marcelo , Pelosi Paolo , Schultz Marcus J.
Published: February 2021

BACKGROUND

One key element of lung-protective ventilation is the use of a low tidal volume (V
T). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.

OBJECTIVES

The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.

DESIGN, PATIENTS AND SETTING

This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.

MAIN OUTCOME MEASURES

Women and men were compared with respect to use of LTVV, defined as V
T of 8 ml kg−1 or less predicted bodyweight (PBW). A V
T was deemed ‘default’ if the set V
T was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.

RESULTS

This analysis includes 9864 patients, of whom 5425 (55%) were women. A default V
T was often set, both in women and men; mode V
T was 500 ml. Median [IQR] V
T was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg−1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients’ height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default V
T.

CONCLUSION

In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher V
T than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.

TRIAL REGISTRATION

The study was registered at Clinicaltrials.gov, NCT01601223
Striatin genotype-based, mineralocorticoid receptor antagonist-driven clinical trial: study rationale and design
Authors: Stone Isabella B. , Green Jessica A.E.M. , Koefoed Andrew W. , Hornik Ezra S. , Williams Jonathan S. , Adler Gail K. , Williams Gordon H.
Published: February 2021

Objectives

In human studies and genetically altered mouse studies, variants in the striatin gene (STRN) are associated with increased blood pressure (BP) and aldosterone on a liberal salt diet. This clinical trial is based on the presumed mechanism for striatin-associated HTN – increased aldosterone. It is designed to determine if participants with the STRN risk alleles will have a greater BP reduction on a liberal salt diet with a specific, mechanism-based therapy – a mineralocorticoid receptor antagonist, eplerenone – as compared with a nonspecific anti-hypertensive therapy – amlodipine.

Methods

One hundred five hypertensive adults with the STRN risk alleles (SNP rs2540923 carriers or rs888083 homozygotes) will be enrolled in a 12-week, double-blind, dose-escalation, clinical trial. After a minimum 2-week washout period and baseline assessment of BP on a liberal salt diet, participants will be randomized to either daily eplerenone or amlodipine. Participants will take daily at-home BP recordings as a safety check. After 4 and 8 weeks of drug therapy, BP will be measured by the study team and medication will be increased, if needed, to achieve a participant goal BP of <140/90 mmHg.

Anticipated results We anticipate that STRN risk allele carriers will demonstrate a greater reduction in BP with eplerenone and will require a lower dose of eplerenone to reach goal BP as compared with amlodipine.

Conclusion

This is a proof-of-concept clinical trial. Positive results support the feasibility of performing genetically-defined, mechanistically-driven trials in HTN. Clinically, it would suggest that genetic biomarkers can identify individuals highly responsive to specific treatment.
Genome-wide association study of letrozole plasma concentrations identifies non-exonic variants that may affect CYP2A6 metabolic activity
Authors: Hertz Daniel L. , Douglas Julie A. , Kidwell Kelley M. , Gersch Christina L. , Desta Zeruesenay , Storniolo Ana-Maria , Stearns Vered , Skaar Todd C , Hayes Daniel F , Henry N. Lynn , Rae James M.
Published: February 2021

Objectives

Letrozole is a nonsteroidal aromatase inhibitor used to treat hormone-receptor-positive breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism, including cytochrome P450 2A6 (CYP2A6). The objective of this genome-wide association study (GWAS) was to identify polymorphisms associated with steady-state letrozole concentrations.

Methods

The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized postmenopausal patients with hormone-receptor-positive nonmetastatic breast cancer to letrozole or exemestane treatment. Germline DNA was collected pretreatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole (and exemestane) plasma concentrations via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array (>650 000 variants) followed by imputation. The association of each germline variant with age- and BMI-adjusted letrozole concentrations was tested in self-reported white patients via linear regression assuming an additive genetic model.

Results

There were 228 patients who met the study-specific inclusion criteria and had both DNA and letrozole concentration data for this GWAS. The association for one genotyped polymorphism (rs7937) with letrozole concentration surpassed genome-wide significance (P = 5.26 × 10−10), explaining 13% of the variability in untransformed steady-state letrozole concentrations. Imputation around rs7937 and in silico analyses identified rs56113850, a variant in the CYP2A6 intron that may affect CYP2A6 expression and activity. rs7937 was associated with age- and BMI-adjusted letrozole levels even after adjusting for genotype-predicted CYP2A6 metabolic phenotype (P = 3.86 × 10−10).

Conclusion

Our GWAS findings confirm that steady-state letrozole plasma concentrations are partially determined by germline polymorphisms that affect CYP2A6 activity, including variants near rs7937 such as the intronic rs56113850 variant. Further research is needed to confirm whether rs56113850 directly affects CYP2A6 activity and to integrate nonexonic variants into CYP2A6 phenotypic activity prediction systems.
Pharmacogenetics: a perspective and preparedness of Pharm-D and medical students in Jordan
Authors: Zawiah Mohammed , Yousef Al-Motassem , Al-Ashwal Fahmi Y. , Abduljabbar Rami , Al-Jamei Sayida , Hayat Khan Amer , Alkhawaldeh Batool
Published: February 2021

Background

Pharmacogenetics (PGx) science has evolved significantly with a huge number of studies exploring the effect of genetic variants on interindividual variability of drug response. In this study, we assessed the knowledge, attitudes and preparedness of Pharm-D vs. medical students toward PGx.

Method

A paper-based cross-sectional survey was performed. A pilot-tested questionnaire consisting of 21 questions (demographics 5, knowledge 6, attitude 6, and preparedness 4) was administered to 900 healthcare students at different years of study. Descriptive and inferential analyses were used.

Results

Out of the 900 students approached, 852 (94.7%) completed the questionnaire. The overall students’ mean (SD) percentage knowledge score (PKS) was poor [46.7% (18.7)]. The mean (SD) attitude and preparedness scores for all students were 4.68 (1.32), and 1.9 (1.40), respectively, indicating overall positive attitudes, but low preparedness to apply PGx to clinical care. Pharm-D students’ overall PKS was significantly higher than medical students (P < 0.0001). However, there was no significant difference in terms of attitude and preparedness scores. Interestingly, as the year of study increased, the knowledge scores increased as well, with 6th-year students had the highest knowledge scores, while preparedness in applying PGx was higher among the junior students (the 3rd and 4th year of study).

Conclusion

Pharm-D and medical students have inadequate knowledge and low preparedness despite the overall positive attitude towards PGx. There is a need to raise knowledge and to enhance the level of preparedness of medical and Pharm-D students towards PGx and its applications in clinical practice.