bluuebunny/crossref_metadata_2025 huggingface dataset:
Hinterlands, City Formation and Growth: Evidence from the U.S. Westward Expansion
Authors: Nagy Dávid Krisztián
Published: February 2023

I study how geography shaped city formation and aggregate development in the U.S. prior to the Civil War. To guide my analysis, I present a conjecture that cities’ farm hinterlands fostered both city development and aggregate growth: the hinterland hypothesis. The hinterland hypothesis has rich implications on how various elements of U.S. geography—railroads, changes in U.S. political borders, and international trade—affected city formation and U.S. growth. To evaluate the hinterland hypothesis and its implications, I assemble a novel historical dataset on population, trading routes, and agricultural productivity at a high spatial resolution. I combine the data with a dynamic quantitative model of economic geography that yields the hinterland hypothesis as a prediction. I find evidence for the hinterland hypothesis by showing that the model can replicate the key patterns of U.S. urbanization and city formation. Finally, I conduct a series of counterfactuals in the model to quantify the effect of geography on cities and growth, guided by the implications of the hinterland hypothesis. Results indicate that railroads were responsible for 1.8% of urban population in 1860 and for 25% of real GDP growth between 1830 and 1860. The effect of international trade was similar in magnitude, while the effect of political border changes was small during the period.
Investigating the effect of myricetin against arsenic-induced cardiac toxicity in rats
Authors: Aminzadeh Azadeh , Darijani Mohammad Hossein , Bashiri Hamideh
Published: February 2023

Arsenic intoxication is a serious health hazard worldwide. Its toxicity is associated with several disorders and health problems in humans. Recent studies revealed that myricetin has various biological effects, including anti-oxidation. The aim of this study is to investigate the protective effect of myricetin against arsenic-induced cardiotoxicity in rats. Rats were randomized to one of the following groups: control, myricetin (2 mg/kg), arsenic (5 mg/kg), myricetin (1 mg/kg) + arsenic, and myricetin (2 mg/kg) + arsenic. Myricetin was given intraperitoneally 30 min before arsenic administration (5 mg/kg for 10 days). After treatments, the activity of lactate dehydrogenase (LDH) and the levels of aspartate aminotransferase (AST), creatine kinase myocardial band (CK-MB), lipid peroxidation (LPO), total antioxidant capacity (TAC), and total thiol molecules (TTM) were determined in serum samples and cardiac tissues. Also, histological changes in cardiac tissue were evaluated. Myricetin pretreatment inhibited arsenic-induced increase in LDH, AST, CK-MB, and LPO levels. Pretreatment with myricetin also enhanced the decreased TAC and TTM levels. In addition, myricetin improved histopathological alterations in arsenic-treated rats. In conclusion, the results of the present study demonstrated that treatment with myricetin prevented arsenic-induced cardiac toxicity at least in part by decreasing oxidative stress and restoring the antioxidant system.
Inner Workings of Modern Campaigns
Authors: Johnson Dennis W.
Published: February 2023

Why can’t candidates just run on their own, without the need for consultants or handlers? Major political campaigns, everything from big-city mayoral contests to presidential campaigns, rely on a battery of professional campaign consultants and operatives. Without these professionals, candidates would have a very difficult time navigating through the landmines and pitfalls of campaigns. What kinds of services do political consultants provide? What are the key elements of a successful campaign? Hillary Clinton had one of the most experienced campaign teams in 2016; why did she lose? Who ran Trump and Biden’s 2020 presidential campaigns?
Direct Democracy—Ballot Campaigns
Authors: Johnson Dennis W.
Published: February 2023

Many campaigns have no candidates involved, just issues. Since the early twentieth century and especially in the past forty years, ballot campaigns have become an integral part of American policymaking, and immigration reform, tax increases, marijuana legalization, and other hot-button issues are often decided directly by the citizenry. Running a ballot issue campaign involves petition gatherers, legal teams, and often a different approach to convincing the electorate than seen in traditional candidate-focused campaigns. While they are all ballot issues that go directly to votes, there are important differences between referendums, initiatives, and recalls. Many political consultants now specialize in ballot issues, rather than concentrate on candidate-centered campaigns. While citizen-generated lawmaking has some advantages, there are several downsides, and the impact on representative democracy can be significant.
Extreme Weather and Climate Change
Authors: Romm Joseph
Published: February 2023

Extreme weather is the earliest manifestation of climate change that most people will be exposed to. This chapter will focus on what science tells us about the remarkable spate of once-in-a-century (and rarer) extreme weather events we have observed in the last few years. It...
Projected Climate Impacts
Authors: Romm Joseph
Published: February 2023

This chapter will discuss what climate science projects will happen this century. The focus will be on the so-called business-as-usual case, which assumes no significant global action to reduce greenhouse gas emissions trends in the foreseeable future. The primary source will be the latest scientific...
The Role of Clean Energy
Authors: Romm Joseph
Published: February 2023

This chapter will focus on the clean energy revolution and the technologies most widely discussed for a transition to a low-carbon economy. It will explore the scale of the energy transition needed to explain why some energy technologies are considered likely to be major contributors...
Prevalence and Importance of the Necrotrophic Effector Gene ToxA in Bipolaris sorokiniana Populations Collected from Spring Wheat and Barley
Authors: Manan Fazal , Shi Gongjun , Gong Hongmei , Hou Hongyan , Khan Hannah , Leng Yueqiang , Castell-Miller Claudia , Ali Shaukat , Faris Justin D. , Zhong Shaobin , Steffenson Brian Joel , Liu Zhaohui
Published: February 2023

Bipolaris sorokiniana is a necrotrophic fungal pathogen that causes foliar and root diseases on wheat and barley. These diseases are common in all wheat- and barley-growing regions, with more severe outbreaks occurring under warm and humid conditions. B. sorokiniana can also infect a wide range of grass species in the family Poaceae and secrete ToxA, an important necrotrophic effector also identified other wheat leaf spotting pathogens. In this study, the prevalence and virulence role of ToxA were investigated in a collection of 278 B. sorokiniana isolates collected from spring wheat and barley in the Upper Midwest of the United States or other places, including 169 from wheat leaves, 75 from wheat roots, 30 from barley leaves, and 4 from wild quack grass leaves. ToxA was present in the isolates from wheat leaves, wheat roots, and wild grass leaves but was absent from isolates collected from barley leaves. Prevalence of ToxA in wheat leaf isolates (34.3%) was much higher than that in wheat root isolates (16%). Sequencing analysis revealed the presence of two haplotypes, with the majority being BsH2. All ToxA+ isolates produced the functional effector in liquid cultures. Pathogenicity assays revealed that ToxA+ isolates caused significantly more disease on spring wheat lines harboring Tsn1 than their tsn1 mutants, suggesting that the ToxA–Tsn1 interaction plays an important role in spot blotch development. This work confirms the importance of ToxA in B. sorokiniana populations infecting wheat and, thus, the need to eliminate Tsn1 from spring wheat cultivars to reduce susceptibility to spot blotch.
Phylogeny, Morphology, Distribution, and Pathogenicity of Seven Calonectria Species from Leaf-Blighted Eucalyptus in HaiNan Island, China
Authors: Liang XueYing , Wang QuanChao , Chen ShuaiFei
Published: February 2023

Leaf blight caused by Calonectria species constrains Eucalyptus trees in China. Calonectria leaf disease on Eucalyptus in China was first reported in HaiNan Island in 1985. No systematic investigation of Calonectria species associated with diseased Eucalyptus in HaiNan has been performed. To understand the species diversity, distribution, and pathogenicity of these Calonectria, 400 Calonectria isolates were obtained from 278 diseased Eucalyptus planted in 17 sites in five regions. All 400 isolates were identified by DNA sequences of translation elongation factor 1-alpha, β-tubulin, calmodulin, and histone H3 gene regions and on morphology. Seven species, C. acaciicola (198 isolates), C. pseudoreteaudii (161 isolates), C. reteaudii (29 isolates), C. hawksworthii (6 isolates), C. hongkongensis (4 isolates), C. auriculiformis (1 isolate), and C. chinensis (1 isolate), were identified. This is the first report of C. acaciicola in China. C. acaciicola, C. pseudoreteaudii, and C. reteaudii belong to the C. reteaudii species complex and accounted for 97% of all isolates. The three species overlapped in vesicle shape, macroconidia size, and macroconidia septa number. Region significantly influenced C. acaciicola and C. pseudoreteaudii distribution. Representative isolates of C. acaciicola, C. pseudoreteaudii, C. reteaudii, and C. hawksworthii producing abundant macroconidia were used in conidial suspension inoculation on Eucalyptus seedlings; all were highly pathogenic to the two tested genotypes. The tolerances of two Eucalyptus genotypes were significantly different. This first systematic investigation of Calonectria species associated with Eucalyptus leaf blight in HaiNan will aid selection of disease-resistant genotypes for managing Eucalyptus leaf blight caused by Calonectria species in China.
Genetic Analysis and Physical Mapping of Oat Adult Plant Resistance Loci Against Puccinia coronata f. sp. avenae
Authors: Nazareno Eric S. , Fiedler Jason D. , Ardayfio Naa Korkoi , Miller Marisa E. , Figueroa Melania , Kianian Shahryar F.
Published: February 2023

Six quantitative trait loci (QTLs) for adult plant resistance against oat crown rust ( Puccinia coronata f. sp. avenae) were identified from mapping three recombinant inbred populations. Using genotyping-by-sequencing with markers called against the OT3098 v1 reference genome, the QTLs were mapped on six different chromosomes: Chr1D, Chr4D, Chr5A, Chr5D, Chr7A, and Chr7C. Composite interval mapping with marker cofactor selection showed that the phenotypic variance explained by all identified QTLs for coefficient of infection range from 12.2 to 46.9%, whereas heritability estimates ranged from 0.11 to 0.38. The significant regions were narrowed down to intervals of 3.9 to 25 cM, equivalent to physical distances of 11 to 133 Mb. At least two flanking single-nucleotide polymorphism markers were identified within 10 cM of each QTL that could be used in marker-assisted introgression, pyramiding, and selection. The additive effects of the QTLs in each population were determined using single-nucleotide polymorphism haplotype data, which showed a significantly lower coefficient of infection in lines homozygous for the resistant alleles. Analysis of pairwise linkage disequilibrium also revealed high correlation of markers and presence of linkage blocks in the significant regions. To further facilitate marker-assisted breeding, polymerase chain reaction allelic competitive extension (PACE) markers for the adult plant resistance loci were developed. Putative candidate genes were also identified in each of the significant regions, which include resistance gene analogs that encode for kinases, ligases, and predicted receptors of avirulence proteins from pathogens.
Upregulation of sphingosine kinase 1 in response to doxorubicin generates an angiogenic response via stabilization of Snail
Authors: Bonica Joseph , Clarke Christopher J. , Obeid Lina M. , Luberto Chiara , Hannun Yusuf A.
Published: February 2023

Sphingosine kinase 1 (SK1) converts the pro‐death lipid sphingosine to the pro‐survival sphingosine‐1‐phosphate (S1P) and is upregulated in several cancers. DNA damaging agents, such as the chemotherapeutic doxorubicin (Dox), have been shown to degrade SK1 protein in cancer cells, a process dependent on wild‐type p53. As mutations in p53 are very common across several types of cancer, we evaluated the effects of Dox on SK1 in p53 mutant cancer cells. In the p53 mutant breast cancer cell line MDA‐MB‐231, we show that Dox treatment significantly increases SK1 protein and S1P. Using MDA‐MB‐231 cells with CRISPR‐mediated knockout of SK1 or the selective SK1 inhibitor PF‐543, we implicated SK1 in both Dox‐induced migration and in a newly uncovered proangiogenic program induced by Dox. Mechanistically, inhibition of SK1 suppressed the induction of the cytokine BMP4 and of the EMT transcription factor Snail in response to Dox. Interestingly, induction of BMP4 by SK1 increased Snail levels following Dox treatment by stabilizing Snail protein. Furthermore, we found that SK1 was required for Dox‐induced p38 MAP kinase phosphorylation and that active p38 MAPK in turn upregulated BMP4 and Snail, positioning p38 downstream of SK1 and upstream of BMP4/Snail. Modulating production of S1P by inhibition of de novo sphingolipid synthesis or knockdown of the S1P‐degrading enzyme S1P lyase identified S1P as the sphingolipid activator of p38 in this model. This work establishes a novel angiogenic pathway in response to a commonly utilized chemotherapeutic and highlights the potential of SK1 as a secondary drug target for patients with p53 mutant cancer.
Echinacoside from Cistanche tubulosa ameliorates alcohol‐induced liver injury and oxidative stress by targeting Nrf2
Authors: Ding Yuhao , Zhang Yuan , Wang Zhonghao , Zeng Fanle , Zhen Qianzhen , Zhao Huizi , Li Jun , Ma Taotao , Huang Cheng
Published: February 2023

Cistanche tubulosa (Schrenk) Wight, named Guan hua Rou Cong‐Rong in Chinese, is a traditional plant with liver, kidney, and intestine protective effects. Echinacoside (ECH) is its active constituent and has been found to have various biological effects, including antioxidative stress and anti‐inflammatory effects. Liver injury caused by acetaminophen or CCL4 has been proven to benefit from ECH; however, the effects of ECH against alcoholic liver disease (ALD) remain unclear. This study was used to estimate the effect of echinacoside on nuclear factor erythroid 2‐related factor 2 (Nrf2), which ameliorates ALD by inhibiting oxidative stress and cell apoptosis through affecting Nrf2.A mouse model of ALD was established with ethanol using hematoxylin and eosin (HE) staining, oiled staining, and biochemical indices. Alpha Mouse Liver 12 (AML‐12) cells were induced with ethanol in vitro and analyzed using western blotting, flow cytometry, and biochemical assays. In the animal model of ALD, ECH dramatically reduced liver damage, as proven by the downregulation of aspartate aminotransferase (AST) and HE staining. In vitro, ECH distinctly reduced the damage caused by ethanol through the decreased expression of cleaved caspase‐3 measured by western blotting. ECH significantly increased the activity of Nrf2 in vivo and in vitro. Nrf2 knockout may diminish the influence of ECH on ALD. Meanwhile, ECH also increased the expression of haem oxygenase‐1 (HO‐1) and glutamate‐cysteine ligase catalytic subunit (GCLC), while it inhibited levels of oxidative stress and cell apoptosis. Our findings suggest that ECH protects against ethanol‐induced liver injuries by alleviating oxidative stress and cell apoptosis by increasing the activity of Nrf2. Therefore, ECH is promising for the treatment of ALD.
Human umbilical cord mesenchymal stem cells‐derived exosomal circDLGAP4 promotes angiogenesis after cerebral ischemia–reperfusion injury by regulating miR‐320/KLF5 axis
Authors: Feng Jie , He Wei , Xia Jian , Huang Qing , Yang Jie , Gu Wen‐Ping , Zhang Ning , Liu Yun‐Hai
Published: February 2023

Accumulating evidence suggests that human umbilical cord mesenchymal stem cell‐derived exosomes (hUC‐MSCs‐Exos) are a promising therapeutic strategy for cerebral ischemia–reperfusion injury (CIRI). However, the underlying mechanism remains unclear. hUC‐MSCs‐Exos were identified by electron microscopy, NTA, and Western blotting. In the hypoxia/reoxygenation (H/R) cell model, human brain microvascular endothelial cells (HBMECs) were cocultured with hUC‐MSCs‐Exos. Then, cell viability, migration, apoptosis, and tube formation were measured by MTT, flow cytometry, transwell, and tube formation assays. RT‐qPCR and Western blotting were used to detect the changes in RNA and protein. RNA pull‐down and dual luciferase reporter assays confirmed the relationship between circDLGAP4, miR‐320, and KLF5. Ischemia–reperfusion (I/R) rat model was established for in vivo experiments. hUC‐MSCs‐Exos increased the expression levels of circDLGAP4 and KLF5 but decreased miR‐320 in H/R‐treated HBMECs by transferring exosomal circDLGAP4. Knockdown of circDLGAP4 in hUC‐MSCs‐Exos reversed the promoting effects of hUC‐MSCs‐Exos on cell viability, migration, and tube formation in H/R‐treated HBMECs in vitro and also abolished the protective effects of hUC‐MSCs‐Exos on cerebrovascular injury in I/R rats. Mechanistically, exosomal circDLGAP4 negatively regulated miR‐320 in HBMECs, which directly bound to KLF5. In addition, the downregulation of miR‐320 could reverse the regulatory effect of exosomal shcircDLGAL5 in H/R‐treated HBMECs by upregulating KLF5. hUC‐MSCs‐Exos‐derived circDLGAP4 reduced cerebrovascular injury by regulating miR‐320/KLF5 signaling. These results provide a stem cell‐based approach to treat CIRI.
DNAJB8 facilitates autophagic‐lysosomal degradation of viral Vif protein and restricts HIV‐1 virion infectivity by rescuing APOBEC3G expression in host cells
Authors: Chand Kailash , Barman Muneesh Kumar , Ghosh Payel , Mitra Debashis
Published: February 2023

HSP40/DNAJ family of proteins is the most diverse chaperone family, comprising about 49 isoforms in humans. Several reports have demonstrated the functional role of a few of these isoforms in the pathogenesis of various viruses, including HIV‐1. Our earlier study has shown that several isoforms of HSP40 get significantly modulated at the mRNA level during HIV‐1 infection in T cells. To explore the biological role of these significantly modulated isoforms, we analyzed their effect on HIV‐1 gene expression and virus production using knockdown and overexpression studies. Among these isoforms, DNAJA3, DNAJB1, DNAJB7, DNAJC4, DNAJC5B, DNAJC5G, DNAJC6, DNAJC22, and DNAJC30 seem to positively regulate virus replication, whereas DNAJB3, DNAJB6, DNAJB8, and DNAJC5 negatively regulate virus replication. Further investigation on the infectivity of the progeny virion demonstrated that only DNAJB8 negatively regulates the progeny virion infectivity. It was further identified that DNAJB8 protein is involved in the downregulation of Vif protein, required for the infectivity of HIV‐1 virions. DNAJB8 seems to direct Vif protein for autophagic‐lysosomal degradation, leading to rescue of the cellular restriction factor APOBEC3G from Vif‐mediated proteasomal degradation, resulting in enhanced packaging of APOBEC3G in budding virions and release of less infective progeny virion particles. Finally, our results also indicate that during the early stage of HIV‐1 infection, enhanced expression of DNAJB8 promotes the production of less infective progeny virions, but at the later stage or at the peak of infection, reduced expression of DNJAB8 protein allows the HIV‐1 to replicate and produce more infective progeny virion particles.
The Power of One Word to Paint a Halo or a Horn: Demonstrating the Halo Effect in Learner Handover and Subsequent Evaluation
Authors: Seehusen Dean A. , Kleinheksel A.J. , Huang Hannah , Harrison Zachary , Ledford Christy J.W.
Published: February 2023

Purpose

Learner evaluation based upon direct observation is a cornerstone of modern competency-based medical education. Learner handover has become a widely accepted practice. Cognitive attribution bias is a potential threat to the validity of learner evaluation following learner handover.

Method

In this 2 x 2 (learner handover: halos/horns x learner gender: man/woman) factorial, nonequivalent comparison group experimental design, registered attendees at a national medical education conference watched 1 of 2 videos (depicting a woman learner or man learner) of simulated learner–patient encounters. Data were collected on April 30 and May 1, 2022. Participants received learner handover conditioning before watching the video. The conditioning was randomized to suggest the learner they were about to watch was either “above-average” (halos) or “below-average” (horns). Following the video, participants completed an evaluation form.

Results

Participants rated the learner in a video encounter preceded by a horns statement significantly lower than the learner in a video encounter preceded by a halo statement, F (1,65) = 10.15, P < .01, η2
= .14, horns meanadj = 12.49 (CI 11.34, 13.63), halo meanadj = 15.10 (CI 13.93, 16.28). This represented a scoring difference of 2.61 points on a 30-point scale. More years of teaching experience was negatively associated with the score, F (1,65) = 13.44, P < .001, η2
= .17.

Conclusions

Learner conditioning differing by a single word, labeling a learner as either “above-average” or “below-average” resulted in a large difference in scoring by medical educators.
Association Between Hypocholesterolemia and Mortality in Critically Ill Patients With Sepsis: A Systematic Review and Meta-Analysis
Authors: Hofmaenner Daniel A. , Arina Pietro , Kleyman Anna , Black Lauren Page , Salomao Reinaldo , Tanaka Sébastien , Guirgis Faheem W. , Arulkumaran Nishkantha , Singer Mervyn
Published: February 2023

OBJECTIVE:

To ascertain the association between cholesterol and triglyceride levels on ICU admission and mortality in patients with sepsis.

DATA SOURCES:

Systematic review and meta-analysis of published studies on PubMed and Embase.

STUDY SELECTION:

All observational studies reporting ICU admission cholesterol and triglyceride levels in critically ill patients with sepsis were included. Authors were contacted for further data.

DATA EXTRACTION:

Eighteen observational studies were identified, including 1,283 patients with a crude overall mortality of 33.3%. Data were assessed using Revman (Version 5.1, Cochrane Collaboration, Oxford, United Kingdom) and presented as mean difference (MD) with 95% CIs, p values, and I

2
values.

DATA SYNTHESIS:

Admission levels of total cholesterol (17 studies, 1,204 patients; MD = 0.52 mmol/L [0.27–0.77 mmol/L]; p < 0.001; I

2
= 91%), high-density lipoprotein (HDL)-cholesterol (14 studies, 991 patients; MD = 0.08 mmol/L [0.01–0.15 mmol/L]; p = 0.02; I

2
= 61%), and low-density lipoprotein (LDL)-cholesterol (15 studies, 1,017 patients; MD = 0.18 mmol/L [0.04–0.32 mmol/L]; p = 0.01; I

2
= 71%) were significantly lower in eventual nonsurvivors compared with survivors. No association was seen between admission triglyceride levels and mortality (15 studies, 1,070 patients; MD = 0.00 mmol/L [–0.16 to 0.15 mmol/L]; p = –0.95; I

2
= 79%).

CONCLUSIONS:

Mortality was associated with lower levels of total cholesterol, HDL-cholesterol, and LDL-cholesterol, but not triglyceride levels, in patients admitted to ICU with sepsis. The impact of cholesterol replacement on patient outcomes in sepsis, particularly in at-risk groups, merits investigation.
Haploidentical γδ T Cells Induce Complete Remission in Chemorefractory B-cell Non-Hodgkin Lymphoma
Authors: Bold Anna , Gaertner Johannes , Bott Alexander , Mordstein Volker , Schaefer-Eckart Kerstin , Wilhelm Martin
Published: February 2023

The transformation of chronic lymphocytic leukemia to an aggressive lymphoma, called Richter transformation, is often accompanied by resistance to chemotherapy and high mortality. Thus, novel therapeutic strategies are required for the successful treatment of these patients. One possibility is cellular immunotherapy with chimeric antigen receptor T cells. However, the time delay until cells are available and the limited number of effector cells due to the impaired immune system of these patients potentially compromises the efficacy of this approach. Another promising attempt might be the therapy with γδ T cells. Once activated, they exhibit various antitumor effects against several types of malignancies. Furthermore, they can be safely used in an allogeneic setting and can be multiplied in vivo as already demonstrated in clinical studies. In vitro data, in addition, show that the cytotoxicity of γδ T cells can be significantly enhanced by monoclonal antibodies. Here we present a patient, who suffered from Richter transformation and did not respond to several lines of immunochemotherapy. Due to the lack of further therapy options, we conducted an individual therapy with adoptive transfer of haploidentical γδ T cells combined with the application of the monoclonal antibody obinutuzumab. A histologically confirmed complete remission was achieved through this therapy approach, whereby relevant side effects were not seen. This case highlights the potential of γδ T cells and the feasibility of this therapeutic approach for further clinical trials.
Immunogenicity and reactogenicity of heterologous immunization schedules with COVID-19 vaccines: a systematic review and network meta-analysis
Authors: Li Pei , Wang Weiwei , Tao Yiming , Tan Xiaoyu , Li Yujing , Mao Yinjun , Gao Le , Feng Lei , Zhan Siyan , Sun Feng
Published: February 2023

Background:

Data on the immunogenicity and safety of heterologous immunization schedules are inconsistent. This study aimed to evaluate the immunogenicity and safety of homologous and heterologous immunization schedules.

Methods:

Multiple databases with relevant studies were searched with an end date of October 31, 2021, and a website including a series of Coronavirus disease 2019 studies was examined for studies before March 31, 2022. Randomized controlled trials (RCTs) that compared different heterologous and homologous regimens among adults that reported immunogenicity and safety outcomes were reviewed. Primary outcomes included neutralizing antibodies against the original strain and serious adverse events (SAEs). A network meta-analysis (NMA) was conducted using a random-effects model.

Results:

In all, 11 RCTs were included in the systematic review, and nine were ultimately included in the NMA. Among participants who received two doses of CoronaVac, another dose of mRNA or a non-replicating viral vector vaccine resulted in a significantly higher level of neutralizing antibody than a third CoronaVac 600 sino unit (SU); a dose of BNT162b2 induced the highest geometric mean ratio (GMR) of 15.24, 95% confidence interval [CI]: 9.53–24.39. Following one dose of BNT162b2 vaccination, a dose of mRNA-1273 generated a significantly higher level of neutralizing antibody than BNT162b2 alone (GMR = 1.32; 95% CI: 1.06–1.64), NVX-CoV2373 (GMR = 1.60; 95% CI: 1.16–2.21), or ChAdOx1 (GMR = 1.80; 95% CI: 1.25–2.59). Following one dose of ChAdOx1, a dose of mRNA-1273 was also more effective for improving antibody levels than ChAdOx1 (GMR = 11.09; 95% CI: 8.36–14.71) or NVX-CoV2373 (GMR = 2.87; 95% CI: 1.08–3.91). No significant difference in the risk for SAEs was found in any comparisons.

Conclusions:

Relative to vaccination with two doses of CoronaVac, a dose of BNT162b2 as a booster substantially enhances immunogenicity reactions and has a relatively acceptable risk for SAEs relative to other vaccines. For primary vaccination, schedules including mRNA vaccines induce a greater immune response. However, the comparatively higher risk for local and systemic adverse events introduced by mRNA vaccines should be noted.

Registration:

No.CRD42021278149
HIV and chronic lung disease
Authors: Leung Janice M.
Published: February 2023

Purpose of review

As people living with human immunodeficiency virus (HIV, PLWH) age, aging-related comorbidities have come into focus as major challenges to their overall health. In this review, an in-depth overview of the two most commonly encountered chronic lung diseases in PLWH, chronic obstructive pulmonary disease (COPD) and lung cancer, is provided.

Recent findings

The risk for both COPD and lung cancer remains significantly higher in PLWH compared to the HIV-uninfected population, although fortunately rates of lung cancer appear to be declining over the last two decades. Outcomes for PLWH with these conditions, though, continue to be poor with worse survival rates in comparison to the general population. PLWH still face major barriers in accessing care for these conditions, including a higher likelihood of being underdiagnosed with COPD and a lower likelihood of being referred for lung cancer screening or treatment. A lack of evidence for optimal treatment strategies for both COPD and lung cancer still hampers the care of PLWH with these conditions.

COPD and lung cancer represent substantial burdens of disease in PLWH. Improved access to standard-of-care screening and treatment and greater investigation into therapeutic responses specifically in this population are recommended.
Do sleep disturbances contribute to comorbidities in HIV?
Authors: Kunisaki Ken M.
Published: February 2023

Purpose of review

To highlight recent publications about sleep disorders and sleep health in adult persons with HIV (PWH), with a focus on how sleep relates to comorbidities in PWH.

Recent findings

Sleep disorders are more common in PWH than in seronegative controls, especially insomnia, with four different recent studies estimating insomnia prevalence in PWH at 21–35%. Sleep apnea prevalence estimates in PWH have varied widely. Most studies suggest PWH do not have higher sleep apnea prevalence compared with controls, though definitions of sleep apnea may affect these analyses. Comorbidities recently associated with sleep in PWH include myocardial infraction (insomnia), depressive symptoms (insomnia and restless legs syndrome), and pain (insomnia). Cognition associations with sleep were inconsistent and may depend on data collection and analytic methods. Sleep health dimensions are uncommonly reported, but PWH appear to report worse sleep health dimensions and these demonstrated mixed associations with cognition and depressive symptoms in recent studies.

Sleep disorders and poor sleep health are common in PWH and are related to comorbidities. More data from longitudinal studies and clinical trials are needed. Clinical trials of insomnia interventions in PWH are especially warranted.
Gender and sex considerations in HIV and bone health
Authors: Tang Mei J. , Alexander Adrian , Hoy Jennifer F.
Published: February 2023

Purpose of review

People with HIV (PWHIV) are at increased risk for osteoporosis and fractures, because of the effects of HIV and inflammation and antiretroviral therapy (ART) initiation as well as traditional risk factors. This review from recent literature focuses on sex differences in rates of bone disease, risk of fractures, and effects of ART.

Recent findings

Women with HIV in resource-constrained settings experience bone loss because of the additive effect of initiating TDF-containing ART during pregnancy, lactation, and menopause. Children and adolescents experience lower bone accrual during the pubertal growth years. There has been less focus on bone health in recent trials of ART containing tenofovir alafenamide and/or integrase inhibitors. Very few clinical trials or studies compare sex-specific changes in inflammation, immune activation, response to ART and bone turnover or change in BMD resulting in significant knowledge gaps.

More data is needed to determine changes in prevalence of osteopenia, osteoporosis, and fractures in the era of immediate initiation of ART at high CD4 cell counts and the use of more bone-friendly ART. The long-term effects of ART and low bone mass on fractures in the ageing population of PWHIV is yet to be realized.
Emulating a Target Trial of Interventions Initiated During Pregnancy with Healthcare Databases: The Example of COVID-19 Vaccination
Authors: Hernández-Díaz Sonia , Huybrechts Krista F. , Chiu Yu-Han , Yland Jennifer J. , Bateman Brian T. , Hernán Miguel A.
Published: February 2023

Background:

Observational studies are often the only option to estimate effects of interventions during pregnancy. Causal inference from observational data can be conceptualized as an attempt to emulate a hypothetical pragmatic randomized trial: the target trial.

Objective:

To provide a step-by-step description of how to use healthcare databases to estimate the effects of interventions initiated during pregnancy. As an example, we describe how to specify and emulate a target trial of COVID-19 vaccination during pregnancy, but the framework can be generally applied to point and sustained strategies involving both pharmacologic and non-pharmacologic interventions.

Methods:

First, we specify the protocol of a target trial to evaluate the safety and effectiveness of vaccination during pregnancy. Second, we describe how to use observational data to emulate each component of the protocol of the target trial. We propose different target trials for different gestational periods because the outcomes of interest vary by gestational age at exposure. We identify challenges that affect (i) the target trial and thus its observational emulation (censoring and competing events), and (ii) mostly the observational emulation (confounding, immortal time, and measurement biases).

Conclusion:

Some biases may be unavoidable in observational emulations, but others are avoidable. For instance, immortal time bias can be avoided by aligning the start of follow-up with the gestational age at the time of the intervention, as we would do in the target trial. Explicitly emulating target trials at different gestational ages can help reduce bias and improve the interpretability of effect estimates for interventions during pregnancy.
Why and How Epidemiologists Should Use Mixed Methods
Authors: Houghton Lauren C. , Paniagua-Avila Alejandra
Published: February 2023

The field of epidemiology’s current focus on causal inference follows a quantitative approach and limits research questions to those that are strictly quantifiable. How can epidemiologists study biosociocultural public health problems that they cannot easily quantify? The mixed-methods approach offers a possible solution by incorporating qualitative sociocultural factors as well as the perspective and context from the population under study into quantitative studies. After a pluralist perspective of causal inference, this article provides a guide for epidemiologists interested in applying mixed methods to their observational studies of causal identification and explanation. We begin by reviewing the current paradigms guiding quantitative, qualitative, and mixed methodologies. We then describe applications of convergent and sequential mixed-methods designs to epidemiologic concepts including confounding, mediation, effect modification, measurement, and selection bias. We provide concrete examples of how epidemiologists can use mixed methods to answer research questions of complex bio-socio-cultural health outcomes. We also include a case study of using mixed methods in an observational study design. We describe how mixed methods can enhance how epidemiologists define underlying causal structures. Our alignment of mixed-methods study designs with epidemiologic concepts addresses a major gap in current epidemiology education— how do epidemiologists systematically determine what goes into causal structures?
Maternal Smoking During Pregnancy and Risk of Appendicitis in the Offspring
Authors: Fuglsang Cecilia Hvitfeldt , Bakos Istvan , Laugesen Kristina , Troelsen Frederikke Schønfeldt , Horváth-Puhó Erzsébet , Sørensen Henrik Toft
Published: February 2023

Background:

Existing evidence on the link between smoking and appendicitis is scarce and ambiguous. We therefore conducted a population-based cohort study in Denmark to investigate whether smoking during pregnancy is associated with an increased risk of appendicitis in offspring.

Methods:

We used the Danish Birth Registry to include all singletons born during 1991–2017 and to identify maternal smoking status during pregnancy. We followed the children from birth until date of appendicitis, emigration, death, or administrative end of study (31 December 2018), whichever came first. We calculated crude and adjusted hazard ratios (HRs) of appendicitis with 95% confidence intervals (CIs) comparing children of mothers who smoked during pregnancy to children of nonsmokers. Further, we conducted a bias analysis and sibling analysis.

Results:

We included 1,659,526 singletons of whom 19% were born to mothers who smoked during pregnancy. After maximum 28 years of follow-up, hazard rates for children of smokers were slightly higher than for children of nonsmokers [adjusted HR: 1.07 (95% CI = 1.04, 1.10)]. Stratification by sex revealed no association for males [adjusted HR: 1.02 (95% CI = 0.99, 1.06)], but a higher HR for females [adjusted HR: 1.13 (95% CI = 1.09, 1.18)]. This association increased with increasing length of follow-up, indicating that the association may be mediated by later-life exposures. The bias analysis indicated that misclassification of maternal smoking could attenuate a true association, while the sibling analysis showed no association.

Conclusions:

Maternal smoking during pregnancy and appendicitis in the offspring may be associated.
Validation of Insurance Billing Codes for Monitoring Antenatal Screening
Authors: Nethery Elizabeth , Hutcheon Jennifer A. , Law Michael R. , Janssen Patricia A.
Published: February 2023

Background:

Prevalence statistics for pregnancy complications identified through screening such as gestational diabetes usually assume universal screening. However, rates of screening completion in pregnancy are not available in many birth registries or hospital databases. We validated screening-test completion by comparing public insurance laboratory and radiology billing records with medical records at three hospitals in British Columbia, Canada.

Methods:

We abstracted a random sample of 140 delivery medical records (2014–2019), and successfully linked 127 to valid provincial insurance billings and maternal–newborn registry data. We compared billing records for gestational diabetes screening, any ultrasound before 14 weeks gestational age, and Group B streptococcus screening during each pregnancy to the gold standard of medical records by calculating sensitivity and specificity, positive predictive value, negative predictive value, and prevalence with 95% confidence intervals (CIs).

Results:

Gestational diabetes screening (screened vs. unscreened) in billing records had a high sensitivity (98% [95% CI = 93, 100]) and specificity (>99% [95% CI = 86, 100]). The use of specific glucose screening approaches (two-step vs. one-step) were also well characterized by billing data. Other tests showed high sensitivity (ultrasound 97% [95% CI = 92, 99]; Group B streptococcus 96% [95% CI = 89, 99]) but lower negative predictive values (ultrasound 64% [95% CI = 33, 99]; Group B streptococcus 70% [95% CI = 40, 89]). Lower negative predictive values were due to the high prevalence of these screening tests in our sample.

Conclusions:

Laboratory and radiology insurance billing codes accurately identified those who completed routine antenatal screening tests with relatively low false-positive rates.
Self-reported Human Papillomavirus Vaccination and Vaccine Effectiveness Among Men Who Have Sex with Men: A Quantitative Bias Analysis
Authors: Chambers Catharine , Deeks Shelley L. , Sutradhar Rinku , Cox Joseph , de Pokomandy Alexandra , Grennan Troy , Hart Trevor A. , Lambert Gilles , Moore David M. , Grace Daniel , Grewal Ramandip , Jollimore Jody , Lachowsky Nathan J. , Mah Ashley , Nisenbaum Rosane , Ogilvie Gina , Sauvageau Chantal , Tan Darrell H.S. , Yeung Anna , Burchell Ann N.
Published: February 2023

Background:

Self-report of human papillomavirus (HPV) vaccination has ~80–90% sensitivity and ~75–85% specificity. We measured the effect of nondifferential exposure misclassification associated with self-reported vaccination on vaccine effectiveness (VE) estimates.

Methods:

Between 2017–2019, we recruited sexually active gay, bisexual, and other men who have sex with men aged 16–30 years in Canada. VE was derived as 1−prevalence ratio × 100% for prevalent anal HPV infection comparing vaccinated (≥1 dose) to unvaccinated men using a multivariable modified Poisson regression. We conducted a multidimensional and probabilistic quantitative bias analysis to correct VE estimates.

Results:

Bias-corrected VE estimates were relatively stable across sensitivity values but differed from the uncorrected estimate at lower values of specificity. The median adjusted VE was 27% (2.5–97.5th simulation interval = −5–49%) in the uncorrected analysis, increasing to 39% (2.5–97.5th simulation interval = 2–65%) in the bias-corrected analysis.

Conclusion:

A large proportion of participants erroneously reporting HPV vaccination would be required to meaningfully change VE estimates.
Joint Associations of Short-Term Exposure to Ambient Air Pollutants with Hospital Admission of Ischemic Stroke
Authors: Liu Tao , Jiang Yong , Hu Jianxiong , Li Zixiao , Li Xing , Xiao Jianpeng , Yuan Lixia , He Guanhao , Zeng Weilin , Rong Zuhua , Zhu Sui , Ma Wenjun , Wang Yongjun
Published: February 2023

Background:

Studies have estimated the associations of short-term exposure to ambient air pollution with ischemic stroke. However, the joint associations of ischemic stroke with air pollution as a mixture remain unknown.

Methods:

We employed a time-stratified case–crossover study to investigate 824,808 ischemic stroke patients across China. We calculated daily mean concentrations of particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5), maximum 8-h average for O3 (MDA8 O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO) across all monitoring stations in the city where the IS patients resided. We conducted conditional logistic regression models to estimate the exposure–response associations.

Results:

Results from single-pollutant models showed positive associations of hospital admission for ischemic stroke with PM2.5 (excess risk [ER] = 0.38%, 95% confidence interval [CI]: 0.29% to 0.47%, for 10 μg/m3), MDA8 O3 (ER = 0.29%, 95% CI: 0.18% to 0.40%, for 10 μg/m3), NO2 (ER = 1.15%, 95% CI: 0.92% to 1.39%, for 10 μg/m3), SO2 (ER = 0.82%, 95% CI: 0.53% to 1.11%, for 10 μg/m3) and CO (ER = 3.47%, 95% CI: 2.70% to 4.26%, for 1 mg/m3). The joint associations (ER) with all air pollutants (for interquartile range width increases in each pollutant) estimated by the single-pollutant model was 8.73% and was 4.27% by the multipollutant model. The joint attributable fraction of ischemic stroke attributable to air pollutants based on the multipollutant model was 7%.

Conclusions:

Short-term exposures to PM2.5, MDA8 O3, NO2, SO2, and CO were positively associated with increased risks of hospital admission for ischemic stroke. The joint associations of air pollutants with ischemic stroke might be overestimated using single-pollutant models. See video abstract at, http://links.lww.com/EDE/C8.
Adipose Tissue Transfer in Dynamic Definition Liposculpture—PART I. Back: Latissimus Dorsi and Trapezius Muscles
Authors: Hoyos Alfredo E. , Stefanelli Matt , Perez Mauricio E. , Brenes-Leñero Eduardo , Padilla Mauricio
Published: February 2023

Background:

The aesthetics for the male posterior torso remain a topic not fully studied in body contouring surgery, neither the lipoinjection of its muscles have been considered before. As a result, we carried out a retrospective cohort study including patients who underwent fat grafting of either the trapezius or the latissimus dorsi muscles as part of dynamic definition liposculpture (HD2).

Methods:

We performed cadaveric dissections to support the fat grafting technique for both the trapezius and the latissimus dorsi muscles. We also searched our records for patients who underwent fat grafting of these muscles in addition to HD2 from January 2016 to November 2021 at a single center in Bogotá, Colombia.

Results:

Thirty-five consecutive patients met the inclusion criteria. In total, 22 (63%) and 7 (20%) of 35 underwent fat grafting at the trapezius and the latissimus dorsi muscles alone, respectively, and 6 out of 35 (17%) of both. Mean age is 39 years (range = 22–63). All patients were men. No complications were recorded related to fat grafting. Almost all patients were satisfied with the procedure (97%). Follow-up period ranged from 2 to 48 months.

Conclusions:

Liposuction might not be enough to achieve the ideal V-shape of the men’s back in some cases; hence, fat grafting of the power muscles becomes the best option. Recognition of the main neurovascular pedicle, proper preoperative markings, and a correct surgical technique ensure both the safety and the reproducibility of the technique.
Do Plastic Surgery Residents Get Sued? An Analysis of Malpractice Lawsuits
Authors: Gibstein Alexander R. , Jabori Sinan K. , Watane Arjun , Slavin Benjamin R. , Elabd Rawan , Singh Devinder
Published: February 2023

Background:

Trainees may be implicated in malpractice lawsuits. Our study examines malpractice cases involving plastic surgery trainees.

Methods:

Using the LexisNexis database, verdicts and settlements from appellate state and federal cases between February 1988 and 2020 were queried. A nonrepresentative sample of 300 cases was compiled.

Results:

During a 32-year period, 21 lawsuits involving plastic surgery trainees were identified. Of these, 14 (66.67%) involved claims when a trainee was directly named as a defendant. Eighteen (85.7%) cases were due to procedural-related adverse outcomes, while three (14.3%) cases were associated with clinical or diagnostic-related adverse outcomes. Of the procedure-related cases, five (27.8%) occurred when the trainee was the lead surgeon. Allegations included lack of informed consent of procedure complications (11, 52.4%), procedural error (11, 52.4%), failure to supervise trainee (11, 52.4%), inexperience of trainee (eight, 38.1%), incorrect diagnosis or treatment (five, 23.8%), delay in evaluation (three, 14.3%), lack of awareness of resident involvement (three, 14.3%), lack of follow-up (three, 14.3%), and prolonged operative time (one, 4.8%). Median time from injury to lawsuit resolution was 3.8 years [interquartile range (IQR), 3–5 years]. Verdicts were ruled in favor of the defense in eight (38.1%) cases and for plaintiff in six (28.6%) cases. A settlement was made in seven (33.3%) cases. Median payout for plaintiff-won cases was $5,100,000 (IQR, $1,530,000–$17,500,000); the median settlement was $2,500,000 (IQR, $262,500–$4,410,000).

Conclusions:

Procedural error, improper informed consent, improper trainee supervision, and resident inexperience were the most common allegations. These factors can lead to financial and psychological burdens early in a physician’s career.