bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunosuppression after Kidney Transplantation
Authors: Cherukuri Aravind , Baker Richard J.
Published: June 2024

Immunosuppression remains the cornerstone of medical management in kidney transplantation. Progress in the field of therapeutic immunosuppression has been the key to successful kidney transplantation and long-term allograft survival. Induction immunosuppression refers to the intense immunosuppression used in the initial days post-transplantation to circumvent early acute rejection, while maintenance immunosuppression is the lower intensity immunosuppression used for the life of the transplant to maintain allograft function and prevent rejection as the graft becomes less immunogenic. These agents are also used to reverse established rejection. The chapter highlights the immunological pathways that cause allograft rejection and how immunosuppressive agents block these pathways with the intent of reducing the incidence of rejection. It summarizes the mechanisms of action and adverse effects of commonly used agents and the immunosuppression strategies applicable to routine clinical management for certain high-risk patients.
Cancers after Kidney Transplantation
Authors: Saleem Nida , Wong Germaine , Chapman Jeremy
Published: June 2024

Cancer, infections, and cardiovascular diseases (CVDs) are known to be the mortality-defining outcomes after kidney transplants. However, there has been marked improvement in medical management and preventive strategies, resulting in a decline in infectious and CVD complications. CVD and post-transplant infections are discussed in chapters 8 and 9. There has been a progressive rise in cancer incidence after transplant, owing to improved post-transplant survival and the longer-term adverse effects of immunosuppression. In Australia and worldwide, cancer is one of the common causes of death in kidney transplant recipients. Kidney transplant patients consider cancer the most feared outcome because cancer impacts survival and the quality of life. This chapter discusses cancer epidemiology, risk factors, pathogenesis, surveillance, and management strategies in kidney transplant recipients.
Long-term Care of Kidney Transplant Patients—Conclusion
Authors: Rabb Hamid
Published: June 2024

The Conclusion summarizes all chapters of the book, highlighting the progression in the field of organ transplantation over seventy years and the importance of various immunological and nonimmunological events impacting kidney transplantation. Key highlights include: wellness after kidney transplantation, which covers important elements such as immunization, parenthood, travel and return to work for transplant recipients; acute and chronic active T-cell-mediated and antibody-mediated rejection, cardiovascular diseases, infections, cancers, and recurrent diseases, and pathways toward transplant tolerance; potential advances such as wearable kidney, implantable bioartificial kidney, and generating nephrons, which could potentially impact the management of patients with end-stage kidney disease; and pathways such as donor bone marrow transplantation, cell based and nanoparticle-based therapies potentially leading to transplant tolerance. The breadth and depth of information provided through this book will make it a desk reference for all those who are caring for kidney transplant patients across the globe.
9
Authors: Cohen Lewis
Published: June 2024

This chapter begins with an exploration of factors that can lead to an increased risk of dementia. These include hearing impairment, disturbed sleep, and behaviors that contribute to poor vascular health. Hearing impairment is cited as being the single most important modifiable risk factor: moderate hearing loss triples the risk, and people with a severe hearing impairment are five times more likely to develop a dementia. Genetic factors (particularly the APOE gene) are likewise explored, as is the question of why Dan believed that he would eventually receive a dementia diagnosis, just as his father did. New drugs that are available for the treatment of dementia (including those that have been rejected) are also addressed.
Fusarium species,Scedosporium species, and Lomentospora prolificans: A systematic review to inform the World Health Organization priority list of fungal pathogens
Authors: Marinelli Tina , Kim Hannah Yejin , Halliday Catriona L , Garnham Katherine , Bupha-Intr Olivia , Dao Aiken , Morris Arthur J , Alastruey-Izquierdo Ana , Colombo Arnaldo , Rickerts Volker , Perfect John , Denning David W , Nucci Marcio , Hamers Raph L , Cassini Alessandro , Oladele Rita , Sorrell Tania C , Ramon-Pardo Pilar , Fusire Terence , Chiller Tom M , Wahyuningsih Retno , Forastiero Agustina , Al-Nuseirat Adi , Beyer Peter , Gigante Valeria , Beardsley Justin , Sati Hatim , Alffenaar Jan-Willem , Morrissey C Orla
Published: June 2024

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of infections caused by Fusarium spp., Scedosporium spp., and Lomentospora prolificans to inform the first FPPL. PubMed and Web of Sciences databases were searched to identify studies published between January 1, 2011 and February 23, 2021, reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 20, 11, and 9 articles were included for Fusarium spp., Scedosporium spp., and L. prolificans, respectively. Mortality rates were high in those with invasive fusariosis, scedosporiosis, and lomentosporiosis (42.9%–66.7%, 42.4%–46.9%, and 50.0%–71.4%, respectively). Antifungal susceptibility data, based on small isolate numbers, showed high minimum inhibitory concentrations (MIC)/minimum effective concentrations for most currently available antifungal agents. The median/mode MIC for itraconazole and isavuconazole were ≥16 mg/l for all three pathogens. Based on limited data, these fungi are emerging. Invasive fusariosis increased from 0.08 cases/100 000 admissions to 0.22 cases/100 000 admissions over the time periods of 2000–2009 and 2010–2015, respectively, and in lung transplant recipients, Scedosporium spp. and L. prolificans were only detected from 2014 onwards. Global surveillance to better delineate antifungal susceptibility, risk factors, sequelae, and outcomes is required.
Aspergillus fumigatus—a systematic review to inform the World Health Organization priority list of fungal pathogens
Authors: Morrissey C Orla , Kim Hannah Y , Duong Tra-My N , Moran Eric , Alastruey-Izquierdo Ana , Denning David W , Perfect John R , Nucci Marcio , Chakrabarti Arunaloke , Rickerts Volker , Chiller Tom M , Wahyuningsih Retno , Hamers Raph L , Cassini Alessandro , Gigante Valeria , Sati Hatim , Alffenaar Jan-Willem , Beardsley Justin
Published: June 2024

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of invasive infections caused by Aspergillus fumigatus to inform the first FPPL. The pre-specified criteria of mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence were used to search for relevant articles between 1 January 2016 and 10 June 2021. Overall, 49 studies were eligible for inclusion. Azole antifungal susceptibility varied according to geographical regions. Voriconazole susceptibility rates of 22.2% were reported from the Netherlands, whereas in Brazil, Korea, India, China, and the UK, voriconazole susceptibility rates were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively. Cross-resistance was common with 85%, 92.8%, and 100% of voriconazole-resistant A. fumigatus isolates also resistant to itraconazole, posaconazole, and isavuconazole, respectively. The incidence of invasive aspergillosis (IA) in patients with acute leukemia was estimated at 5.84/100 patients. Six-week mortality rates in IA cases ranged from 31% to 36%. Azole resistance and hematological malignancy were poor prognostic factors. Twelve-week mortality rates were significantly higher in voriconazole-resistant than in voriconazole-susceptible IA cases (12/22 [54.5%] vs. 27/88 [30.7%]; P = .035), and hematology patients with IA had significantly higher mortality rates compared with solid-malignancy cases who had IA (65/217 [30%] vs. 14/78 [18%]; P = .04). Carefully designed surveillance studies linking laboratory and clinical data are required to better inform future FPPL.
Mucorales: A systematic review to inform the World Health Organization priority list of fungal pathogens
Authors: Morrissey C Orla , Kim Hannah Yejin , Garnham Katherine , Dao Aiken , Chakrabarti Arunaloke , Perfect John R , Alastruey-Izquierdo Ana , Harrison Thomas S , Bongomin Felix , Galas Marcelo , Siswanto Siswanto , Dagne Daniel Argaw , Roitberg Felipe , Gigante Valeria , Sati Hatim , Alffenaar Jan-Willem , Beardsley Justin
Published: June 2024

The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list (FPPL). This systematic review aimed to evaluate the epidemiology and impact of invasive fungal disease due to Mucorales. PubMed and Web of Science were searched to identify studies published between January 1, 2011 and February 23, 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 24 studies were included. Mortality rates of up to 80% were reported. Antifungal susceptibility varied across agents and species, with the minimum inhibitory concentrations lowest for amphotericin B and posaconazole. Diabetes mellitus was a common risk factor, detected in 65%–85% of patients with mucormycosis, particularly in those with rhino-orbital disease (86.9%). Break-through infection was detected in 13.6%–100% on azole or echinocandin antifungal prophylaxis. The reported prevalence rates were variable, with some studies reporting stable rates in the USA of 0.094–0.117/10 000 discharges between 2011 and 2014, whereas others reported an increase in Iran from 16.8% to 24% between 2011 and 2015. Carefully designed global surveillance studies, linking laboratory and clinical data, are required to develop clinical breakpoints to guide antifungal therapy and determine accurate estimates of complications and sequelae, annual incidence, trends, and global distribution. These data will provide robust estimates of disease burden to refine interventions and better inform future FPPL.
Candida parapsilosis: A systematic review to inform the World Health Organization fungal priority pathogens list
Authors: Asogan Mrudhula , Kim Hannah Yejin , Kidd Sarah , Alastruey-Izquierdo Ana , Govender Nelesh P , Dao Aiken , Shin Jong-Hee , Heim Jutta , Ford Nathan Paul , Gigante Valeria , Sati Hatim , Morrissey C Orla , Alffenaar Jan-Willem , Beardsley Justin
Published: June 2024

Candida parapsilosis is globally distributed and recognised for causing an increasing proportion of invasive Candida infections. It is associated with high crude mortality in all age groups. It has been particularly associated with nosocomial outbreaks, particularly in association with the use of invasive medical devices such as central venous catheters. Candida parapsilosis is one of the pathogens considered in the WHO priority pathogens list, and this review was conducted to inform the ranking of the pathogen in the list. In this systematic review, we searched PubMed and Web of Science to find studies between 2011 and 2021 reporting on the following criteria for C. parapsilosis infections: mortality, morbidity (hospitalisation and disability), drug resistance, preventability, yearly incidence, and distribution/emergence. We identified 336 potentially relevant papers, of which 51 were included in the analyses. The included studies confirmed high mortality rates, ranging from 17.5% to 46.8%. Data on disability and sequelae were sparse. Many reports highlighted concerns with azole resistance, with resistance rates of >10% described in some regions. Annual incidence rates were relatively poorly described, although there was clear evidence that the proportion of candidaemia cases caused by C. parapsilosis increased over time. While this review summarises current data on C.parapsilosis, there remains an urgent need for ongoing research and surveillance to fully understand and manage this increasingly important pathogen.
Histoplasmosis: A systematic review to inform the World Health Organization of a fungal priority pathogens list
Authors: Dao Aiken , Kim Hannah Yejin , Halliday Catriona L , Oladele Rita , Rickerts Volker , Govender MMed Nelesh P , Shin Jong-Hee , Heim Jutta , Ford Nathan Paul , Nahrgang Saskia Andrea , Gigante Valeria , Beardsley Justin , Sati Hatim , Morrissey C Orla , Alffenaar Jan-Willem , Alastruey-Izquierdo Ana
Published: June 2024

Histoplasmosis, a significant mycosis primarily prevalent in Africa, North and South America, with emerging reports globally, poses notable health challenges, particularly in immunocompromised individuals such as people living with HIV/AIDS and organ transplant recipients. This systematic review, aimed at informing the World Health Organization’s Fungal Priority Pathogens List, critically examines literature from 2011 to 2021 using PubMed and Web of Science, focusing on the incidence, mortality, morbidity, antifungal resistance, preventability, and distribution of Histoplasma. We also found a high prevalence (22%–44%) in people living with HIV, with mortality rates ranging from 21% to 53%. Despite limited data, the prevalence of histoplasmosis seems stable, with lower estimates in Europe. Complications such as central nervous system disease, pulmonary issues, and lymphoedema due to granuloma or sclerosis are noted, though their burden remains uncertain. Antifungal susceptibility varies, particularly against fluconazole (MIC: ≥32 mg/l) and caspofungin (MICs: 4–32 mg/l), while resistance to amphotericin B (MIC: 0.125–0.16 mg/l), itraconazole (MICs: 0.004–0.125 mg/l), and voriconazole (MICs: 0.004–0.125 mg/l) remains low. This review identifies critical knowledge gaps, underlining the need for robust, globally representative surveillance systems to better understand and combat this fungal threat.
Eumycetoma causative agents: A systematic review to inform the World Health Organization priority list of fungal pathogens
Authors: Clark Julia E , Kim Hannah Yejin , van de Sande Wendy W J , McMullan Brendan , Verweij Paul , Alastruey-Izquierdo Ana , Chakrabarti Arunaloke , Harrison Thomas S , Bongomin Felix , Hay Roderick J , Oladele Rita , Heim Jutta , Beyer Peter , Galas Marcelo , Siswanto Siswanto , Dagne Daniel Argaw , Roitberg Felipe , Gigante Valeria , Beardsley Justin , Sati Hatim , Alffenaar Jan-Willem , Morrissey C Orla
Published: June 2024

The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list. This systematic review aimed to evaluate the epidemiology and impact of eumycetoma. PubMed and Web of Science were searched to identify studies published between 1 January 2011 and 19 February 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 14 studies were eligible for inclusion. Morbidity was frequent with moderate to severe impairment of quality of life in 60.3%, amputation in up to 38.5%, and recurrent or long-term disease in 31.8%–73.5% of patients. Potential risk factors included male gender (56.6%–79.6%), younger age (11–30 years; 64%), and farming occupation (62.1%–69.7%). Mycetoma was predominantly reported in Sudan, particularly in central Sudan (37%–76.6% of cases). An annual incidence of 0.1/100 000 persons and 0.32/100  000 persons/decade was reported in the Philippines and Uganda, respectively. In Uganda, a decline in incidence from 3.37 to 0.32/100  000 persons between two consecutive 10-year periods (2000–2009 and 2010–2019) was detected. A community-based, multi-pronged prevention programme was associated with a reduction in amputation rates from 62.8% to 11.9%. With the pre-specified criteria, no studies of antifungal drug susceptibility, mortality, and hospital lengths of stay were identified. Future research should include larger cohort studies, greater drug susceptibility testing, and global surveillance to develop evidence-based treatment guidelines and to determine more accurately the incidence and trends over time.
Testing the near-far connection with FIRE simulations: inferring the stellar mass function of the proto-Local Group at z > 6 using the fossil record of present-day galaxies
Authors: Gandhi Pratik J , Wetzel Andrew , Boylan-Kolchin Michael , Sanderson Robyn E , Savino Alessandro , Weisz Daniel R , Tollerud Erik J , Sun Guochao , Faucher-Giguère Claude-André
Published: June 2024

The shape of the low-mass (faint) end of the galaxy stellar mass function (SMF) or ultraviolet luminosity function (UVLF) at $z \gtrsim 6$ is an open question for understanding which galaxies primarily drove cosmic reionization. Resolved photometry of Local Group low-mass galaxies allows us to reconstruct their star formation histories, stellar masses, and UV luminosities at early times, and this fossil record provides a powerful ‘near-far’ technique for studying the reionization-era SMF/UVLF, probing orders of magnitude lower in mass than direct HST/JWST observations. Using 882 low-mass ($M_{\rm star}\lesssim 10^{9}\, \rm {M_\odot }$) galaxies across 11 Milky Way (MW)- and Local Group-analogue environments from the FIRE-2 cosmological baryonic zoom-in simulations, we characterize their progenitors at $z=6\!-\!9$, the mergers/disruption of those progenitors over time, and how well their present-day fossil record traces the high-redshift SMF. A present-day galaxy with $M_{\rm star}\sim 10^5\, \rm {M_\odot }$ ($\sim 10^9\, \rm {M_\odot }$) had $\approx 1$ ($\approx 30$) progenitors at $z\approx 7$, and its main progenitor comprised $\approx 100~{{\ \rm per\ cent}}$ ($\approx 10~{{\ \rm per\ cent}}$) of the total stellar mass of all its progenitors at $z\approx 7$. We show that although only $\sim 15~{{\ \rm per\ cent}}$ of the early population of low-mass galaxies survives to present day, the fossil record of surviving Local Group galaxies accurately traces the low-mass slope of the SMF at $z \sim 6 \!-\! 9$. We find no obvious mass dependence to the mergers and accretion, and show that applying this reconstruction technique to just low-mass galaxies at $z = 0$ and not the MW/M31 hosts correctly recovers the slope of the SMF down to $M_{\rm star} \sim 10^{4.5}\, \rm {{\rm M}_{\odot }}$ at $z \gtrsim 6$. Thus, we validate the ‘near-far’ approach as an unbiased tool for probing low-mass reionization-era galaxies.
Measuring the substructure mass power spectrum of 23 SLACS strong galaxy–galaxy lenses with convolutional neural networks
Authors: Fagin Joshua , Vernardos Georgios , Tsagkatakis Grigorios , Pantazis Yannis , Shajib Anowar J , O’Dowd Matthew
Published: June 2024

Strong gravitational lensing can be used as a tool for constraining the substructure in the mass distribution of galaxies. In this study we investigate the power spectrum of dark matter perturbations in a population of 23 Hubble Space Telescope images of strong galaxy–galaxy lenses selected from The Sloan Lens ACS (SLACS) survey. We model the dark matter substructure as a Gaussian random field perturbation on a smooth lens mass potential, characterized by power-law statistics. We expand upon the previously developed machine learning framework to predict the power-law statistics by using a convolutional neural network (CNN) that accounts for both epistemic and aleatoric uncertainties. For the training sets, we use the smooth lens mass potentials and reconstructed source galaxies that have been previously modelled through traditional fits of analytical and shapelet profiles as a starting point. We train three CNNs with different training set: the first using standard data augmentation on the best-fitting reconstructed sources, the second using different reconstructed sources spaced throughout the posterior distribution, and the third using a combination of the two data sets. We apply the trained CNNs to the SLACS data and find agreement in their predictions. Our results suggest a significant substructure perturbation favouring a high frequency power spectrum across our lens population.
Systematic comparison of neural networks used in discovering strong gravitational lenses
Authors: More Anupreeta , Cañameras Raoul , Jaelani Anton T , Shu Yiping , Ishida Yuichiro , Wong Kenneth C , Inoue Kaiki Taro , Schuldt Stefan , Sonnenfeld Alessandro
Published: June 2024

Efficient algorithms are being developed to search for strong gravitational lens systems owing to increasing large imaging surveys. Neural networks have been successfully used to discover galaxy-scale lens systems in imaging surveys such as the Kilo Degree Survey, Hyper-Suprime Cam (HSC) Survey, and Dark Energy Survey over the last few years. Thus, it has become imperative to understand how some of these networks compare, their strengths and the role of the training data sets which are essential in supervised learning algorithms used commonly in neural networks. In this work, we present the first-of-its-kind systematic comparison and benchmarking of networks from four teams that have analysed the HSC Survey data. Each team has designed their training samples and developed neural networks independently but coordinated a priori in reserving specific data sets strictly for test purposes. The test sample consists of mock lenses, real (candidate) lenses, and real non-lenses gathered from various sources to benchmark and characterize the performance of each of the network. While each team’s network performed much better on their own constructed test samples compared to those from others, all networks performed comparable on the test sample with real (candidate) lenses and non-lenses. We also investigate the impact of swapping the training samples among the teams while retaining the same network architecture. We find that this resulted in improved performance for some networks. These results have direct implications on measures to be taken for lens searches with upcoming imaging surveys such as the Rubin-Legacy Survey of Space and Time, Roman, and Euclid.
ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer
Authors: Qian Chen , Yang Qian , Rotinen Mirja , Huang Rongrong , Kim Hyoyoung , Gallent Brad , Yan Yiwu , Cadaneanu Radu M , Zhang Baohui , Kaochar Salma , Freedland Stephen J , Posadas Edwin M , Ellis Leigh , Di Vizio Dolores , Morrissey Colm , Nelson Peter S , Brady Lauren , Murali Ramachandran , Campbell Moray J , Yang Wei , Knudsen Beatrice S , Mostaghel Elahe A , Ye Huihui , Garraway Isla P , You Sungyong , Freeman Michael R
Published: June 2024

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.
Functional analysis of protein interactions using coupled bi-fluorescence complementation/GFP nanobody techniques
Authors: Miyake Tetsuaki , McDermott John C
Published: June 2024

Transcription factors (TFs) form homo- or hetero-dimeric DNA binding complexes along with associated co-regulators that can have transcriptional repressor or activator functions. Defining the specific composition of the complexes is therefore key to understanding their biological role. Here, we utilized bimolecular fluorescence complementation (BiFC) to visualize the formation of defined TF dimers and associated co-regulators derived from the activator protein-1 (AP-1) and myocyte enhancer factor 2 (MEF2) families. Firstly, BiFC signals were observed in cells co-expressing TFs tagged with complimentary combinations of the split fluorescent protein, demonstrating the engineered formation of defined dimer complexes. Next, we applied this approach and determined that defined AP-1 dimers localized at discrete sub-nuclear locations. Subsequently, a combination of BiFC coupled with GFP binding peptide (GBP)-nanotrap allowed observation of protein-protein interactions between a co-regulator, HDAC4, and defined BiFC-MEF2 engineered dimers. To determine transactivation properties of defined TF dimers in a cellular system, the Gal4-DNA binding domain fused to GBP was utilized to assess the transcriptional properties of the BiFC-TF dimers using a generically applicable Gal4/UAS luciferase reporter gene assay system. Here, we report efficacy of a BiFC/GBP-nanobody approach that allows engineering, visualization, and functional analysis of defined TF dimers.
Swarming caddisflies in the mid-cretaceous
Authors: Wang Jiajia , Engel Michael S , Zhang Weiting , Shih Chungkun , Qiu Rui , Ren Dong
Published: June 2024

Swarming, as a special form of mating aggregation, is most noteworthy in insects of the orders Ephemeroptera, Diptera, and Trichoptera. Swarming in extant trichopterans is well understood in terms of sex composition, specific mating behaviors, and functional morphological specializations of adults, but an exploration of the evolution of such aggregative behaviors is hampered by the dearth of available examples from the fossil record as well as the ability to reliably distinguish the few gatherings as the result of swarming relative to other taphonomic or behavioral factors. Herein we describe five new fossil species of caddisflies preserved in mid-Cretaceous amber from Myanmar, all preserved as large aggregations. Monospecific aggregations of these five new species can be positively identified as swarms based on morphological traits of wing shape, as well as the presence of particular forms of sexual dimorphism. Results of a phylogenetic reconstruction of both molecular and morphological data as well as ancestral-trait reconstructions and tip-dating analyses indicate that swarming was likely present in the Triassic as a feature of the trichopteran groundplan. Since most Mesozoic insectivorous predators were diurnal based on morphological evidence, largely nocturnal caddisflies would have been freed from such pressures. The phylogeny also shows a correlation between the rise of nocturnal bat predators from the Paleocene or early Eocene and the repeated loss of swarming from various clades of caddisflies, revealing the potential impact of bat predation on reshaping the behavioral landscape of Trichoptera during the Cenozoic.
“Keep it a secret”: Leaked Documents Suggest Philip Morris International, and Its Japanese Affiliate, Continue to Exploit Science for Profit
Authors: Braznell Sophie , Laurence Louis , Fitzpatrick Iona , Gilmore Anna B
Published: June 2024

Introduction

The tobacco industry has a long history of manipulating science to conceal the harms of its products. As part of its proclaimed transformation, the world’s largest tobacco company, Philip Morris International (PMI), states it conducts “transparent science.” This paper uses recently leaked documents from PMI and its Japanese affiliate, Philip Morris Japan (PMJ), to examine its contemporary scientific practices.

Aims and Methods

Twenty-four documents dating 2012 through 2020 available from the Truth Tobacco Industry Documents Library were examined using Forster’s hermeneutic approach to analyzing corporate documentation. Thematic analysis using the Science for Profit Model was conducted to assess whether PMI and PMJ employed known corporate strategies to influence science in their interests.

Results

PMJ contracted third-party external research organization, CMIC, to covertly fund a study on smoking cessation conducted by Kyoto University academics. No public record of PMJ’s funding or involvement in this study was found. PMJ paid life sciences consultancy, FTI-Innovations, ¥3 000 000 (approx. £20 000) a month between 2014 and 2019 to undertake extensive science-adjacent work, including building relationships with key scientific opinion leaders and using academic events to promote PMI’s science, products and messaging. FTI-Innovation’s work was hidden internally and externally. These activities resemble known strategies to influence the conduct, publication and reach of science, and conceal scientific activities.

Conclusions

The documents reveal PMI and PMJ’s recent activities mirror past practices to manipulate science, undermining PMI’s proclaimed transformation. Tobacco industry scientific practices remain a threat to public health, highlighting the urgent need for reform to protect science from the tobacco industry’s vested interests.

Implications

Japan is a key market for PMI, being a launch market for IQOS and having the highest heated tobacco product use globally. Our findings, in conjunction with other recent evidence, challenge PMI’s assertion that it is a source of credible science and cast doubt on the quality and ethical defensibility of its research, especially its studies conducted in Japan. This, in turn, brings into question the true public health impacts of its products. There is an urgent need to reform the way tobacco-related science is funded and conducted. Implementation of models through which research can be funded using the industry’s profits while minimizing its influence should be explored.
The nature and magnitude of cognitive impairment in narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia: a meta-analysis
Authors: Harel Brian T , Gattuso James J , Latzman Robert D , Maruff Paul , Scammell Thomas E , Plazzi Giuseppe
Published: June 2024

People with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH) often report cognitive impairment which can be quite burdensome but is rarely evaluated in routine clinical practice. In this systematic review and meta-analysis, we assessed the nature and magnitude of cognitive impairment in NT1, NT2, and IH in studies conducted from January 2000 to October 2022. We classified cognitive tests assessing memory, executive function, and attention by cognitive domain. Between-group differences were analyzed as standardized mean differences (Cohen’s d), and Cohen’s d for individual tests were integrated according to cognitive domain and clinical disease group. Eighty-seven studies were screened for inclusion; 39 satisfied inclusion criteria, yielding 73 comparisons (k): NT1, k = 60; NT2, k = 8; IH, k = 5. Attention showed large impairment in people with NT1 (d = −0.90) and IH (d = −0.97), and moderate impairment in NT2 (d = −0.60). Executive function was moderately impaired in NT1 (d = −0.30) and NT2 (d = −0.38), and memory showed small impairments in NT1 (d = −0.33). A secondary meta-analysis identified sustained attention as the most impaired domain in NT1, NT2, and IH (d ≈ −0.5 to −1). These meta-analyses confirm that cognitive impairments are present in NT1, NT2, and IH, and provide quantitative confirmation of reports of cognitive difficulties made by patients and clinicians. These findings provide a basis for the future design of studies to determine whether cognitive impairments can improve with pharmacologic and nonpharmacologic treatments for narcolepsy and IH.
Quality and Patient Safety Metrics: Developing a Structured Program for Improving Patient Care in the Department of Medicine at The Ottawa Hospital
Authors: Hasimja-Saraqini Delvina , McNeill Kylie , Kuk Hanna , Forster Alan J. , Wells Philip S. , Hamilton Samantha , Gannon Ed , Mielniczuk Lisa M.
Published: June 2024

Problem

Despite increasing recognition of the importance of quality and patient safety in academic medicine, challenges remain with ensuring physician participation in quality assurance and quality improvement efforts, such as lack of compensation and enabling resources. An organizational culture that includes physician leadership and a supportive infrastructure is needed to encourage physician backing of quality and patient safety initiatives.

Approach

The authors describe the development of a robust quality and patient safety program in the Department of Medicine at The Ottawa Hospital over the past 7 years and highlight how the department changed its organizational culture by prioritizing quality and patient safety and establishing the necessary infrastructure to support this program. Program development was characterized by 4 overarching themes: incentives, administrative structure and physician leadership, training and support, and system enhancements.

Outcomes

As a result of the program, the department broadly implemented a standardized framework for conducting quality committee meetings and morbidity and mortality rounds and reviewing patient safety incidents and patient experience across its 16 divisions. This has led to 100% departmental compliance on corporate quality assurance metrics each year (e.g., regular multidisciplinary divisional quality committee meetings), along with physician participation in formal quality improvement initiatives that align with larger corporate goals.

Next Steps

The authors reflect on lessons learned during the implementation of the program and the essential elements that contributed to its success. Next steps for the program include using a centralized repository of quality and patient safety data, including patient safety incident dashboards, to encourage greater divisional collaboration on quality improvement initiatives and continuous institutional learning over time. Another important avenue will be to create an academic hub for excellence in quality and a formal approach to reward and promote physicians for their quality work.
Bias in Observed Assessments in Medical Education: A Scoping Review
Authors: Ismaeel Romaisa , Pusic Luka , Gottlieb Michael , Chan Teresa M. , Oyedokun Taofiq O. , Thoma Brent
Published: June 2024

Purpose

Observed assessments are integral to medical education but may be biased against structurally marginalized communities. Current understanding of assessment bias is limited because studies have focused on single specialties, levels of training, or social identity characteristics (SIDCs). This scoping review maps studies investigating bias in observed assessments in medical education arising from trainees’ observable SIDCs at different medical training levels, with consideration of medical specialties, assessment environments, and assessment tools.

Method

MEDLINE, Embase, ERIC, PsycINFO, Scopus, Web of Science Core Collection, and Cochrane Library were searched for articles published between January 1, 2008, and March 15, 2023, on assessment bias related to 6 observable SIDCs: gender (binary), gender nonconformance, race and ethnicity, religious expression, visible disability, and age. Two authors reviewed the articles, with conflicts resolved by consensus or a third reviewer. Results were interpreted through group review and informed by consultation with experts and stakeholders.

Results

Sixty-six of 2,920 articles (2.3%) were included. These studies most frequently investigated graduate medical education [44 (66.7%)], used quantitative methods [52 (78.8%)], and explored gender bias [63 (95.5%)]. No studies investigated gender nonconformance, religious expression, or visible disability. One evaluated intersectionality. SIDCs were described inconsistently. General surgery [16 (24.2%)] and internal medicine [12 (18.2%)] were the most studied specialties. Simulated environments [37 (56.0%)] were studied more frequently than clinical environments [29 (43.9%)]. Bias favoring men was found more in assessments of intraoperative autonomy [5 of 9 (55.6%)], whereas clinical examination bias often favored women [15 of 19 (78.9%)]. When race and ethnicity bias was identified, it consistently favored White students.

Conclusions

This review mapped studies of gender, race, and ethnicity bias in the medical education assessment literature, finding limited studies on other SIDCs and intersectionality. These findings will guide future research by highlighting the importance of consistent terminology, unexplored SIDCs, and intersectionality.
Special Supplemental Nutrition Program for Women, Infants, and Children Enrollment and Adverse Pregnancy Outcomes Among Nulliparous Individuals
Authors: Venkatesh Kartik K. , Huang Xiaoning , Cameron Natalie A. , Petito Lucia C. , Garner Jennifer , Headings Amy , Hanks Andrew S. , Grobman William A. , Khan Sadiya S.
Published: June 2024

OBJECTIVE:

To evaluate the relationship between changes in Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) enrollment during pregnancy from 2016 to 2019 and rates of adverse pregnancy outcomes in U.S. counties in 2019.

METHODS:

We conducted a serial, cross-sectional ecologic study at the county level using National Center for Health Statistics natality data from 2016 to 2019 of nulliparous individuals eligible for WIC. The exposure was the change in county-level WIC enrollment from 2016 to 2019 (increase [more than 0%] vs no change or decrease [0% or less]). Outcomes were adverse pregnancy outcomes assessed in 2019 and included maternal outcomes (ie, gestational diabetes mellitus [GDM], hypertensive disorders of pregnancy, cesarean delivery, intensive care unit [ICU] admission, and transfusion) and neonatal outcomes (ie, large for gestational age [LGA], small for gestational age [SGA], preterm birth, and neonatal intensive care unit [NICU] admission).

RESULTS:

Among 1,945,914 deliveries from 3,120 U.S. counties, the age-standardized rate of WIC enrollment decreased from 73.1 (95% CI, 73.0–73.2) per 100 live births in 2016 to 66.1 (95% CI, 66.0–66.2) per 100 live births in 2019, for a mean annual percent change decrease of 3.2% (95% CI, −3.7% to −2.9%) per year. Compared with individuals in counties in which WIC enrollment decreased or did not change, individuals living in counties in which WIC enrollment increased had lower rates of maternal adverse pregnancy outcomes, including GDM (adjusted odds ratio [aOR] 0.71, 95% CI, 0.57–0.89), ICU admission (aOR 0.47, 95% CI, 0.34–0.65), and transfusion (aOR 0.68, 95% CI, 0.53–0.88), and neonatal adverse pregnancy outcomes, including preterm birth (aOR 0.71, 95% CI, 0.56–0.90) and NICU admission (aOR 0.77, 95% CI, 0.60–0.97), but not cesarean delivery, hypertensive disorders of pregnancy, or LGA or SGA birth.

CONCLUSION:

Increasing WIC enrollment during pregnancy at the county level was associated with a lower risk of adverse pregnancy outcomes. In an era when WIC enrollment has decreased and food and nutrition insecurity has increased, efforts are needed to increase WIC enrollment among eligible individuals in pregnancy.
Impact of Early Depressive Burden on Patient-Reported Outcomes Following Minimally Invasive Transforaminal Lumbar Interbody Fusion
Authors: Wolf Jacob C. , Anwar Fatima N. , Roca Andrea M. , Loya Alexandra C. , Medakkar Srinath S. , Kaul Aayush , Khosla Ishan , Hartman Timothy J. , Nie James W. , MacGregor Keith R. , Oyetayo Omolabake O. , Zheng Eileen , Federico Vincent P. , Sayari Arash J. , Lopez Gregory D. , Singh Kern
Published: June 2024

Study Design:

Retrospective review.

Objective:

To evaluate mental health influence on minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) patients.

Summary of Background Data:

Poor mental health has been postulated to indicate inferior patient perceptions of surgical outcomes in spine literature. Few studies have assessed mental health as a dynamic metric throughout the perioperative period.

Methods:

A single-surgeon database was retrospectively searched for patients who underwent primary, elective MIS-TLIF for degenerative or isthmic spondylolisthesis. Summative depressive burden (SDB) was defined by the sum of preoperative and 6-week postoperative 9-item Patient Health Questionnaire (PHQ-9), with Lesser Burden (LB, SDB<10) and Greater Burden (GB, SDB≥10) cohorts. Patient-reported outcomes measures (PROMs) were compared preoperatively, at 6 weeks, and at final postoperative follow-up (11.4±10.9 mo), using Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF), Oswestry disability index (ODI), visual analog scale-back (VAS-B), VAS-leg (VAS-L), and PHQ-9. Improvements at 6-week (∆PROM-6W), final follow-up (∆PROM-FF), and minimum clinically important difference (MCID) achievement were compared.

Results:

The GB cohort consisted of 44 of 105 patients. Demographic variations included older age, higher Charlson comorbidity index, increased hypertension prevalence, and private insurance in the LB cohort (P≤0.018). The LB cohort demonstrated better baseline and 6-week PROMIS-PF/ODI/VAS-L (P≤0.032) and better final PROMIS-PF/ODI/VAS-L/PHQ-9 (P≤0.031). Both cohorts improved in all PROMs at 6 weeks and final follow-up (P≤0.029), except for PROMIS-PF at 6 weeks in the GB cohort. ∆PROM-6W, ∆PROM-FF, and MCID achievement rate for PHQ-9 were greater in the GB cohort (P≤0.001).

Conclusion:

On average, patients undergoing MIS-TLIF for degenerative or isthmic spondylolisthesis improved in all PROMs by final follow-up. Patients with GB suffered inferior perceptions of physical function, disability, and leg pain. MCID rates in mental health were higher for GB cohort. Surgeons are encouraged to adopt a compassionate understanding of depressive burden and educate the patient on possible consequential postoperative outcomes.
The Best Second Arterial Conduit for Coronary Artery Bypass Grafting: A Meta-Analysis of Reconstructed Individual Patient Data
Authors: Al-Tawil Mohammed , Alqeeq Basel F. , Jaffar-Karballai Mona , Khalefa Basma B. , Ayyad Mohammed , AlBandak Maram , AboAbdo Mohammed , Sabry Haytham , Harky Amer , Haneya Assad
Published: June 2024

Multiple arterial conduit revascularization in coronary bypass surgery is being advocated over the use of venous conduits. However, there is a critical gap regarding the optimal sequence of arterial conduit selection following the left internal thoracic artery. This study is the first individual patient data meta-analysis, which aimed to compare the right internal thoracic artery (RITA) versus the radial artery (RA) as a second-best arterial conduit. A comprehensive literature search was conducted in MEDLINE, Embase, Scopus, and CENTRAL. A forward-backward citation check was performed to identify other relevant studies. The study protocol was registered in the PROSPERO (CRD42023455543). Eligible studies included randomized controlled trials and propensity-score-matched cohort studies reporting long-term outcomes (>3 years) after coronary bypass surgery using the RITA versus RA as the second arterial conduit after left internal thoracic artery. Overall, long-term survival between the RITA and RA groups showed no significant difference. Landmark analyses demonstrated the superiority of RITA as a second arterial conduit at 1 [hazard ratio (HR): 0.86 (95% CI, 0.75–0.99), P = 0.036], 2 [0.83 (95% CI, 0.72–0.96), P = 0.011], and 5 years [HR: 0.80 (95% CI, 0.68–0.95), P = 0.036] post-surgery. Freedom from major cardiovascular events was significantly higher using the RITA conduit [HR: 0.72 (95% CI, 0.59–0.89), P = 0.002]. This study supports the use of RITA, especially when used in a skeletonized in situ fashion, as a second choice following the left internal thoracic artery as it has the potential to enhance long-term survival and outcomes. Further research with standardized surgical techniques is warranted.
Ethylene Oxide Hemoglobin Adducts in Cord Blood and Offspring’s Size at Birth: The NewGeneris European Cohort Study
Authors: Harding Barbara N. , Agramunt Silvia , Pedersen Marie , Knudsen Lisbeth E. , Nielsen Jeanette K. S. , Wright John , Vafeiadi Marina , Merlo Domenico F. , Stayner Leslie , Kelly-Reif Kaitlin , Espinosa Ana , Bustamante Mariona , Gützkow Kristine Bjerve , Granum Berit , von Stedingk Hans , Rydberg Per , Alexander Jan , Törnqvist Margareta , Kogevinas Manolis
Published: June 2024

Background:

Prenatal ethylene oxide exposure may have adverse effects on fetal development. We examined the relationships between ethylene oxide hemoglobin (Hb) adduct levels and offspring’s size at birth in a prospective European mother–child study.

Methods:

This study included 1106 singletons from the NewGeneris project (2006–2010) with ethylene oxide Hb adducts measured in cord blood. We examined the relationships between adduct levels and offspring’s size at birth among all infants and separately among infants of nonsmokers, using linear regression models for birth weight and birth head circumference and logarithmic binomial regression models for small for gestational age. We examined potential interactions between CYP2E1 single nucleotide polymorphisms in cord blood and the effects of ethylene oxide Hb adduct levels on offspring birth size.

Results:

Higher quartiles of adduct levels as a measure of exposure were associated with decreasing birth weight and head circumference in the overall population. Compared to infants in the lowest quartile, those in the highest quartile exhibited lower birth weight (−70.73 g, 95% confidence interval = −141.16, −0.30) and reduced head circumference (−0.30 cm, 95% confidence interval = −0.58, −0.02). We observed similar, albeit less pronounced, patterns among infants of nonsmokers. There was no evidence of an association between ethylene oxide Hb adducts and risk of small for gestational age, nor consistent evidence of an interaction with CYP2E1 polymorphisms on the association between EO Hb adduct levels and offspring’s size at birth.

Conclusion:

Results suggest that higher ethylene oxide Hb adduct levels in cord blood are associated with a reduction in offspring birth size.
Treating Lows: Management of Orthostatic Hypotension
Authors: Kulkarni Spoorthy , Jenkins Danny , Dhar Arko , Mir Fraz
Published: June 2024

Orthostatic hypotension is a prevalent clinical condition, caused by heterogenous etiologies and associated with significant morbidity and mortality. Management is particularly challenging in patients with uncontrolled hypertension. A thorough assessment is needed to draw an appropriate management plan. The treatment aims to improve postural symptoms while minimizing side effects and reducing iatrogenic exacerbation of supine hypertension. A personalized management plan including rationalizing medications, patient education, identification, and avoidance of triggers, as well as nonpharmacological therapies such as compression devices, dietary modifications, and postural aids, make the first steps. Among pharmacological therapies, midodrine and fludrocortisone are the most prescribed and best studied; pyridostigmine, atomoxetine, and droxidopa are considered next. Yohimbine remains an investigational agent. A multidisciplinary team may be required in some patients with multiple comorbidities and polypharmacy. However, there is a lack of robust efficacy and safety evidence for all therapies. Building robust real-world and stratified clinical trials based on underlying pathophysiology may pave the way for further drug development and better clinical strategies and in this challenging unmet medical need.