bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of anatomical liver resection for hepatocellular carcinoma: a systematic review and meta-analysis
Authors: Shin Seong Wook , Kim Tae-Seok , Ahn Keun Soo , Kim Yong Hoon , Kang Koo Jeong
Published: May 2023

Background:

Despite retrospective studies comparing anatomical liver resection (AR) and nonanatomical liver resection (NAR), the efficacy and benefits of AR for hepatocellular carcinoma (HCC) remain unclear.

Materials and Methods:

We systemically reviewed MEDLINE, Embase, and Cochrane Library for propensity score matched (PSM) cohort studies that compared AR and NAR for HCC. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS). Secondary outcomes were recurrence patterns and perioperative outcomes.

Results:

Overall, 22 PSM studies (AR, n=2,496; NAR, n=2,590) were included. AR including systemic segmentectomy was superior to NAR regarding the 3- and 5-year OS. AR showed significantly better 1-, 3-, and 5-year RFS than NAR, with low local and multiple intrahepatic recurrence rates. In the subgroup analyses of tumor diameter ≤5 cm and tumors with microscopic spread, the RFS in the AR group was significantly better than that in the NAR group. Patients with cirrhotic liver in the AR group showed comparable 3- and 5-year RFS with the NAR group. Postoperativeoverall complications were comparable between AR and NAR.

Conclusions:

This meta-analysis demonstrated that AR showed better OS and RFS with a low local and multiple intra-hepatic recurrence rate than NAR, especially in patients with tumor diameter ≤5 cm and non-cirrhotic liver.
Safety and Outcomes of Outpatient Pleural Drainage in Symptomatic Postoperative Cardiac Surgery Patients
Authors: Gilbert Christopher R. , Meggyesy Austin M. , Bograd Adam J. , Chiu Shih Ting , Wilshire Candice L. , Gorden Jed A.
Published: May 2023

Background:

Symptomatic pleural effusions and anticoagulant/antiplatelet medication use in postoperative cardiac surgery are common. Guidelines and recommendations are currently mixed regarding medication management related to invasive procedure performance. We aimed to describe the outcomes of postoperative cardiac surgery patients referred for outpatient, symptomatic pleural effusion management.

Methods:

A retrospective study of post-cardiac surgery patients undergoing outpatient thoracentesis from 2016 to 2021 was performed. Demographics, operative details, pleural disease characteristics, outcomes, and complications were collected. Odds ratios with confidence intervals were estimated and adjusted by multivariate logistic regression to investigate the association with multiple thoracenteses.

Results:

A total of 110 patients underwent 332 thoracenteses. The median age was 68 years and most common operation was coronary artery bypass. Anticoagulation or antiplatelet use was identified in 97%. Thirteen complications were identified, with all major complications (n=3) related to bleeding. The amount of fluid present at the time of initial thoracentesis (>1500 milliliters) was associated with increased odds ratio of subsequent multiple thoracentesis (Unadjusted odds ratio, 6.75 (CI – 1.43 to 31.9). No other variables had a significant association with the need for multiple procedures.

Conclusion:

Within a postoperative cardiac surgery population presenting with symptomatic pleural disease, we observed that thoracentesis performed on antiplatelet and/or anticoagulant medication is relatively safe. We also identified that many patients can be managed as outpatients and that most pleural effusions remain self-limited. The presence of larger amounts of pleural fluid at initial thoracentesis may be associated with increased odds for additional drainage.
Efficacy of Urinary Kallidinogenase Plus Intravenous Recombinant Tissue Plasminogen Activator for Stroke Patients With Extended Window
Authors: Li Xueyuan , Zhang Xin , Yang Ying , Wang Hongzhi , Zhang Jingbo
Published: May 2023

Background:

To assess the outcome of human urinary kallidinogenase (HUK) plus recombinant tissue plasminogen activator (rT-PA) intravenous thrombolysis for stroke patients with an extended time window(4.5 to 9 h).

Methods:

A total of 92 acute ischemic stroke patients who fulfilled the criteria were included in this study. All patients received basic treatment and intravenous rT-PA, and 49 patients received additional injections of HUK (HUK group) once a day for 14 consecutive days. Outcomes were indicated by the thrombolysis in cerebral infarction score as the primary endpoint and the National Institute of Health Stroke Scale, modified Rankin Scale, and Barthel Index as the secondary endpoints. The safety outcomes were the rate of symptomatic intracranial hemorrhage, bleeding, angioedema, and mortality.

Results:

The National Institute of Health Stroke Scale scores were significantly lower in the HUK group at hospital discharge (4.55 ± 3.78 vs 7.88 ± 7.31, P = 0.009) and day 90 (4.04 ± 3.51 vs 8.12 ± 9.53, P = 0.011). The improvements in the Barthel Index scores were more obvious in the HUK group. Patients in the HUK group achieved favorable functional independence (67.35% vs 46.51%; odds ratio: 2.37; 95% CI: 1.01-5.53) at 90 days. The recanalization rate of the HUK group was 64.10%, whereas that was 41.48% in the control group (P = 0.050). The complete reperfusion rates were 42.9% and 23.3% in the HUK group and the control group, respectively. No significant differences were observed for adverse events between the two groups.

Conclusions:

Combination therapy of HUK plus rT-PA in patients with acute ischemic stroke with an extended time window can safely improve their functional outcomes.
International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer. Working Group 1
Authors: Downes Michelle R. , Hartmann Arndt , Shen Steven , Tsuzuki Toyonori , van Rhijn Bas W.G. , Bubendorf Lukas , van der Kwast Theodorus H. , Cheng Liang ,   the Members of the ISUP Bladder Tumor Consensus Panel
Published: May 2023

Grade is a key prognostic factor in determining progression in nonmuscle invasive papillary urothelial carcinomas. The 2 most common grading methods in use worldwide are the World Health Organization (WHO) 2004 and 1973 schemes. The International Society of Urological Pathology (ISUP) organized the 2022 consensus conference in Basel, Switzerland on current issues in bladder cancer and tasked working group 1 to make recommendations for future iterations of bladder cancer grading. For this purpose, the ISUP developed in collaboration with the European Association of Urology a 10-question survey for their memberships to understand the current use of grading schemes by pathologists and urologists and to ascertain the areas of potential improvements. An additional survey was circulated to the ISUP membership for their opinion on interobserver variability in grading, reporting of urine cytology, and challenges encountered in grade assignment. Comprehensive literature reviews were performed on bladder cancer grading prognosis and interobserver variability along with The Paris System for urine cytology. There are notable differences in practice patterns between North American and European pathologists in terms of used grading scheme and diagnosis of papillary urothelial neoplasm of low malignant potential. Areas of common ground include difficulty in grade assignment, a desire to improve grading criteria, and a move towards subclassifying high-grade urothelial carcinomas. The surveys and in-person voting demonstrated a strong preference to refine current grading into a 3-tier scheme with the division of WHO 2004 high grade into clinically relevant categories. More variable opinions were voiced regarding the use of papillary urothelial carcinoma with low malignant potential.
Metopic and Sagittal Craniosynostosis in Williams Syndrome
Authors: Chaisrisawadisuk Sarut , Khampalikit Inthira , Moore Mark H. , Sathienkijkanchai Achara
Published: May 2023

Craniosynostosis has been previously reported in patients with Williams syndrome. Due to the associated significant cardiovascular anomalies, with an attendant increased risk of death under anaesthesia, most patients have been managed conservatively. Here we report the multidisciplinary approach in a 12-month-old female infant with Williams syndrome who has metopic and sagittal craniosynostosis. The child successfully underwent calvarial remodelling procedures, with the clinical outcome demonstrating dramatically improved global development after surgery.
Uvular Dermoid Cyst: More Than Just a Lump in the Throat—Management of Resultant Velopharyngeal Insufficiency
Authors: Harmon Kelly A. , Fegan Alexandra , La-Anyane Okensama , Theis Shannon M. , Tragos Christina
Published: May 2023

To seal the passage between the nasal and oral cavities during speech and swallowing, velopharyngeal closure is required. However, in velopharyngeal dysfunction, uncoupling of the nasal and oral cavities can be impaired, resulting in hypernasality, nasal air emission, and decreased vocal intensity. Velopharyngeal dysfunction can develop following velopharyngeal mislearning, oral surgery, or a congenital palatal malformation. Rare dermoid cysts of the palate may interrupt normal palatal development, resulting in velopharyngeal insufficiency (VPI). While speech therapy is the standard treatment, some cases may necessitate surgical correction of structural insufficiencies. In this report, we present the case of a 7-year-old female with a past surgical history of a uvular dermoid cyst removal at 14 months of age with VPI that was treated with Furlow Z-palatoplasty. To the author’s knowledge, this is one of but a few cases of a uvular dermoid cyst with VPI.
Immunoglobulin G4–Related Bilateral Palpebral Conjunctival Involvement
Authors: Takahashi Yasuhiro , Vaidya Aric
Published: May 2023

The authors show a case with immunoglobulin G4 (IgG4)-related bilateral palpebral conjunctival mass and reviewed 7 similar previously reported cases. Our case was a 42-year-old woman who presented with a 2-year history of a left palpebral conjunctival mass. Pathologic examination of the specimens harvested from the mass revealed marked IgG4-positive plasma cell infiltration. The serum IgG4 level was within the normal limit. Although the mass was completely excised, the lesion recurred 1 month after the surgery, and another new lesion developed in the right upper palpebral conjunctiva. The patient was given 30 mg of oral prednisolone daily, which was tapered gradually. At a 10-month follow-up, the patient continued to take 15 mg of oral prednisolone. The lesions subsided on both sides. On the basis of the literature review, normal serum IgG4 level and upper eyelid lesions may be features of IgG4-related bilateral palpebral conjunctival lesions, and systemic steroids may be effective for this entity.
Early veno-venous extracorporeal membrane oxygenation is an effective strategy for traumatically injured patients presenting with refractory respiratory failure
Authors: Powell Elizabeth K. , Reynolds Tyler S. , Webb James K. , Kundi Rishi , Cantu Jody , Keville Meaghan , O’Connor James V. , Stein Deborah M. , Hanson Matthew P. , Taylor Bradley S. , Scalea Thomas M. , Galvagno Samuel M.
Published: May 2023

BACKGROUND

Venovenous extracorporeal membrane oxygenation (VV ECMO) is used for respiratory failure when standard therapy fails. Optimal trauma care requires patients be stable enough to undergo procedures. Early VV ECMO (EVV) to stabilize trauma patients with respiratory failure as part of resuscitation could facilitate additional care. As VV ECMO technology is portable and prehospital cannulation possible, it could also be used in austere environments. We hypothesize that EVV facilitates injury care without worsening survival.

METHODS

Our single center, retrospective cohort study included all trauma patients between January 1, 2014, and August 1, 2022, who were placed on VV ECMO. Early VV was defined as cannulation ≤48 hours from arrival with subsequent operation for injuries. Data were analyzed with descriptive statistics. Parametric or nonparametric statistics were used based on the nature of the data. After testing for normality, significance was defined as a p < 0.05. Logistic regression diagnostics were performed.

RESULTS

Seventy-five patients were identified and 57 (76%) underwent EVV. There was no difference in survival between the EVV and non-EVV groups (70% vs. 61%, p = 0.47). Age, race, and gender did not differ between EVV survivors and nonsurvivors. Time to cannulation (4.5 hours vs. 8 hours, p = 0.39) and injury severity scores (34 vs. 29, p = 0.74) were similar. Early VV survivors had lower lactic acid levels precannulation (3.9 mmol/L vs. 11.9 mmol/L, p < 0.001). A multivariable logistic regression analysis examining admission and precannulation laboratory and hemodynamic values demonstrated that lower precannulation lactic acid levels predicted survival (odds ratio, 1.2; 95% confidence interval, 1.02–1.5; p = 0.03), with a significant inflection point of 7.4 mmol/L corresponding to decreased survival at hospital discharge.

CONCLUSION

Patients undergoing EVV did not have increased mortality compared with the overall trauma VV ECMO population. Early VV resulted in ventilatory stabilization that allowed subsequent procedural treatment of injuries.

LEVEL OF EVIDENCE

Therapeutic Care/Management; Level III.
The last days: The medical response of United States and allied military teams during the Afghanistan Exodus
Authors: Bozzay Joseph D. , Murphy Timothy P. , Baird Michael D. , Dingle Marvin E. , Rokayak Omar A. , Renninger Chris , Boomsma Shawn E. , Milam Brian P. , Horrell Timothy J. , Rittenhouse Bradley A. , McGlone Patrick J. , Kashtan Harris W. , Buzzelli Mark , How Remealle A. , Lynch Bruce A. , Heyda Lauren , Humphries Ashley E. , Jessie Elliot M. , Patel Jigarkumar A. , Hardin Ronald , Nelson Kenneth J. , D’Alleyrand Jean-Claude G. , Bradley Matthew J. , Potter Benjamin K. , Gurney Jennifer M.
Published: May 2023

OBJECTIVES

The objective of this study is to describe the United States and allied military medical response during the withdrawal from Afghanistan.

BACKGROUND

The military withdrawal from Afghanistan concluded with severe hostilities resulting in numerous civilian and military casualties. The clinical care provided by coalition forces capitalized on decades of lessons learned and enabled unprecedented accomplishments.

METHODS

In this retrospective, observational analysis, casualty numbers, and operative information was collected and reported from military medical assets in Kabul, Afghanistan. The continuum of medical care and the trauma system, from the point of injury back to the United States was captured and described.

RESULTS

Prior to a large suicide bombing resulting in a mass casualty event, the international medical teams managed distinct 45 trauma incidents involving nearly 200 combat and non-combat civilian and military patients over the preceding 3 months. Military medical personnel treated 63 casualties from the Kabul airport suicide attack and performed 15 trauma operations. US air transport teams evacuated 37 patients within 15 hours of the attack.

CONCLUSION

Lessons learned from the last 20 years of combat casualty care were successfully implemented during the culmination of the Afghanistan conflict. Ultimately, the effort, teamwork, and system adaptability exemplify not only the attitudes and character of service members who provide modern combat casualty care but also the paramount importance of the battlefield learning health care system. A continued posture to maintain military surgical preparedness in unique environments remain crucial as the US military prepares for the future.

Retrospective observational analysis

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level V.
Peripapillary Vitreous Traction Syndrome: Expanding the Spectrum of Anterior Optic Neuropathies
Authors: Chan Jane W. , Liu Henry , Ma Elise L. , Sadun Alfredo A. , Sadda Srinivas R.
Published: May 2023

Background:

Peripapillary vitreous traction (PVT) occurring without any underlying eye disease has been contemplated as a distinct entity from nonarteritic ischemic optic neuropathy (NAION) for many years and is sometimes difficult to differentiate from classical NAION. We report 6 new cases to analyze the clinical features of PVT syndrome that would expand the clinical spectrum of anterior optic neuropathies.

Methods:

Prospective case series.

Results:

PVT syndrome seems to affect optic discs with a small area with a small cup-to-disc (C/D) ratio. The C/D ratio does not significantly increase in the chronic stage, as in NAION. Vitreous traction without detachment can either lead to mild retinal nerve fiber layer (RNFL) injury with attendant ganglion cell layer/inner plexiform layer (GCL/IPL) thinning in 29% or no injury at all in 71%. Eighty-six percent had good visual acuity (VA) and had no relative afferent pupillary defect (RAPD), whereas 14% had a transient RAPD; 71% had no color defect. Vitreous detachment after a period of severe and persistent traction can lead to more damage to the optic nerve head and RNFL that may look like NAION. Our hypothesized mechanically induced injury to the superficial optic nerve head may not lead to much visual impairment. In our study, no further therapeutic interventions were required.

Conclusions:

Based on our analysis of previously published cases and our own prospective case series of 6 patients, the PVT syndrome falls within the spectrum of anterior optic neuropathies, often affecting small optic discs with a small C/D ratio. Vitreous traction can lead to a partial or complete anterior optic neuropathy. The PVT syndrome may be a “more” anterior optic neuropathy distinct from classical NAION.
Neuro-ophthalmic Complications in Pediatric Leukemia
Authors: Rothfield Lindsay , Falcone Michelle M. , Gaier Eric D. , Heidary Gena , Gise Ryan
Published: May 2023

Background:

Optic neuropathy in childhood leukemia occurs through multiple direct and indirect mechanisms, including leukemic infiltration of the optic nerve, infection, blood dyscrasias, or adverse effects of treatment. We aimed to characterize visual outcomes in pediatric patients with leukemia-associated neuro-ophthalmic manifestations.

Methods:

We retrospectively identified patients with leukemia and optic nerve pathology over 13 years by diagnostic billing codes. We collected information on demographics, presentation, treatment course, and visual outcomes directly from medical records.

Results:

Of the 19 patients who met inclusion criteria, 17 (89.5%) had pseudotumor cerebri and 2 had direct optic nerve infiltration. Causes of increased intracranial pressure included central nervous system infiltration (6 of 17), hyperviscosity/leukemia (2 of 17), venous sinus thrombosis (3 of 17), medication induced (5 of 17), and bacterial meningitis (1 of 17). 47.1% (8 of 17) had papilledema at the time of leukemia diagnosis, and 94.1% (16 of 17) of patients with pseudotumor cerebri were treated with acetazolamide. At presentation, 3 patients had decreased vision secondary to macular ischemia, subhyaloid vitreous hemorrhage, or steroid induced glaucoma. Following treatment of pseudotumor cerebri, binocular visual acuity was ≥20/25 in all patients. One patient with optic nerve infiltration had a final visual acuity of count fingers in the affected eye.

Conclusions:

In our chart review, the most common mechanism of neuro-ophthalmic involvement in pediatric leukemia was elevated intracranial pressure from a myriad of causes. Visual outcomes from patients with elevated intracranial pressure were excellent. Understanding the mechanisms by which leukemia can cause optic nerve disease in pediatric patients can facilitate earlier diagnosis and treatment and potentially improve visual outcomes.
Monitoring the fabric of nature: using allometric trophic network models and observations to assess policy effects on biodiversity
Authors: Navarrete Sergio A. , Ávila-Thieme M. Isidora , Valencia Daniel , Génin Alexandre , Gelcich Stefan
Published: May 2023

Species diversity underpins all ecosystem services that support life. Despite this recognition and the great advances in detecting biodiversity, exactly how many and which species co-occur and interact, directly or indirectly in any ecosystem is unknown. Biodiversity accounts are incomplete; taxonomically, size, habitat, mobility or rarity biased. In the ocean, the provisioning of fish, invertebrates and algae is a fundamental ecosystem service. This extracted biomass depends on a myriad of microscopic and macroscopic organisms that make up the fabric of nature and which are affected by management actions. Monitoring them all and attributing changes to management policies is daunting. Here we propose that dynamic quantitative models of species interactions can be used to link management policy and compliance with complex ecological networks. This allows managers to qualitatively identify ‘interaction-indicator’ species, which are highly impacted by management policies through propagation of complex ecological interactions. We ground the approach in intertidal kelp harvesting in Chile and fishers' compliance with policies. Results allow us to identify sets of species that respond to management policy and/or compliance, but which are often not included in standardized monitoring. The proposed approach aids in the design of biodiversity programmes that attempt to connect management with biodiversity change.

This article is part of the theme issue ‘Detecting and attributing the causes of biodiversity change: needs, gaps and solutions’.
Drivers of the changing abundance of European birds at two spatial scales
Authors: Gregory Richard D. , Eaton Mark A. , Burfield Ian J. , Grice Philip V. , Howard Christine , Klvaňová Alena , Noble David , Šilarová Eva , Staneva Anna , Stephens Philip A. , Willis Stephen G. , Woodward Ian D. , Burns Fiona
Published: May 2023

Detecting biodiversity change and identifying its causes is challenging because biodiversity is multifaceted and temporal data often contain bias. Here, we model temporal change in species' abundance and biomass by using extensive data describing the population sizes and trends of native breeding birds in the United Kingdom (UK) and the European Union (EU). In addition, we explore how species’ population trends vary with species' traits. We demonstrate significant change in the bird assemblages of the UK and EU, with substantial reductions in overall bird abundance and losses concentrated in a relatively small number of abundant and smaller sized species. By contrast, rarer and larger birds had generally fared better. Simultaneously, overall avian biomass had increased very slightly in the UK and was stable in the EU, indicating a change in community structure. Abundance trends across species were positively correlated with species’ body mass and with trends in climate suitability, and varied with species' abundance, migration strategy and niche associations linked to diet. Our work highlights how changes in biodiversity cannot be captured easily by a single number; care is required when measuring and interpreting biodiversity change given that different metrics can provide very different insights.

This article is part of the theme issue ‘Detecting and attributing the causes of biodiversity change: needs, gaps and solutions’.
Effectiveness of BNT162b2 mRNA vaccine third doses and previous infection in protecting against SARS-CoV-2 infections during the Delta and Omicron variant waves; the UK SIREN cohort study September 2021 to February 2022
Authors: Hall Victoria J , Insalata Ferdinando , Foulkes Sarah , Kirwan Peter , Sparkes Dominic , Atti Ana , Cole Michelle , Lacy Elen de , Price Lesley , Corrigan Diane , Brown Colin S , Islam Jasmin ,   The SIREN Study Group Andre Charlett, Charlett Andre , Hopkins Susan
Published: May 2023

Third doses of COVID-19 vaccines were widely deployed following primary vaccine course waning and emergence of the Omicron-variant. We investigated protection from third-dose vaccines and previous infection against SARS-CoV-2 infection during Delta-variant and Omicron-variant (BA.1 & BA.2) waves in our frequently PCR-tested cohort of healthcare-workers.
A consolidated and geolocated facility list in Senegal from triangulating secondary data
Authors: Gueye Daouda M , Ly Alioune Badara , Gueye Babacar , Ndour Papa Ibrahima , Fullman Nancy , Liu Patrick Y , Mbaye Khadim , Diallo Aliou , Diatta Ibrahima , Diatta Saly Amos , Mane Mouhamadou Moustapha , Ikilezi Gloria , Sarr Moussa
Published: May 2023

Having a geolocated list of all facilities in a country – a “master facility list” (MFL) – can provide critical inputs for health program planning and implementation. To the best of our knowledge, Senegal has never had a centralized MFL, though many data sources currently exist within the broader Senegalese data landscape that could be leveraged and consolidated into a single database – a critical first step toward building a full MFL. We collated 12,965 facility observations from 16 separate datasets and lists in Senegal, and applied matching algorithms, manual checking and revisions as needed, and verification processes to identify unique facilities and triangulate corresponding GPS coordinates. Our resulting consolidated facility list has a total of 4,685 facilities, with 2,423 having at least one set of GPS coordinates. Developing approaches to leverage existing data toward future MFL establishment can help bridge data demands and inform more targeted approaches for completing a full facility census based on areas and facility types with the lowest coverage. Going forward, it is crucial to ensure routine updates of current facility lists, and to strengthen government-led mechanisms around such data collection demands and the need for timely data for health decision-making.
FOG2 coding variant Ser657Gly is associated with Coronary Microvascular Disease through altered hypoxia-mediated gene transcription
Authors: Guerraty M.A. , Verma Shefali , Ko Y.A. , McQuillan M.A. , Conlon D. , Tobias J.W. , Levin M.G. , Haury W. , Zhang C. , Judy R. ,   Regeneron Genomics Center,   PennMedicine Biobank, Tishkoff S. , Damrauer S.M. , Arany Z. , Rader D.J.
Published: May 2023

Rationale

The coronary microvasculature is crucial for proper cardiac function, and coronary microvascular disease (CMVD) has emerged as an underdiagnosed and undertreated cause of ischemic heart disease. Friend of GATA 2 (FOG2) is a transcriptional co-regulator crucial for coronary development and the maintenance of the coronary microvasculature in adult mice.Little is known about the role of FOG2 in humans or its role in CMVD.

Objective

Here, we report a genotype-first approach to determine the role of FOG2 in human coronary microvascular disease.

Findings

We performed Phenome-Wide association studies and deep cardiac phenotyping through the Electronic Health record in patients with FOG2 coding variants and identified an association between rs28374544 (A1969G, S657G) and CMVD. Patients with S657G had increased chest pain, smaller burden of obstructive coronary artery disease, and altered coronary blood flow. Differential gene and pathway analysis using several genomic datasets showed that carriers of S657G have increased expression of genes involved in angiogenesis, glycolysis, and the hypoxia-inducible factor (HIF) pathway. In vitro functional studies show that FOG2 S657G promotes angiogenic gene expression and angiogenesis while decreasing oxygen consumption rate. FOG2 also regulates HIF1a occupancy of angiogenic genes.

Conclusions

We identified a human missense variant which is associated with CMVD and established a potential mechanism by which the variant may altered angiogenic gene expression.
Inferring Multi-Organ Genetic Causal Connections using Imaging and Clinical Data through Mendelian Randomization
Authors: Shu Juan , Zheng Rong , Chirinos Julio , Copana Carlos , Li Bingxuan , Fan Zirui , Yang Xiaochen , Yang Yilin , Wang Xiyao , Li Yujue , Xi Bowei , Li Tengfei , Zhu Hongtu , Zhao Bingxin
Published: May 2023

Understanding the complex causal relationships among major clinical outcomes and the causal interplay among multiple organs remains a significant challenge. By using imaging phenotypes, we can characterize the functional and structural architecture of major human organs. Mendelian randomization (MR) provides a valuable framework for inferring causality by leveraging genetic variants as instrumental variables. In this study, we conducted a systematic multi-organ MR analysis involving 402 imaging traits and 372 clinical outcomes. Our analysis revealed 184 genetic causal links for 58 diseases and 56 imaging traits across various organs, tissues, and systems, including the brain, heart, liver, kidney, lung, pancreas, spleen, adipose tissue, and skeletal system. We identified intra-organ causal connections, such as the bidirectional genetic links between Alzheimer’s disease and brain function, as well as inter-organ causal effects, such as the impact of heart diseases on brain health. Metabolic disorders, such as diabetes, exhibited causal effects across multiple organs. These findings shed light on the genetic causal links spanning multiple organs, providing insights into the intricate relationships between organ functions and clinical outcomes.
Brain development mutations in the β-tubulin TUBB result in defective ciliogenesis
Authors: Mollica Antonio , Omer Safia , Evagelou Sonia L. , Naumenko Serhiy , Li Lu Yi , Teeling Aideen , Lindsay Kyle , Erwood Steven , Vernon Robert M. , Forman-Kay Julie D. , Shroff Manohar , Harrison Rene E. , Cohn Ronald D. , Ivakine Evgueni A.
Published: May 2023

Tubulinopathies and neurodevelopmental ciliopathies are two groups of genetic disorders characterized by abnormal brain development resulting in structural brain malformations. Tubulinopathies are caused by dominant missense mutations in genes encoding for tubulins, the building blocks of microtubules. Neurodevelopmental ciliopathies are mostly recessive disorders caused by defects in the function of the primary cilium, a sensory organelle that modulates signaling pathways important for brain development. Though more than 40 genes have been associated with neurodevelopmental ciliopathies, many patients still do not have an identified genetic etiology. Herein, we present a novelde novoheterozygous missense variant in Tubulin Beta Class I (TUBB) identified through whole-genome sequencing analysis in a patient with both ciliopathy and tubulinopathy brain features. While microtubules are fundamental to primary cilia formation and function, no association between mutations in tubulin genes and neurodevelopmental ciliopathies has been found to date. Using patient-derived cells and gene-edited isogenic cell lines, we show that the identified variant impairs the early stages of cilia formation by altering microtubule dynamics and structure. Furthermore, we demonstrate that the disease mechanism is not haploinsufficiency and that other patient mutations inTUBBaffect cilia formationin vitro, putting forward defective ciliogenesis as a contributing pathogenic factor in a subset of tubulinopathy patients.
Environmental Sustainability in England’s NHS Respiratory Prescribing; A grounded theory analysis to define a methodology for estimation of inhaler carbon footprint
Authors: Nettleton Helena R.P. , Masters Gillian A. , Mason Monica M.
Published: May 2023

Background

The impact of climate change on health is increasing, as global warming continues to rise.1Within the health and social care sector, pressurised metered dose inhalers (pMDIs) and breath-actuated pMDIs (BA-pMDIs) have been identified as a significant contributing factor to England’s National Health Service carbon footprint.2

Methods

A grounded theory study design was applied to formulate a process map and methodology for Inhaler carbon footprint estimation, utilising established inhaler carbon footprint values and pharmaceutical principles.

Results

A methodology has been developed to support estimation of inhaler carbon footprint values for those inhalers and refills, that do not have a manufacturer’s independently verified carbon footprint certificate.

Conclusion

Definitive Inhaler carbon footprint values, such as those reported here, are required to enable analysis and monitoring of prescribing against Net Zero targets. Further application can also support sustainability assessment and formulary decision making.
Neurophysiological correlates of gait initiation in individuals with Huntington’s and Parkinson’s disease
Authors: Desai Radhika , Quinn Lori
Published: May 2023

Background

Huntington’s disease (HD) and Parkinson’s disease (PD) are neurodegenerative diseases resulting in motor impairments of gait initiation (GI). However, the neurophysiological underpinnings of GI in HD and PD are not well understood. The aims of this study were to 1) evaluate the feasibility of a wireless EEG system to identify EEG-derived movement-related potentials (MRPs) in individuals with HD and PD during GI, and to 2) determine the tolerance of a high repetition GI protocol.

New Method

3 participants with HD and 3 participants with PD performed 3 blocks of 15 trials of GI. EEG-derived MRPs of readiness potential (RPs) and contingent negative variation (CNV) were identified during GI, using a wireless EEG system synced with kinetic measures of GI. Tolerance of the protocol was determined from changes in COP across GI blocks.

Results

There were no differences between HD and PD for CNV and RP amplitudes and latencies, although they were within acceptable ranges of MRP values in HD and PD. There were no differences of COP values between GI blocks.

Comparison with old method

A wireless EEG system elicits naturalistic GI biomechanical responses as opposed to previous methods employing tethered systems. In contrast to single-trial EEG studies, this study implemented a larger number of GI trials, which produces greater MRP resolution.

Conclusions

This study validated the use of a wireless EEG headset in determining MRP values during GI in HD and PD. Participants within these populations were able to tolerate a high repetition GI protocol. Future work will explore MRPs in larger cross-sectional studies for the development of clinical outcome measures.
The effect of level of injury on diabetes incidence and mortality after spinal cord injury – a longitudinal cohort study
Authors: Hoekstra Sven , Trbovich Michelle , Koek Wouter , Mader Michael , Salehi Marzieh
Published: May 2023

Objective

Persons with spinal cord injury (SCI) are at increased risk to develop diabetes mellitus (DM) compared to their able-bodied counterparts, likely due to body composition alterations and autonomic nervous system dysfunction. These factors are more pronounced in persons with tetraplegia (TP) versus paraplegia (PP), however, the effect of level of injury (LOI) on DM incidence is largely unknown. Therefore, the objective is to examine the effect of LOI on DM incidence in persons with SCI.

Design

Retrospective longitudinal cohort study of veterans with SCI.

Methods

We obtained electronic record data on age, sex, race/ethnicity, LOI and HbA1c concentration from January 1st2001 through December 31st2021. Cox proportional hazard regression analyses were used to assess the association between LOI, DM and all-cause mortality.

Results

Among 728 non-diabetic veterans with SCI (350 TP/ 378 PP, 52±15 years, 690 male/38 female) 243 developed DM, of which 116 with TP and 127 with PP. Despite chronological variations between TP and PP, DM risk over the entire follow-up did not differ among the groups (hazard ratio (HR): 1.06, 95% CI: 0.82 - 1.38). Mortality was higher in TP versus PP (HR: 1.40, 95% CI: 1.09 – 1.78). However, developing DM did not increase the risk of death, regardless of LOI (HR: 1.07, 95% CI: 0.83 – 1.37).

Conclusions

In this cohort of veterans with SCI, the level of injury had minimal effect on long-term DM development but increased mortality as previously reported.

Significance statement

Persons with spinal cord injury are at increased risk for developing diabetes mellitus (DM); however, the effect of level of injury is unclear. In the current study using an electronic health record system we found that the incidence of DM is similar between persons with a high (i.e., tetraplegia) versus low (i.e., paraplegia) lesion level, and that developing DM does not affect the risk for mortality. Additionally, our findings suggest that baseline glycemic level (such as HbA1c), unlike baseline body mass index, is a strong predictor of DM development in this population. Further studies are warranted to explore pathophysiological factors responsible for DM development among patients with higher and lower LOI to develop targeted preventive and therapeutic strategies.
The Brazilian vaccine divide: how some municipalities are being left behind in the Covid-19 vaccine coverage
Authors: Boing Antonio Fernando , Boing Alexandra Crispim , Barberia Lorena , Borges Marcelo Eduardo , Subramanian SV
Published: May 2023

Objectives

This study aims to assess the progress of geographic, socioeconomic, and demographic disparities in Covid-19 vaccination coverage in Brazil over the first two years of the vaccination campaign.

Study design

Ecologic study.

Methods

Data from the National Immunization Program Information System were used to estimate covid-19 vaccine coverage. Brazilian municipalities were divided into two groups based on their vaccine coverage for the booster dose. The first group comprised 20% of municipalities with the lowest coverage, while the second group (80% of municipalities) had higher coverage. The analysis was conducted separately for four age groups: 5-11, 12-17, 18-59, and 60+. Exploratory variables included socioeconomic and health services indicators. Crude and adjusted logistic regression models were used to estimate the probability of a municipality being among those with the worst vaccination coverage according to the categories of exploratory variables.

Results

Between January/2021 and December/2022, Brazil administered 448.2 million doses of the covid-19 vaccine. The booster vaccination coverage varied from 24.8% among adolescents to 79.7% among the elderly. The difference between the group with the highest and lowest coverage increased during the national vaccination campaign. Municipalities with lower education levels, higher proportion of Black population, higher Gini index, and worse health service indicators had a greater likelihood of having lower vaccination coverage.

Conclusions

High and increasing levels of inequality in Covid-19 vaccination were observed in Brazil across all age groups during the vaccination campaign in 2021-2022.
Identification of targets for drug repurposing to treat COVID-19 using a Deep Learning Neural Network
Authors: Wang Si-Han , Tang Yu-Hsuan , Hsu Hao , Yu Chu-Nien , Leea Oscar Kuang-Sheng
Published: May 2023

The COVID-19 pandemic has resulted in a global public health crisis requiring immediate acute therapeutic solutions. To address this challenge, we developed a useful tool deep learning model using the graph-embedding convolution network (GECN) algorithm. Our approach identified COVID-19-related genes and potential druggable targets, including tyrosine kinase ABL1/2, pro-inflammatory cytokine CSF2, and pro-fibrotic cytokines IL-4 and IL-13. These target genes are implicated in critical processes related to COVID-19 pathogenesis, including endosomal membrane fusion, cytokine storm, and tissue fibrosis. Our analysis revealed that ABL kinase inhibitors, lenzilumab (anti-CSF2), and dupilumab (anti-IL4Rα) represent promising therapeutic solutions that can effectively block virus-host membrane fusion or attenuate hyperinflammation in COVID-19 patients. Compared to the traditional drug screening process, our GECN algorithm enables rapid analysis of disease-related human protein interaction networks and prediction of candidate drug targets from a large-scale knowledge graph in a cost-effective and efficient manner. Overall, Overall, our results suggest that the model has the potential to facilitate drug repurposing and aid in the fight against COVID-19.
GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway
Authors: Hoppe Nicholas , Harrison Simone , Hwang Sun-Hee , Chen Ziwei , Karelina Masha , Deshpande Ishan , Suomivuori Carl-Mikael , Palicharla Vivek R. , Berry Samuel P. , Tschaikner Philipp , Regele Dominik , Covey Douglas F. , Stefan Eduard , Marks Debora S. , Reiter Jeremy , Dror Ron O. , Evers Alex S. , Mukhopadhyay Saikat , Manglik Aashish
Published: May 2023

The orphan G protein-coupled receptor (GPCR) GPR161 is enriched in primary cilia, where it plays a central role in suppressing Hedgehog signaling1. GPR161 mutations lead to developmental defects and cancers2,3,4. The fundamental basis of how GPR161 is activated, including potential endogenous activators and pathway-relevant signal transducers, remains unclear. To elucidate GPR161 function, we determined a cryogenic-electron microscopy structure of active GPR161 bound to the heterotrimeric G protein complex Gs. This structure revealed an extracellular loop 2 that occupies the canonical GPCR orthosteric ligand pocket. Furthermore, we identify a sterol that binds to a conserved extrahelical site adjacent to transmembrane helices 6 and 7 and stabilizes a GPR161 conformation required for Gscoupling. Mutations that prevent sterol binding to GPR161 suppress cAMP pathway activation. Surprisingly, these mutants retain the ability to suppress GLI2 transcription factor accumulation in cilia, a key function of ciliary GPR161 in Hedgehog pathway suppression. By contrast, a protein kinase A-binding site in the GPR161 C-terminus is critical in suppressing GLI2 ciliary accumulation. Our work highlights how unique structural features of GPR161 interface with the Hedgehog pathway and sets a foundation to understand the broader role of GPR161 function in other signaling pathways.
Towards course of disease based epidemiological modelling: motivation and computational optimization
Authors: Wu Yu-Heng , Nordling Torbjörn E. M.
Published: May 2023

The ongoing COVID-19 pandemic has demonstrated the shortcoming of epidemiological modelling for guiding policy decisions. Due to the lack of public data on infection spread in contact networks and individual courses of disease, current forecasting models rely heavily on unreliable population statistics andad hocparameters, resulting in forecasts with high uncertainty. To tackle the problem of insufficient public individual data, we develop an agent-based model to generate a synthetic Taiwanese COVID-19 dataset. We collected COVID-19 data from Taiwanese public databases for the period when the original SARS-CoV-2 virus was most prevalent (Jan.-Oct., 2020) and fit our model to it. We used the Firefly algorithm to optimize the 194 epidemiological parameters and validated the synthetic dataset by comparing it to Taiwanese public data. Here we study the difference between population statistics and individual course of disease data, and computational optimization of our code to reduce run time. The discrepancy between serum prevalence and reported cases, as well as excess deaths and reported deaths, show that population statistics are unreliable. Monte Carlo simulations further exemplify the discrepancy between actual and reported infections. By using Python CProfiler and Snakeviz packages, we iteratively optimize our algorithm and has so far decreased the computation time of the core code from 0.11s to 0.07s. The large computation time implies that we need to further optimize the algorithm.
Trends in Prevalence of Cannabis Use Disorders among U.S. Veterans with and without Psychiatric Disorders Between 2005 and 2019
Authors: Livne Ofir , Malte Carol A. , Olfson Mark , Wall Melanie M. , Keyes Katherine M. , Maynard Charles , Gradus Jaimie L. , Saxon Andrew J. , Martins Silvia S. , Keyhani Salomeh , McDowell Yoanna , Fink David S. , Mannes Zachary L. , Gutkind Sarah , Hasin Deborah S.
Published: May 2023

Objective

Cannabis use disorders (CUD) are increasing among U.S. adults and are more prevalent among cannabis users with comorbid psychiatric disorders. Changing cannabis laws, increasing cannabis availability, and higher potency cannabis may have recently placed cannabis users with psychiatric disorders at disproportionately increasing risk for CUD. The authors used Veterans Health Administration (VHA) data to examine whether trends in CUD prevalence among VHA patients differ by whether they have psychiatric disorders.

Methods

VHA electronic health records from 2005 to 2019 (n range=4,332,165-5,657,277) were used to identify overall and age-specific (<35, 35-64, ≥65 years) trends in prevalence of CUD diagnoses among patients with depressive, anxiety, PTSD, bipolar, or psychotic-spectrum disorders, and to compare these to corresponding trends among patients without any of these disorders. Given transitions in ICD coding, differences in trends were tested within two periods: 2005–2014 (ICD-9-CM) and 2016–2019 (ICD-10-CM).

Results

Greater increases in prevalence of CUD diagnoses were observed in veterans with, compared to without, psychiatric disorders (2005-2014: difference in prevalence change=1.91%, 95% CI=1.87%-1.96%; 2016-2019: 0.34%, 95% CI=0.29%-0.38%). Disproportionate increases in CUD prevalence among those with psychiatric disorders were greatest in veterans ages <35 between 2005-2014, and in those ages ≥65 between 2016-2019. Among patients with psychiatric disorders, greatest increases in CUD prevalences were observed in those with bipolar and psychotic-spectrum disorders.

Conclusions

Results highlight disproportionately increasing disparities in risk of CUD among VA patients with common psychiatric disorders. Greater public health and clinical efforts are needed to monitor, prevent and treat CUD among this population.
Missing data and missed infections: Investigating racial and ethnic disparities in SARS-CoV-2 testing and infection rates in Holyoke, Massachusetts
Authors: Sauer Sara M. , Fulcher Isabel R. , Matias Wilfredo R. , Paxton Ryan , Elnaiem Ahmed , Gonsalves Sean , Zhu Jack , Guillaume Yodeline , Franke Molly , Ivers Louise C.
Published: May 2023

Routinely collected testing data has been a vital resource for public health response during the COVID-19 pandemic and has revealed the extent to which Black and Hispanic persons have borne a disproportionate burden of SARS-CoV-2 infections and hospitalizations in the United States. However, missing race and ethnicity data and missed infections due to testing disparities limit the interpretation of testing data and obscure the true toll of the pandemic. We investigated potential bias arising from these two types of missing data through a case study in Holyoke, Massachusetts during the pre-vaccination phase of the pandemic. First, we estimated SARS-CoV-2 testing and case rates by race/ethnicity, imputing missing data using a joint modelling approach. We then investigated disparities in SARS-CoV-2 reported case rates and missed infections by comparing case rate estimates to estimates derived from a COVID-19 seroprevalence survey. Compared to the non-Hispanic white population, we found that the Hispanic population had similar testing rates (476 vs. 480 tested per 1,000) but twice the case rate (8.1% vs. 3.7%). We found evidence of inequitable testing, with a higher rate of missed infections in the Hispanic population compared to the non-Hispanic white population (77 vs. 58 infections missed per 1,000).