bluuebunny/crossref_metadata_2025 huggingface dataset:
Enabling cross-country learning and exchange to support universal health coverage implementation
Authors: Oliveira Hashiguchi Lauren , Conlin Maeve , Roberts Dawn , McGee Kathleen , Marten Robert , Nachuk Stefan , Mukti Ali Ghufron , Nigam Aditi , Ahluwalia Naina , Nagpal Somil
Published: January 2024

As countries transition from external assistance while pursuing ambitious plans to achieve universal health coverage (UHC), there is increasing need to facilitate knowledge sharing and learning among them. Country-led and country-owned knowledge management is foundational to sustainable, more equitable external assistance for health and is a useful complement to more conventional capacity-building modalities provided under external assistance. In the context of external assistance, few initiatives use country-to-country sharing of practitioner experiences, and link learning to receiving guidance on how to adapt, apply and sustain policy changes. Dominant knowledge exchange processes are didactic, implicitly assuming static technical needs, and that practitioners in low- and middle-income countries require problem-specific, time-bound solutions. In reality, the technical challenges of achieving UHC and the group of policymakers involved continuously evolve. This paper aims to explore factors which are supportive of experience-based knowledge exchange between practitioners from diverse settings, drawing from the experience of the Joint Learning Network (JLN) for UHC—a global network of practitioners and policymakers sharing experiences about common challenges to develop and implement knowledge products supporting reforms for UHC—as an illustration of a peer-to-peer learning approach. This paper considers: (1) an analysis of JLN monitoring and evaluation data between 2020 and 2023 and (2) a qualitative inquiry to explore policymakers’ engagement with the JLN using semi-structured interviews (n = 14) with stakeholders from 10 countries. The JLN’s experience provides insights to factors that contribute to successful peer-to-peer learning approaches. JLN relies on engaging a network of practitioners with diverse experiences who organically identify and pursue a common learning agenda. Meaningful peer-to-peer learning requires dynamic, structured interactions, and alignment with windows of opportunity for implementation that enable rapid response to emerging and timely issues. Peer-to-peer learning can facilitate in-country knowledge sharing, learning and catalyse action at the institutional and health system levels.
Predicting host-based, synthetic lethal antiviral targets from omics data
Authors: Staheli Jeannette P , Neal Maxwell L , Navare Arti , Mast Fred D , Aitchison John D
Published: January 2024

Traditional antiviral therapies often have limited effectiveness due to toxicity and the emergence of drug resistance. Host-based antivirals are an alternative, but can cause nonspecific effects. Recent evidence shows that virus-infected cells can be selectively eliminated by targeting synthetic lethal (SL) partners of proteins disrupted by viral infection. Thus, we hypothesized that genes depleted in CRISPR knockout (KO) screens of virus-infected cells may be enriched in SL partners of proteins altered by infection. To investigate this, we established a computational pipeline predicting antiviral SL drug targets. First, we identified SARS-CoV-2-induced changes in gene products via a large compendium of omics data. Second, we identified SL partners for each altered gene product. Last, we screened CRISPR KO data for SL partners required for cell viability in infected cells. Despite differences in virus-induced alterations detected by various omics data, they share many predicted SL targets, with significant enrichment in CRISPR KO-depleted datasets. Our comparison of SARS-CoV-2 and influenza infection data revealed potential broad-spectrum, host-based antiviral SL targets. This suggests that CRISPR KO data are replete with common antiviral targets due to their SL relationship with virus-altered states and that such targets can be revealed from analysis of omics datasets and SL predictions.
Digital Collateral
Authors: Gertler Paul , Green Brett , Wolfram Catherine
Published: January 2024

A new form of secured lending using “digital collateral” has recently emerged, most prominently in low- and middle-income countries. Digital collateral relies on lockout technology, which allows the lender to temporarily disable the flow value of the collateral to the borrower without physically repossessing it. We explore this new form of credit in a model and a field experiment using school-fee loans digitally secured with a solar home system. Securing a loan with digital collateral drastically reduced default rates (by 19 percentage points) and increased the lender’s rate of return (by 49 percentage points). Using a variant of the Karlan and Zinman (2009) methodology, we decompose the total effect on repayment and find that roughly two-thirds is attributable to moral hazard, and one-third to adverse selection. In addition, access to digitally secured school-fee loans significantly increased school enrollment and school-related expenditures without detrimental effects on households’ balance sheets.
The Value of Social Work to Health, Health Systems, and Interprofessional Teams: A Scoping Review
Authors: Ross Abigail M , Jashinski Julia , Lombardo Molly Zatony , Keane Jazmyne , Wilkinson Geoffrey
Published: January 2024

Social workers are an integral part of the U.S. healthcare system, yet specific contributions of social work to health and cost-containment outcomes is sparse. This scoping review describes and evaluates the state of the evidence on how social work interventions impact health and economic outcomes since the passage of the Patient Protection and Affordable Care Act. Three databases (PubMed, PsycINFO, and CINAHL) were searched using the convention [“social work” OR “social services”] AND “health” AND [“cost” OR “utilization” OR “readmission”] for studies published between 2010 and 2022. Unique records were evaluated on inclusion criteria (U.S.-based, reported social work, and cost or health outcomes) using a five-phase scoping review process. Methodological quality was assessed using two validated metrics. Of 1,655 unique records retrieved, 40 (2.4%) met inclusion criteria. Full-text review yielded 15 studies. Most (75%) studies described transitional care interventions for older patients and high utilizers of health services, with the majority (75%) led by social workers. While health and cost outcomes were generally positive, overall methodological quality of the sample was low. Social work intervention can improve health and cost outcomes. More robust economic analyses that inform policy, practice, and health service delivery are needed.
Tropical Origin, Global Diversification, and Dispersal in the Pond Damselflies (Coenagrionoidea) Revealed by a New Molecular Phylogeny
Authors: Willink Beatriz , Ware Jessica L , Svensson Erik I
Published: January 2024

The processes responsible for the formation of Earth’s most conspicuous diversity pattern, the latitudinal diversity gradient (LDG), remain unexplored for many clades in the Tree of Life. Here, we present a densely sampled and dated molecular phylogeny for the most speciose clade of damselflies worldwide (Odonata: Coenagrionoidea) and investigate the role of time, macroevolutionary processes, and biome-shift dynamics in shaping the LDG in this ancient insect superfamily. We used process-based biogeographic models to jointly infer ancestral ranges and speciation times and to characterize within-biome dispersal and biome-shift dynamics across the cosmopolitan distribution of Coenagrionoidea. We also investigated temporal and biome-dependent variation in diversification rates. Our results uncover a tropical origin of pond damselflies and featherlegs ~105 Ma, while highlighting the uncertainty of ancestral ranges within the tropics in deep time. Even though diversification rates have declined since the origin of this clade, global climate change and biome-shifts have slowly increased diversity in warm- and cold-temperate areas, where lineage turnover rates have been relatively higher. This study underscores the importance of biogeographic origin and time to diversify as important drivers of the LDG in pond damselflies and their relatives, while diversification dynamics have instead resulted in the formation of ephemeral species in temperate regions. Biome-shifts, although limited by tropical niche conservatism, have been the main factor reducing the steepness of the LDG in the last 30 Myr. With ongoing climate change and increasing northward range expansions of many damselfly taxa, the LDG may become less pronounced. Our results support recent calls to unify biogeographic and macroevolutionary approaches to improve our understanding of how latitudinal diversity gradients are formed and why they vary across time and among taxa.
Italian resident individuals with interests in Liechtenstein entities: notes on Italian income taxes—Part 1
Authors: Quartana Claudio , Bolis Lodovico
Published: January 2024

It is not uncommon for Italian resident taxpayers to resort to Liechtenstein entities to take advantage of the benefits that they can offer, like asset protection, confidentiality and favorable taxation. This article tries to address some of the Italian income tax implications that Italian resident individuals with interests in Liechtenstein entities should consider. Part 1, after providing an overview on the recent agreement for the elimination of double taxation stipulated between Italy and Liechtenstein, focuses on Liechtenstein foundations and establishments, also covering the potential advantages that may derive from the combination of the Italian lump sum tax regime with the use of these legal entities. Part 2 (to be published soon in 2024), will deal with Liechtenstein limited companies and “the Italian Controlled Foreign Companies regime”.
Understanding the recurrent pulled elbow
Authors: Bezirgan Ugur , Vatansever Göksel , Yoğun Yener , Bozkurt Orhun Eray , Dumlupinar Ebru , Salman Necati , Tekin Deniz
Published: January 2024

Nursemaid elbow is subluxation of the radius head seen in early childhood. The aim of this study was to examine the epidemiology of recurrent dislocations and the effect of hyperlaxity and bone anatomy on recurrent dislocations in these injuries, for which the pathogenesis has not been fully clarified. The study included a total of 329 paediatric patients who presented at the Paediatric Emergency Department (ED) between January 2016 and December 2022, and were diagnosed with Nursemaid Elbow. On presentation at ED, two-directional elbow radiographs were taken of all the patients and the radius head-neck ratio was measured on the lateral elbow radiograph. The Beighton score of joint hyperlaxity was evaluated in all the patients with a history of recurrent dislocation. A statistically significant difference was determined between the Beighton score groups in respect of the number of dislocations in multiple dislocations (P = 0.002). No statistically significant relationship was determined between the number of dislocations and the lateral radius head/neck ratio (P = 0.061). Hyperlaxity syndrome should be kept in mind in the aetiology of multiple dislocations.
Prone Position Increases the Risk of Postoperative Deep Vein Thrombosis in Cervical Spine Surgery by Limiting Venous Return in the Lower Limbs
Authors: Wang Yu , Chen Xiaohui , Wu Qilong , Wang Yefeng , Wang Jing , Teng Honglin , Xu Shihao , Wang Yu
Published: January 2024

Study Design.

Retrospective clinical study with confirmatory evaluation in healthy volunteers

Objective.

To investigate the association between deep vein thrombosis (DVT) and surgical position after cervical spine surgery.

Summary of Background Data.

It is unclear whether posterior cervical surgery using the prone position increases the risk of postoperative DVT relative to anterior cervical surgery.

Methods.

340 patients undergoing surgery for degenerative cervical myelopathy were included. Multivariate analysis was used to identify the predictors of postoperative DVT, adjusting for potential confounders. In addition, 45 healthy volunteers were used to study blood flow velocity and intravascular diameter of the posterior tibial vein (PTV) and popliteal vein (PV) of the subjects were monitored by ultrasound and compared among three positions (supine, prone, and prone with iliac cushions).

Results.

Multivariate analysis showed that advanced age (>63.5 y old), preoperative varicose veins, D-dimer>0.255 mg/L, bleeding volume>303 mL and prone positioning were significantly associated with DVT after cervical spine surgery. The results of vascular ultrasound showed that blood flow velocities of PV and PTV in the prone position with cushions were significantly lower than those in the supine position. The diameter of PV in prone position with cushions was also significantly larger. The blood flow velocity and diameter of PV in the prone position with cushions were significantly lower and larger, respectively, than those in the prone position without cushions.

Conclusions.

Posterior cervical surgery in the prone position was significantly associated with postoperative DVT. The prone position with iliac cushions may decrease venous flow within the lower extremities due to compression of iliac veins, obstructing venous return and thus increasing the incidence of postoperative DVT. The prone position without iliac cushions may reduce the potential for DVT.

Level of Evidence.

3
A Nationwide, Prospective Study of Tracheal Intubation in Critically Ill Adults in Spain: Management, Associated Complications, and Outcomes
Authors: Garnacho-Montero José , Gordillo-Escobar Elena , Trenado Josep , Gordo Federico , Fisac Lourdes , García-Prieto Emilio , López-Martin Cristina , Abella Ana , Jiménez Juan Ramón , García-Garmendia José Luis ,   and the Intubation Prospective (INTUPROS) Study Investigators.
Published: January 2024

Objectives:

Our aims were to explore current intubation practices in Spanish ICUs to determine the incidence and risk factors of peri-intubation complications (primary outcome measure: major adverse events), the rate and factors associated with first-pass success, and their impact on mortality as well as the changes of the intubation procedure observed in the COVID-19 pandemic.

Design:

Prospective, observational, and cohort study.

Setting:

Forty-three Spanish ICU.

Patients:

A total of 1837 critically ill adult patients undergoing tracheal intubation. The enrollment period was six months (selected by each center from April 16, 2019, to October 31, 2020).

Interventions:

None.

Measurement and Main Results

: At least one major adverse peri-intubation event occurred in 40.4 % of the patients (973 major adverse events were registered) the most frequent being hemodynamic instability (26.5%) and severe hypoxemia (20.3%). The multivariate analysis identified seven variables independently associated with a major adverse event whereas the use of neuromuscular blocking agents (NMBAs) was associated with reduced odds of major adverse events. Intubation on the first attempt was achieved in 70.8% of the patients. The use of videolaryngoscopy at the first attempt was the only protective factor (odds ratio 0.43; 95% CI, 0.28–0.66; p < 0.001) for first-attempt intubation failure. During the COVID-19 pandemic, the use of videolaryngoscopy and NMBAs increased significantly. The occurrence of a major peri-intubation event was an independent risk factor for 28-day mortality. Cardiovascular collapse also posed a serious threat, constituting an independent predictor of death.

Conclusions:

A major adverse event occurred in up to 40% of the adults intubated in the ICU. Peri-intubation hemodynamic instability but not severe hypoxemia was identified as an independent predictor of death. The use of NMBAs was a protective factor for major adverse events, whereas the use of videolaringoscopy increases the first-pass success rate of intubation. Intubation practices changed during the COVID-19 pandemic.
Ovarian Leiomyosarcoma as Incidentaloma during Postbariatric Abdominoplasty Surgical Procedure
Authors: Mazzarella Francesca , Brunelli Daniele , Foletto Mirto , Bassetto Franco , Vindigni Vincenzo
Published: January 2024

This case report addresses the discovery, surgical management, histology, and postoperative outcomes of an incidentaloma during the preoperative evaluation of a 58-year-old woman planning to undergo abdominoplasty and hernia correction after bariatric surgery. The patient’s computed tomography scan revealed a large pelvic mass in addition to an enlarged uterus and an umbilical hernia. Subsequent surgical intervention included umbilical hernia repair, subtotal omental excision, and en-bloc removal of the uterine and ovarian structures. Histological analysis confirmed the mass as a high-grade utero-ovarian leiomyosarcoma. The patient received adjuvant chemotherapy and demonstrated a positive response in follow-up imaging at 6 months, with reduced mass size and no significant lymphadenopathy. Both aesthetic and morpho-functional outcomes were satisfactory. The report highlights the challenges of diagnosing and treating incidentalomas, emphasizing the need for individualized management. It discusses the rarity of primary ovarian leiomyosarcoma and the surgical approach used. The case ultimately emphasizes the importance of multidisciplinary clinical evaluations in ensuring comprehensive care for patients with unexpected radiological findings, such as utero-ovarian leiomyosarcoma.
Alpha Defensin-1 Level Correlates with Periprosthetic Infection Severity following Implant-based Breast Reconstruction
Authors: Sobti Nikhil , Vishwanath Neel , Stead Thor , Rao Vinay , Soliman Luke , Breuing Karl , Kwan Daniel , Liu Paul , Schmidt Scott
Published: January 2024

Background:

Accurate diagnosis of periprosthetic infections following breast reconstructions is paramount to reduce morbidity. Alpha defensin-1 (AD-1) is an antimicrobial peptide released by neutrophils. This study evaluates the relationship between quantitative AD-1 levels and infection severity in patients with suspected periprosthetic infection.

Methods:

Retrospective review was conducted of patients with prior breast implant reconstruction undergoing surgery for either suspected infection or prosthesis exchange and revision. The AD-1 level in periprosthetic fluid was sent for quantitative analysis. Association between AD-1 levels with outcomes, management, systemic markers of infection, and overall infection severity was evaluated.

Results:

Thirty-eight breasts were included. Infected breasts had higher AD-1 levels (3.91 versus 0.14, P < 0.01), greater odds of erythema [odds ratio (OR) 2.98 (1.53–5.82), P = 0.01], purulence [OR 2.84 (1.51–5.35), P = 0.01], fever [OR 1.84 (1.15–2.93), P = 0.01], threatened implant exposure [OR 2.97 (1.48–5.95), P < 0.01], and true implant exposure [OR 1.79 (1.04–3.08), P = 0.04]. Increasing AD-1 was an independent risk factor for washout (P < 0.01), and explant [OR 2.48 (1.47–4.2), P < 0.01]. AD-1 positively correlated with white blood cell count (β = 1.81 cells/µL, P < 0.01), and serum lactate (β = 0.19 meq/L, P < 0.04). Increasing AD-1 level was an independent predictor of infection severity (χ² = 22.77, P < 0.01).

Conclusions:

AD-1 levels correlate with infection severity, highlighting its potential both when clinical examination is ambiguous and when treatment response is being monitored. Although further evaluation is warranted, AD-1 may demonstrate utility in novel breast implant salvage algorithms.
Methods of determining clinical questions in the formulation of acupuncture-moxibustion clinical practice guideline: take “clinical practice guideline for acupuncture-moxibustion treatment of mild to moderate depression in adults” as an example
Authors: Fan Qi , Guo Lihua , Feng Yixuan , Kuang Hongjun , Xu Yuqin , Tang Han , Zaslawski Chris , Zhao Hong
Published: January 2024

Taking “Clinical practice guideline for acupuncture-moxibustion treatment of mild to moderate depression in adults,” the standard issued by the World Federation of Acupuncture-Moxibustion Societies as an example, this study aims to investigate the methods of determining clinical questions in the formulation of acupuncture-moxibustion clinical practice guideline and provide a methodological reference for developing high-quality, well-applied acupuncture-moxibustion guidelines.
Quality evaluation tool for animal experiments and the usage specifications
Authors: Li Jinlong , Dai Yuxiang , Ding Xing , Yan Ming , Zhu Ke , Wu Wei , Wu Ziming , Sun Yueli , Yao Min , Cui Xuejun , Wang Yongjun
Published: January 2024

The animal experiment is the best method for therapeutic efficacy testing of various treatment methods before clinical application and serves as an irreplaceable “live reagent” and “live precise instrument,” thus playing a vital role in biomedical science research. However, there were significant differences between the results of animal experiments and clinical efficacy in previous findings that are hard to ignore, especially in cerebrovascular accident research due to the unsatisfactory specification of animal experiments. Accordingly, more prescriptive and standard tools are required for evaluating the quality of animal experiments. This study will introduce the current commonly used quality evaluation tools for animal experiments.
The impact of perceived injustice on pain and psychological outcomes after traumatic injury: a longitudinal analysis
Authors: Trost Zina , Sturgeon John , Agtarap Stephanie , McMinn Kenleigh , McShan Evan , Boals Adriel , Arewasikporn Anne , Foreman Michael , Warren Ann Marie
Published: January 2024

Individuals' appraisals regarding the injustice of their pain or physical injury have emerged as a significant risk factor for worse physical and psychological outcomes. Injustice appraisals are defined by perceptions of external blame for pain or injury and viewing pain or injury as a source of irreparable loss. To date, research on the impact of injustice appraisal has been primarily cross sectional, and existing longitudinal studies have examined injustice appraisals at only 2 time points in the context of rehabilitation treatment. This study examined the trajectory of injustice appraisals in 171 patients admitted for traumatic injury at admission, as well as 3, 6, and 12 months after discharge and examined injustice appraisals as a potential moderator of recovery after injury. Findings can be summarized as follows: First, injustice perception was largely stable in the 12 months after hospital discharge. Second, elevated injustice perception was associated with decreased recovery in pain intensity and depressive symptomatology over the study period but did not moderate changes in pain catastrophizing or posttraumatic stress symptomatology over time. This study is the first naturalistic prospective analysis of injustice appraisal following trauma admission within the American healthcare system. Findings indicate that injustice appraisals do not naturally decrease in the aftermath of traumatic injury and may be a risk factor for poorer physical and psychological recovery. Future research should examine additional sociodemographic and psychosocial factors that may contribute to elevated injustice appraisal, as well as ways of addressing the potential deleterious impact of injustice appraisals in treatment settings.
Robot-assisted radical cystectomy with intracorporeal urinary diversion: an updated systematic review and meta-analysis of its differential effect on effectiveness and safety
Authors: Fu Shi , Shi HongJin , Fan Zhinan , Li Jinze , Luan Ting , Dong Haonan , Wang Jincheng , Chen Shuwen , Zhang Jinsong , Wang Jiansong , Ding Mingxia , Wang Haifeng
Published: January 2024

Background:

Robot-assisted laparoscopic cystectomy with intracorporeal urinary diversion (iRARC) is increasingly being used in recent years. Whether iRARC offers advantages over open radical cystectomy (ORC) remains controversial. This study aimed to compare the difference of perioperative outcomes, oncological outcomes and complications between iRARC and ORC.

Methods:

The PubMed, Embase, Cochrane Library, Web of Science and CNKI databases were searched in July 2023 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were identified to be eligible if they compared perioperative outcomes, oncological outcomes and complications in patients who underwent iRARC with ORC.

Results:

Twenty-two studies involving 7020 patients were included. Compared to ORC, iRARC was superior for estimated blood loss [estimated blood loss (EBL) weighted mean difference (WMD): −555.52; 95% CI, −681.64 to −429.39; P<0.001], blood transfusion rate [odds ratio (OR): 0.16; 95% CI, 0.09–0.28; P<0.001], length of hospital stay [length of hospital stay (LOS) WMD: −2.05; 95% CI, −2.93 to −1.17; P<0.001], Clavien–Dindo grades ≥III complication rate [30 days: OR: 0.57; 95% CI 0.44–0.75; P<0.001; 90 days: OR: 0.71; 95% CI 0.60–0.84; P<0.001], and positive surgical margin [positive surgical margin (PSM) OR: 0.65; 95% CI 0.49–0.85; P=0.002]. However, iRARC had a longer operative time [operative time (OT) WMD: 68.54; 95% CI 47.41–89.67; P<0.001] and a higher rate of ureteroenteric stricture [ureteroenteric stricture (UES) OR: 1.56; 95% CI 1.16–2.11; P=0.003]. Time to flatus, time to bowel, time to regular diet, readmission rate, Clavien–Dindo grades less than III complication rate for iRARC were similar to that for ORC. Interestingly, the results of subgroup analysis revealed no difference in EBL between iRARC and ORC when the diversion type was neobladder. When the ileal conduit was selected as the diversion type, the LOS was similar in both procedures.

Conclusion:

Robot-assisted laparoscopic cystectomy with intracorporeal urinary diversion appears to be superior to open radical cystectomy in terms of effectiveness and safety. However, attention should be paid to the occurrence of ureteroenteric stricture during follow-up.
Systemic Hemodynamics, Cardiac Mechanics, and Signaling Pathways Induced by Extracorporeal Membrane Oxygenation in a Cardiogenic Shock Model
Authors: Beurton Antoine , Michot Maxime , Hérion François-Xavier , Rienzo Mario , Oddos Claire , Couffinhal Thierry , Imbault Julien , Ouattara Alexandre
Published: January 2024

Peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly being used in patients suffering from refractory cardiogenic shock (CS). Although considered life-saving, peripheral VA-ECMO may also be responsible for intracardiac hemodynamic changes, including left ventricular overload and dysfunction. Venoarterial extracorporeal membrane oxygenation may also increase myocardial wall stress and stroke work, possibly affecting the cellular cardioprotective and apoptosis signaling pathways, and thus the infarct size. To test this hypothesis, we investigated the effects of increasing the peripheral VA-ECMO blood flow (25–100% of the baseline cardiac output) on systemic and cardiac hemodynamics in a closed-chest CS model. Upon completion of the experiment, the hearts were removed for assessment of infarct size, histology, apoptosis measurements, and phosphorylation statuses of p38 and protein Kinase B (Akt), and extracellular signal-regulated kinase mitogen-activated protein kinases (ERK-MAPK). Peripheral VA-ECMO restored systemic perfusion but induced a significant and blood flow-dependent increase in left ventricular preload and afterload. Venoarterial extracorporeal membrane oxygenation did not affect infarct size but significantly decreased p38-MAPK phosphorylation and cardiac myocyte apoptosis in the border zone.
Management of Gastrointestinal Symptoms in Parkinson’s Disease
Authors: Pasricha Trisha S. , Guerrero-Lopez Ingrid L. , Kuo Braden
Published: January 2024

Gastrointestinal symptoms in Parkinson’s disease (PD) are among the most prevalent and debilitating of complications and present unique diagnostic and management challenges. Patients with PD commonly experience dysphagia, nausea, bloating, and constipation related to pathologic involvement of the enteric nervous system. In turn, gastrointestinal complications may impact motor fluctuations and the efficacy of levodopa therapy. This review will explore the common gastrointestinal manifestations of PD with an emphasis on clinical presentation, workup, and treatment strategies.
Fatal Case of Exercise Collapse Associated with Sickle Cell Trait with Novel Underlying LAMA2 Mutation
Authors: Jaramillo Couger Jimenez , Gibbons Thomas , Rose Rachel , Walsh John
Published: January 2024

Sickle cell trait is typically thought to be an asymptomatic carrier state, but it is rarely associated with exertional rhabdomyolysis in cases termed Exercise Collapse Associated with Sickle Cell Trait (ECAST). In a subset of these cases, underlying disease contributes to the development and/or severity of the ensuing medical complications. We describe the first ever case of ECAST reported in a previously asymptomatic, multiply deployed, highly physically active service member with an underlying heterozygousLAMA2mutation. Moreover, the mutation identified via whole exome sequencing is a novel, likely pathogenic variant that has yet to be described in the literature.
Development and validation of a nomogram prognostic model for small cell lung cancer optimized by age and metastatic pattern
Authors: Guo Hanfei , Tuerxun Halahati , Li Wenqian , He Hua , Yang Wang , Bai Yuansong , Li Yarong , Yang Yu , Li Lingyu , Cui Jiuwei
Published: January 2024

Background:

The objective of this study is to establish and validate a novel nomogram by optimizing the eighth edition of the TNM classification by adding age and metastatic pattern.

Methods:

Clinical data of 1085 patients with small cell lung cancer (SCLC) from a Chinese multi-institutional registry were subjected to bootstrap external validation based on a prognostic nomogram built by integrating significant prognostic factors for survival from 21,707 cases from the Surveillance, Epidemiology, and End Results (SEER) database (training cohort). Kaplan–Meier survival analyses and concordance index (c-index) were used to test the application of the risk stratification system.

Results:

Both cohorts exhibited significant mortality increases with age (SEER hazard ratio [HR], 1.319; China HR, 1.237; both P < 0.001). The patterns of organ metastasis, liver (HR = 3.219), lung (HR = 1.750), brain (HR = 1.509), and bone (HR = 2.614), had significantly disparate prognoses. The nomogram based on the TNM classification of lung cancer was optimized by age and organ metastatic pattern, with an improvement in the C-index (from 0.617 to 0.661 in the training cohort and from 0.620 to 0.668 in the external validation cohort).

Conclusion:

This model provides useful quantitative tool for physicians to make critical diagnostic and treatment decisions for patients with SCLC.
Prospective Evaluation of Circulating Tumor DNA using Next Generation Sequencing as a Biomarker during Neoadjuvant Chemotherapy in Localized Pancreatic Cancer
Authors: Shah Dhavan , Wells Amy , Cox Madison , Dawravoo Kevin , Abad John , D’Souza Arlene , Suh Grace , Bayer Robert , Chaudhry Sohail , Zhang Qiang , Cristofanilli Massimo , Bentrem David , Chawla Akhil
Published: January 2024

Objective:

In this prospective study, we aim to characterize the prognostic value of circulating tumor DNA (ctDNA) by next-generation-sequencing (NGS) in patients undergoing neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC).

Summary Background Data:

Circulating tumor DNA is a promising blood-based biomarker that is prognostic in several malignancies. Detection of ctDNA by NGS may provide insights regarding the mutational profiles in PDAC to help guide clinical decisions for patients in a potentially curative setting. However, the utility of ctDNA as a biomarker in localized PDAC remains unclear.

Methods:

Patients with localized PDAC were enrolled in a prospective study at Northwestern Medicine between October 2020 and October 2022. Blood samples were collected to perform targeted tumor agnostic NGS utilizing the Tempus x|F 105 gene panel at three timepoints: pre-therapy (at diagnosis), post-NAC, and after local therapy, including surgery. The relationship between ctDNA detection and CA19-9, and the prognostic significance of ctDNA detection were analyzed.

Results:

56 patients were included in the analysis. ctDNA was detectable in 48% at diagnosis, 33% post-NAC, and 41% after local therapy. After completion of NAC, patients with detectable ctDNA had higher CA19-9 levels versus those without (78.4 vs. 30.0, P=0.02). The presence of baseline ctDNA was associated with a CA19-9 response; those without ctDNA had a significant CA19-9 response following NAC (109.0 U/mL vs. 31.5 U/mL; P=0.01), while those with ctDNA present at diagnosis did not (198.1 U/mL vs. 113.8 U/mL; P=0.77). In patients treated with NAC, the presence of KRAS ctDNA at diagnosis was associated with and independently predicted worse progression-free-survival.

Conclusion:

This report demonstrates the prognostic value of ctDNA analysis with NGS in localized PDAC. NGS ctDNA is a biomarker of treatment response to NAC. KRAS ctDNA at diagnosis independently predicts worse survival in patients treated with NAC.
Comparative chemical characters of Ziziphi Spinosae Semen from geographical origins of China
Authors: Wang Pengwang , Sha Miao , Zhang Weimei , Tian Hongyue , Liang Xu , Tian Wei , Xu Bo , Chang Guanglu , Li Xia , Gao Wenyuan
Published: January 2024

Background

Ziziphi Spinosae Semen (ZSS) contains a wide range of active components. Because existing methods cannot fully evaluate these components, a new quantitative method needs to be established for component characterization.

Objective

Ziziphi Spinosae Semen has gained increasing attention in recent years, primarily as a medicinal and edible plant. The content determination of ZSS is not specified in the Chinese Pharmacopeia (2020 edition). Environmental conditions in different production areas can influence the quality of ZSS. This study aims to identify ZSS collected from various geographical origins in China.

Materials and methods

High-performance liquid chromatography (HPLC) fingerprints were established using optimized HPLC-photo-diode array methods. Subsequently, similarity analysis and quantification of ZSS from different sources were conducted. Metabolites of ZSS were identified and evaluated using the UHPLC-Q Exactive HF Orbitrap MS system. Principal component analysis, hierarchical cluster analysis, and orthogonal partial least squares discriminant analysis were performed based on all peak areas.

Results

In this study, the components of ZSS against insomnia were screened through network pharmacology. As revealed by the results of protein-protein interaction network analysis, Gene Ontology analysis, and Kyoto Encyclopedia of Genes and Genomes pathway analysis, 14 core components, 10 core targets, and 25 pathways were identified. Thirty-four batches of ZSS fingerprints were established through the HPLC method, which identified 12 characteristic peaks, with 6 being qualitatively identified. An identification method for assessing differences in the chemical composition of ZSS from different origins was developed by using UHPLC-Q Exactive HF Orbitrap MS. Differential markers from various origins were screened and identified. Through multiple analyses such as principal component analysis and orthogonal partial least squares discriminant analysis, it was concluded that there were differences in ZSS metabolites from Hebei, Shandong, and Shaanxi provinces. Seventeen differential metabolites of different origins were identified.

Conclusions

This study confirmed that ZSS played a synergistic role in improving insomnia through multiple components, targets, and pathways. The content of all 5 components was high, except for jujuboside B. In addition, 6 compounds in ZSS extracts from different origins differed in content, indicating that different growth environments might impact the quality of ZSS.
Automated Synthesis of Wireframe DNA Nanotubes
Authors: Islas Patricia , Platnich Casey M. , Gidi Yasser , Karimi Ryan , Ginot Lorianne , Cosa Gonzalo , Sleiman Hanadi F.
Published: January 2024

DNA nanotechnology has revolutionized our ability to position matter at the nanoscale, but the preparation of DNA-based architectures remains laborious. To facilitate the formation of custom structures, we report a fully automated method to produce sequence- and size-defined DNA nanotubes. By programming the sequential addition of desired building blocks, rigid DX-tile-based DNA nanotubes (and flexible wireframe DNA structures) are attained, where the total number of possible constructs increases as a power function of the number of different units available. Using single-molecule fluorescence imaging, the kinetics and yield of each synthetic step can be quantitatively determined, revealing differences in self-assembly dynamics as the nanotube is built up from the solid support and providing new insights into DNA self-assembly. The exploitation of automation for both assembly and analysis (tthrough anad-hocdeveloped K-means clustering algorithm) facilitates a workflow wherein the synthesis parameters may be iteratively improved upon, demonstrating how a single-molecule ‘assembly-analysis-optimization’ sequence can be used to generate complex, non-covalent materials in good yield. The presented synthetic strategy is generalizable, making use of equipment already available in most standard laboratories and represents the first fully automated supramolecular assembly on a solid support.
Biologically Driven In Vivo Occlusion Design Provides a Reliable Experimental Glaucoma Model
Authors: Hong Eunji , Tian Feng , Glynn Christopher , Tsekov Sophia , Huang Sizhe , Zhou Songlin , He Zhigang , Rao Siyuan , Wang Qianbin
Published: January 2024

Fluid flow transport through the trabecular meshwork tissues is a major regulator of intraocular pressure (IOP) modulation in healthy and glaucomatous individuals. Microbead occlusion models of ocular hypertension regulate aqueous humor drainage to induce high IOP to allow for in vivo study of pressure-related glaucomatous pathology. However, the reliability and application of current injectable microbeads are hindered by inadequate design of the beads-tissue interfaces to maintain a stable IOP elevation over the long term. Considering the graded, porous architecture and fluid transport of the trabecular meshwork, we developed a tailored, injectable “viscobeads” technique, which induced a sustained elevation of IOP for at least 8 weeks. These composite viscobeads contain a non-degradable polystyrene (PS) core for structural support and a biodegradable polylactic-co-glycolic acid (PLGA) viscoelastic surface. This approach enhances the obstruction of aqueous humor drainage through heterogeneous sizes of trabecular meshwork fenestrations and reliably modulates the magnitude and duration of ocular hypertension. In a mouse model, a single viscobeads injection resulted in sustained IOP elevation (average 21.4±1.39 mm Hg), leading to a 34% retinal ganglion cell (RGC) loss by 56 days. In an earlier stage of glaucoma progression, we conducted non-invasive electroretinography (ERG) recording and revealed glaucomatous progression by analyzing high-frequency oscillatory potentials. To further explore the application of the viscobeads glaucoma models, we assayed a series of genes through adeno-associated virus (AAV)-mediated screening in mice and assessed the impact of genetic manipulation on RGC survivals. CRISPR mediated disruption of the genes, PTEN, ATF3 and CHOP enhanced RGC survival while LIN 28 disruption negatively impacted RGC survival. This biologically driven viscobeads design provides an accessible approach to investigate chronic intraocular hypertension and glaucoma-like neurodegeneration and ultimately tenders the opportunity to evaluate genetic and pharmacological therapeutics.
A Multiomics, Spatiotemporal, and Single Cell Atlas for Mapping Cell-Type-Specific Dysregulation at the Maternal-Fetal Interface
Authors: Wang Cheng , Zhou Yan , Wang Yuejun Jessie , Guha Tuhin Kumar , Luo Zhida , McIntyre Tara I. , Schwab Marisa E. , Davidson Brittany R. , Reeder Gabriella C. , Wong Ronald J. , England Sarah , Gonzalez Juan M. , Blelloch Robert , Combes Alexis J. , Giudice Linda C. , Erlebacher Adrian , MacKenzie Tippi C. , Stevenson David K. , Shaw Gary M. , Snyder Michael P. , Fisher Susan J. , Winn Virginia D. , Li Jingjing
Published: January 2024

The placenta, the first organ to functionally mature, undergoes disordered development in many pregnancy complications. Molecular investigations have been hampered by the extreme cellular heterogeneity of the placenta, and this complexity is further exaggerated at the maternal-fetal interface where maternal and fetal cells co-mingle. We generated the paired single nucleus epigenomes and transcriptome for each of ∼200,000 cells at the human maternal-fetal interface from early pregnancy to term. These data identified cell-type-specific transcriptional regulatory programs and uncovered key transcription factors driving the lineage differentiation of placental cytotrophoblasts. Integrating spatial single cell proteomics profiling, we localized the observed cell typesin situ, and characterized the dynamic stages and distinct features of endothelial cells of maternal spiral arteries remodeled by extravillous cytotrophoblasts. Integrative analyses of the single cell data across gestation enabled fine-mapping of the developmental trajectories of cytotrophoblasts and decidual stromal cells, and defining the signature molecular profiles of known and novel cell (sub)types. To demonstrate clinical value, we integrated the reference single cell data with large-scale population genomes from pregnancy complications and identified the most vulnerable maternal and fetal cell types in preeclampsia, preterm birth, and miscarriage. This study presents the most comprehensive placental and decidual single cell resource across gestation to date, reveals new insights into the drivers of normal human placentation, and uncovers the cellular basis of dysfunction associated with common pregnancy complications.
Application of Elevated Atmospheric Pressure and Hypoxia Enhance Pluripotency and Stem Cell Differentiation
Authors: Pappalardo Zachary , Downie Bryan , Adams Bruce A. , Lim James
Published: January 2024

Physical forces regulate stem cell differentiation in-vivo, however few simple and precise methods exist to better understand this biology in-vitro. Here we describe the use of a novel bioreactor that enables addition of physical force in the form of elevated atmospheric pressure during reprogramming of human fibroblasts and culture of human induced pluripotent stem cell (iPSC) and neural stem cell (NSC) lines. We demonstrate that elevated atmospheric pressure and hypoxia can positively regulate reprogramming of human fibroblasts to iPSCs across multiple donors. Prolonged culture of iPSCs in elevated atmospheric pressure (+ 2 PSI) and 15% oxygen exhibited progressive differentiation with concomitant metabolic and epigenetic gene expression changes. Furthermore, elevated atmospheric pressure positively regulates differentiation of iPSCs to neural-ectodermal and hematopoietic lineages when combined with appropriate soluble factors and oxygen concentration. In summary, these results demonstrate the significance of applied atmospheric pressure for stem cell applications and warrants further investigation.
Aging and injury drive neuronal senescence in the dorsal root ganglia
Authors: Donovan Lauren J. , Brewer Chelsie L. , Bond Sabrina F. , Lopez Aleishai Pena , Hansen Linus H. , Jordan Claire E. , González Oscar C. , de Lecea Luis , Kauer Julie A. , Tawfik Vivianne L.
Published: January 2024

Aging negatively impacts central nervous system function; however, the cellular impact of aging in the peripheral nervous system remains poorly understood. Aged individuals are more likely to experience increased pain and slower recovery after trauma. Such injury can damage vulnerable peripheral axons of dorsal root ganglion (DRG) neurons resulting in somatosensory dysfunction. One cellular mechanism common to both aging and injury is cellular senescence, a complex cell state that can contribute to the aged pro-inflammatory environment. We uncovered, for the first time, DRG neuron senescence in the context of aging and pain-inducing peripheral nerve injury in young and aged mice. Aged DRG neurons displayed multiple markers of senescence (SA-β-gal, p21, p16, IL6) when compared to young DRG neurons. Peripheral nerve injury triggered a further accumulation of senescent DRG neurons over time post-injury in young and aged DRG. These senescent neurons were dynamic and heterogeneous in their expression of senescence markers, p16, p21, and senescence-associated secretory phenotype (SASP) expression of IL6, which was influenced by age. An electrophysiological characterization of senescence marker-expressing neurons revealed high-firing and nociceptor-like phenotypes within these populations. In addition, we observed improvement in nociceptive behaviors in young and aged nerve-injured mice after treatment with a senolytic agent that eliminates senescent cells. Finally, we confirmed in human post-mortem DRG samples that neuronal senescence is present and increases with age. Overall, we describe a susceptibility of the peripheral nervous system to neuronal senescence with age or injury that may be a targetable mechanism to treat sensory dysfunction, such as chronic pain, particularly in aged populations.
Lipid Dysregulation Unveil the Intricate Interplay of Lysosomal and Mitochondrial Changes in Frontotemporal Dementia with GRN Haploinsufficiency
Authors: Ondaro Jon , Zúñiga-Elizari Jose Luis , Zufiría Mónica , Garciandia-Arcelus Maddi , Zulaica Miren , Lafarga Miguel , Riancho Javier , Holt Ian James , López de Munaín Adolfo , Moreno Fermin , Gil-Bea Francisco Javier , Gereñu Gorka
Published: January 2024

This study investigates the cellular pathology resulting from haploinsufficiency of progranulin (PGRN) in frontotemporal dementia (FTD) associated with granulin (GRN) mutations. Utilizing fibroblasts from FTD patients carrying a distinctive GRN mutation (c.709-1G>A), we observed lysosomal and lipofuscin accumulation, impaired lysosomal function, compromised autophagic flux, and mitochondrial abnormalities. Notably, recombinant human progranulin (rhPGRN) treatment restored lysosomal acidification, mitigated mitochondrial defects, and demonstrated beneficial effects. FTD-GRN fibroblasts exhibited abnormal lipid metabolism with increased lipid droplet formation, influenced by GRN haploinsufficiency and modulated by rhPGRN. Under nutrient-rich conditions, lipid droplet dynamics were shaped by autophagy and mitochondrial processes, potentially due to impaired fatty acid oxidation. These findings highlight a direct association between GRN deficiency and altered lysosomal-mitochondrial interactions, influencing lipid metabolism and contributing to FTD pathogenesis. The documented lysosomal dysfunction, impaired autophagy, mitochondrial anomalies, and altered lipid metabolism collectively suggest a complex interplay of cellular processes in the development of FTD-GRN.