bluuebunny/crossref_metadata_2025 huggingface dataset:
Circular stable intronic RNAs possess distinct biological features and are deregulated in bladder cancer
Authors: Rasmussen Asta M , Okholm Trine Line H , Knudsen Michael , Vang Søren , Dyrskjøt Lars , Hansen Thomas B , Pedersen Jakob S
Published: August 2023

Until recently, intronic lariats were regarded as short-lasting splicing byproducts with no apparent function; however, increasing evidence of stable derivatives suggests regulatory roles. Yet little is known about their characteristics, functions, distribution, and expression in healthy and tumor tissue. Here, we profiled and characterized circular stable intronic sequence RNAs (sisRNAs) using total RNA-Seq data from bladder cancer (BC; n = 457, UROMOL cohort), healthy tissue (n = 46), and fractionated cell lines (n = 5). We found that the recently-discovered full-length intronic circles and the stable lariats formed distinct subclasses, with a surprisingly high intronic circle fraction in BC (∼45%) compared to healthy tissues (0–20%). The stable lariats and their host introns were characterized by small transcript sizes, highly conserved BP regions, enriched BP motifs, and localization in multiple cell fractions. Additionally, circular sisRNAs showed tissue-specific expression patterns. We found nine circular sisRNAs as differentially expressed across early-stage BC patients with different prognoses, and sisHNRNPK expression correlated with progression-free survival. In conclusion, we identify distinguishing biological features of circular sisRNAs and point to specific candidates (incl. sisHNRNPK, sisWDR13 and sisMBNL1) that were highly expressed, had evolutionary conserved sequences, or had clinical correlations, which may facilitate future studies and further insights into their functional roles.
Development of a core outcome set for use in adult primary glioma phase III interventional trials: A mixed methods study
Authors: Retzer Ameeta , Baddeley Elin , Sivell Stephanie , Scott Hannah , Nelson Annmarie , Bulbeck Helen , Seddon Kathy , Grant Robin , Adams Richard , Watts Colin , Aiyegbusi Olalekan Lee , Kearns Pamela , Rivera Samantha Cruz , Dirven Linda , Calvert Melanie , Byrne Anthony
Published: August 2023

Background

Glioma interventional studies should collect data aligned with patient priorities, enabling treatment benefit assessment and informed decision-making. This requires effective data synthesis and meta-analyses, underpinned by consistent trial outcome measurement, analysis, and reporting. Development of a core outcome set (COS) may contribute to a solution.

Methods

A 5-stage process was used to develop a COS for glioma trials from the UK perspective. Outcome lists were generated in stages 1: a trial registry review and systematic review of qualitative studies and 2: interviews with glioma patients and caregivers. In stage 3, the outcome lists were de-duplicated with accessible terminology, in stage 4 outcomes were rated via a 2-round Delphi process, and stage 5 comprised a consensus meeting to finalize the COS. Patient-reportable COS outcomes were identified.

Results

In Delphi round 1, 96 participants rated 35 outcomes identified in stages 1 and 2, to which a further 10 were added. Participants (77/96) rated the resulting 45 outcomes in round 2. Of these, 22 outcomes met a priori threshold for inclusion in the COS. After further review, a COS consisting of 19 outcomes grouped into 7 outcome domains (survival, adverse events, activities of daily living, health-related quality of life, seizure activity, cognitive function, and physical function) was finalized by 13 participants at the consensus meeting.

Conclusions

A COS for glioma trials was developed, comprising 7 outcome domains. Additional research will identify appropriate measurement tools and further validate this COS.
A Comparative Study of the Effects of Electronic Cigarette and Traditional Cigarette on the Pulmonary Functions of C57BL/6 Male Mice
Authors: Zhao Han-Zhi , Guo Zi-Wei , Wang Zhang-Li , Wang Chen , Luo Xian-Yu , Han Ning-Ning , Li Chen-Rui , Zheng Hua-Dong , Hui Zi-Yi , Long Yang , Zhao Yan-Lei , Li Qiu-Jin , Wang Sheng-Yu , Zhang Guang-Wei
Published: August 2023

Introduction

Electronic cigarettes (E-cigs) are in a controversial state. Although E-cig aerosol generally contains fewer harmful substances than smoke from burned traditional cigarettes, aerosol along with other compounds of the E-cigs may also affect lung functions and promote the development of lung-related diseases. We investigated the effects of E-cig on the pulmonary functions of male C57BL/6 mice and reveal the potential underlying mechanisms.

Methods

A total of 60 male C57BL/6 mice were randomly divided into four groups. They were exposed to fresh-air, traditional cigarette smoke, E-cig vapor with 12 mg/mL of nicotine, and E-cig with no nicotine for 8 weeks. Lung functions were evaluated by using quantitative analysis of the whole body plethysmograph, FlexiVent system, lung tissue histological and morphometric analysis, and RT-PCR analysis of mRNA expression of inflammation-related genes. In addition, the effects of nicotine and acrolein on the survival rate and DNA damage were investigated using cultured human alveolar basal epithelial cells.

Results

Exposure to E-cig vapor led to significant changes in lung functions and structures including the rupture of the alveolar cavity and enlarged alveolar space. The pathological changes were also accompanied by increased expression of interleukin-6 and tumor necrosis factor-α.

Conclusions

The findings of the present study indicate that the safety of E-cig should be further evaluated.

Implications

Some people currently believe that using nicotine-free E-cigs is a safe way to smoke. However, our research shows that E-cigs can cause lung damage regardless of whether they contain nicotine.
Effects of Nicotine Content and Preferred Flavor on Subjective Responses to E-cigarettes: A Randomized, Placebo-controlled Laboratory Study
Authors: Bremmer Michael P , Campbell Alana M , Xia Kai , Tarran Robert , Girdler Susan S , Hendershot Christian S
Published: August 2023

Introduction

Evidence suggests that e-liquid flavor and nicotine concentration are important factors in the initiation and maintenance of e-cigarette use (vaping). Flavors may increase the initiation and maintenance of vaping, and nicotine content is a factor in e-cigarette dependence and the efficacy of e-cigarettes for cigarette smoking cessation. Few human laboratory studies have assessed the joint and interactive effects of flavor and nicotine on subjective responses to e-cigarettes.

Methods

Regular e-cigarette users (N = 89) completed a multi-session study involving a paced vaping procedure with e-liquid cartridges containing their preferred flavor (berry, menthol, or tobacco) or no flavor, with or without nicotine (18 mg). Subjective effects of vaping (satisfaction, reward, aversion, airway sensations, and craving relief) were assessed.

Results

Nicotine significantly increased psychological reward and craving relief, whereas flavor significantly increased vaping satisfaction and taste. Nicotine dependence severity moderated the effect of nicotine on reward, such that those with the greatest dependence severity reported the greatest reward.

Conclusions

These findings support differential and noninteractive effects of e-liquid nicotine content and flavor on reinforcing effects of e-cigarettes.

Implications

E-liquid flavor and nicotine content have independent, non-interactive effects on subjective responses to vaping under controlled laboratory conditions. Among regular e-cigarette users, vaping a preferred flavor increased taste and satisfaction, but did not interact with nicotine to alter reward or craving. Further research on the ways in which these subjective effects may motivate vaping behavior among different populations of e-cigarette users would be useful to inform regulatory policy of ENDS products.
A Phase I Dose-Escalation Study of LY3405105, a Covalent Inhibitor of Cyclin-Dependent Kinase 7, Administered to Patients With Advanced Solid Tumors
Authors: Garralda Elena , Schram Alison M , Bedard Philippe L , Schwartz Gary K , Yuen Eunice , McNeely Samuel C , Ribeiro Silvia , Cunningham Jason , Wang Yi , Urunuela Arantxa , Xu Xiaojian , LoRusso Patricia
Published: August 2023

Background

This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors.

Materials and Methods

LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity.

Results

Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n = 3; 35 mg: n = 3; 25 mg: n = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at ≥15 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed.

Conclusion

The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development.

ClinicalTrials.gov Identifier

NCT03770494.
Early Tumor Shrinkage and Depth of Response as Predictors of Survival for Advanced Biliary Tract Cancer: An Exploratory Analysis of JCOG1113
Authors: Okano Naohiro , Morizane Chigusa , Okusaka Takuji , Sadachi Ryo , Kataoka Tomoko , Kobayashi Satoshi , Ikeda Masafumi , Ozaka Masato , Mizutani Tomonori , Sugimori Kazuya , Todaka Akiko , Shimizu Satoshi , Mizuno Nobumasa , Yamamoto Tomohisa , Sano Keiji , Tobimatsu Kazutoshi , Katanuma Akio , Gotoh Kunihito , Yamaguchi Hironori , Ishii Hiroshi , Ohba Akihiro , Furuse Junji , Ueno Makoto ,   Hepatobiliary and Pancreatic Oncology Group of Japan Clinical Oncology Group (JCOG)
Published: August 2023

Background

Recent studies suggest that early tumor shrinkage (ETS) and depth of response (DpR) reflect outcomes of chemotherapy in various cancers. This study evaluated the association of ETS and DpR with clinical outcomes using data from JCOG1113, which demonstrated the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for chemotherapy-naïve advanced biliary tract cancer.

Material and Methods

In total, 354 (289 with measurable target lesions) patients enrolled in JCOG1113 were divided into ETS-unachieved and ETS-achieved groups (≥20% tumor reduction at week 6) and DpR-low and DpR-high groups (≥40% maximum shrinkage) until 12 weeks after enrollment. The impact of ETS and DpR on survival outcome was evaluated using the multivariable Cox proportional hazard model.

Results

The proportions of patients in the ETS-achieved and DpR-high groups were similar between the 2 treatment arms. The hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for the ETS-achieved group were 0.70 (95% confidence interval (CI), 0.52-0.93) and 0.60 (95%CI, 0.44-0.81), respectively. The HRs of PFS and OS for the DpR-high group were 0.67 (95%CI, 0.48-0.94) and 0.64 (95%CI, 0.46-0.90), respectively. In the subpopulation treatment effect pattern plot analysis, most patients in the ETS-achieved group in the GC arm did not experience disease progression after 12 weeks from the landmark.

Conclusion

As on-treatment markers, ETS and DpR were effective tools. ETS was clinically useful, because it can be used to evaluate the outcomes of treatment early at a specific time.
COVID-19 and Hospital-Acquired Pressure Injuries: A Systematic Review
Authors: Bourkas Adrienn N. , Zaman Michele , Sibbald R. Gary
Published: August 2023

OBJECTIVE

To investigate the relationship between COVID-19-related variables and hospital-acquired pressure injury (HAPI) incidence.

DATA SOURCES

The authors searched four databases: Cochrane, MEDLINE, EMBASE, and CINAHL. The literature search contained key terms such as “COVID-19,” “hospital-acquired pressure injuries,” “pressure ulcer,” “pressure injury,” “decubitus ulcer,” and “hospitalization.”

STUDY SELECTION

The systematic search of the literature identified 489 publications that matched the inclusion criteria. Articles were included in the review if they were peer-reviewed publications that reported HAPI incidence for patients who were hospitalized and COVID-19 positive. Two reviewers performed the screen simultaneously, and 19 publications were included.

DATA EXTRACTION

Two reviewers followed a standardized extraction form that included study and patient characteristics, COVID-19 status, HAPI characteristics, prone positioning, length of hospitalization, and HAPI prevention and treatment strategies.

DATA SYNTHESIS

The authors carried out a narrative synthesis of the extracted data because the data obtained were too heterogeneous for meta-analysis. The primary outcome was HAPI incidence.

CONCLUSIONS

This review identified that HAPI incidence was high among men who were COVID-19 positive, had longer hospital stays, experienced prone positioning, and had care teams without a skin and wound care expert. Future research should use more robust methodology and focus on quantitative modeling to iteratively improve inpatient HAPI guidelines.
One-Year Outcomes of Patients Requiring Tracheostomy Placement Due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection
Authors: Abunasser Jafar J. , Perez Oscar , Wang Xiaofeng , Wang Yifan , Khouli Hassan , Duggal Abhijit
Published: August 2023

BACKGROUND:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease it causes (COVID-19) have resulted in an increase in critical illness and in the prevalence of acute respiratory failure with the need for tracheostomy. The characteristics and long-term outcomes of this patient cohort are not well identified.

RESEARCH QUESTION:

What are the characteristics of patients who develop the need for tracheostomy due to SARS-CoV-2 with acute respiratory distress syndrome (ARDS)? What is their 90-day and 1-year survival and are there any identifiable risk factors for mortality and ventilator dependency?

STUDY DESIGN AND METHODS:

Retrospective, follow-up cohort study of adult patients with COVID-19 infection and ARDS who required tracheostomy placement in a large healthcare system.

RESULTS:

One hundred sixty-four consecutive patients with SARS-CoV-2 admitted to ICUs for ARDS who required tracheostomy placement between March 2020 and March 2021 were identified. One hundred nine (66.5%) were male. Average age was 63.5 years. The most common comorbidities were obesity, hypertension, diabetes mellitus, congestive heart failure, chronic kidney disease, chronic obstructive pulmonary disease (COPD), atrial fibrillation, and asthma. The most common complications during hospitalization were delirium, secondary infections, acute kidney injury, pneumothorax, and venous thromboembolism. Ninety-day and 1-year mortality were 29.9% and 44.5%, respectively. Ninety-six patients (58.5%) were liberated from the ventilator, and 84 (51.2%) had the tracheostomy tube decannulated. Asthma, COPD, atrial fibrillation, and renal replacement therapy requirement in the ICU correlated with increased risk of ventilator dependency. Among survivors at 1 year, 71 patients (43.3%) were residing at home and 20 patients (12.2%) remained in a skilled nursing facility.

INTERPRETATION:

COVID-19 has resulted in a significant burden of acute critical illness and acute respiratory failure with the need for tracheostomy. A significant percentage of patients with SARS-CoV-2 requiring tracheostomy were alive and at home 1 year after tracheostomy placement. Long-term care support, including tracheostomy, beyond 90 days appears to be beneficial in this patient population and warrants further investigation.
New Therapy Update Aprocitentan: An Endothelin Receptor Antagonist for the Treatment of Drug-Resistant Systemic Hypertension
Authors: Airo Michael , Frishman WIlliam H. , Aronow Wilbert S.
Published: August 2023

Resistant hypertension (RH) is the state of uncontrolled blood pressure in the face of ostensibly optimal pharmacological intervention. It accounts for roughly one in six cases of hypertension, and is associated with more severe morbidity and mortality outcomes than is non-RH. The prevalence of RH implies a currently unmanaged pathology, which may involve the potent vasoconstrictor endothelin. Several endothelin receptor antagonists are currently marketed for pulmonary arterial hypertension, but none so far has been marketed for RH. Aprocitentan is currently in development, an endothelin receptor antagonist that effectively produces clinically significant and sustained decreases in systolic and diastolic blood pressure in the setting of RH.
Cardiac Allograft Rejection: Strategies for Success in the Face of Immune Challenges
Authors: Patail Haris , Khan Shazli , Aggarwal-Gupta Chhaya , Aronow Wilbert S.
Published: August 2023

Heart transplantation for patients with end-stage heart failure refractory to medical therapy has remained definitive treatment with significant advances in posttransplant care. Despite improvement in postoperative morbidity and mortality, acute cellular rejection (ACR) and antibody-mediated rejection (AMR) remain substantial challenges that can lead to allograft failure and patient mortality. Immunosuppressive agents have been the mainstay of both prevention and treatment for ACR and AMR; however, many challenges exist with traditional therapies. There are a multitude of molecular pathways involved in mediating the humoral and cellular response to rejection, offering various targets for treatment. This review summarizes therapies used in the management of ACR and AMR as extrapolated from use in induction therapy and treatment of other solid-organ transplant rejection. Future studies focused on cardiac transplant recipients are needed to expand therapeutic options.
Zymosan A produces a rapid and sustained antidepressant effect in chronically stressed mice by stimulating hippocampal microglia
Authors: Zhu Tao , Chen Bingran , Han Han , Lu Xu , Chen Zhuo , Ye Ting , Zhao Hui , Zheng Meng , Huang Chao
Published: August 2023

Recent studies had reported that compounds that stimulate microglia could be developed as potential drugs for the treatment of depression due to their reversal effect on depression-like behaviors in chronically stressed mice. Zymosan A is a cell wall preparation of Saccharomyces cerevisiae composed of β-glucans. Based on its immuno-stimulatory activities, we hypothesized that zymosan A might have a therapeutic effect on depression. Our results showed that a single injection of zymosan A 5 h before behavioral tests at a dose of 1 or 2 mg/kg, but not at a dose of 0.5 mg/kg, reversed chronic unpredictable stress (CUS)-induced depression-like behaviors in mice in the tail suspension test, forced swimming test, and sucrose preference test. Time-dependent analysis showed that the antidepressant effect of zymosan A (2 mg/kg) in CUS mice became statistically significant at 5 and 8 h, but not at 3 h, and persisted for at least 7 days. Fourteen days after a single injection of zymosan A, no antidepressant effect was observed anymore. However, the disappeared antidepressant effect of zymosan A was restored by a second zymosan A injection (2 mg/kg, 5 h) 14 days after the first zymosan A injection. Stimulation of microglia was essential for the antidepressant effect of zymosan A because pre-inhibition of microglia by minocycline or pre-depletion of microglia by PLX3397 prevented the antidepressant effect of zymosan A. Based on these effects of zymosan A, zymosan A administration could be developed as a new strategy for the treatment of depression.
Recommendations for Patient-Reported Outcomes Measurement Information System pediatric measures in youth with chronic pain: a COnsensus-based Standards for the selection of health Measurement INstruments systematic review of measurement properties
Authors: Li Rui , Gibler Robert C. , Rheel Emma , Slack Katherine , Palermo Tonya M.
Published: August 2023

The Patient-Reported Outcome Measurement Information System (PROMIS) pediatric measures assess physical, emotional, and social health among children and adolescents. However, their measurement properties have not been systematically examined in youth with chronic pain. A systematic review applying the COnsensus based Standards for the selection of health Measurement INstruments (COSMIN) methodology was conducted to evaluate self-reported PROMIS pediatric measures in youth with chronic pain, assessing 8 measurement properties across all versions (item bank, short form, and computer adaptive testing) from 63 studies covering 25 measures. Moderate or high-quality evidence was most available for content validity, structural validity, internal consistency (measurement precision), and construct validity. Four short-form PROMIS pediatric measures—mobility, anxiety, depressive symptoms, and physical stress experiences—achieved recommendation for the use in chronic pain clinical trials; 7 approached recommendation and 14, including the commonly used PROMIS Pediatric Pain Interference Scale, would be recommended with further evidence. Recommendations were also provided for the use of each measure in observational studies. Overall, based on the existing evidence, a total of 11 self-reported PROMIS pediatric short-form measures, including pain intensity, pain behavior, mobility, sleep disturbance, sleep-related impairment, anxiety, depressive symptoms, psychological stress experiences, physical stress experiences, family relationships, and positive effect, are recommended or approaching recommendation for use in youth ages 8 to 19 years with chronic pain. Research is needed to further establish test–retest reliability, measurement errors, cross-cultural validity, and responsiveness. Future work should expand the evaluation of PROMIS pediatric measures in subpopulations of youth with chronic pain, particularly young children and those with neurodevelopmental disabilities.
Early effects of very early cochlear implant activation on tinnitus
Authors: Chau Ivy Yenwen , Li Sophia Yung-Hsia , Shiao An-Suey , Islam Albina S. , Coelho Daniel H.
Published: August 2023

Background:

Cochlear implantation (CI) has long been the standard of care for patients with severe-to-profound hearing impairment. Yet the benefits of CI extend far beyond speech understanding, with mounting recent literature supporting its role in tinnitus abatement. However, those studies have uniformly analyzed the effects of tinnitus after the traditional 3–4 weeks waiting period between CI surgery and device activation. As many clinics are shifting these waiting intervals to become shorter (in some cases within 24 hours, little is known about tinnitus abatement very early in the postoperative period. The aim of this study was to compare preoperative and postoperative tinnitus handicaps in this unique but growing population of very early-activated patients.

Methods:

Twenty-seven adults with severe-to-profound hearing impairment with chronic tinnitus (>6 months) were included. Patients with concomitant psychiatric disorders were excluded. All patients were implanted with the same array and were switched on within 24 hours after the surgery. Tinnitus Handicap Inventory (THI) was recorded preoperatively, immediately after activation at 24 hours postoperatively, at 1 week, 2 weeks, and I month after activation. Wilcoxon signed-rank test was used to compare values between preoperative assessment and respective fitting sessions.

Results:

Mean THI 24 hours after implantation increased in comparison to that assessed preoperatively (77.6 vs 72.5, p = 0.001). By 1 week after surgery, the THI had decreased to 54.9 (p < 0.001). This trend continued and was statistically significant at 2 weeks (36.0, p < 0.001) and 1 month (28.5, p < 0.001).

Conclusion:

On average, most patients with tinnitus will note a significant improvement in their tinnitus handicap when activated within 24 hours of CI. However, tinnitus does increase between surgery and 24 hours, most likely reflecting not only intracochlear changes, but modulation of the entire auditory pathway. Following this early rise, the tinnitus continues to abate over the following month. Patients with tinnitus may benefit from early activation, although should be counseled that they may experience an exacerbation during the very early postoperative period.
Technical Surgical Skill Assessment of Neurovascular Bundle Dissection and Urinary Continence Recovery After Robotic-Assisted Radical Prostatectomy
Authors: Ma Runzhuo , Cen Steven , Forsyth Edward , Probst Patrick , Asghar Aeen , Townsend William , Hui Alvin , Desai Aditya , Tzeng Michael , Cheng Emily , Ramaswamy Ashwin , Wagner Christian , Hu Jim C. , Hung Andrew J.
Published: August 2023

Purpose:

To examine the association between the quality of neurovascular bundle dissection and urinary continence recovery after robotic-assisted radical prostatectomy.

Materials and Methods:

Patients who underwent RARPs from 2016 to 2018 in 2 institutions with ≥1-year postoperative follow-up were included. The primary outcomes were time to urinary continence recovery. Surgical videos were independently assessed by 3 blinded raters using the validated dissection assessment for robotic technique (DART) tool after standardized training. Cox regression was used to test the association between DART scores and urinary continence recovery while adjusting for relevant patient features.

Results:

One hundred twenty one RARP performed by 23 surgeons with various experience levels were included. The median follow-up was 24 months (95% confidence interval [CI] 20-28 months). The median time to continence recovery was 7.3 months (95% CI 4.7-9.8 months). After adjusting for patient age, higher scores of certain DART domains, specifically tissue retraction and efficiency, were significantly associated with increased odds of continence recovery (P < .05).

Conclusions:

Technical skill scores of neurovascular bundle dissection vary among surgeons and correlate with urinary continence recovery. Unveiling the specific robotic dissection skillsets which affect patient outcomes has the potential to focus surgical training.
Lung function decline is mitigated following liver transplantation in people with cystic fibrosis: A retrospective cohort study
Authors: Albaiz Faisal A. , Ramos Kathleen J. , Sykes Jenna , Stanojevic Sanja , Ma Xiayi , Quon Bradley S. , Marshall Bruce C. , Cromwell Elizabeth A. , Ostrenga Joshua S. , Faro Albert , Elbert Alexander , Goss Christopher H. , Stephenson Anne L.
Published: August 2023

There is paucity of literature on the health outcomes following liver transplantation (LT) in people with cystic fibrosis (pwCF). We aim to evaluate changes in lung function following LT in pwCF. We performed a retrospective cohort study of pwCF who underwent LT between 1987 and 2019 in the United States and Canada. Simultaneous lung-liver transplants and individuals who had lung transplant prior to LT were excluded. We analyzed pre-LT and post-LT percent predicted forced expiratory volume in 1 second, body mass index, rates of pulmonary exacerbation, and post-LT overall survival. A total of 402 LT recipients were included. The median age of transplant was 14.9 years and 69.7% of the transplants were performed in children less than 18 years old. The rate of decline in percent predicted forced expiratory volume in 1 second was attenuated after LT from −2.2% to −0.7% predicted per year with a difference of 1.5% predicted per year (95% CI, 0.8, 2.2; p < 0.001). Following LT, the rate of decline in body mass index was reduced, and there were fewer pulmonary exacerbations (0.6 pre vs. 0.4 post; rate ratio 0.7, p < 0.01). The median survival time post-transplant was 13.9 years and the overall probability of survival at 5 years was 77.6%. Those with higher lung function pre-LT had a lower risk of death post-LT, and those with genotypes other than F508 deletion had worse survival. LT in pwCF occurs most often in children and adolescents and is associated with a slower rate of decline in lung function and nutritional status, and a reduction in pulmonary exacerbations.
Long-Term Physical, Cognitive, and Psychological Outcomes in Severe COVID-19 Patients Managed With Extracorporeal Membrane Oxygenation: A Prospective Study
Authors: Pozzi Matteo , Giani Marco , Andreossi Mara , Annoni Alice , Villa Marta , Bellin Valeria , Ferlicca Daniela , Piva Simone , Rona Roberto , Avalli Leonello , Lucchini Alberto , Foti Giuseppe ,   the Monza Follow-Up Study Group
Published: August 2023

Extracorporeal membrane oxygenation (ECMO) has been used in highly selected COVID-19 patients with severe respiratory failure. Scarce data exist on long-term outcomes of these patients. We performed a single-center prospective evaluation of consecutive COVID-19 ECMO patients successfully discharged from the intensive care unit between February 2020 and January 2022. Physical, cognitive and psychological outcome was assessed at 3, 6, and 12 months by in-person evaluation. All the 34 discharged patients (median age 49 years old) were alive at one year, and 25 of them were evaluated at the follow-up clinic. 67% of patients had muscle weakness, with improvement over time (p = 0.032). The percentage of patients able to return to work progressively increased, up to 86% at 1 year. 23% of patients experienced fatigue. Participation restriction improved over time for both physical (p = 0.050) and emotional (p = 0.005) problems. Cognitive impairment, anxiety, and depression occurred in 29%, 29%, and 23% of patients, respectively, with no changes over time. Health-related quality of life was good. In conclusion, COVID-19 ECMO patients suffer from significant long-term sequelae. However, multidimensional outcomes continued to improve over the follow-up time.
Therapeutic Hypothermia for Refractory Hypoxemia on Venovenous Extracorporeal Membrane Oxygenation: An In Silico Study
Authors: Joyce Christopher J. , Udy Andrew , Burrell Aidan , Brown Alastair
Published: August 2023

Patients with respiratory failure may remain hypoxemic despite treatment with venovenous extracorporeal membrane oxygenation (VV-ECMO). Therapeutic hypothermia is a potential treatment for such hypoxia as it reduces cardiac output (

) and oxygen consumption. We modified a previously published mathematical model of gas exchange to investigate the effects of hypothermia during VV-ECMO. Partial pressures were expressed as measured at 37°C (α-stat). The effect of hypothermia on gas exchange was examined in four clinical scenarios of hypoxemia on VV-ECMO, each with different physiological derangements. All scenarios had arterial partial pressure of oxygen (PaO2) ≤ 46 mm Hg and arterial oxygen saturation of hemoglobin (SaO2) ≤ 81%. Three had high

with low extracorporeal blood flow to

ratio (

). The problem in the fourth scenario was recirculation, with normal

. Cooling to 33°C increased SaO2 to > 89% and PaO2 to > 50 mm Hg in all scenarios. Mixed venous oxygen saturation of hemoglobin as % (

) increased to > 70% and mixed venous partial pressure of oxygen in mm Hg (

) increased to > 34 mm Hg in scenarios with low

. In the scenario with high recirculation,

and

increased, but to < 50% and < 27 mm Hg, respectively. This in silico study predicted cooling to 33°C will improve oxygenation in refractory hypoxemia on VV-ECMO, but the improvement will be less when the problem is recirculation.
Metabolomic profiles and pathogenesis of nephrolithiasis
Authors: Kowalczyk Nicholas S. , Prochaska Megan L. , Worcester Elaine M.
Published: August 2023

Purpose of review

Kidney stone disease is caused by supersaturation of urine with certain metabolites and minerals. The urine composition of stone formers has been measured to prevent stone recurrence, specifically calcium, uric acid, oxalate, ammonia, citrate. However, these minerals and metabolites have proven to be unreliable in predicting stone recurrence. Metabolomics using high throughput technologies in well defined patient cohorts can identify metabolites that may provide insight into the pathogenesis of stones as well as offer possibilities in therapeutics.

Recent findings

Techniques including 1H-NMR, and liquid chromatography paired with tandem mass spectroscopy have identified multiple possible metabolites involved in stone formation. Compared to formers of calcium oxalate stones, healthy controls had higher levels of hippuric acid as well as metabolites involved in caffeine metabolism. Both the gut and urine microbiome may contribute to the altered metabolome of stone formers.

Although metabolomics has offered several potential metabolites that may be protective against or promote stone formation, the mechanisms behind these metabolomic profiles and their clinical significance requires further investigation.
Regulation of the WNK4-SPAK-NCC pathway by the calcium-sensing receptor
Authors: Chávez-Canales María , García Janeth Alejandra , Gamba Gerardo
Published: August 2023

Purpose of review

Regulation of the sodium chloride cotransporter (NCC) in the distal convoluted tubule (DCT) plays a crucial role in renal salt handling. The calcium-sensing receptor (CaSR) has been shown to activate NCC through the WNK4-SPAK pathway, which is independent of the Renin-Angiotensin-Aldosterone system. In this review, we examine new information about the mechanism of how the CaSR regulates NCC through the WNK4-SPAK pathway and its physiological and therapeutic implications.

Recent findings

The activation of CaSR in TALH cells during hypercalcemia inhibits NKCC2 and ROMK activity, reducing paracellular Ca2+ reabsorption but decreasing salt reabsorption. This pathway enables NaCl reabsorption in the DCT while promoting Ca2+ excretion. CaSR activation in the apical DCT stimulates a signaling pathway involving PKC, WNK4, and SPAK, which increases NCC activation to recover the NaCl not reabsorbed in TAHL. Glucose or fructose acting as calcimimetics enhance apical CaSR sensitivity, increasing NCC activity, which contribute to the mechanism of hypertension prevalence in diabetic patients or in those with high fructose consumption.

These findings reveal the importance of the CaSR-mediated activation of the WNK4-SPAK pathway in regulating salt and calcium homeostasis and its potential as a therapeutic target for hypertension and related diseases.
Using Texture Analysis of Neck Computed Tomography Images to Differentiate Primary Hyperparathyroidism From Normal Controls
Authors: Kawashima Yusuke , Fujita Akifumi , Buch Karen , Qureshi M. Mustafa , Li Baojun , Takumi Koji , Rai Aayushi , Chapman Margaret N. , Sakai Osamu
Published: August 2023

Objective

To investigate the utility of texture analysis in detecting osseous changes associated with hyperparathyroidism on neck CT examinations compared with control patients and to explore the best regions in the head and neck to evaluate changes in the trabecular architecture secondary to hyperparathyroidism.

Methods

Patients with hyperparathyroidism who underwent a 4D CT of the neck with contrast were included in this study. Age-matched control patients with no history of hyperparathyroidism who underwent a contrast-enhanced neck CT were also included. Mandibular condyles, bilateral mandibular bodies, the body of the C4 vertebra, the manubrium of the sternum, and bilateral clavicular heads were selected for analysis, and oval-shaped regions of interest were manually placed. These segmented areas were imported into an in-house developed texture analysis program, and 41 texture analysis features were extracted. A mixed linear regression model was used to compare differences in the texture analysis features contoured at each of the osseous structures between patients with hyperparathyroidism and age-matched control patients.

Results

A total of 30 patients with hyperparathyroidism and 30 age-matched control patients were included in this study. Statistically significant differences in texture features between patients with hyperparathyroidism and control patients in all 8 investigated osseous regions. The sternum showed the greatest number of texture features with statistically significant differences between these groups.

Conclusions

Some CT texture features demonstrated statistically significant differences between patients with hyperparathyroidism and control patients. The results suggest that texture features may discriminate changes in the osseous architecture of the head and neck in patients with hyperparathyroidism.
Thoracic Complications of Liver-Directed Therapy and Interventions
Authors: Pham Kaylee H. , Stowell Justin T. , Grage Rolf A. , Sella David M. , LeGout Jordan D. , Paz-Fumagalli Ricardo , Rojas Carlos A.
Published: August 2023

Liver-directed percutaneous and endovascular therapies are effective methods to diagnose and treat various hepatic disorders and malignancies. Because of the close anatomic proximity of the liver to the right hemidiaphragm, pleura, and lung bases, complications can arise involving these structures. Although they are rare, awareness of intrathoracic complications associated with liver-directed therapies and their imaging features will ensure timely detection and management. We aim to review the clinical and imaging features of thoracic complications related to liver-directed therapy and interventions.
The Role of the Autonomic Nervous System in the Mediation of the Resolution of Suicidal Ideation With Electroconvulsive Therapy
Authors: McCall William V. , Thomas Alvin , Miller Brian J. , Rosenquist Peter B.
Published: August 2023

Longitudinal observational studies have shown a meaningful decrease in suicidal thinking and suicidal behavior after receipt of electroconvulsive therapy (ECT). The antisuicide effect of ECT may be related to success in the global relief of the presenting syndrome such as depressive or psychotic illness. However, it is possible that the antisuicide effect is specific to ECT per se, over and above the relief of the clinical syndrome. Electroconvulsive therapy is associated with many observable neurochemical and physiologic effects, and some of these may plausibly be specifically linked to an antisuicide effect. The phenomenon of physiologic hyperarousal has been named as a candidate mechanism driving the risk for suicide. Hyperarousal is associated with decreased neuropsychological executive function responsible for response inhibition and can lead to impulsive action. The level of arousal within the autonomic nervous system (ANS) can be assayed with the pupillary light reflex, electrodermal activity, or with heart rate variability (HRV). This article summarizes the literature on the effects of ECT on HRV 24 to 72 hours after a course of ECT and finds evidence for increases in HRV, which indicates lower levels of arousal in the ANS. This finding suggests that ECT-related reductions in ANS arousal, presumably with corresponding improvements in response inhibition, may be one mechanism whereby ECT reduces risk for suicide.
Kenneth John Packer. 18 May 1938—18 September 2021
Authors: Jonsen FRS Paul
Published: August 2023

Ken Packer began his research career as an inorganic chemist, but he became enthralled with nuclear magnetic resonance (NMR) when it identified a PhD reaction product as SF
5
OSO
2
F. He progressed, as a pioneer, to answer pressing materials science problems with application of NMR to materials from pharmaceutical compounds through to porous solids. He did this by forging strong collaborations with colleagues in academia and industry, eventually joining BP Research as head of Spectroscopy Branch before returning to academia. He was always approachable, warm, supportive and friendly, making many friends across the world. However, nothing gave him more joy than his family: his wife Christine, his children and grandchildren.
Roger Philip Ekins. 22 September 1926—26 July 2016
Authors: Vincent FRS Angela
Published: August 2023

Roger Philip Ekins was born in London and educated at Westminster School. He studied natural sciences at Emmanuel College, Cambridge, and then returned to London, where he spent the rest of his career. His work initially focused on the thyroid gland and its disorders. In the 1950s, measurements of circulating hormones and other substances relied on biological assays. These were very time-consuming, inaccurate and unsuitable for routine clinical laboratories. In 1960, Ekins published the first radioactive assay for measuring the thyroid hormone thyroxine, using an approach he called ‘saturation analysis’; this and other work led to the systematic and accurate diagnosis of different forms of thyroid disease. He also developed tests for low-concentration biological substances, such as vitamin B
12
, always using simple and elegant techniques. In 1986, he was the first to propose the use of microarray ‘chip’ technologies for measuring these biological molecules simultaneously, recognizing that this could be applied to many other substances, such as oligonucleotides or peptides; he then worked with Boehringer Mannheim-Roche to develop the methodology. Meanwhile, he helped to identify the importance of thyroid hormones during human development, demonstrating that reduced levels of maternal thyroxine predicted the severity of the resulting ‘cretinism’ in their children. As a result, he went on to study the effects of abnormal levels of maternal thyroid hormones on fetal development, developing a rat model of maternal hypothyroidism. He travelled widely giving courses on standardization of the radioactive clinical assays, sponsored by the World Health Organization and the International Atomic Energy Agency. He received many UK and international awards for his work, including the Prince of Wales Award for Innovation in 1991 and the Dale Medal from the Society of Endocrinology in 1998. He was elected FRS in 2001.
Self-organization in Slovenian public spending
Authors: Joksimović Jelena , Perc Matjaž , Levnajić Zoran
Published: August 2023

Private businesses are often entrusted with public contracts, wherein public money is allocated to a private company. This process raises concerns about transparency, even in the most developed democracies. But are there any regularities guiding this process? Do all private companies benefit equally from the state budgets? Here, we tackle these questions focusing on the case of Slovenia, which keeps excellent records of this kind of public spending. We examine a dataset detailing every transfer of public money to the private sector from January 2003 to May 2020. During this time, Slovenia has conducted business with no less than 248 989 private companies. We find that the cumulative distribution of money received per company can be reasonably well explained by a power-law or lognormal fit. We also show evidence for the first-mover advantage, and determine that companies receive new funding in a way that is roughly linear over time. These results indicate that, despite all human factors involved, Slovenian public spending is at least to some extent regulated by emergent self-organizing principles.
Pliocene sigmodontine rodents (Mammalia: Cricetidae) in northernmost South America: test of biogeographic hypotheses and revised evolutionary scenarios
Authors: Ronez Christophe , Carrillo-Briceño Jorge D. , Hadler Patrícia , Sánchez-Villagra Marcelo R. , Pardiñas Ulyses F. J.
Published: August 2023

We document the first occurrence of Sigmodontinae (Mammalia, Rodentia, Cricetidae) from the Pliocene of northern South America, from the San Gregorio Formation of northwestern Venezuela. The recovered isolated molars are identified as
Oligoryzomys
sp. and
Zygodontomys
sp., two currently widespread sigmodontines in South America. These records constitute the oldest representatives of these genera, potentially new species, and the first Pliocene occurrence for Oryzomyini and the whole subfamily outside Argentina. Hypotheses on the historical biogeography of sigmodontines have been constructed almost exclusively using genetic data and the fossils we report provide a new kind of evidence. The occurrence of
Oligoryzomys
sp. and
Zygodontomys
sp. in Venezuela provides novel information for the diversification models suggested for
Oligoryzomys
, by supporting a potential eastern corridor of open environments from northern to southern South America. The presence of sigmodontines from the locality home of the new reports, Norte Casa Chiguaje, is consistent with the palaeoenvironmental conditions originally proposed for it based on mammals and botanical records, being characterized as mixed open grassland/forest areas surrounding permanent freshwater systems. The new sigmodontine evidence is used to discuss the putative scenarios of the ancient evolution of the subfamily in South America, favouring a model in which open areas (savannahs) to the east of the Andes played crucial role aiding or obstructing Late Miocene–Pliocene sigmodontine dispersion southwards.
The response of coral skeletal nano structure and hardness to ocean acidification conditions
Authors: Tan Chao Dun , Hähner Georg , Fitzer Susan , Cole Catherine , Finch Adrian A. , Hintz Chris , Hintz Ken , Allison Nicola
Published: August 2023

Ocean acidification typically reduces coral calcification rates and can fundamentally alter skeletal morphology. We use atomic force microscopy (AFM) and microindentation to determine how seawater pCO
2
affects skeletal structure and Vickers hardness in a
Porites lutea
coral. At 400 µatm, the skeletal fasciculi are composed of tightly packed bundles of acicular crystals composed of quadrilateral nanograins, approximately 80–300 nm in dimensions. We interpret high adhesion at the nanograin edges as an organic coating. At 750 µatm the crystals are less regular in width and orientation and composed of either smaller/more rounded nanograins than observed at 400 µatm or of larger areas with little variation in adhesion. Coral aragonite may form via ion-by-ion attachment to the existing skeleton or via conversion of amorphous calcium carbonate precursors. Changes in nanoparticle morphology could reflect variations in the sizes of nanoparticles produced by each crystallization pathway or in the contributions of each pathway to biomineralization. We observe no significant variation in Vickers hardness between skeletons cultured at different seawater pCO
2
. Either the nanograin size does not affect skeletal hardness or the effect is offset by other changes in the skeleton, e.g. increases in skeletal organic material as reported in previous studies.