bluuebunny/crossref_metadata_2025_split huggingface dataset:
DoD-VA Trauma Infection Research Collaboration
Authors: McDonald Jay , Liang Stephen Y , Li Ping , Stewart Laveta , Tribble David R 
Published: May 2022

ABSTRACT

Background
In the aftermath of wars, there is a surge in the number of wounded service members who leave active duty and become eligible for healthcare through the Department of Veterans Affairs (VA). Collaborations between the Department of Defense (DoD) and VA are crucial to capture comprehensive data and further understand the long-term impact of battlefield trauma. We provide a summary of the development, methodology, and status of an effective collaboration between the Infectious Disease Clinical Research Program and the St. Louis VA Health Care System with the multicenter, observational Trauma Infectious Disease Outcomes Study (TIDOS), which examines the short- and long-term outcomes of deployment-related trauma.

Methods
As part of TIDOS, wounded service members who transitioned to participating military hospitals in the United States (2009–2014) were given the opportunity to enroll in a prospective follow-up cohort study to continue to capture infection-related data after their hospital discharge. Enrollees in the TIDOS cohort who left military service and received health care through the VA also had the option of consenting to have relevant VA medical records abstracted and included with the study data. Infections considered to be complications resulting from the initial trauma were examined.

Results
Among 1,336 TIDOS enrollees, 1,221 (91%) registered and received health care through the VA with 633 (47%) consenting to follow-up using VA records and comprising the TIDOS-VA cohort. Of the first 337 TIDOS-VA cohort enrollees, 38% were diagnosed with a new trauma-related infection following hospital discharge (median: 88 days; interquartile range: 18–351 days). Approximately 71% of the infections were identified through DoD sources (medical records and follow-up) and 29% were identified through VA electronic medical records, demonstrating the utility of DoD-VA collaborations. The TIDOS DoD-VA collaboration has also been utilized to assess intermediate and long-term consequences of specific injury patterns. Among 89 TIDOS-VA cohort enrollees with genitourinary trauma, 36% reported sexual dysfunction, 21% developed at least one urinary tract infection, 14% had urinary retention/incontinence, and 8% had urethral stricture. The rate of urinary tract infections was 0.05/patient-year during DoD follow-up time and 0.07/patient-year during VA follow-up time.

Conclusions
Wider capture of infection-related outcome data through the DoD-VA collaboration provided a clearer picture of the long-term infection burden resulting from deployment-related trauma. Planned analyses include assessment of osteomyelitis among combat casualties with amputations and/or open fractures, evaluation of mental health and social factors related to injury patterns, and examination of health care utilization and cost in relation to infectious disease burdens.
Earliest Photic Zone Niches Probed by Ancestral Microbial Rhodopsins
Authors: Sephus Cathryn D. , Fer Evrim , Garcia Amanda K. , Adam Zachary R. , Schwieterman Edward W. , Kacar Betul 
Published: May 2022

AbstractFor billions of years, life has continuously adapted to dynamic physical conditions near the Earth’s surface. Fossils and other preserved biosignatures in the paleontological record are the most direct evidence for reconstructing the broad historical contours of this adaptive interplay. However, biosignatures dating to Earth’s earliest history are exceedingly rare. Here, we combine phylogenetic inference of primordial rhodopsin proteins with modeled spectral features of the Precambrian Earth environment to reconstruct the paleobiological history of this essential family of photoactive transmembrane proteins. Our results suggest that ancestral microbial rhodopsins likely acted as light-driven proton pumps and were spectrally tuned toward the absorption of green light, which would have enabled their hosts to occupy depths in a water column or biofilm where UV wavelengths were attenuated. Subsequent diversification of rhodopsin functions and peak absorption frequencies was enabled by the expansion of surface ecological niches induced by the accumulation of atmospheric oxygen. Inferred ancestors retain distinct associations between extant functions and peak absorption frequencies. Our findings suggest that novel information encoded by biomolecules can be used as “paleosensors” for conditions of ancient, inhabited niches of host organisms not represented elsewhere in the paleontological record. The coupling of functional diversification and spectral tuning of this taxonomically diverse protein family underscores the utility of rhodopsins as universal testbeds for inferring remotely detectable biosignatures on inhabited planetary bodies.
MO013: Relationship between Disease Awareness and Severity of Kidney Disease in Autosomal Dominant Polycystic Kidney Disease Patients
Authors: Dogan Ege , Eren Necmi , Gül Özcan Şeyda , Altunoren Orcun , Gungor Ozkan , Dheir Hamad , Tanrisev Mehmet , Kocyigit Hafsa , ülmecit Yıldız Abd , Kocyigit Ismail , Seyahi Nurhan , Tatar Erhan 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease with diffuse cysts in both kidneys and is responsible for 5–10% of end-stage renal disease Levy and Feingold (Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int. 2000;58(3):925). Recently, tolvaptan, which can improve kidney survival, was approved for the management of the disease (Drug Approval Package: Jynarque (tolvaptan) Otsuka Pharmaceutical Development & Commercialization, Inc. application Number: 204 441, Approval Date: 04/23/2018). We examined the relationship between renal and extrarenal findings, disease severity and the level of consciousness of patients with ADPKD patients.

METHOD
About 516 patients who applied to nephrology clinics of seven different centers in Turkey were asked to answer the questionnaire about ADPKD that consisted of 38 questions. Disease severity was determined according to e-GFR, and disease awareness was assessed on a four-point scale by adapting the Disease Perception Scale to ADPKD. Awareness of patients was evaluated comparatively with chronic kidney disease stage, age, region and symptoms.

RESULTS
One out of five patients does not know that this disease is inherited. Mean awareness scores of the patients decreased significantly with increasing age. The average awareness score of the Central Anatolia region was significantly higher compared to other regions. Awareness scores were significantly higher in patients with flank pain and urinary tract stones.

CONCLUSION
To the best of our knowledge, this is the first study about ADPKD awareness. Although ADPKD is the most common hereditary kidney disease, the rate of patients’ knowledge on this subject is low. Awareness levels may vary according to age, regional differences or symptoms. Increased awareness might lead to better treatment and improved survival in those patients.
MO014: Development and Validation of the Thirst Distress Scale for Patients with Autosomal Dominant Polycystic Kidney Disease
Authors: Gül Özcan Şeyda , Bek Sibel , Eren Necmi , Atli Zeynep , Yıldız Abdülmecit , Kocyigit Ismail , Cavdar Caner , Seyahi Nurhan , Ecder Tevfik , Waldreus Nana 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Abundant water intake is advised for patients with autosomal dominant polycystic kidney disease (ADPKD) Meijer and Casteleijn (Riding the waves: evidence for a beneficial effect of increased water intake in autosomal dominant polycystic kidney disease patients? Nephrol Dialysis Transpl. 2014;29(9):1615–1617). Thirst, which can be defined as a sensation of dryness in the mouth and throat associated with a desire for liquids, is the main driver for fluid consumption Fitzsimons (Thirst. Physiol Rev 1972;52(2):468–561). However, daily routines may limit water intake. There is no established tool to quantify the drivers of water intake in ADPKD patients. In this study, it was aimed to develop and validate a thirst distress scale (TDS) to quantify the factors of water intake in ADPKD patients.

METHOD
The TDS-heart failure questionnaire was first (i) translated to Turkish using the approach recommended by the guidelines of the World Health Organization and finally (ii) modified to adapt to patients with ADPKD with totally 12 questions assessing (a) what may affect water intake, (b) what limit water intake and (c) what disturbing effects thirst may have on quality of life. The guidelines of the World Health Organization were used to translate the questionnaire to Turkish. An electronic survey with SurveyMonkey platform was used to collect data on thirst with TDS-PKD and thirst intensity (visual analog scale, VAS). Internal consistency of the TDS-PKD was evaluated with Cronbach’s alpha. Exploratory factor analysis was conducted to reveal the validity and the factor structure of the questions in the questionnaire.

RESULTS
The questionnaire was filled in by 154 ADPKD patients, of which 116 were on tolvaptan therapy. The time taken to answer the questions was about 4 min. The TDS-PKD questionnaire showed good internal consistency with a Cronbach's alpha value of 0.867. According to the exploratory factor analysis, a three-factor structure was obtained, meaning that there are three constructs about thirst in the TDS-PKD. Three factors explained 62.57% of the total variance. Factor one consisted of questions 1–7, factor two 8–10 and factor three 11–12. All three factors were significantly associated with thirst intensity (r = 0.505, r = 0.244 and r = 197, respectively). The average score of TDS-PDK was 40.2 ± 10.5, and the average VAS score was 8.5 ± 0.7.

CONCLUSION
The TDS-PKD questionnaire is a valid and reliable tool for evaluating the thirst distress in ADPKD patients.
MO025: Long-term follow-up of patients with autosomal dominant polycystic kidney disease treated with tolvaptan
Authors: Martins Muñoz Judith , De Lorenzo Alberto , Espinel Laura , Tarragon Blanca , Teresa Naya and Alfonso Cubas Maria 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease characterized by the formation of cysts that destroy normal renal parenchyma. Tolvaptan (vasopressin antagonist) is the only drug approved today to slow disease progression. To assess the efficacy and tolerability of long-term treatment in patients with ADPKD.

METHOD
Retrospective observational study of ADPKD patients on tolvaptan treatment after its approval in Spain in 2017.

RESULTS
Of the 182 patients with ADPKD in follow-up in our practice, 18% (n = 33) initiated treatment because they met criteria for rapid progression. A total of 60.6% (n = 20) males with age 47.64 ± 8.64 years, a baseline GFR of 65.24 ± 20.14 mL/min and a height-adjusted total kidney volume (TKV) of 1137.45 ± 667.58 mL. A total of 72.7% reached the maximum dose (120 mg) with a mean maximum dose of 108.18 ± 22.42 mg and a mean time to reach it of 5.8 ± 9.3 weeks. A total of 90.9% (n = 33) presented side effects: 81.8% (n = 27) aquaretic and 12.1% (n = 4) hepatotoxicity. Other side effects observed were as follows: hypernatremia 9.1% (n = 3), hyperuricemia in 24% (n = 8). No other side effects were described. A total of 39.4% (n = 13) of the patients temporarily abandoned treatment after a mean time of 3.01 ± 2.17 months. The reasons for discontinuation were as follows: aquaretic effects 35.7% (n = 5), hepatotoxicity 35.7% (n = 5), 3.03% desire for pregnancy (n = 1), 3.03% cerebral hemorrhage (n = 1) and 3.03 (n = 1) worsening of renal function. Some 30.76% (n = 4) of the patients restarted treatment at 5.5 ± 6.76 months. The reason for previous withdrawal was hepatotoxicity (n = 2) and aquaretic effects (n = 2). Therefore, the definitive abandonment of treatment was 27.2%. The mean follow-up time of the patients was 39.85 ± 10.04 months.

CONCLUSION
Long-term use of tolvaptan in patients with ADPKD can be considered safe both from the point of view of renal function and side effects. The aquaretic effects are the most frequent. The aquaretic effects and hepatotoxicity are the main reasons for treatment discontinuation. All cases of hepatotoxicity reverted to normal, thus not being considered a serious effect in our experience.
MO026: IgA-nephropathy in Alport syndrome patients: one center data
Authors: Aksenova Marina , Stolyarevich Ekaterina , Povilaitite Patrisia 
Published: May 2022

Abstract

BACKGROUND AND AIMS
The association between Alport syndrome (AS) and IgA-nephropathy (IgAN) recently shown suggests that the abnormal glomerular basement membrane (GBM) resulting from the pathogenic COL4A3/A4/A5 variants may predispose to immune-mediated injury. The aim of study was to identify the frequency of IgAN in children with AS.

METHOD
We analyzed the morphological (light, immunofluorescence, electron microscopy), clinical [sensorineural deafness (SND)], laboratory [eGFR, proteinuria (Pr)] data of 102 children (12 ± 4 years at biopsy) with AS observed in nephrology department since 1993. AS was confirmed by next-generation sequencing (NGS) based genetic tests in 65 points (q = 0.64). The IgAN was diagnosed by the presence of glomerular proliferative lesions with predominant IgA immunofluorescence and electron dense deposits in the mesangial area.

RESULTS
IgAN was revealed in 3 points (q = 0.03) with AS (Table 1) and presented by acute development of steroid-resistant nephrotic syndrome (SRNS) (one case) and nephrotic proteinuria in top of gross hematuria (2 points). Immunosuppressive treatment led to complete SRNS remission and was ineffective in one child.

CONCLUSION
IgAN was revealed in 3% of our points with AS and probably led to serious disease flare-ups in these points. Immunosuppression treatment was effective in children with IgA-related SRNS.
MO033: Parathyroid hormone determination as an early predictor of progression in autosomal dominant polycystic kidney disease
Authors: Viera Ramírez Elizabeth , Castillo Rodriguez Esmeralda , Martin Irene , Fernandez Lucas Milagros 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Total kidney volume (TKV) in patients with autosomal dominant polycystic kidney disease (ADPKD) is a known progression factor in these patients. Low levels of klotho and high levels of FGF23 in the blood of patients with ADPKD have been correlated with higher TKV even in early stages of the disease, even with glomerular filtration rate (eGFR) &gt;90 mL/min/1.73 m2. Therefore, alterations in the levels of parathyroid hormone (PTH), vitamin D, tubular reabsorption of phosphates or urinary calcium could be correlated with the TKV and serve as an early serum biomarker of progression of kidney disease.

METHOD
Observational, cross-sectional, single-center study in a population of 87 patients under follow-up at our center during 2019–2020 for ADPKD. The TKV, obtained by the ellipsoid formula measured by magnetic resonance imaging (MRI) and the values of PTH, vitamin D, tubular phosphate reabsorption and urinary calcium were retrospectively collected. Subsequently, a statistical analysis of correlation between the different variables was performed.

RESULTS
Spearman's Rho correlation analysis obtained a positive correlation of moderate–strong intensity between the TKR of the sample and PTH levels (r = 0.638, P &lt;0 0.0001) and a negative correlation of moderate intensity with tubular phosphate reabsorption (r = −0.479, P &lt; 0.005). No statistically significant correlation was obtained between the TKV and the levels of urinary calcium or serum vitamin D. TKV was higher among patients with an eGFR &gt;90 mL/min/1.73 m2 (CKD-EPI) with an elevated PTH (&gt; 65 pg/mL), with a median of 530 mL (interquartile range 403–1184 mL), compared with the TKV of those patients with an eGFR &gt;90 mL/min/1.73 m2 with normal PTH, whose median was 405 mL (interquartile range 258–576 mL). Despite this trend, the Mann–Whitney U test did not show a statistically significant difference between medians in the subgroup of patients with eGFR &gt;90 mL/min/1.73 m2. However, the comparison of medians in the subgroup of patients with eGFR &lt;90 mL/min/1.73 m2 was statistically significant with a P &lt; 0.019, with higher TKR in those patients with high PTH.

CONCLUSION
The increase in PTH in patients with ADPKD has a strong positive correlation with TKV. Even with normal eGFR, elevated PTH is associated with a higher TKV, which could be an early serum biomarker of kidney disease progression in this group of patients.
MO036: Detection of copy number variations by single-nucleotide-polymorphism array in patients with end-stage renal disease of unknown etiology
Authors: Granhøj Jeff , Venborg Pedersen Katja , Birn Henrik , Lildballe Dorte L , Jørgensen Mads , Aagaard Graakjær Jesper , Rasmussen Maria 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Establishing the genetic basis of renal disease is pivotal to improve diagnostic and treatment strategies. Pathogenic copy number variations (CNVs) caused by chromosomal imbalances contribute significantly to the pediatric renal disease burden, especially in children with congenital anomalies of the kidney and urinary tract (CAKUT). The role of CNVs in chronic kidney disease of unknown etiology (uCKD) is scarcely investigated, although this group comprises about 20% of adults with end-stage renal disease (ESRD). We screened for causal CNVs in a preliminary sample of patients with ESRD from unknown etiology.

METHOD
We recruited 94 patients registered with ESRD ≤age 50 from uCKD or hypertension from the Danish Nephrology Registry. Medical records and previous kidney biopsies were initially reviewed, and patients were excluded if a specific cause of kidney disease other than hypertension was identified (n = 35). We performed genome-wide single-nucleotide-polymorphism (SNP) array in 59 patients to identify copy number gains and losses. All CNVs were systematically evaluated as possible causes of kidney disease and broadly classified into three main categories: ‘Normal’, ‘Pathogenic’ or ‘Variant of uncertain significance.’

RESULTS
The SNP array results were normal in 57 patients (96.6%). In the remaining two patients (3.4%), we detected pathogenic CNVs with incomplete penetrance in hot spot loci associated with CAKUT: One male patient with ESRD at age 18 was a heterozygous carrier of a 545 kb microdeletion on chromosome 16p11.2 (29.63 Mb to 30.18 Mb). He had left-side renal agenesis and a hypoplastic right kidney at presentation, but no history of developmental delay or dysmorphic features. The microdeletion was considered likely causal, because it included the CAKUT driver gene TBX6 similar to other heterozygous carriers of 16p11.2 microdeletions with isolated renal agenesis or dysplasia. A second patient with ESRD at age 49 had 3.66 Mb duplication on chromosome 1q21.1 (145.43 Mb to 149.09 Mb) in heterozygous form. The patient had no reported CAKUT or other features associated with CNVs in the 1q21.1 loci, and the duplication was therefore deemed unrelated to his renal disease.

CONCLUSION
Disease-causing CNVs are not frequent in this limited sample of patients with ESRD from unknown etiology. CNV analysis by SNP-array may be most effective in patients with uCKD combined with CAKUT features.
MO040: Development of BBP-711, a small molecule inhibitor of glycolate oxidase for primary hyperoxaluria type 1 and recurrent kidney stone formers
Authors: Sinha Uma , Rajasingham Thulashitha , Xavier Fernandez Miguel , Ji Alan , Sukhun Rajaa , Rao Satish , Henry Chris , D'souza Kahlil , Lafountaine Justin 
Published: May 2022

Abstract

BACKGROUND AND AIMS
BBP-711 is an investigational small molecule inhibitor of glycolate oxidase (GO), currently in development for the treatment of primary hyperoxaluria type 1 (PH1) and recurrent nephrolithiasis. Selection of BBP-711 as a drug candidate followed structural activity optimization and a pharmacological testing strategy that included functional activity in enzyme assays, target engagement in cellular assays and efficacy studies in a rodent model (Agxt−/− mice) of primary hyperoxaluria type 1.

METHOD
BBP-711 was developed by iterative synthesis and study of the structure–activity relationship of more than 50 GO inhibitors. Lead molecules including BBP-711 were assessed for functional activity by determining inhibition of the conversion of glycolate to oxalate with purified human, mouse and rat HAOX1 enzymes. The ability of BBP-711 to bind directly to immobilized purified hGO (HAOX1 gene product) was evaluated by surface plasmon resonance. Selectivity of BBP-711 was assessed by determining its inhibition of several physiologically related gene products including that from HAOX2. In vitro efficacy of BBP-711 was tested via inhibition of oxalate production in primary hepatocytes cultured from hyperoxaluric Agxt−/− mice. In vivo efficacy of BBP-711 on urinary oxalate excretion was assessed at various doses given by oral gavage in Agxt −/− mice. Pharmacokinetics of BBP-711 was investigated to assess plasma and liver concentrations associated with efficacy.

RESULTS
BBP-711 is a potent inhibitor of human, rat and mouse GO (IC50 = 15.4 nM, 22.4 nM and 149 nM, respectively). BBP-711 demonstrated stronger direct binding to hGO1 (KD = 6.31 nM) than to rGO2 (KD = 12.8 nM), indicating its preference for GO1 as a target. BBP-711 specificity was demonstrated with &lt;10% activity against off-target enzymes D-amino acid oxidase, dihydroorotate dehydrogenase and lactate dehydrogenase-A at 10 µM. BBP-711 demonstrated concentration-dependent inhibition of oxalate production by Agxt−/− hepatocytes (IC50 = 24.2 nM at 24 hours, IC50 = 42.9 nM at 48 hours). When orally dosed at 7 mg/kg for 5 days in Agxt−/− mice, BBP-711 produced a maximum reduction of urinary oxalate (60%) as well as maximum inhibition of GO activity (&gt;88%). Higher doses did not result in greater reduction in urinary oxalate. Liver exposures (AUC0-24hr) were higher than plasma exposures at all doses tested. GO engagement by BBP-711 was also assessed in an ex vivo assay. Liver extracts from Agxt−/− and wild-type mice dosed with BBP-711 show a dose-dependent reduction in ex vivo GO activity at 1 and 4-hour post-dose.

CONCLUSION
Iterative and rational optimization of small molecule GO inhibitors resulted in BBP-711, a potent and specific inhibitor of GO with drug-like properties.