bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macular Findings of Patients on Pentosan Polysulfate Sodium
Authors: Blackorby Barton L , Banda Himanshu , Smith Bradley T , Shah Gaurav K 
Published: July 2021

ABSTRACTIntroductionIn 2018, a unique maculopathy associated with chronic pentosan polysulfate sodium (PPS) use for the treatment of interstitial cystitis (IC) was described, where the authors detailed macular retinal pigment epithelial abnormalities in six patients. In this paper, a retrospective study of a larger patient pool at one large tertiary retina practice was undertaken to evaluate patients taking PPS and their macular findings.Materials and methodsA retrospective chart review was performed on all patients presenting to a single large retina practice between 2011 and 2019. Patient’s macular diagnosis, findings, optical coherence tomography scans, and macular auto-fluorescent scans were assessed. This project was Institutional Review Board (IRB) approved by the St Luke’s Hospital IRB board (St Louis, MO, USA).ResultsFifty-five patients were identified as taking PPS for IC. Fifty-three patients were found to have a diagnosis consistent with changes attributable to known macular diseases to include macular degeneration and pattern dystrophies. Two (4%) of fifty-five patients had macular findings suggestive of PPS toxicity. The first was a 58-year-old female with subtle retinal pigment epithelium (RPE) deposits on optical coherence tomography that exhibited hyper-autofluorescence. The second was a 72-year-old female with 14 years of PPS use who exhibited RPE excrescences and parafoveal areas of atrophy.ConclusionsPentosan polysulfate sodium may be the cause of macular findings in a small percentage of patients referred to a tertiary retina practice. Although causation of macular changes with PPS use has yet to be elucidated, clinicians should be aware of this possibility when assessing patients with atypical macular findings. Future longitudinal studies are necessary to evaluate a definitive relationship. This paper should remind all clinicians of the importance of a throughout review of the patient’s medication list as novel toxicities may become apparent years after initial FDA trials. The strength of this study is the larger patient population compared to earlier studies, and the main weaknesses include the retrospective nature of the study, lack of family and genetic testing, and lack of multimodal imaging for all patients.
Defective Satellite DNA Clustering into Chromocenters Underlies Hybrid Incompatibility in Drosophila
Authors: Jagannathan Madhav , Yamashita Yukiko M 
Published: July 2021

Abstract
Although rapid evolution of pericentromeric satellite DNA repeats is theorized to promote hybrid incompatibility (HI) (Yunis and Yasmineh 1971; Henikoff et al. 2001; Ferree and Barbash 2009; Sawamura 2012; Jagannathan and Yamashita 2017), how divergent repeats affect hybrid cells remains poorly understood. Recently, we demonstrated that sequence-specific DNA-binding proteins cluster satellite DNA from multiple chromosomes into “chromocenters,” thereby bundling chromosomes to maintain the entire genome in a single nucleus (Jagannathan et al. 2018, 2019). Here, we show that ineffective clustering of divergent satellite DNA in the cells of Drosophila hybrids results in chromocenter disruption, associated micronuclei formation, and tissue atrophy. We further demonstrate that previously identified HI factors trigger chromocenter disruption and micronuclei in hybrids, linking their function to a conserved cellular process. Together, we propose a unifying framework that explains how the widely observed satellite DNA divergence between closely related species can cause reproductive isolation.
Integrated stress response control of granulosa cell translation and proliferation during normal ovarian follicle development
Authors: Cari Evelyn Llerena , Hagen-Lillevik Synneva , Giornazi Asma , Post Miriam , Komar Anton A , Appiah Leslie , Bitler Benjamin , Polotsky Alex J , Santoro Nanette , Kieft Jeffrey , Lai Kent , Johnson Joshua 
Published: July 2021

Abstract
Mechanisms that directly control mammalian ovarian primordial follicle (PF) growth activation and the selection of individual follicles for survival are largely unknown. Follicle cells produce factors that can act as potent inducers of cellular stress during normal function. Consistent with this, we show here that normal, untreated ovarian cells, including pre-granulosa cells of dormant PFs, express phenotype and protein markers of the activated integrated stress response (ISR), including stress-specific protein translation (phospho-Serine 51 eukaryotic initiation factor 2 α ; P-EIF2 α ), active DNA damage checkpoints, and cell cycle arrest. We further demonstrate that mRNAs upregulated in primary (growing) follicles versus arrested PFs mostly include stress-responsive upstream open reading frames (uORFs). Treatment of a granulosa cell (GC) line with the PF growth trigger tumor necrosis factor alpha results in the upregulation of a ‘stress-dependent’ translation profile. This includes further elevated P-eIF2 α and a shift of uORF-containing mRNAs to polysomes. Because the active ISR corresponds to slow follicle growth and PF arrest, we propose that repair and abrogation of ISR checkpoints (e.g. checkpoint recovery) drives the GC cell cycle and PF growth activation (PFGA). If cellular stress is elevated beyond a threshold(s) or, if damage occurs that cannot be repaired, cell and follicle death ensue, consistent with physiological atresia. These data suggest an intrinsic quality control mechanism for immature and growing follicles, where PFGA and subsequent follicle growth and survival depend causally upon ISR resolution, including DNA repair and thus the proof of genomic integrity.
A novel mechanism of enhanced transcription activity and fidelity for influenza A viral RNA-dependent RNA polymerase
Authors: Xu Xinzhou , Zhang Lu , Chu Julie Tung Sem , Wang Yuqing , Chin Alex Wing Hong , Chong Tin Hang , Dai Zixi , Poon Leo Lit Man , Cheung Peter Pak-Hang , Huang Xuhui 
Published: July 2021

Abstract
During RNA elongation, the influenza A viral (IAV) RNA-dependent RNA polymerase (RdRp) residues in the active site interact with the triphosphate moiety of nucleoside triphosphate (NTP) for catalysis. The molecular mechanisms by which they control the rate and fidelity of NTP incorporation remain elusive. Here, we demonstrated through enzymology, virology and computational approaches that the R239 and K235 in the PB1 subunit of RdRp are critical to controlling the activity and fidelity of transcription. Contrary to common beliefs that high-fidelity RdRp variants exert a slower incorporation rate, we discovered a first-of-its-kind, single lysine-to-arginine mutation on K235 exhibited enhanced fidelity and activity compared with wild-type. In particular, we employed a single-turnover NTP incorporation assay for the first time on IAV RdRp to show that K235R mutant RdRp possessed a 1.9-fold increase in the transcription activity of the cognate NTP and a 4.6-fold increase in fidelity compared to wild-type. Our all-atom molecular dynamics simulations further elucidated that the higher activity is attributed to the shorter distance between K235R and the triphosphate moiety of NTP compared with wild-type. These results provide novel insights into NTP incorporation and fidelity control mechanisms, which lay the foundation for the rational design of IAV vaccine and antiviral targets.
The lane-switch mechanism for nucleosome repositioning by DNA translocase
Authors: Nagae Fritz , Brandani Giovanni B , Takada Shoji , Terakawa Tsuyoshi 
Published: July 2021

Abstract
Translocases such as DNA/RNA polymerases, replicative helicases, and exonucleases are involved in eukaryotic DNA transcription, replication, and repair. Since eukaryotic genomic DNA wraps around histone octamers and forms nucleosomes, translocases inevitably encounter nucleosomes. A previous study has shown that a nucleosome repositions downstream when a translocase collides with the nucleosome. However, the molecular mechanism of the downstream repositioning remains unclear. In this study, we identified the lane-switch mechanism for downstream repositioning with molecular dynamics simulations and validated it with restriction enzyme digestion assays and deep sequencing assays. In this mechanism, after a translocase unwraps nucleosomal DNA up to the site proximal to the dyad, the remaining wrapped DNA switches its binding lane to that vacated by the unwrapping, and the downstream DNA rewraps, completing downstream repositioning. This mechanism may have broad implications for transcription through nucleosomes, histone recycling, and nucleosome remodeling.
NMPylation and de-NMPylation of SARS-CoV-2 nsp9 by the NiRAN domain
Authors: Wang Bing , Svetlov Dmitri , Artsimovitch Irina 
Published: July 2021

AbstractThe catalytic subunit of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) contains two active sites that catalyze nucleotidyl-monophosphate transfer (NMPylation). Mechanistic studies and drug discovery have focused on RNA synthesis by the highly conserved RdRp. The second active site, which resides in a Nidovirus RdRp-Associated Nucleotidyl transferase (NiRAN) domain, is poorly characterized, but both catalytic reactions are essential for viral replication. One study showed that NiRAN transfers NMP to the first residue of RNA-binding protein nsp9; another reported a structure of nsp9 containing two additional N-terminal residues bound to the NiRAN active site but observed NMP transfer to RNA instead. We show that SARS-CoV-2 RdRp NMPylates the native but not the extended nsp9. Substitutions of the invariant NiRAN residues abolish NMPylation, whereas substitution of a catalytic RdRp Asp residue does not. NMPylation can utilize diverse nucleotide triphosphates, including remdesivir triphosphate, is reversible in the presence of pyrophosphate, and is inhibited by nucleotide analogs and bisphosphonates, suggesting a path for rational design of NiRAN inhibitors. We reconcile these and existing findings using a new model in which nsp9 remodels both active sites to alternately support initiation of RNA synthesis by RdRp or subsequent capping of the product RNA by the NiRAN domain.
The Initial Step Towards Establishing a Quantitative, Magnetic Resonance Imaging-Based Framework for Response Assessment of Spinal Metastases After Stereotactic Body Radiation Therapy
Authors: Jabehdar Maralani Pejman , Tseng Chia-Lin , Baharjoo Hamidreza , Wong Erin , Kapadia Anish , Dasgupta Archya , Howard Peter , Chan Aimee K M , Atenafu Eshetu G , Lu Hua , Tyrrell Pascal , Das Sunit , Payabvash Seyedmehdi , Detsky Jay , Husain Zain , Myrehaug Sten , Soliman Hany , Chen Hanbo , Heyn Chris , Symons Sean , Sahgal Arjun 
Published: July 2021

Abstract

BACKGROUND
There are no established threshold values regarding the degree of growth on imaging when assessing response of spinal metastases treated with stereotactic body radiation therapy (SBRT).

OBJECTIVE
To determine a magnetic resonance imaging-based minimum detectable difference (MDD) in gross tumor volume (GTV) and its association with 1-yr radiation site-specific (RSS) progression-free survival (PFS).

METHODS
GTVs at baseline and first 2 post-SBRT scans (Post1 and Post2, respectively) for 142 spinal segments were contoured, and percentage volume change between scans calculated. One-year RSS PFS was acquired from medical records. The MDD was determined. The MDD was compared against optimal thresholds of GTV changes associated with 1-yr RSS PFS using Youden's J index, and receiver operating characteristic curves between timepoints compared to determine which timeframe had the best association.

RESULTS
A total of 17 of the 142 segments demonstrated progression. The MDD was 10.9%. Baseline-Post2 demonstrated the best performance (area under the curve [AUC] 0.90). Only Baseline-Post2 had an optimal threshold > MDD at 14.7%. Due to large distribution of GTVs, volumes were split into tertiles. Small tumors (GTV < 2 cc) had optimal thresholds of 42.0%, 71.3%, and 37.2% at Baseline-Post1 (AUC 0.81), Baseline-Post2 (AUC 0.89), and Post1-Post2 (AUC 0.77), respectively. Medium tumors (2 ≤ GTV ≤ 8.3 cc) all demonstrated optimal thresholds < MDD, with AUCs ranging from 0.65 to 0.84. Large tumors (GTV > 8.3 cc) had 2 timepoints where optimal thresholds > MDD: Baseline-Post2 (13.3%; AUC 0.97) and Post1-Post2 (11.8%; AUC 0.66). Baseline-Post2 had the best association with RSS PFS for all tertiles.

CONCLUSION
Given a MDD of 10.9%, for small GTVs, larger (>37%) changes were required before local failure could be determined, compared to 11% to 13% for medium/large tumors.
Incidence, Duration, and Risk Factors Associated With Missed Opportunities to Diagnose Herpes Simplex Encephalitis: A Population-Based Longitudinal Study
Authors: Miller Aaron C , Koeneman Scott H , Arakkal Alan T , Cavanaugh Joseph E , Polgreen Philip M 
Published: July 2021

Abstract

Background
Delays in diagnosing herpes simplex encephalitis (HSE) are associated with increased morbidity and mortality. The purpose of this paper is to determine the frequency and duration of diagnostic delays for HSE and risk factors for diagnostic delays.

Methods
Using data from the IBM Marketscan Databases, 2001–2017, we performed a retrospective cohort study of patients with HSE. We estimated the number of visits with HSE-related symptoms before diagnosis that would be expected to occur in the absence of delays and compared this estimate to the observed pattern of visits. Next, we used a simulation-based approach to compute the number of visits representing a delay, the number of missed diagnostic opportunities per case patient, and the duration of delays. We also investigated potential risk factors for delays.

Results
We identified 2667 patients diagnosed with HSE. We estimated 45.9% (95% confidence interval [CI], 43.6%–48.1%) of patients experienced at least 1 missed opportunity; 21.9% (95% CI, 17.3%–26.3%) of these patients had delays lasting &gt;7 days. Risk factors for delays included being seen only in the emergency department, age &lt;65, or a history of sinusitis or schizophrenia.

Conclusions
Many patients with HSE experience multiple missed diagnostic opportunities before diagnosis.
GLABRA2-based selection efficiently enriches Cas9-generated nonchimeric mutants in the T1 generation
Authors: Kong Xiangjiu , Pan Wenbo , Sun Nengxu , Zhang Tingyu , Liu Lijing , Zhang Huawei 
Published: July 2021

Abstract
The CRISPR/Cas9 system is a widely used tool for genome editing in plants. In Arabidopsis (Arabidopsis thaliana), egg cell-specific promoters driving Cas9 expression have been applied to reduce the proportion of T1 transformants that are chimeras; however, this approach generally leads to relatively low mutagenesis rates. In this study, a GLABRA2 mutation-based visible selection (GBVS) system was established to enrich nonchimeric mutants among T1 plants generated by an egg cell-specific CRISPR/Cas9 system. GBVS generally enhanced mutation screening, increasing the frequency by 2.58- to 7.50-fold, and 25%–48.15% of T1 plants selected through the GBVS system were homozygous or biallelic mutants, which was 1.71- to 7.86-fold higher than the percentage selected using the original system. The mutant phenotypes of T2 plants were not obviously affected by the glabrous background for all four target genes used in this study. Additionally, the nonchimeric pyrabactin resistance 1 (PYR1)/PYR1-like 1 (PYL1) and PYL2 triple mutant pyr1/pyl1/pyl2 could be obtained in the T1 generation with a ratio of 26.67% when GBVS was applied. Collectively, our results show that compared with the known CRISPR/Cas9 systems, the GBVS system described here saves more time and labor when used for the obtainment of homozygous or biallelic monogenic mutants and nonchimeric polygenic mutants in Arabidopsis.
Costs of Guillain-Barré Syndrome in the Brazilian Federal District: the patients’ perspective
Authors: Oliveira Ana Flávia de Morais , Gallo Luciana Gerra , Bastos Mábia Milhomem , Abrahão Amanda Amaral , Garcia Klauss Kleydmann Sabino , de Carvalho Jeane Kelly Silva , Macedo Lilian de Paula , de Araújo Wildo Navegantes , Peixoto Henry Maia 
Published: July 2021

Abstract

Background
Although rare, Guillain-Barré Syndrome (GBS) has a high economic burden, with consequences for families and society. This study aimed to estimate the total cost of GBS, per individual and per variant of the disease, as well as its effect on household income, from the perspective of patients.

Methods
This was a cost-of-illness study from the perspective of patients and their families, with a time horizon from disease onset to 6 mo after discharge. The total cost of GBS was estimated by bottom-up microcosting, considering direct and indirect costs.

Results
The median cost of GBS per individual was US$1635.5, with direct costs accounting for 64.3% of this amount. Among the variants analyzed, acute motor sensory axonal neuropathy (US$4660.1) and acute inflammatory demyelinating polyneuropathy (US$2017.0) exhibited the highest costs compared with acute motor axonal neuropathy (US$1635.5) and Miller Fisher Syndrome (US$1464.8). The costs involved compromise more than 20% of the household income of 22 (47.8%) patients.

Conclusions
This study demonstrated how costly GBS can be. It is hoped that decision-makers will analyze these results with a view to improving the structure of healthcare services.
Cryptosporidiosis is predominantly an urban, anthroponotic infectious disease among Zambian children
Authors: Banda Barbara , Siwila Joyce , Mukubesa Andrew N , Chitanga Simbarashe , Kaonga Patrick , Changula Katendi , Simulundu Edgar , Saasa Ngonda , Kelly Paul 
Published: July 2021

Abstract

Background
Cryptosporidium species are leading causes of diarrhoea in children and immunocompromised individuals. This study aimed to characterise Cryptosporidium species from children in rural and urban settings of Zambia.

Methods
Stool samples collected from 490 children aged &lt;5 y with diarrhoea were assessed for Cryptosporidium oocysts microscopically. A structured questionnaire was used to collect demographic and socioeconomic characteristics. Positive samples were subjected to PCR and gp60 sequence analysis.

Results
The overall prevalence was 10% (50/490, 95% CI 7.8 to 13.2) with a peak in March, the late rainy season. Children who came from households where boiling water was not practised (OR=2.5, 95% CI 1.29 to 5.17; p=0.007) or who had experienced recurrent episodes of diarrhoea (OR=9.31, 95% CI 3.02 to 28.73; p=0.001) were more likely to have Cryptosporidium infection. Genotyping of 16 positive samples (14 from urban and 2 from rural sources) revealed Cryptosporidium hominis (14/16) and Cryptosporidium parvum (2/16). The Cryptosporidium hominis subtypes identified were Ia, Ib and Ie with subtype families IeAIIG3 (1), IbA9G3R2 (2), IaA31R3 (3), IbA9G3 (5), IaA27R3 (1), IaA30R3 (1) and Ia (1). Subtypes IbA9G3 and Ia were identified in children from a rural area. Cryptosporidium parvum subtypes were IIcA5G3R2 (1) and IIcA5G3a (1).

Conclusions
All isolates successfully genotyped were C. hominis or anthroponotic C. parvum, suggesting that anthroponotic transmission dominates in Lusaka and the surrounding countryside.
Perioperative management considerations in patients taking prescribed psychoactive medications (including those for depression and Parkinson's disease)
Authors: Ho Serene , Wong Adrian 
Published: July 2021

Purpose of review
Given the number of drugs available in the anaesthetist's armamentarium, drug interactions need to be managed. This is particularly true of psychoactive medications which primarily act on the central nervous system, targeting neurotransmitter pathways often affected by anaesthetic agents. This review gives an overview of the potential interactions of commonly used psychoactive medications with anaesthetic agents and hence their perioperative considerations. As anaesthetists will already be very familiar with the benzodiazepines, they will not be discussed here. Electroconvulsive therapy will also not be discussed.

Recent findings
A wide range of psychoactive medications can interact with drugs commonly used in perioperative care including anaesthetic agents. There is limited clinical research into their effects and hence these interactions are based on known pharmacological actions.

Summary
A cautious, pragmatic approach is recommended when managing patients on psychoactive medications requiring anaesthesia as part of their medical care.
Geographic variations in the incidence of congenital hypothyroidism in China: a retrospective study based on 92 million newborns screened in 2013–2018
Authors: Yao Yong-Na , Yuan Xue-Lian , Zhu Jun , Xiang Liang-Cheng , Li Qi , Deng Kui , Li Xiao-Hong , Liu Han-Min 
Published: July 2021

Abstract

Background:
Although congenital hypothyroidism (CH) has been widely studied in Western countries, CH incidence at different administrative levels in China during the past decade remains unknown. This study aimed to update the incidence and revealed the spatial pattern of CH incidence in the mainland of China, which could be helpful in the planning and implementation of preventative measures.

Methods:
The data used in our study were derived from 245 newborns screening centers that cover 30 provinces of the Chinese Newborn Screening Information System. Spatial auto-correlation was analyzed by Global Moran I and Getis-Ord Gi statistics at the provincial level. Kriging interpolation methods were applied to estimate a further detailed spatial distribution of CH incidence at city level throughout the mainland of China, and Kulldorff space scanning statistical methods were used to identify the spatial clusters of CH cases at the city level.

Results:
A total of 91,921,334 neonates were screened from 2013 to 2018 and 42,861 cases of primary CH were identified, yielding an incidence of 4.66 per 10,000 newborns screened (95% confidence interval [CI]: 4.62–4.71). Neonates in central (risk ratio [RR] = 0.84, 95% CI: 0.82–0.85) and western districts (RR = 0.71, 95% CI: 0.69–0.73) had lower probability of CH cases compared with the eastern region. The CH incidence indicated a moderate positive global spatial autocorrelation (Global Moran I value = 0.394, P
< 0.05), and the CH cases were significantly clustered in spatial distribution. A most likely city-cluster (log-likelihood ratio [LLR] = 588.82, RR = 2.36, P
< 0.01) and 25 secondary city-clusters of high incidence were scanned. The incidence of each province and each city in the mainland of China was estimated by kriging interpolation, revealing the most affected province and city to be Zhejiang Province and Hangzhou city, respectively.

Conclusion:
This study offers an insight into the space clustering of CH incidence at provincial and city scales. Future work on environmental factors need to focus on the effects of CH occurrence.