bluuebunny/crossref_metadata_2025 huggingface dataset:
Single sample pathway analysis in metabolomics: performance evaluation and application
Authors: Wieder Cecilia , Lai Rachel P. J. , Ebbels Timothy M. D.
Published: November 2022

Background

Single sample pathway analysis (ssPA) transforms molecular level omics data to the pathway level, enabling the discovery of patient-specific pathway signatures. Compared to conventional pathway analysis, ssPA overcomes the limitations by enabling multi-group comparisons, alongside facilitating numerous downstream analyses such as pathway-based machine learning. While in transcriptomics ssPA is a widely used technique, there is little literature evaluating its suitability for metabolomics. Here we provide a benchmark of established ssPA methods (ssGSEA, GSVA, SVD (PLAGE), and z-score) alongside the evaluation of two novel methods we propose: ssClustPA and kPCA, using semi-synthetic metabolomics data. We then demonstrate how ssPA can facilitate pathway-based interpretation of metabolomics data by performing a case-study on inflammatory bowel disease mass spectrometry data, using clustering to determine subtype-specific pathway signatures.

Results

While GSEA-based and z-score methods outperformed the others in terms of recall, clustering/dimensionality reduction-based methods provided higher precision at moderate-to-high effect sizes. A case study applying ssPA to inflammatory bowel disease data demonstrates how these methods yield a much richer depth of interpretation than conventional approaches, for example by clustering pathway scores to visualise a pathway-based patient subtype-specific correlation network. We also developed the sspa python package (freely available at https://pypi.org/project/sspa/), providing implementations of all the methods benchmarked in this study.

Conclusion

This work underscores the value ssPA methods can add to metabolomic studies and provides a useful reference for those wishing to apply ssPA methods to metabolomics data.
Combining genetic constraint with predictions of alternative splicing to prioritize deleterious splicing in rare disease studies
Authors: Cormier Michael J. , Pedersen Brent S. , Bayrak-Toydemir Pinar , Quinlan Aaron R.
Published: November 2022

Background

Despite numerous molecular and computational advances, roughly half of patients with a rare disease remain undiagnosed after exome or genome sequencing. A particularly challenging barrier to diagnosis is identifying variants that cause deleterious alternative splicing at intronic or exonic loci outside of canonical donor or acceptor splice sites.

Results

Several existing tools predict the likelihood that a genetic variant causes alternative splicing. We sought to extend such methods by developing a new metric that aids in discerning whether a genetic variant leads to deleterious alternative splicing. Our metric combines genetic variation in the Genome Aggregate Database with alternative splicing predictions from SpliceAI to compare observed and expected levels of splice-altering genetic variation. We infer genic regions with significantly less splice-altering variation than expected to be constrained. The resulting model of regional splicing constraint captures differential splicing constraint across gene and exon categories, and the most constrained genic regions are enriched for pathogenic splice-altering variants. Building from this model, we developed ConSpliceML. This ensemble machine learning approach combines regional splicing constraint with multiple per-nucleotide alternative splicing scores to guide the prediction of deleterious splicing variants in protein-coding genes. ConSpliceML more accurately distinguishes deleterious and benign splicing variants than state-of-the-art splicing prediction methods, especially in “cryptic” splicing regions beyond canonical donor or acceptor splice sites.

Conclusion

Integrating a model of genetic constraint with annotations from existing alternative splicing tools allows ConSpliceML to prioritize potentially deleterious splice-altering variants in studies of rare human diseases.
Meta-analysis of 16S rRNA microbial data identified alterations of the gut microbiota in COVID-19 patients during the acute and recovery phases
Authors: Cheng Xiaomin , Zhang Yali , Li Yifan , Wu Qin , Wu Jiani , Park Soo-Kyung , Guo Cheng , Lu Jiahai
Published: November 2022

Background

Dozens of studies have demonstrated gut dysbiosis in COVID-19 patients during the acute and recovery phases. However, a consensus on the specific COVID-19 associated bacteria is missing. In this study, we performed a meta-analysis to explore whether robust and reproducible alterations in the gut microbiota of COVID-19 patients exist across different populations.

Methods

A systematic review was conducted for studies published prior to May 2022 in electronic databases. After review, we included 16 studies that comparing the gut microbiota in COVID-19 patients to those of controls. The 16S rRNA sequence data of these studies were then re-analyzed using a standardized workflow and synthesized by meta-analysis.

Results

We found that gut bacterial diversity of COVID-19 patients in both the acute and recovery phases was consistently lower than non-COVID-19 individuals. Microbial differential abundance analysis showed depletion of anti-inflammatory butyrate-producing bacteria and enrichment of taxa with pro-inflammatory properties in COVID-19 patients during the acute phase compared to non-COVID-19 individuals. Analysis of microbial communities showed that the gut microbiota of COVID-19 recovered patients were still in unhealthy ecostates.

Conclusions

Our results provided a comprehensive synthesis to better understand gut microbial perturbations associated with COVID-19 and identified underlying biomarkers for microbiome-based diagnostics and therapeutics.
Insights into adaptive evolution of plastomes in Stipa L. (Poaceae)
Authors: Krawczyk Katarzyna , Myszczyński Kamil , Nobis Marcin , Sawicki Jakub
Published: November 2022

Background

The study presents results of research on the evolution of plastid genomes in Stipa L. which is a large genus of the Poaceae family, comprising species diverse in terms of geographic distribution, growing under highly variated habitat conditions. Complete plastome sequences of 43 taxa from Stipeae and Ampelodesmae tribes were analyzed for the variability of the coding regions against the background of phylogenetic relationships within the genus Stipa. The research hypothesis put forward in our research was that some of coding regions are affected by a selection pressure differentiated between individual phylogenetic lines of Stipa, potentially reducing the phylogenetic informativeness of these CDS. The study aimed to answer the question, which genes evolve in Stipa most rapidly and what kind of changes in the properties of encoded amino acids this entails. Another goal of this research was to find out whether individual genes are affected by positive selection and finally, whether selective pressure is uniform within the genus or does it vary between particular evolutionary lines within the genus.

Results

Results of our study proved the presence of selective pressure in 11 genes: ccsA, matK, ndhC, ndhF, ndhK, rbcL, rpoA rpoC1, rpoC2, rps8 and rps11. For the first time the effect of positive selection on the rps8, rps11, and ndhK genes was documented in grasses. The varied pace of evolution, different intensity and effects of selective pressure have been demonstrated between particular phylogenetic lines of the genus tested.

Conclusions

Positive selection in plastid genome in Stipa mostly affects photosynthetic genes. The potential strongest adaptive pressure was observed in the rbcL gene, especially in the oldest evolutionary group comprising Central Asian high-mountain species: S. basiplumosa, S. klimesii, S. penicillata and S. purpurea, where adaptive pressure probably affected the amino acids directly related to the efficiency of CO2 assimilation.
Seizures in adults with suspected central nervous system infection
Authors: Olie Sabine E. , van Zeggeren Ingeborg E. , ter Horst Liora ,   I.-PACE Study Group, Citroen J. , van Geel B. M. , Heckenberg S. G. B. , Jellema K. , Kester M. I. , Killestein J. , Mook B. B. , Titulaer M. J. , van Veen K. E. B. , Verschuur C. V. M. , van de Beek Diederik , Brouwer Matthijs C.
Published: November 2022

Background

Seizures can be part of the clinical presentation of central nervous system (CNS) infections. We describe patients suspected of a neurological infection who present with a seizure and study diagnostic accuracy of clinical and laboratory features predictive of CNS infection in this population.

Methods

We analyzed all consecutive patients presenting with a seizure from two prospective Dutch cohort studies, in which patients were included who underwent cerebrospinal fluid (CSF) examination because of the suspicion of a CNS infection.

Results

Of 900 episodes of suspected CNS infection, 124 (14%) presented with a seizure. The median age in these 124 episodes was 60 years (IQR 45–71) and 53% of patients was female. CSF examination showed a leukocyte count ≥ 5/mm3in 41% of episodes. A CNS infection was diagnosed in 27 of 124 episodes (22%), a CNS inflammatory disorder in 8 (6%) episodes, a systemic infection in 10 (8%), other neurological disease in 77 (62%) and in 2 (2%) episodes another systemic disease was diagnosed. Diagnostic accuracy of clinical and laboratory characteristics for the diagnosis of CNS infection in this population was low. CSF leukocyte count was the best predictor for CNS infection in patients with suspected CNS infection presenting with a seizure (area under the curve 0.94, [95% CI 0.88 – 1.00]).

Conclusions

Clinical and laboratory features fail to distinguish CNS infections from other causes of seizures in patients with a suspected CNS infection. CSF leukocyte count is the best predictor for the diagnosis of CNS infection in this population.
Cultural influence on the expression of labour-associated pain
Authors: Navarro-Prado S , Sánchez-Ojeda MA , Marmolejo-Martín J , Kapravelou G , Fernández-Gómez E , Martín-Salvador A
Published: November 2022

Background

Every woman expresses pain differently during birth since it depends on a multitude of predictive factors. The medical care received, companionship during birth, cultural background and language barriers of the women in labour can influence on the expression of pain. This study aims to evaluate the expression of pain during birth and its associated factors in women treated in a Spanish border town.

Methods

The study included 246 women in labour. The expression of pain during labour was evaluated using the validated ESVADOPA scale. A descriptive analysis and association study were performed between cultural identity and dimensions of the scale. Multiple linear regression models were performed to assess the association between cultural identity, origin, language barrier, and companionship during labour.

Results

The women included in the study comprised 68.7% Berbers, 71.5% Muslims and 82.1% were accompanied during labour. An association between cultural identity and greater body expression of pain (p = 0.020; Cramer’s V = 0.163) in addition to its verbal expression was found during the latent phase of labour, (p = 0.028; Cramer’s V = 0.159). During the active phase of labour, cultural identity was associated with pain expression through greater body response, verbal expression, expression of the facial muscles, anxiety, inability to relax and vegetative symptoms. The different factors studied that had a predictive value were companionship (p = 0.027) during the latent phase of labour and Berber origin (p = 0.000), language barrier (p = 0.014) and companionship (p = 0.005) during the active phase of labour. The models designed predict pain expression in the latent phase by companionship and type of companionship (β = 1.483; 95%CI = 0.459–2.506, β = 0.238; 95%CI = 0.029–0. 448, respectively), and in the active phase by background, language barrier and companionship (β = 0.728; 95%CI = 0.258–1.198, β = 0.738; 95%CI = 0.150–1.326, β = 1.888; 95%CI = 0.984–2.791, respectively).

Conclusion

Culture, origin, language barrier and companionship during labour influences the manner in which women in labour express their pain. An understanding of this may help midwives correctly interpret the signs of pain expression and be able to offer the appropriate assistance depending on a woman's particular characteristics. There is a clear need for new models of maternity care that will take the cultural and language characteristics of women in labour into consideration.
Venetoclax combined with low dose cytarabine compared to standard of care intensive chemotherapy for the treatment of favourable risk adult acute myeloid leukaemia (VICTOR): Study protocol for an international, open-label, multicentre, molecularly-guided randomised, phase II trial
Authors: Dillon Richard , Maycock Shanna , Jackson Aimee , Fox Sonia , Freeman Sylvie , Craddock Charles , Thomas Catherine , Homer Emma , Leahy Jane , Mamwell Anna , Potter Nicola , Russell Nigel , Wei Andrew , Ommen Hans Beier , Hemmaway Claire , Knapper Steve , Billingham Lucinda
Published: November 2022

Background

For patients with acute myeloid leukaemia (AML), the only potentially curative treatment is intensive chemotherapy (IC). This is highly toxic, particularly for patients > 60 years, potentially leading to prolonged hospitalisations requiring intensive supportive care, and sometimes treatment-related death. This also results in extensive healthcare costs and negatively impacts quality of life (QoL). Venetoclax with low-dose cytarabine (VEN + LDAC) is a novel, low-intensity treatment for AML patients who cannot receive IC. VEN + LDAC is given as an outpatient and toxicity appears significantly lower than with IC. Analysis of clinical trials performed to date are promising for patients with the genotype NPM1mutFLT3 ITDneg, where remission and survival rates appear comparable to those achieved with IC.

Methods

VICTOR is an international, two-arm, open-label, multi-centre, non-inferiority, randomised-controlled phase II trial to assess VEN + LDAC compared to standard of care (IC) as first-line treatment in older patients (initially aged ≥ 60 years) with newly diagnosed AML. The trial will recruit patients with a NPM1mutFLT3 ITDneg genotype; those with a favourable risk in relation to the experimental treatment. University of Birmingham is the UK co-ordinating centre, with national hubs in Aarhus University Hospital, Denmark, and Auckland District Health Board, New Zealand. The primary outcome is molecular event-free survival time where an event is defined as failure to achieve morphological complete response (CR) or CR with incomplete blood count recovery after two cycles of therapy; molecular persistence, progression or relapse requiring treatment change; morphological relapse, or; death. Secondary outcomes include cumulative resource use at 12- and 24-months, and QoL as assessed by EORTCQLQ-C30 and EQ-5D-3L at 3-, 6-, 12-, 18- and 24-months. The trial employs an innovative Bayesian design with target sample size of 156 patients aged > 60 years.

Discussion

The principle underpinning the VICTOR trial is that the chance of cure for patients in the experimental arm should not be compromised, therefore, an adaptive design with regular checks on accumulating data has been employed, which will allow for a staged expansion of the trial population to include younger patients if, and when, there is sufficient evidence of non-inferiority in older patients.

Trial registration

EudraCT: 2020–000,273-24; 21-Aug-2020.

ISRCTN: 15,567,173; 08-Dec-2020.
Silva cumulative score and its relationship with prognosis in Endocervical adenocarcinoma
Authors: Li Yuemin , Jia Meng , Cao Lanqing , Yu Jiaqi , Gao Hongwen , Sun Ping-Li
Published: November 2022

Background

The Silva system has been demonstrated to have a good predictive value of lymph node metastasis (LNM) in endocervical adenocarcinoma (EAC). Tumours were classified based on the highest identified pattern of invasion in this system, this may not exactly reflect the true situation when it presents with a “mixed pattern” in some cases. Recent study has shown that patients with lymphovascular invasion (LVI) have worse prognosis in EAC. Here we design a Silva cumulative score (SCS) system which also combined the LVI status to explore its prognostic role in EAC patients.

Methods

A total of 120 patients with EAC were included in this study. Clinicopathological characteristics were retrospectively retrieved from the medical records and follow-up data were obtained. The clinicopathological information included age at diagnosis, depth of invasion (DOI), LNM, LVI, Silva classification, and SCS. SCS is a classification system based on the sum score of different Silva pattern which is founded on morphological phenomena. The relationships between the pathological characteristics and prognoses were analyzed.

Results

According to the Silva system, 11 (9.2%), 22 (18.3%) and 87 (72.5%) patients had patterns A, B, and C, respectively. Patients with pattern C had the highest incidence of LVI and LNM (p < 0.05). Although the Kaplan-Meier curves demonstrated that survival decreased with increasing Silva classification for A-C cancers, there was no statistically significant difference [disease-free survival (DFS): p = 0.181; overall survival (OS): p = 0.205]. There were 45 cases presented as mixed-type of Silva patterns. According to the SCS, 23 cases (19.2%) were rated as grade I, 31 cases (25.8%) as grade II and 66 (55.0%) cases as grade III. Patients with SCS grade III had the highest incidence of LVI and LNM (p < 0.05). Kaplan–Meier analysis revealed that patients with higher SCS had significantly shorter DFS and OS than those with lower SCS (p < 0.05). High SCS was an independent predictor of poorer OS and DFS (p < 0.05) in patients with EAC.

Conclusions

The application of the Silva system could effectively predict the LNM of patients and may be helpful in selecting an appropriate surgical procedure. The SCS system we designed showed a good predictive value for DFS and OS in EAC.
Participatory disease surveillance for a mass gathering — a prospective cohort study on COVID-19, Germany 2021
Authors: Hohmuth Nils , Khanyaree Ifrah , Lang Anna-Lena , Duering Ohad , Konigorski Stefan , Višković Vukašin , Heising Tobias , Egender Friedemann , Remschmidt Cornelius , Leistner Rasmus
Published: November 2022

Background

Mass gatherings (MGs) such as music festivals and sports events have been associated with a high risk of SARS-CoV-2 transmission. On-site research can foster knowledge of risk factors for infections and improve risk assessments and precautionary measures at future MGs. We tested a web-based participatory disease surveillance tool to detect COVID-19 infections at and after an outdoor MG by collecting self-reported COVID-19 symptoms and tests.

Methods

We conducted a digital prospective observational cohort study among fully immunized attendees of a sports festival that took place from September 2 to 5, 2021 in Saxony-Anhalt, Germany. Participants used our study app to report demographic data, COVID-19 tests, symptoms, and their contact behavior. This self-reported data was used to define probable and confirmed COVID-19 cases for the full “study period” (08/12/2021 – 10/31/2021) and within the 14-day “surveillance period” during and after the MG, with the highest likelihood of an MG-related COVID-19 outbreak (09/04/2021 – 09/17/2021).

Results

A total of 2,808 of 9,242 (30.4%) event attendees participated in the study. Within the study period, 776 individual symptoms and 5,255 COVID-19 tests were reported. During the 14-day surveillance period around and after the MG, seven probable and seven PCR-confirmed COVID-19 cases were detected. The confirmed cases translated to an estimated seven-day incidence of 125 per 100,000 participants (95% CI [67.7/100,000, 223/100,000]), which was comparable to the average age-matched incidence in Germany during this time. Overall, weekly numbers of COVID-19 cases were fluctuating over the study period, with another increase at the end of the study period.

Conclusion

COVID-19 cases attributable to the mass gathering were comparable to the Germany-wide age-matched incidence, implicating that our active participatory disease surveillance tool was able to detect MG-related infections. Further studies are needed to evaluate and apply our participatory disease surveillance tool in other mass gathering settings.
Impact of anticancer therapy on the quality of life of Sudanese patients with breast cancer at Khartoum oncology hospital
Authors: Aldaak Mawada , Suliman Hayat M. , Abd-Elgadir Elsadig Elgailany , Abdoon Iman Hassan
Published: November 2022

Background

Chemotherapy-related toxicity affects the quality of life (QOL) of patients with cancer. Measuring the QOL in breast cancer (BC) patients has been the focus of clinical practices and research in recent decades. This study aimed to assess the impact of BC medications on QOL of Sudanese patients with BC.

Methods

A cross-sectional study was conducted in Khartoum Oncology Hospital, Sudan, from November 2020 to March 2021. All patients diagnosed with BC were included in the study. QOL was assessed using the European Organization for Research and Treatment of Cancer quality of life (EORTC QLQ-C-30) and breast cancer supplementary module (QLQ-BR23). ANOVA, independent t-test and logistic regression analysis were used to assess the association between variables.

Results

Two hundred patients were enrolled in the study, with a mean age of 50 ± 11.7 years. 52.5% of the patients were on a conventional therapy whereas 40.5% and 7% received hormonal and HER2-targeted therapies, respectively. In QLQ-C30 scale, the global health-QOL status score was (53.2 ± 1.9), with 54.0% of patients having poor global health-QOL status. In the functional scale, the cognitive functioning was the highest score (80.7 ± 1.8). In QLQ-C30 symptom scale, the most distressing issue was financial difficulties (63.7 ± 2.9). In QLQ-BR23 scale, body image scored the worse functioning (47.7 ± 2.7), with 54.5% of patients having poor QOL. In QLQ-BR23 symptoms scale, “being upset by hair loss” was the highest disturbing symptom (62.1 ± 3.3), with 68.6% of patients having poor QOL. Global health status (P = 0.000), social (P = 0.000), emotional (P = 0.002) and role functioning (P = 0.000) were significantly higher in patients taking HER2-targeted or hormonal therapy compared to conventional therapy. The level of symptomatology was significantly low in patients taking HER2-targeted therapy or hormonal therapy (P = 0.000) than those on conventional therapy. Hormonal (OR = 3.7, p = 0.01) and HER2-targeted therapies (OR = 10.2, p = 0.04 ) were positive predictors of QOL.

Conclusion

BC survivors in Sudan had a low QOL/global health status. Hormonal and HER2-targeted therapies were predictors of good QOL.
Construct and clinical verification of a nurse-led rapid response systems and activation criteria
Authors: Wu Yuchen , Wang Jiaming , Luo Fan , Li Dan , Ran Xue , Ren Xuanlin , Zhang Lixiu , Wei Jingyun
Published: November 2022

Background

Effective team leadership and good activation criteria can effectively initiate rapid response system (RRS) to reduce hospital mortality and improve quality of life. The first reaction time of nurses plays an important role in the rescue process. To construct a nurse-led (nurse-led RRS) and activation criteria and then to conduct a pragmatic evaluation of the nurse-led RRS.

Methods

We used literature review and the Delphi method to construct a nurse-led RRS and activation criteria based on the theory of “rapid response system planning.” Then, we conducted a quasi-experimental study to verify the nurse-led RRS. The control group patients were admitted from August to October 2020 and performed traditional rescue procedures. The intervention group patients were admitted from August to October 2021 and implemented nurse-led RRS. The primary outcome was success rate of rescue.

Setting

Emergency department, Gansu Province, China.

Results

The nurse-led RRS and activation criteria include 4 level 1 indicators, 14 level 2 indicators, and 88 level 3 indicators. There were 203 patients who met the inclusion criteria to verify the nurse-led RRS. The results showed that success rate of rescue in intervention group (86.55%) was significantly higher than that in control group (66.5%), the rate of cardiac arrest in intervention group (33.61%) was significantly lower than that in control group (72.62%), the effective rescue time of intervention group (46.98 ± 12.01 min) was shorter than that of control group (58.67 ± 13.73 min), and the difference was statistically significant (P < 0.05). The rate of unplanned ICU admissions in intervention group (42.85%) was lower than that in control group (44.04%), but the difference was not statistically significant (P > 0.05).

Conclusions

The nurse-led RRS and activation criteria can improve the success rate of rescue, reduce the rate of cardiac arrest, shorten the effective time of rescue, effectively improve the rescue efficiency of patients.
Using measures of quality of care to assess equity in health care funding for primary care: analysis of Indonesian household data
Authors: Haemmerli Manon , Asante Augustine , Susilo Dwidjo , Satrya Aryana , Fattah Rifqi Abdul , Cheng Qinglu , Kosen Soewarta , Novitasari Danty , Puteri Gemala Chairunnisa , Adawiyah Eviati , Hayen Andrew , Gilson Lucy , Mills Anne , Tangcharoensathien Viroj , Jan Stephen , Thabrany Hasbullah , Wiseman Virginia
Published: November 2022

Background

Many countries implementing pro-poor reforms to expand subsidized health care, especially for the poor, recognize that high-quality healthcare, and not just access alone, is necessary to meet the Sustainable Development Goals. As the poor are more likely to use low quality health services, measures to improve access to health care need to emphasise quality as the cornerstone to achieving equity goals. Current methods to evaluate health systems financing equity fail to take into account measures of quality. This paper aims to provide a worked example of how to adapt a popular quantitative approach, Benefit Incidence Analysis (BIA), to incorporate a quality weighting into the computation of public subsidies for health care.

Methods

We used a dataset consisting of a sample of households surveyed in 10 provinces of Indonesia in early-2018. In parallel, a survey of public health facilities was conducted in the same geographical areas, and information about health facility infrastructure and basic equipment was collected. In each facility, an index of service readiness was computed as a measure of quality. Individuals who reported visiting a primary health care facility in the month before the interview were matched to their chosen facility. Standard BIA and an extended BIA that adjusts for service quality were conducted.

Results

Quality scores were relatively high across all facilities, with an average of 82%. Scores for basic equipment were highest, with an average score of 99% compared to essential medicines with an average score of 60%. Our findings from the quality-weighted BIA show that the distribution of subsidies for public primary health care facilities became less ‘pro-poor’ while private clinics became more ‘pro-rich’ after accounting for quality of care. Overall the distribution of subsidies became significantly pro-rich (CI = 0.037).

Conclusions

Routine collection of quality indicators that can be linked to individuals is needed to enable a comprehensive understanding of individuals’ pathways of care. From a policy perspective, accounting for quality of care in health financing assessment is crucial in a context where quality of care is a nationwide issue. In such a context, any health financing performance assessment is likely to be biased if quality is not accounted for.
Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases: a prospective cohort study (GASTO 1028)
Authors: Li Meichen , Chen Jing , Zhang Baishen , Yu Juan , Wang Na , Li Delan , Shao Yang , Zhu Dongqin , Liang Chuqiao , Ma Yutong , Ou Qiuxiang , Hou Xue , Chen Likun
Published: November 2022

Background

Due to the blood-brain barrier, plasma is not an ideal source to evaluate the genetic characteristics of central nervous system tumors. Thus, cerebrospinal fluid (CSF) is becoming an alternative biopsy type to evaluate the genetic landscape of intracranial tumors. We aimed to explore the genetic profiles of CSF-derived circulating tumor DNA (ctDNA) to predict intracranial tumor responses and monitor mutational evolution during the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases.

Methods

We conducted a prospective study of 92 newly diagnosed NSCLC patients with brain metastases. Paired CSF and plasma samples were collected at baseline, 8 weeks after treatment initiation, and disease progression. All samples underwent next-generation sequencing of 425 cancer-related genes.

Results

At baseline, the positive detection rates of ctDNA in CSF, plasma, and extracranial tumors were 63.7% (58/91), 91.1% (82/90), and 100% (58/58), respectively. A high level of genetic heterogeneity was observed between paired CSF and plasma, while concordance in driver mutations was also observed. A higher number of unique copy number variations was detected in CSF-ctDNA than in plasma. ctDNA positivity of CSF samples at baseline was associated with poor outcomes (HR=2.565, P=0.003). Moreover, patients with ≥ 50% reductions in the concentrations of CSF ctDNA after 8 weeks of treatment had significantly longer intracranial progression-free survivals (PFS) than patients with < 50% reductions in CSF ctDNA concentrations (13.27 months vs 6.13 months, HR=0.308, P=0.017). A ≥ 50% reduction in CSF ctDNA concentrations had better concordance with radiographic intracranial tumor responses than plasma. A ≥ 50% reduction in plasma ctDNA concentrations was also associated with longer extracranial PFS (11.57 months vs 6.20 months, HR=0.406, P=0.033). Based on clonal evolution analyses, the accumulation of subclonal mutations in CSF ctDNA was observed after 8 weeks of treatment. The clonal mutations that remained in more than 80% in CSF after 8 weeks also predicted shorter intracranial PFS (HR=3.785, P=0.039).

Conclusions

CSF ctDNA exhibited unique genetic profiles of brain metastases, and dynamic changes in CSF ctDNA could better predict intracranial tumor responses and track clonal evolution during treatment in NSCLC patients with brain metastases.

Trial registration

ClinicalTrials.gov identifier: NCT 03257735.
Inequalities in the impact of COVID-19-associated disruptions on tuberculosis diagnosis by age and sex in 45 high TB burden countries
Authors: McQuaid C. Finn , Henrion Marc Y. R. , Burke Rachael M. , MacPherson Peter , Nzawa-Soko Rebecca , Horton Katherine C.
Published: November 2022

Background

Tuberculosis remains a major public health priority and is the second leading cause of mortality from infectious disease worldwide. TB case detection rates are unacceptably low for men, the elderly and children. Disruptions in TB services due to the COVID-19 pandemic may have exacerbated these and other inequalities.

Methods

We modelled trends in age- and sex- disaggregated case notifications for all forms of new and relapse TB reported to the World Health Organization for 45 high TB, TB/HIV and MDR-TB burden countries from 2013 to 2019. We compared trend predicted notifications to observed notifications in 2020 to estimate the number of people with TB likely to have missed or delayed diagnosis. We estimated the risk ratio (RR) of missed or delayed TB diagnosis for children (aged < 15 years) or the elderly (aged ≥ 65 years) compared to adults (aged 15–64 years) and women compared to men (both aged ≥ 15 years) using a random-effects meta-analysis.

Results

An estimated 195,449 children (95% confidence interval, CI: 189,673–201,562, 37.8% of an expected 517,168), 1,126,133 adults (CI: 1,107,146–1,145,704, 21.8% of an expected 5,170,592) and 235,402 elderly (CI: 228,108–243,202, 28.5% of an expected 826,563) had a missed or delayed TB diagnosis in 2020. This included 511,546 women (CI: 499,623–523,869, 22.7%, of an expected 2,250,097) and 863,916 men (CI: 847,591–880,515, 23.0% of an expected 3,763,363). There was no evidence globally that the risk of having TB diagnosis missed or delayed was different for children and adults (RR: 1.09, CI: 0.41–2.91), the elderly and adults (RR: 1.40, CI: 0.62–3.16) or men and women (RR: 0.59, CI: 0.25–1.42). However, there was evidence of disparities in risk by age and/or sex in some WHO regions and in most countries.

Conclusions

There is no evidence at an aggregate global level of any difference by age or sex in the risk of disruption to TB diagnosis as a result of the COVID-19 pandemic. However, in many countries, disruptions in TB services have been greater for some groups than others. It is important to recognise these context-specific inequalities when prioritising key populations for catch-up campaigns.
Cryptosporidium in human-animal-environment interphase at Adama and Asella areas of Oromia regional state, Ethiopia
Authors: Berhanu Kassahun , Ayana Dinka , Megersa Bekele , Ashenafi Hagos , Waktole Hika
Published: November 2022

Background

In Ethiopia, several studies have reported the occurrence of Cryptosporidium infection in young calves, lambs, and HIV positive patients. However, research on cattle and sheep of all ages, as well as humans, has been limited.

Methods

A cross-sectional study was conducted to investigate the occurrence of Cryptosporidium in dairy cattle, sheep, humans, and manure samples. Dairy cattle and sheep were stratified according to their age groups and randomly sampled. Stool samples from volunteered dairy farm workers and rural household members were collected purposefully. A semi-structured questionnaire was also used to collect information about manure handling practices and socio-demographic variables. All collected samples were processed with the sugar floatation technique and the modified Ziehl–Neelsen staining method. Logistic regression was used to analyze the association of risk factors with the occurrence of Cryptosporidium in study subjects (p < 0.05).

Results

The overall prevalence of Cryptosporidium in dairy cattle, sheep, humans, and manure samples was 20.5%, 14%, 16%, and 13.20%, respectively. Cryptosporidium infection was significantly higher in dairy cattle aged 1–12 months and 13–36 months with odds of 3.48 and 3.07 times higher, respectively, compared to others. Similarly, its occurrence was 2.69 times higher in sheep aged 1–6 months than those above 6 months. And also, a higher average oocyst count (above 10 oocysts) per-field was observed in cattle aged 1–12 months, followed by sheep aged 1–6 months. Furthermore, the likelihood of infection was 13 times greater in farm workers compared to household members of smallholder farmers. In addition, the occurrence of oocysts was 22.8 times higher in manures from dairy cattle than that of sheep. About 16.8% of the study respondents had manure disposal pit, 98.1% of them used manure as fertilizer for crop and vegetable production without any treatment.

Conclusions

The study revealed the occurrence of Cryptosporidium infection in all age groups of dairy cattle and sheep, humans engaged in animal production. Occurrence of Cryptosporidium in manure suggests it potential contamination of environment and water sources.
MiRNA/mRNA network topology in hepatitis virus B-related liver cirrhosis reveals miR-20a-5p/340-5p as hubs initiating fibrosis
Authors: Yao Heng , Li Peng , Xin Jiaojiao , Liang Xi , Jiang Jing , Shi Dongyan , Li Jiang , Hassan Hozeifa Mohamed , Chen Xin , Li Jun
Published: November 2022

Background

The pathophysiology of hepatitis B-related liver cirrhosis (HBV-LC) remains unclear. This study aimed to explore the disease mechanisms using topological analysis of the miRNA/mRNA network.

Methods

Paired miRNA/mRNA sequencing was performed with thirty-three peripheral blood mononuclear cell samples (LC, n = 9; chronic hepatitis B, n = 12; normal controls, n = 12) collected from a prospective cohort to identify the miRNA/mRNA network. Topological features and functional implications of the network were analyzed to capture pathophysiologically important miRNAs/mRNAs, whose expression patterns were confirmed in the validation group (LC, n = 15; chronic hepatitis B, n = 15; normal controls, n = 10), and functional potentials initiating fibrogenesis were demonstrated in vitro.

Results

The miRNA/mRNA network contained 3121 interactions between 158 differentially expressed (DE) miRNAs and 442 DE-mRNAs. The topological analysis identified a core module containing 99 miRNA/mRNA interactions and two hub nodes (miR-20a-5p/miR-340-5p), which connected to 75 DE-mRNAs. The expression pattern along the disease progression of the core module was found associated with a continuous increase in wound healing, inflammation, and leukocyte migration but an inflection of immune response and lipid metabolic regulation, consistent with the pathophysiology of HBV-LC. MiR-20a-5p/miR-340-5p were found involved in macrophage polarization and hepatic stellate cell (HSC) activation in vitro (THP-1, LX-2 cell lines), and their expression levels were confirmed in the validation group independently.

Conclusion

Topological analysis of the miRNA/mRNA network in HBV-LC revealed the association between fibrosis and miR-20a-5p/miR-340-5p involving initiating activations of macrophage and HSC. Further validations should be performed to confirm the HSC/macrophage activations and the interactions between miR-20a-5p/miR-340-5p and their potential targets, which may help to develop non-invasive prognostic markers or intervention targets for HBV-LC.
Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential
Authors: Tang Ling , Peng Lin , Tan Chao , Liu Huai , Chen Pan , Wang Hui
Published: November 2022

HOXA9 functioning as a transcription factor is one of the members of HOX gene family, which governs multiple cellular activities by facilitating cellular signal transduction. In addition to be a driver in AML which has been widely studied, the role of HOXA9 in solid tumor progression has also received increasing attention in recent years, where the aberrant expression of HOXA9 is closely associated with the prognosis of patient. This review details the signaling pathways, binding partners, post-transcriptional regulation of HOXA9, and possible inhibitors of HOXA9 in solid tumors, which provides a reference basis for further study on the role of HOXA9 in solid tumors.
Low lipoprotein(a) concentration is associated with atrial fibrillation: a large retrospective cohort study
Authors: Tao Junjie , Yang Xinlei , Qiu Qingkai , Gao Feng , Chen Wenchong , Hu Lijuan , Xu Yuan , Yi Yingping , Hu Hui , Jiang Long
Published: November 2022

Background and aims

The role of serum lipoprotein(a) [Lp(a)] levels in atrial fibrillation (AF) is still uncertain, especially in the Chinese population. Here, we aimed to elucidate the potential relationship between Lp(a) quantiles and AF.

Methods

All data were collected through inpatients with electronic health records from the Second Affiliated Hospital of Nanchang University, Jiangxi Province, China. The propensity score matching (PSM) method was used to match control and case groups. Interactions between AF, Lp(a) quantiles, and other clinical indices were analyzed by logistic regression and stratified analysis. Statistical analyses were performed with IBM SPSS statistical software and R software.

Results

From 2017 to 2021, 4,511 patients with AF and 9,022 patients without AF were 1:2 matched by the propensity score matching method. A total of 46.9% of the study group was women, and the baseline mean age was 65 years. The AF group exhibited lower median Lp(a) than the non-AF group (15.95 vs. 16.90 mg/dL; P < 0.001). Based on the Lp(a) quantiles, the study population was divided into four groups: Q1 (≤ 8.71 mg/dL), Q2 (8.71–16.54 mg/dL), Q3 (16.54–32.42 mg/dL) and Q4 (> 32.42 mg/dL). The AF prevalence of each group decreased from 34.2% (Q1) to 30.9% (Q4) (P < 0.001). Lp(a) quantiles 1–3 significantly increased AF to 1.162-fold (1.049–1.286), 1.198-fold (1.083–1.327), and 1.111-fold (1.003–1.231) in the unadjusted logistic regression model, respectively. In the adjusted model, Lp(a) < 32.42 mg/dL still showed a significant inverse association with AF. In the stratified analysis, Lp(a) levels in female patients exhibited a significant negative correlation with AF (OR of Q1: 1.394[1.194–1.626], P = 0.001). Age and hypertension did not affect the adverse correlation.

Conclusion

Low circulating Lp(a) levels were associated with AF, especially in the female Han population, suggesting that Lp(a) may be useful for risk stratification of AF in female individuals.
Prognostic and clinicopathological value of Slug protein expression in breast cancer: a systematic review and meta-analysis
Authors: Zhang Zhihao , Fang Tian , Lv Yonggang
Published: November 2022

Background

Many studies have reported the relationship between prognosis and Slug protein expression in breast cancer patients, but the results are discrepant. Therefore, there is a need for meta-analyses with high statistical power to investigate and further explore their relationship.

Methods

We used PubMed, Embase, the Cochrane Library, Scopus, MEDLINE, and the Web of Science to find studies on breast cancer and Slug. Overall survival (OS) and disease-free survival (DFS) were the study’s primary endpoints. We pooled hazard ratios (HRs) and odds ratios (ORs) to assess the association between Slug protein expression and prognostic and clinicopathological parameters. This study was performed using STATA version 14.0 for data analysis. (Stata Corporation, TX, USA).

Results

We conducted a literature search by searching six online databases. Ultimately, we obtained eight studies including 1458 patients through strict exclusion criteria. The results showed that increased Slug protein expression resulted in poorer OS (HR = 2.21; 95% CI = 1.47–3.33; P < 0.001) and DFS (HR = 2.03; 95% CI = 1.26–3.28; P = 0.004) in breast cancer patients. In addition, the results suggested that breast cancer patients with increased Slug protein expression had a higher TNM stage (I–II vs III–IV; OR = 0.42; 95% CI = 0.25–0.70; P = 0.001), a greater tendency to have axillary lymph node metastases (N+ vs N0; OR = 2.16; 95% CI = 1.31–3.56; P = 0.003) and were more prone to estrogen receptor deficiency (positive vs negative; OR = 0.67; 95% CI = 0.45–0.99; P = 0.042). However, Slug protein expression was not associated with age, histological grade, tumor size, progesterone receptor status, or human epidermal growth factor receptor 2 status in breast cancer patients.

Conclusion

This meta-analysis showed that elevated Slug protein expression may be related to poor outcomes in patients with breast cancer. Therefore, Slug is not only an indicator of patient survival but may also become a new target for breast cancer therapy.
JAK1 inactivation promotes proliferation and migration of endometrial cancer cells via upregulating the hypoxia-inducible factor signaling pathway
Authors: Lin Qin , Chen Zheng , Shi Wei , Lv Zeheng , Wan Xiaoping , Gao Kun
Published: November 2022

Background

Loss-of-function (LOF) mutations of JAK1, a member of the JAK kinase family, were frequently observed in EC, indicating that JAK1 may act as a tumor suppressor, at least in EC. However, the mechanism of JAK1 mediated regulation of tumorigenesis remains poorly understood.

Methods

The genetic alterations of JAK1 in EC using latest sequencing dataset of EC deposited in TCGA database. The RNA-Seq dataset of EC and normal endometrial tissues from TCGA cohort was analyzed. The expression of JAK1 in EC and normal endometrial tissues were investigated using immunohistochemistry. The expression levels of genes in endometrial cancer cells were detected by quantitative reverse transcription-PCR (RT-qPCR) and western blotting. JAK1 protein was efficiently depleted by the two shRNAs. HIF1/2-α protein was efficiently depleted by siRNAs. JAK1 overexpressed EC cells were generated by an expressing plasmid. The proliferation and migration ability of cancer cells were evaluated by CCK8, colony formation assays and transwell assays. The global transcriptomic changes in JAK1-depleted KLE cells were investigated using RNA-Seq. Gene Ontology (GO) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to identify the most significant pathways that were altered in JAK1-depleted KLE cells. The physical association between HIF-1/2α and JAK1 using co-immunoprecipitation (co-IP) assays.

Results

In the present study, we found that JAK1 was frequently mutated and downregulated in EC. JAK1 knockdown promotes EC cell proliferation and migration. JAK1 overexpression reduces EC cell proliferation and migration. We examined the transcriptional profiling changes in JAK1-depleted EC cells and unexpectedly found that the hypoxia inducible factor (HIF) pathway was activated. Mechanistically, JAK1 interacts with HIF-1/2α, and reduces HIF1/2-α protein expression under hypoxia. HIF-1/2α knockdown reverses the JAK1 knockdown–induced growth and migration of EC cells under hypoxia. JAK1 knockdown or pharmacological inhibition of JAK1 kinase activity by Ruxolitinib upregulates transcription of HIF target genes under hypoxia. JAK1 overexpression downregulates transcription of HIF target genes under hypoxia.

Conclusions

These findings provide novel insights into the functional link between JAK1 LOF mutations and abnormal HIF pathway activation in EC and suggest that pharmacological inhibition of HIF1/2 represents a promising therapeutic strategy targeting JAK1-mutated ECs.
Epidemiological and genetic characteristics of porcine circovirus 3 in 15 provinces and municipalities of China between 2016 and 2020
Authors: Ku Xugang , Zhang Chengjun , Li Panpan , Yu Xuexiang , Sun Qi , Xu Fengqin , Qian Ping , He Qigai
Published: November 2022

Porcine circovirus 3 (PCV3) is a newly emerging virus and has been found associated with porcine dermatitis and nephropathy syndrome in pigs. Compared with PCV2, research into PCV3 cap gene sequencing is deficient. To investigate the prevalence and genotype distribution of PCV3, we collected 1291 samples from 211 pig farms throughout 15 provinces and municipalities. 312 out of 1291 samples were tested positive by PCR. We further sequenced and analyzed 164 PCR-positive samples. The majority (61.8%) of isolates we sequenced belong to genotype PCV3c. PCV3c is also the dominant genotype in Hubei, Hunan, Hebei province and Chongqing city. We found 3 sites under positive selection and located in predicted epitope peptide, revealing that the pig’s immunity may be a reason those sites are undergoing highly positive selection.