bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic accuracy of three mpox lateral flow assays for antigen detection in the Democratic Republic of Congo and the United Kingdom
Authors: Ishara-Nshombo Elie , Somasundaran Anushri , Romero-Ramirez Alessandra , Kontogianni Konstantina , Mukadi-Bamuleka Daniel , Mukoka-Ntumba Marithé , Muhindo-Milonde Emile , Mirimo-Nguee Hugues , Parkes Jacob , Hussain Yusra , Gould Susan , Williams Christopher T. , Wooding Dominic , Nkeramahame Juvenal , Watson Mikaela , Hardwick Hayley E , Semple Malcolm G , Baillie J Kenneth , Dunning Jake , Fletcher Thomas E , Edwards Thomas , Emperador Devy M. , Kavunga-Membo Hugo , Cubas-Atienzar Ana
Published: November 2024

Background

The ongoing outbreaks of mpox, the disease caused by monkeypox virus (MPXV) highlight the urgent need for a rapid and low-cost MPXV diagnostic test to accurately detect and control mpox disease. In this study we assessed the diagnostic accuracy of three brands of rapid diagnostic tests for antigen detection (Ag–RDT) of MPXV.

Methods

We estimated the clinical diagnostic performance of FlowFlex Monkeypox Virus Antigen Rapid Test (ACON Biotech Co., Ltd., Hangzhou, China), Ecotest Monkeypox Antigen Rapid Test (Assure Tech. Co., Ltd, Hangzhou, China), and STANDARD Q Monkeypox Ag Test (SD Biosensor, Inc. Republic of Korea) using skin lesion swabs (SS) and upper–respiratory tract swabs (URS) from 68 participants in the Democratic Republic of the Congo (DRC) and from 16 in the United Kingdom (UK). The limit of detection (LOD) of the three Ag–RDT brands was evaluated using viral culture of the MPXV of the IIb lineage (EVAg, France).

Findings

Although the specificity of the three Ag–RDT was high (100%), sensitivity was estimated as 15·79% (95% CI, 5·52–37·57%) for Flowflex and Ecotest and as 10·53% (95% CI, 2·94–31·39%) for Standard–Q using SS in the DRC. The sensitivity was estimated as 0.00% (95% CI, 0·0–20·6%) among URS in the DRC. In the UK, the sensitivity of the three Ag-RDT was 0.00% among SS (95% CI, 0·0–12·7%) and among URS (95% CI, 0·0–21·5%). The LOD of all Ag–RDT was determined to be 1·0× 104pfu/ml (1·3×105copies/mL) using viral culture.

Interpretation

None of the three Ag–RDT reached the target clinical sensitivity and thus we do not recommend these as diagnostic or screening tool for suspected mpox cases. Marked improvement in sensitivity are needed for these Ag–RDT prior adoption. The recommended analytical LOD in the WHO target product profile (TPP) is at 106pfu/mL, being fulfilled by the three brands of Ag–RDTs suggesting that the analytical LOD stated in the TPP does not align with the desired clinical sensitivity. There remains an urgent need for accurate rapid Ag-RDTs for mpox diagnosis.
Reference interval of optimal vitamin D level for an adult population of Bangladesh
Authors: Haque Wasim Md Mohosin Ul , Haq Jalaluddin Ashraful , Pathan Md. Faruque , Sayeed Mohammed Abu
Published: November 2024

Vitamin D deficiency presents a significant public health concern, especially in regions where reference intervals from Western populations may not apply due to differences in sun exposure and ethnicity. This study aimed to establish population-specific reference intervals for serum 25-hydroxyvitamin D [25(OH)D] and to determine a deficiency cutoff for healthy adults in Bangladesh. In a cross-sectional design, we assessed serum 25(OH)D and intact parathyroid hormone (iPTH) levels in 125 coastal fishermen (Group 1) and 371 urban residents (Group 2), comprising healthy adults aged 18 years or older. Group 1 served as a reference to establish baseline vitamin D levels, while Group 2 data aided in determining the deficiency cutoff. Measurements were conducted using chemiluminescent immunoassay, and reference intervals were calculated according to Clinical and Laboratory Standards Institute (CLSI) Guidelines C28-A3. The deficiency cutoff was identified at the deflection point of iPTH levels. Results indicate a reference interval for serum 25(OH)D of 15.88–45.27 ng/ml among coastal fishermen. Among urban residents, mean serum 25(OH)D was 21.53 ± 15.98 ng/ml, with iPTH levels showing significant increases below 12.16 ng/ml (95% CI: 11.04–13.28), establishing this as the deficiency cutoff. Urban residents exhibited significantly lower vitamin D levels than coastal fishermen (21.53 ng/ml vs. 27.36 ng/ml, p < 0.001). Limitations include potential selection bias due to convenience sampling and the use of chemiluminescent immunoassay instead of the gold-standard LC-MS/MS assay. This study provides the first population-specific reference intervals for serum 25(OH)D in Bangladesh, accounting for unique sun exposure patterns and ethnic factors, and sets a deficiency threshold at 12.16 ng/ml. These findings are critical for guiding targeted interventions against vitamin D deficiency in this region.
A mixed methods process evaluation of a peer coaching intervention to improve the implementation of preventive tasks by occupational physicians
Authors: Orhan Pees Suzanne , van Oostrom Sandra , Schaafsma Frederieke , Proper Karin
Published: November 2024

Objectives This study aimed to evaluate the process of implementation of a peer coaching intervention program for occupational physicians (OPs) to improve the execution of preventive tasks. Specifically, the evaluation seeks to: (1) describe the reach and uptake of the intervention program; (2) determine the extent to which the program was implemented as intended; (3) provide insights into experiences of OPs, and (4) identify factors influencing the implementation. Methods This study employed a mixed-methods approach to assess seven main process indicators: acceptability, adoption, appropriateness, feasibility, fidelity, penetration and sustainability. Data were collected between March and June 2024 by means of an online questionnaire (N=98), and 17 semi-structured interviews with group coordinators and OPs. Results 20 out of 21 groups allocated to the intervention program participated in the intervention and 98 out of 115 participants (85%) filled in the questionnaire. Three-quarters of the participants completed the entire program. 96% of the OPs successfully discussed barriers to the execution of preventive tasks, and 83% were able to formulate strategies for these barriers. Most participants managed to implement their formulated goals in practice. When they were unable to do so, time constraints and resistance from employers and their occupational health services often played a role. OPs valued the program’s structure, interaction with colleagues, and the increased awareness it generated. Discussion and conclusion The peer coaching group program was well-implemented and positively evaluated by OPs. The program can be improved by allocating more time to it, for instance by integrating it into the educational curriculum, and by paying more attention to the specific working conditions of OPs, such as the different sectors in which they are employed.
Esketamine rapid antidepression combined with dexmedetomidine sleep modulation for patients with depression and insomnia
Authors: Zuo Muyan , Li Yaozu , Williams John P , Sun Lina , Li Yongxiang , Wang Ruoguo , Ren Guoqiang , Xu Qinyan , An Jianxiong
Published: November 2024

Purpose: Depression combined with insomnia is a complex bidirectional relationship that is more difficult to treat versus a single disorder, and there is a lack of effective treatments available. In this study, we carried out a novel way to simultaneously intervene in depression combined with insomnia and examined functional magnetic resonance imaging (fMRI) to help further elucidate the mechanisms. Patients and methods: A total of 105 patients with depression and insomnia were included in this observational and prospective study. 17-item Hamilton Depression Scale (HAMD-17), Pittsburgh Sleep Quality Index (PSQI) were collected from medical records at baseline (T0), 24 hours (T1), 7 days (T2), 14 days (T3), 21 days (T4), one month (T5), two months (T6), three months (T7) follow-up. fMRI scans were performed at baseline and two hours after treatment. Results: Compared with baseline, the symptoms of depression in T1-T7 were significantly reduced. At two hours after treatment, the left amygdala, the left hippocampus, the left superior temporal gyrus, the left anterior cingulate gyrus, and the left paracingulate gyrus showed a consistent reduction in spontaneous neural functional activity. In contrast, the right dorsolateral superior frontal gyrus, middle frontal gyrus, infraorbital frontal gyrus, middle orbital frontal gyrus and right caudate nucleus showed increased consistency of spontaneous neural function. No unanticipated safety issues were detected, and the rate of side effects was equivalent to those reported in RCTs. Conclusion: Our findings support the efficacy and safety of esketamine combined with dexmedetomidine (Dex) in patients with depression and insomnia, which provides a new approach to clinical improvement of depression combined with insomnia.
Assessment of Vaccine Managers’ Knowledge and Observance of Vaccination Norms and Standards in an Urban Health District of Yaounde (Cameroon) during the COVID-19 Pandemic
Authors: Lekeumo Cheuyem Fabrice Zobel , Amani Adidja , Ajong Brian Ngongheh , Noa Otsali Raissa Katy , Nouko Ariane , Guissana Edwige Omona , Ngos Christelle Sandrine , Mohamadou Adama , Nloga Guy Stephane , Edzamba Michel Franck , Bitye Bi Mvondo Esther Andriane , Eyenga Ntsek Larissa Linda , Mouangue Christian , Nkongo Florence Kissougle
Published: November 2024

Background

Routine childhood immunization remains a highly cost-effective public health intervention. Global immunization efforts have increased the coverage of proxy antigens in recent decades. However, annual reports indicated a progressive decline in immunization coverage in Yaounde. This study aimed to identify knowledge gaps and organizational deficiencies in the implementation of routine immunization in health facilities (HFs) in the Efoulan Health District (HD) of Yaounde.

Methods

A descriptive cross-sectional study was conducted in Efoulan, an urban HD of Yaounde, the capital of Cameroon, in May 2022. A self-administered questionnaire was used to collect knowledge data from consenting HCWs. An observation grid was used to assess the implementation of some relevant national EPI guidelines and recommendations.

Results

A total of 46 HCWs providing vaccinations in the nine health areas of HDs were enrolled in the study. Almost all participants (93.5%) were unable to name all the diseases that the pentavalent vaccine protects against. More than half of the respondents (59%) were aware of the 15-month booster dose of the measles-rubella (MR) vaccine included in the EPI. Half of the respondents were aware of the type of antigen contained in the BCG vaccine (52%). More than two-thirds of the respondents (72%) had not identified the 6-month MR vaccine as recommended without risk for HIV+ children. Most of the respondents were not aware of the management of opened nonlyophilized vials (50%), calculation of the wastage factor (89%) or vaccine requirements (98%). Almost all the respondents (87%) had poor knowledge of vaccination norms and standards. Most of the visited HFs did not follow the monthly EPI monitoring curve (87%), did not store vaccines according to standards (80%), or had an EPI case reporting form (93%). Most of the consultants in visited HFs were not familiar with the case definitions of common vaccine- preventable diseases.

Conclusions

The implementation of routine immunization remained poor in most of the HFs in Efoulan HDs because of the lack of knowledge of the EPI norms and standards of the staff. There is a need to strengthen the capacities of HCWs through ongoing training and supervision.
The retina across the psychiatric spectrum: a systematic review and meta-analysis
Authors: Kallen Nils M. , Cecere Giacomo , Palpella Dario , Rabe Finn , Georgiadis Foivos , Badstübner Paul , Edkins Victoria , Trindade Miriam , Homan Stephanie , Omlor Wolfgang , Seifritz Erich , Homan Philipp
Published: November 2024

The identification of structural retinal layer differences between patients diagnosed with certain psychiatric disorders and healthy controls has provided a potentially promising route to the identification of biomarkers for these disorders. Optical coherence tomography has been used to study whether retinal structural differences exist in schizophrenia spectrum disorders (SSD), bipolar disorder (BPD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), and alcohol and opiate use disorders. However, there is considerable variation in the amount of available evidence relating to each disorder and heterogeneity in the results obtained. We conducted the first systematic review and meta-analysis of evidence across all psychiatric disorders for which data was available. The quality of the evidence was graded and key confounding variables were accounted for. Of 381 screened articles, 87 were included. The evidence was of very low to moderate quality. Meta-analyses revealed that compared to healthy controls, the peripapillary retinal nerve fiber layer (pRNFL) was significantly thinner in SSD (SMD = -0.32; p<0.001), BPD (SMD = -0.4; p<0.001), OCD (SMD = -0.26; p=0.041), and ADHD (SMD = -0.48; p=0.033). Macular thickness was only significantly less in SSD (SMD = -0.59; p<0.001). pRNFL quadrant analyses revealed that reduced pRNFL thickness in SSD and BPD was most prominent in the superior and inferior quadrants. Macular subfield analyses indicated that BPD may have region-specific effects on retinal thickness. In conclusion, these findings suggest substantial retinal differences in SSD and BPD, reinforcing their potential as biomarkers in clinical settings.
Safety and Immunogenicity of Omicron Protein Vaccines in mRNA-Vaccinated Adolescents: A Phase 3, Randomised Trial
Authors: Bennett Chijioke , Chau Gordon , Clayton Erika , Chu Laurence , Alvarez Jacqueline , Hidalgo Ausberto B , Palanpurwala Khozema , Plested Joyce S. , Zhu Mingzhu , Cloney-Clark Shane , Cai Zhaohui , Kalkeri Raj , Hegazy Karim , Smith Katherine , Neal Susan , Noriega Fernando , Mallory Raburn M. , Adelglass Jeffrey M.
Published: November 2024

Objectives

Safety and immunogenicity assessment of updated monovalent and bivalent SARS-CoV-2 vaccines in adolescents.

Methods

This phase 3, double-blinded study randomised 12–<18-year-old participants, who received ≥2 prior doses of an approved/authorised mRNA-based COVID-19 vaccine, 1:1 to receive NVX-CoV2601 (XBB.1.5) or a bivalent vaccine (NVX-CoV2373 [Wuhan] + NVX-CoV2601). The primary immunogenicity endpoint was day-28 neutralizing antibody (nAb) geometric mean titres (GMTs) against XBB.1.5. Safety endpoints were solicited reactogenicity ≤7 days and unsolicited adverse events (AEs) ≤28 days post vaccination and frequency/severity of predefined AEs of special interest through day 180.

Results

Of 401 randomised participants, nAb GMTs against XBB.1.5 increased (GMFR [95% CI]) for both NVX-CoV2601 (12.2 [9.5–15.5]) and the bivalent vaccine (8.4 [6.8–10.3]); post-vaccination responses to ancestral SARS-CoV-2 and the JN.1 variant were also observed. Increases in anti-spike IgG levels were comparable between the groups. Solicited and unsolicited AEs were mild to moderate, with similar occurrence among the groups. Severe and serious events were rare and unrelated to the study vaccines; no PIMMCs or myocarditis/pericarditis were reported.

Conclusions

NVX-CoV2601 elicited more robust antibody responses to XBB.1.5 and ancestral virus, compared with a bivalent formulation. The safety profile within each group was consistent with the prototype vaccine (NVX-CoV2373).
Detection of TP53 mutations by IHC in acute myeloid leukemia varies with interpreter expertise and mutation status
Authors: Richman Lee P. , Waller Brianna , Lovitch Scott B. , Jambhekar Ashwini
Published: November 2024

TP53mutations, including missense and inactivating (frameshift, splice site, and nonsense) mutations, occur in approximately 10% of myeloid neoplasms and confer adverse outcomes. Classification of myeloid neoplasms by both the World Health Organization and the International Consensus Classification standards now recognize the prognostic and therapeutic importance of early detection ofTP53mutations. p53 immunohistochemistry (IHC) is a simple and rapid method commonly used to detect p53 mutations. More recently, sequencing via targeted panels has also seen increased use. While highly accurate, sequencing is resource intensive and not universally available. IHC represents a more accessible option for mutation detection, however previous studies have demonstrated variable accuracy, especially for inactivatingTP53mutations. Using 134 bone marrow core samples of acute myeloid leukemia (AML) evaluated forTP53mutation by a sequencing panel, we assessed the concordance of p53 IHC with sequencing as well as the inter-rater reliability for IHC intensity and percent positivity. Consistent with previous studies, we found that p53 IHC was strongly specific and modestly sensitive for missense mutations, and that overall performance improved with dedicated hematopathology training. We also found that IHC performed poorly for inactivating mutations and was even variable between cases harboring identical amino acid changes. Low predicted transcriptional activity ofTP53missense mutations correlated with a mutant pattern of IHC staining. The status of the second allele in missense mutations and variant allele fraction also affected the accuracy of p53 IHC as a surrogate forTP53allele status. AMLs expressing p53 mutations that were predicted to have low transcriptional activity correlated with reduced overall survival. Our results demonstrate limited practical utility of p53 immunohistochemistry for accurate evaluation ofTP53mutation status due to multifactorial confounders.
IL-8 as a potential link between aging and impaired influenza antibody responses in older adults
Authors: Quach Huy Quang , Goergen Krista M. , Grill Diane E. , Ovsyannikova Inna G. , Poland Gregory A. , Kennedy Richard B.
Published: November 2024

Background

Antibody responses to MF59-adjuvanted (MF59Flu) and high-dose (HDFlu) influenza vaccines have been well-characterized in older adults, yet corresponding cellular response data remain limited.

Methods

Blood samples were collected from 106 MF59Flu recipients and 112 HDFlu recipients before vaccination (Day 0), and on Days 1, 8, and 28 post-vaccination. Antibody responses were assessed on Days 0, 8, and 28 using a hemagglutination inhibition (HAI) assay. Eight pro-inflammatory cytokines and chemokines, including IFN-α2a, IFN-γ, IP-10, MCP-1, MIP-1α, IL-1β, IL-6, IL-8, were quantified from PBMCs collected on Days 0 and 1 following stimulation with live influenza A/H3N2 virus using a multiplex assay. Associations between cytokine/chemokine levels and HAI titers were examined, along with the effect of sex, age, body mass index (BMI), and cytomegalovirus infection status.

Results

Vaccine type (MF59Flu or HDFlu), sex, BMI and cytomegalovirus infection did not significantly impact cytokine and chemokine levels. However, age was positively correlated with IL-8 level on Day 1 (r = 0.24,p= 0.0003) as well as the change in IL-8 levels from Day 1 to Day 0 (r = 0.16,p= 0.021). Notably, the change in IL-8 levels was negatively associated with peak antibody responses at Day 28 (r = −0.15,p= 0.026).

Conclusion

Our findings underscore IL-8 as a potential link between aging and impaired antibody responses to influenza vaccination in older adults, suggesting that IL-8 inhibition could be a promising molecular intervention to improve immunogenicity and efficacy of influenza vaccines in this high-risk population.
Predicting factors of heart arrhythmia in patients with permanent heart pacemaker
Authors: Vu Thanh Tri , Le Lac Duy , Nguyen Hoang Minh Vo
Published: November 2024

Purpose

Identify some factors predicting arrhythmia after permanent pacemaker placement to treat atrioventricular block and sinus node dysfunction.

Methods

Prospective study in 312 patients with permanent pacemakers due to atrioventricular block and sinus node dysfunction being monitored at Thong Nhat Hospital and Thu Duc city hospital from March 2022 to September 2022

Results

The rate of arrhythmia after pacemaker insertion was 41%, of which 20.2% atrial fibrillation; 10.9% atrial tachycardia; 1.3% sinus arrest; 9.9% ventricular premature beats; 1.3% ventricular tachycardia and 2.2% supraventricular tachycardia. Factors that determine the possibility of arrhythmia after permanent pacemaker placement include ejection fraction index, blood potassium, blood chloride, blood HDL-Cholesterol concentration, smoking and pacemaker mode (VVIR). /DDDR).

Conclusions

Cardiac arrhythmia in patients with permanent pacemakers is always likely to occur, related factors predict 57.8% of the possibility of this event occurring.
Characteristic and Outcomes of Patients with ST-segment Elevation Myocardial Infarction who have Non-System Reasons for Delay in Treatment: A Report from the AHA GWTG CAD Registry
Authors: Lee Tetz C. , Jollis James G. , Hong Haoyun , Jiang Tian , Zhao Juan , Henry Timothy D. , Jacobs Alice K. , Goyal Abhinav , Granger Christopher B. , Thomas Kathie , Tamis-Holland Jacqueline E
Published: November 2024

Background

The past two decades have witnessed reductions in time to diagnosis and reperfusion therapy in patients with ST elevation myocardial infarction (STEMI), largely through improvements in STEMI systems of care. While studies have demonstrated important benefits of timely coronary reperfusion in STEMI patients, those with non-system reasons for delay (NSD) are often excluded from these analyses, limiting insights into the overall quality of care for these patients.

Methods

We analyzed the NSD in patients with STEMI undergoing primary PCI who were enrolled in the GWTD-CAD registry from January 1st, 2019, to December 31st, 2021. We examined the patient-level characteristics and outcomes for patients with and without reported NSD. We performed multivariable logistic regression models to examine the association between NSD and in-hospital mortality, adjusting for patient demographics, clinical variables, and social factors. We then categorized hospitals into four groups based on proportion of STEMI patients with NSD and examined the hospital-level characteristics across the quartiles. We further grouped hospitals by quality metric achievement of timely coronary reperfusion and examined the rates of NSD and treatment times for each category of achievement of the quality metric.

Results

74,372 patients were included in the study. 17,741 (23.9%) patients were reported to have NSD. Patients with NSD were older, and more likely to be female, of Black race, and have significant comorbidities including higher rates of cardiac arrest, heart failure and cardiogenic shock on presentation. In-hospital mortality rate was significantly higher in patients with NSD (15.4% vs 2.7%), (Adjusted OR 2.78, [95% CI:2.54-3.04]). Although high-achieving hospitals (those meeting the metrics ≥75%) excluded more patients, they consistently maintained shorter treatment times, even when NSD patients were included in the analysis.

Conclusion

NSD in STEMI care is prevalent and linked to higher in-hospital mortality. While concerns about selective case exclusion exist, high-achieving hospitals consistently demonstrated excellent time-to-treatment even when patients with NSD are included.
Genetically predicted plasma levels of amino acids and stroke risk: a Mendelian randomization study
Authors: Li Zeheng , Zhang Yutong , Zhou Hongjie , Xu Yu , Sun Lulu , Zhang Zhen , Gao Zhongyu , Wang Suyu , Ni Jianqiang , Miao Zhigang
Published: November 2024

Stroke, including ischemic stroke (IS) and small vessel stroke (SVS), is a major cause of morbidity and mortality globally. The role of amino acids in stroke risk and outcomes is not well understood. This study investigates the causal effects of genetically determined amino acid levels on stroke and its functional outcomes using Mendelian randomization (MR). We analyzed data by single nucleotide polymorphisms (SNPs), Inverse-variance weighted (IVW) and so on. After False discovery rate (FDR) correction, we found that Higher genetically determined levels of CSF glycine (odds ratio [OR] per standard deviation [SD] increase, 1.34; 95% confidence interval [CI], 1.14-1.56; P=2.46×10-4), glutamate (odds ratio [OR] per standard deviation [SD] increase, 1.48; 95% confidence interval [CI], 1.17-1.87; P=9.50×10-4), glutamine (odds ratio [OR] per standard deviation [SD] increase, 1.58; 95% confidence interval [CI], 1.29-1.94; P=1.30×10-5), and phenylalanine (odds ratio [OR] per standard deviation [SD] increase, 1.58; 95% confidence interval [CI], 1.32-1.89; P=7.37×10-7) were associated with increased risks of SVS. Higher phenylalanine (odds ratio [OR] per standard deviation [SD] increase, 1.79; 95% confidence interval [CI], 1.26-2.55; P=1.15×10-3) was linked to increased risks of worse IS functional outcomes (modified Rankin Scale score≥3). These findings suggest amino acids as potential biomarkers and therapeutic targets for stroke.
Using evidence-based strategies, including coverage of remote cardiac rehabilitation, to increase cardiac rehabilitation participation - a community health insurance plan’s experience
Authors: Magdon-Ismail Zainab , Murphy Sheree , Gauthier Vickie , Wyrick Tiana , Rowe Cori , Austin Rachael , Cuevas Pennie , Pickreign Jeremy , Coplin Bruce
Published: November 2024

Background

Barriers to referral, enrollment, and participation in cardiac rehabilitation (CR) contribute to low rates of completion despite known benefits. Barriers are system, provider and patient related. In this observational cohort quality improvement study, we examined the impact a community-based, not-for-profit health insurance plan had on barriers to CR participation.

Methods

The Capital District Physicians’ Health Plan (CDPHP) in Albany, New York developed and implemented a cardiac rehabilitation initiative (CRI) to increase CR rates using evidence-based strategies. CDPHP: 1) eliminated patient cost-share, 2) covered remote CR (RCR), 3) implemented physician valued-based incentives, 4) presented metrics to providers, 5) educated providers and patients, and 6) dedicated staff to facilitating enrollment. Chi-square tests were used to identify differences among patients who enrolled in facility-based CR (FBCR), RCR and no CR. CR enrollment rate distributions were evaluated between Q1, 2021 and Q2, 2022.

Results

A total of 1,736 patients with varying cardiac conditions were eligible for CR in the study period. Between Q1, 2021 and Q2, 2022, enrollment went from 11.1% (32/286) to 16.2% (50/308) in FBCR; 0.7% (2/286) to 10.7% (33/308) in RCR; and 11.9% (34/286) to 26.9% (83/308) overall (P<.0001). Time to enrollment went from 40 to 47 days for FBCR (P=0.1792), 53 to 20 days for RCR (P<.0001) and 43 to 36 days overall (P=0.3348). Older patients were more likely to enroll in CR as were patients who underwent cardiac procedures.

Conclusions

The CRI created a call-to-action among providers to address CR referral and enrollment. RCR increased CR rates and were additive to FBCR rates, suggesting that the introduction of RCR will not displace FBCR. Time to enrollment improved overall, driven by improvement in those enrolling in RCR. Increasing CR engagement requires coordinated effort from stakeholders—cardiology providers, hospitals, CR providers and health plans.
Dipstick-based pathogen detection for wastewater surveillance: Variability analysis using gage repeatability and reproducibility
Authors: Ahuja Shruti , Kulkarni Avani , Kondabagil Kiran , Tallur Siddharth
Published: November 2024

COVID-19 redefined the outlook on pandemic preparedness, accelerating research toward establishing a global consortium for wastewater surveillance. Due to sample heterogeneity and low pathogen loads, microbial concentration remains a key challenge in developing low-cost, point-of-use wastewater monitoring assays. To address this challenge, we have developed a simplified version of dipstick method for RNA capture and isolation from sub-milliliter sample volumes, which simplifies RNA isolation. Given the manual steps involved in executing the dipstick method, variability is a major concern. In this work, we assessed dipstick variability through a multi-operator gage repeatability & reproducibility (gage R&R) study. We focused on detecting pepper mild mottle virus (PMMoV) and bacteriophage Phi6 in wastewater samples collected from a sewage pumping station at IIT Bombay. Our study demonstrated that the repeatability and reproducibility for the dipstick method are less than the acceptability limit of 30%, and could detect changes in PMMoV load associated with change in the population density due to summer break in our campus. Phi6 is a widely accepted surrogate for enveloped viruses such as SARS-CoV-2, and was therefore also chosen to demonstrate utility of this method for monitoring spread of infectious diseases. This work underscores the effectiveness of gage R&R in assessing and understanding the sources of variations in such assays, including operator-induced and part-to-part differences, essential for developing robust, manually-operated assays.
Optimizing Genome Editing in Bovine Cells: A Comparative Study of Cas9 Variants and CRISPR Delivery Methods
Authors: Du Xiaofeng , Quinn Alexander , Mahony Timothy , Xia Di , Porto-Neto Laercio
Published: November 2024

To assist in the establishment of an efficient CRISPR/Cas9 gene editing workflow in bovine cells, we compared the efficiency of four Streptococcus pyogenes Cas9 (SpCas9) nuclease variants (produced in-house or commercially) and two different Cas9/sgRNA ribonucleoprotein (RNP) delivery methods applied to Madin-Darby bovine kidney (MDBK) cells (Bos taurus). We targeted three genes for simple sequence deletion or modification via a single-stranded oligodeoxynucleotide donor template: the testis-determining gene Sry (sex-determining region on Y chromosome), germ cell-specific gene Nanos2 (nanos C2HC-type zinc finger 2) and PRLR (prolactin receptor). RNPs and donor templates were delivered into cells via lipofectamine CRISPRMAX transfection or Neon electroporation. The efficiency of gene editing was determined by target-specific PCR genotyping, real-time PCR assays and next generation sequencing analyses. When targeting Sry, the commercial Alt-R High-Fidelity (HiFi) SpCas9 nuclease exhibited the highest deletion efficiency, followed by the in-house generated Sniper2L, HiFi SpCas9 and wild-type SpCas9. Notably, for PRLR and Nanos2, Sniper2L induced comparable editing outcomes to Alt-R HiFi SpCas9. The two delivery methods, lipofectamine CRISPRMAX transfection and Neon electroporation, demonstrated similar efficiency (60% to 83%) in producing indels in all three target genes. However, Neon electroporation (5.5% to 11%) was superior to CRISPRMAX lipofection (1.5% to 4.8%) at inducing target-specific sequence knock-ins. Strategies to inhibit NHEJ repair and/or enhance HDR may be necessary to improve HDR efficiency in these bovine cells. These findings provide valuable insights for improving gene editing outcomes in bovines and may assist in accelerating the widespread application of genome editing technology in large animals.
DeFrND: detergent-free reconstitution into native nanodiscs with designer membrane scaffold peptides
Authors: Ren Qian , Wang Jing , Idikuda Vinay , Zhang Shanwen , Shin Jeehae , Ludlam W. Grant , Real Hernandez Luis M , Levental Ilya , Martemyanov Kirill , Chanda Baron , Bao Huan
Published: November 2024

Membrane scaffold proteins-based nanodiscs (NDs) have facilitated unprecedented structural and biophysical analysis of membrane proteins in a near-native lipid environment. However, successful reconstitution of membrane proteins in NDs requires prior solubilization and purification in detergents, which may impact their physiological structure and function. Furthermore, the detergent-mediated reconstitution of NDs is unlikely to recapitulate the precise composition or asymmetry of native membranes. To circumvent this fundamental limitation of traditional ND technology, we herein describe the development of membrane-solubilizing peptides to directly extract membrane proteins from native cell membranes into nanoscale discoids. By systematically protein engineering and screening, we created a new class of chemically modified Apolipoprotein-A1 mimetic peptides to enable the formation of detergent-free NDs (DeFrNDs) with high efficiency. NDs generated with these engineered membrane scaffold peptides are suitable for obtaining high-resolution structures using single-particle cryo-EM with native lipids. To further highlight the versatility of DeFrNDs, we directly extract a sampling of membrane signaling proteins with their surrounding native membranes for biochemical and biophysical interrogations.
The BumbleBox: An open-source platform for quantifying behavior in bumblebee colonies
Authors: Easton-Calabria August , Crall James D.
Published: November 2024

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Bumblebees (Apini:Bombus) are important pollinators globally and an emerging model system for studying the ecology and evolution of social behavior and effects of environmental stressors on bees.

Behavioral studies of bumblebees have conventionally relied on labor and time-intensive manual observations. While recent years have seen rapid advances in automated behavioral tracking in social insects, these tracking technologies are often expensive and require extensive programming experience, limiting accessibility and widespread adoption.

Here we introduce the BumbleBox, an open-source system for automated tracking and behavioral quantification of individual bumblebees that can be built using low-cost consumer components and DIY fabrication (i.e., 3D-printing and laser-cutting). We provide an integrated pipeline for data collection and analysis, including nest arena design, software for automated collection of video data, and the quantification of individual behavior.

The BumbleBox system is designed to be (a)accessible, requiring no prior experience with programming or hardware design to operate; (b)scalable, allowing long-term, automated tracking across many units in parallel at low-cost; and (c)modular, allowing for flexible adoption to unique applications in bumblebees and other systems. We validate the use of this system in a widespread bumblebee species (Bombus impatiens) that is both commercially and ecologically important. Finally, we highlight widespread potential applications in quantifying behavior and pollinator health in bumblebees and other social insects, including screening impacts of pesticides and other environmental stressors on social behavior.
Convolutional neural network models describe the encoding subspace of local circuits in auditory cortex
Authors: Wingert Jereme C. , Parida Satyabrata , Norman-Haignere Sam , David Stephen V.
Published: November 2024

Auditory cortex encodes information about nonlinear combinations of spectro-temporal sound features. Convolutional neural networks (CNNs) provide an architecture for generalizable encoding models that can predict time-varying neural activity evoked by natural sounds with substantially greater accuracy than established models. However, the complexity of CNNs makes it difficult to discern the computational properties that support their improved performance. To address this limitation, we developed a method to visualize the tuning subspace captured by a CNN. Single-unit data was recorded using high channel-count microelectrode arrays from primary auditory cortex (A1) of awake, passively listening ferrets during presentation of a large natural sound set. A CNN was fit to the data, replicating approaches from previous work. To measure the tuning subspace, the dynamic spectrotemporal receptive field (dSTRF) was measured as the locally linear filter approximating the input-output relationship of the CNN at each stimulus timepoint. Principal component analysis was then used to reduce this very large set of filters to a smaller subspace, typically requiring 2-10 filters to account for 90% of dSTRF variance. The stimulus was projected into the subspace for each neuron, and a new model was fit using only the projected values. The subspace model was able to predict time-varying spike rate nearly as accurately as the full CNN. Sensory responses could be plotted in the subspace, providing a compact model visualization. This analysis revealed a diversity of nonlinear responses, consistent with contrast gain control and emergent invariance to spectrotemporal modulation phase. Within local populations, neurons formed a sparse representation by tiling the tuning subspace. Narrow spiking, putative inhibitory neurons showed distinct patterns of tuning that may reflect their position in the cortical circuit. These results demonstrate a conceptual link between CNN and subspace models and establish a framework for interpretation of deep learning-based models.

Significance statement

Auditory cortex mediates the representation and discrimination of complex sound features. Many models have been proposed for cortical sound encoding, varying in their generality, interpretability, and ease of fitting. It has been difficult to determine if/what different functional properties are captured by different models. This study shows that two families of encoding models, convolutional neural networks (CNNs) and tuning subspace models account for the same functional properties, providing an important analytical link between accurate models that are easy to fit (CNNs) and models that are straightforward to interpret (tuning subspace).
Random subsamples of animal populations can reveal intrinsic differences in sociality with key implications in ecology, conservation and disease transmission
Authors: Conteddu Kimberly , Kaur Prabhleen , Brown Michael , Fennessy Julian , Fennessy Stephanie , Hart Emma , Amin Bawan , David Anna , Griffin Laura L. , Faull Jane , Grignolio Stefano , Brivio Francesca , Haigh Amy , Kirwan Liam , Salter-Townshend Michael , Ciuti Simone
Published: November 2024

Animal populations are under mounting stress from the dual threats of climate change and rapid global human population growth, raising significant concerns about declining wildlife and the rising risk of zoonotic diseases. In many species, social interactions can be a highly plastic suite of behaviours that are responsive to these disturbances and are consequential to other processes like disease transmission and population dynamics. Studying social interactions can be challenging in that researchers often rely on wildlife population subsamples due to practical constraints and costs, which can introduce biases in the reliability of social network metrics. We investigated the extent to which subsamples can depict intrinsic characteristics of wildlife populations using data from three distinct species: peri-urban fallow deer, Alpine ibex and Angolan giraffe. We showed that random subsamples of these populations could still reveal differences in their social behaviour, indicating that, as long as researchers have a reliable estimate of population size, subsampling animal populations can be an effective and precise method to infer their sociality and offer valuable empirical data for management, conservation and zoonotic disease ecology. Furthermore, we demonstrate that non-random sampling, influenced for instance by animal personality and related trappability, can introduce significant biases in social network estimates. These findings underscore the importance of accounting for sampling biases in social network analysis and offer a robust framework for using partial networks in ecological studies and conservation management.
Glycophagy is an ancient bilaterian pathway supporting metabolic adaptation through STBD1 structural evolution
Authors: Ren Liting , Bai Yitian , Shi Chenyu , Tan Ying , Zhao Shuyan , Li Qi , Macqueen Daniel J , Liu Shikai
Published: November 2024

The selective autophagy of glycogen (glycophagy) has recently emerged as being crucial to glucose homeostasis in vertebrates, yet its origins remain elusive. Here, we provide evidence that starch-binding domain-containing protein 1 (STBD1), the key glycophagy receptor in vertebrates, is functionally conserved in the Pacific oyster, revealing its conserved position within ancient autophagy networks. We show that STBD1 in oysters - as seen in other invertebrate groups - possesses an N-terminal carbohydrate binding module family 20 (CBM20) domain, representing the ancestral state for this protein, while a shuffling of CBM20 to the C- terminus occurred during early chordate evolution. Structural modelling and functional studies reveal that the N-terminal CBM20 organization of STBD1 enhances glycogen binding. Functional experiments demonstrate that an STBD1-glycogen complex, anchored by GABARAPL2, facilitates an increased glycogen flux into autophagosomes for lysosomal degradation. We conclude that glycophagy is deeply conserved in bilaterians and that STBD1 structural evolution underlies potentially adaptive variation in metabolic strategies across distinct animal clades.
Aberrant expression of CD14 in breast tumor cells is associated with poor outcome
Authors: Katayama Hiroyuki , Dou Rongzhang , León-Letelier Ricardo A. , Irajizad Ehsan , Sevillano Alejandro , Park Soyoung , Hsiao Fu Chung , Cai Yining , Vykoukal Jody , Fahrmann Johannes , Dennison Jennifer , Barrientos-Toro Elizve , Raso Maria Gabriela , Sahin Aysegul , Hanash Sam
Published: November 2024

Emerging evidence suggests that cancer cells can mimic features of immune cells during oncogenic transformation to drive disease progression. We assessed the occurrence of immunological markers in breast cancer cells to determine their expression pattern. We initially analyzed 18 immune protein markers (CCR4, CCR6, CCR7, CD11, CD123, CD14, CD16, CD19, CD24, CD25, CD27, CD3, CD38, CD4, CD45, CD56, CD8 and CXCR3) expressed on the surface of 28 breast cancer cell lines using mass spectrometry. CD14 protein expression in tumor cells and its association with clinical outcomes was subsequently evaluated by tissue microarray (TMA) analysis of 346 breast tumors. Single-cell RNA sequencing data from breast cancer tumors and bulk transcriptomic data of breast cancer cell lines were interrogated for molecular signatures associated with CD14 tumor cell expression. Among the markers interrogated, CD14proteinwas aberrantly expressed on the surface of 13 out of 15 triple-negative breast cancer (TNBC), one of six hormone receptor positive (HR+), one of five hormone receptors negative (HR-)/Her2+ cell lines. Likewise, RNA expression revealed higher levels of CD14 in TNBC cell lines compared to other subtypes. Tumor tissue microarray analysis revealed elevated levels of CD14 membrane expression predominantly in TNBC and was associated with higher tumor grade and increased incidence of disease recurrence compared to CD14-negative tumors. The CD14-positive subgroup exhibited Nuclear Factor Kappa Beta (NFkB) and TGF-β centric networks at both the protein and Single-cell RNA levels. We have uncovered a novel subset of breast cancers characterized by aberrant surface expression of CD14 associated with aggressive disease. CD14 identifies a subset of breast cancers with poor outcome and is a potential therapeutic target.
Perineuronal nets on CA2 pyramidal cells and parvalbumin-expressing cells differentially regulate hippocampal dependent memory
Authors: Alexander Georgia M. , Nikolova Viktoriya D. , Stöber Tristan M. , Gruzdev Artiom , Moy Sheryl S. , Dudek Serena M.
Published: November 2024

Perineuronal nets (PNNs) are a specialized extracellular matrix that surround certain populations of neurons, including (inhibitory) parvalbumin (PV) expressing-interneurons throughout the brain and (excitatory) CA2 pyramidal neurons in hippocampus. PNNs are thought to regulate synaptic plasticity by stabilizing synapses and as such, could regulate learning and memory. Most often, PNN functions are queried using enzymatic degradation with chondroitinase, but that approach does not differentiate PNNs on CA2 neurons from those on adjacent PV cells. To disentangle the specific roles of PNNs on CA2 pyramidal cells and PV neurons in behavior, we generated conditional knockout mouse strains with the primary protein component of PNNs, aggrecan (Acan), deleted from either CA2 pyramidal cells (Amigo2AcanKO) or from PV cells (PVAcanKO). Male and female animals of each strain were tested for social, fear, and spatial memory, as well as for reversal learning. We found that Amigo2AcanKO animals, but not PVAcanKO animals, had impaired social memory and reversal learning. PVAcanKOs, but not Amigo2AcanKOs had impaired contextual fear memory. These findings demonstrate independent roles for PNNs on each cell type in regulating hippocampal-dependent memory. We further investigated a potential mechanism of impaired social memory in the Amigo2AcanKO animals and found reduced input to CA2 from the supramammillary nucleus (SuM), which signals social novelty. Additionally, Amigo2AcanKOs lacked a social novelty-related local field potential response, suggesting that CA2 PNNs may coordinate functional SuM connections and associated physiological responses to social novelty.

SIGNIFICANCE STATEMENT

Perineuronal nets (PNNs) surround both inhibitory parvalbumin (PV)-expressing neurons and excitatory CA2 pyramidal neurons, but previous studies using enzymatic degradation cannot differentiate the relative roles of PNNs in the two populations. By conditionally deleting aggrecan (Acan) from CA2 pyramidal neurons without affecting PNNs on PV cells, and vice versa, we discovered distinct roles of PNNs on each cell type in behavior. Social memory, which requires CA2 activity, was impaired in mice lacking CA2 PNNs, but not in those lacking PV PNNs. Cognitive flexibility, assessed by reversal learning was also impaired in mice lacking CA2 PNNs, whereas contextual fear memory was impaired in those lacking PV PNNs. Thus, PNNs on each cell type differentially contribute to different forms of hippocampal-dependent memory.
Interpretable and Robust Machine Learning for Exploring and Classifying Soundscape Data
Authors: Omprakash Arpit , Balakrishnan Rohini , Ewers Robert , Sethi Sarab
Published: November 2024

The adoption of machine learning in Passive Acoustic Monitoring (PAM) has improved prediction accuracy for tasks like species-specific call detection and habitat quality estimation. However, these models often lack interpretability, and PAM generates vast amounts of non-informative data, as soundscapes are typically information sparse.

Here, we developed ecologically interpretable methods that accurately predict land use from audio while filtering unwanted data. Audio from habitats in Southern India (evergreen forests, deciduous forests, scrublands, grasslands) was collected and categorised by land use (reference, disturbed, and agriculture). We used Gaussian Mixture Models (GMMs) on top of a Convolutional Neural Network (CNN)-based feature extractor to predict land use.

Thresholding based on likelihood values from GMMs improved model accuracy by excluding uninformative data, enabling our method to outperform models such as Random Forests and Support Vector Machines. By analysing areas of acoustic feature space driving predictions, we identified “keystone” soundscape elements for each land use, including both biotic and anthropogenic sources.

Our approach provides a novel method for ecologically meaningful interpretation and exploration of large acoustic datasets independent of specific feature extractors. Our study paves the way for soundscape monitoring to deliver robust and trustworthy habitat assessments on scales that would not otherwise be possible.