bluuebunny/crossref_metadata_2025 huggingface dataset:
DRONet: effectiveness-driven drug repositioning framework using network embedding and ranking learning
Authors: Yang Kuo , Yang Yuxia , Fan Shuyue , Xia Jianan , Zheng Qiguang , Dong Xin , Liu Jun , Liu Qiong , Lei Lei , Zhang Yingying , Li Bing , Gao Zhuye , Zhang Runshun , Liu Baoyan , Wang Zhong , Zhou Xuezhong
Published: December 2022

As one of the most vital methods in drug development, drug repositioning emphasizes further analysis and research of approved drugs based on the existing large amount of clinical and experimental data to identify new indications of drugs. However, the existing drug repositioning methods didn’t achieve enough prediction performance, and these methods do not consider the effectiveness information of drugs, which make it difficult to obtain reliable and valuable results. In this study, we proposed a drug repositioning framework termed DRONet, which make full use of effectiveness comparative relationships (ECR) among drugs as prior information by combining network embedding and ranking learning. We utilized network embedding methods to learn the deep features of drugs from a heterogeneous drug-disease network, and constructed a high-quality drug-indication data set including effectiveness-based drug contrast relationships. The embedding features and ECR of drugs are combined effectively through a designed ranking learning model to prioritize candidate drugs. Comprehensive experiments show that DRONet has higher prediction accuracy (improving 87.4% on Hit@1 and 37.9% on mean reciprocal rank) than state of the art. The case analysis also demonstrates high reliability of predicted results, which has potential to guide clinical drug development.
SiameseCPP: a sequence-based Siamese network to predict cell-penetrating peptides by contrastive learning
Authors: Zhang Xin , Wei Lesong , Ye Xiucai , Zhang Kai , Teng Saisai , Li Zhongshen , Jin Junru , Kim Min Jae , Sakurai Tetsuya , Cui Lizhen , Manavalan Balachandran , Wei Leyi
Published: December 2022

Background

Cell-penetrating peptides (CPPs) have received considerable attention as a means of transporting pharmacologically active molecules into living cells without damaging the cell membrane, and thus hold great promise as future therapeutics. Recently, several machine learning-based algorithms have been proposed for predicting CPPs. However, most existing predictive methods do not consider the agreement (disagreement) between similar (dissimilar) CPPs and depend heavily on expert knowledge-based handcrafted features.

Results

In this study, we present SiameseCPP, a novel deep learning framework for automated CPPs prediction. SiameseCPP learns discriminative representations of CPPs based on a well-pretrained model and a Siamese neural network consisting of a transformer and gated recurrent units. Contrastive learning is used for the first time to build a CPP predictive model. Comprehensive experiments demonstrate that our proposed SiameseCPP is superior to existing baseline models for predicting CPPs. Moreover, SiameseCPP also achieves good performance on other functional peptide datasets, exhibiting satisfactory generalization ability.
Incorporating higher order network structures to improve miRNA–disease association prediction based on functional modularity
Authors: He Yizhou , Yang Yue , Su Xiaorui , Zhao Bowei , Xiong Shengwu , Hu Lun
Published: December 2022

As microRNAs (miRNAs) are involved in many essential biological processes, their abnormal expressions can serve as biomarkers and prognostic indicators to prevent the development of complex diseases, thus providing accurate early detection and prognostic evaluation. Although a number of computational methods have been proposed to predict miRNA–disease associations (MDAs) for further experimental verification, their performance is limited primarily by the inadequacy of exploiting lower order patterns characterizing known MDAs to identify missing ones from MDA networks. Hence, in this work, we present a novel prediction model, namely HiSCMDA, by incorporating higher order network structures for improved performance of MDA prediction. To this end, HiSCMDA first integrates miRNA similarity network, disease similarity network and MDA network to preserve the advantages of all these networks. After that, it identifies overlapping functional modules from the integrated network by predefining several higher order connectivity patterns of interest. Last, a path-based scoring function is designed to infer potential MDAs based on network paths across related functional modules. HiSCMDA yields the best performance across all datasets and evaluation metrics in the cross-validation and independent validation experiments. Furthermore, in the case studies, 49 and 50 out of the top 50 miRNAs, respectively, predicted for colon neoplasms and lung neoplasms have been validated by well-established databases. Experimental results show that rich higher order organizational structures exposed in the MDA network gain new insight into the MDA prediction based on higher order connectivity patterns.
Improving therapeutic synergy score predictions with adverse effects using multi-task heterogeneous network learning
Authors: Yue Yang , Liu Yongxuan , Hao Luoying , Lei Huangshu , He Shan
Published: December 2022

Drug combinations could trigger pharmacological therapeutic effects (TEs) and adverse effects (AEs). Many computational methods have been developed to predict TEs, e.g. the therapeutic synergy scores of anti-cancer drug combinations, or AEs from drug–drug interactions. However, most of the methods treated the AEs and TEs predictions as two separate tasks, ignoring the potential mechanistic commonalities shared between them. Based on previous clinical observations, we hypothesized that by learning the shared mechanistic commonalities between AEs and TEs, we could learn the underlying MoAs (mechanisms of actions) and ultimately improve the accuracy of TE predictions. To test our hypothesis, we formulated the TE prediction problem as a multi-task heterogeneous network learning problem that performed TE and AE learning tasks simultaneously. To solve this problem, we proposed Muthene (multi-task heterogeneous network embedding) and evaluated it on our collected drug–drug interaction dataset with both TEs and AEs indications. Our experimental results showed that, by including the AE prediction as an auxiliary task, Muthene generated more accurate TE predictions than standard single-task learning methods, which supports our hypothesis. Using a drug pair Vincristine—Dasatinib as a case study, we demonstrated that our method not only provides a novel way of TE predictions but also helps us gain a deeper understanding of the MoAs of drug combinations.
Turning biology to life: some reflections
Authors: Vane-Wright Richard I
Published: December 2022

This essay presents various reflections on living systems, what they are and how they evolve, prompted by editing Teleonomy in Living Systems (a special issue of the Biological Journal of the Linnean Society). Conclusions include the suggestion that the linked notions of teleonomy and agency represent fundamental properties of matter that become apparent only when organized in the way that we consider to be that of a living system. As such, they are factors that form part of the intrinsic ‘a priori’ of living systems, as they evolve in form through space and time. Biology, the science of life and living systems, needs to be ‘biological’ if it is to be anything at all. Understanding the role of teleonomy (internal, inherent goal-seeking) will always play a necessary part in this endeavour: teleonomy represents one of the fundamental properties of living systems.
An individual-level weighted artificial neural network method to improve the systematic bias in BrainAGE analysis
Authors: Lu Chunying , Li Bowen , Zhang Qianyue , Chen Xue , Pang Yajing , Lu Fengmei , Wu Yifei , Li Min , He Bifang , Chen Heng
Published: December 2022

BrainAGE is a commonly used machine learning technique to measure the accelerated/delayed development pattern of human brain structure/function with neuropsychiatric disorders. However, recent studies have shown a systematic bias (“regression toward mean” effect) in the BrainAGE method, which indicates that the prediction error is not uniformly distributed across Chronological Ages: for the older individuals, the Brain Ages would be under-estimated but would be over-estimated for the younger individuals. In the present study, we propose an individual-level weighted artificial neural network method and apply it to simulation datasets (containing 5000 simulated subjects) and a real dataset (containing 135 subjects). Results show that compared with traditional machine learning methods, the individual-level weighted strategy can significantly reduce the “regression toward mean” effect, while the prediction performance can achieve the comparable level with traditional machine learning methods. Further analysis indicates that the sigmoid active function for artificial neural network shows better performance than the relu active function. The present study provides a novel strategy to reduce the “regression toward mean” effect of BrainAGE analysis, which is helpful to improve accuracy in exploring the atypical brain structure/function development pattern of neuropsychiatric disorders.
Intrinsic excitability of human right parietal cortex shapes the experienced visual size illusions
Authors: Wu Baoyu , Feng Bengang , Han Xue , Chen Lihong , Luo Wenbo
Published: December 2022

Converging evidence has found that the perceived visual size illusions are heritable, raising the possibility that visual size illusions might be predicted by intrinsic brain activity without external stimuli. Here we measured resting-state brain activity and 2 classic visual size illusions (i.e. the Ebbinghaus and the Ponzo illusions) in succession, and conducted spectral dynamic causal modeling analysis among relevant cortical regions. Results revealed that forward connection from right V1 to superior parietal lobule (SPL) was predictive of the Ebbinghaus illusion, and self-connection in the right SPL predicted the Ponzo illusion. Moreover, disruption of intrinsic activity in the right SPL by repetitive transcranial magnetic stimulation (TMS) temporally increased the Ebbinghaus rather than the Ponzo illusion. These findings provide a better mechanistic understanding of visual size illusions by showing the causal and distinct contributions of right parietal cortex to them, and suggest that spontaneous fluctuations in intrinsic brain activity are relevant to individual difference in behavior.
Ambient noise autocorrelation scheme for imaging theP-wave reflectivity of the lithosphere
Authors: Gómez-García Clara , Lebedev Sergei , Meier Thomas , Xu Yihe , Le Pape Florian , Wiesenberg Lars
Published: December 2022

Ambient noise autocorrelations can be used to reconstruct the seismic reflection response of the Earth structure beneath single stations using continuous recordings without the need for either active sources or earthquakes. In the last decade, this technique has emerged as an inexpensive approach with the potential to provide similar information to that from the classical receiver function (RF) analysis. Previous studies have located and mapped discontinuities at different crustal depths with ambient noise autocorrelations by applying different processing techniques. An ambient noise autocorrelation function (ACF) provides the body-wave reflectivity of the local structure, assuming a homogeneous distribution of noise sources. However, an effective method design is required in order to determine a reliable reflection response. Here, we review the theory behind the ambient noise ACF method and design a workflow to obtain the P-wave reflectivity with a special focus on the Moho depth. In particular, we calculate a smooth function to fit and subtract the zero-lag component in the time domain, that is, the large-amplitude signal near 0 lag time in the ACF. The zero-lag component can interfere with the reflection component, so its removal allows us to increase the frequency band to use. We bandpass filter the ACFs between 1 and 6 s. We also derive and apply a phase shift correction in the ACFs due to the integration of a homogeneously distributed noise field dominated by distant sources from deep below, such as teleseismic sources. Both linear and nonlinear, phase-weighted stacks are used. Linear stacking is used to identify the main interfaces since it ensures the linearity of the processing steps; nevertheless, nonlinear, phase-weighted stacking help validate the coherent signals. We test and apply our method to continuous vertical recordings from three stations in Ireland and five stations in different cratons and obtain clear P-wave reflection from the Moho and other crustal and upper-mantle discontinuities in most cases. However, noise coming from local heterogeneities, non-homogeneous distribution of the ambient noise sources or instrumental noise is also expected. Therefore, additional, a priori information is desirable to help identify key phases in single ACFs. We compute synthetic ACFs using P-wave velocity (VP) models from controlled-source profiles in Ireland. The relatively complex ACF traces obtained at the stations in Ireland show a close data-synthetic match for the Moho and mid-crustal discontinuities. The ACF traces from the stations in different cratons are directly compared with receiver functions showing overall agreement and offering complementary information on the origin of the signal.
Distinctive seismic reflections from the subducting Pacific slab for earthquakes in the Ryukyu arc
Authors: Furumura Takashi , Kennett Brian L N
Published: December 2022

During moderate to deep (35–260 km) earthquakes within the Philippine-sea slab along the Ryukyu arc, distinctive later phases after S are observed across the Japanese archipelago for epicentral distances from 1500 to 2200 km, producing anomalous amplification of ground motion in central and northern Japan. Broad-band observations show that these later phases have a faster apparent wave speed (7–9.5 km s−1) than S, and are dominant at low frequencies (0.05–1 Hz), indicating S-wave reflections returned from the upper mantle with strong attenuation for high frequencies. Numerical simulation of seismic wave propagation in 3-D models including subduction of both the Pacific (PAC) and Philippine-sea (PHS) plates reveal the origin of these reflections. The triplicated S wave front from the 410 km discontinuity undergoes wide-angle reflection at the top of the Pacific slab bringing strong amplitudes in a narrow band of epicentral distance near 1500 km. Also, wide-angle S reflections at the 660 km discontinuity are reinforced by refraction when travelling through the high-wave speed Pacific slab; these arrive at the surface beyond 2000 km epicentral distance. The characteristics of the deep mantle reflections and the distribution of large ground motion across Japan due to the reflections are strongly dependent on the source depth and distance to the Ryukyu earthquakes. Tomographic imagery for western Japan indicates loss of the high-wave speed signal of the PAC slab below 200 km depth; the character of the large S reflections and pattern of enhanced ground motions favours a model in which the PAC slab is thinned rather than fully broken. The peculiar pattern of ground motion from Ryukyu earthquakes can be useful for constraining deep slab structures that are difficult to identify based on tomography.
RR Lyrae stars as probes of the outer Galactic halo: chemical and kinematic analysis of a pilot sample
Authors: Medina Gustavo E , Hansen Camilla J , Muñoz Ricardo R , Grebel Eva K , Vivas A Katherina , Carlin Jeffrey L , Martínez-Vázquez Clara E
Published: December 2022

We report the spectroscopic analysis of 20 halo ab-type RR Lyrae stars with heliocentric distances between 15 and 165 kpc, conducted using medium-resolution spectra from the Magellan Inamori Kyocera Echelle (MIKE) spectrograph. We obtain the systemic line-of-sight velocities of our targets with typical uncertainties of 5–10 km s−1 and compute orbital parameters for a subsample out to 50 kpc from the Galactic centre, including proper motion data from Gaia DR3. The orientation of our stars’ orbits, determined for an isolated Milky Way and for a model perturbed by the Large Magellanic Cloud, appears to suggest an accreted origin for at least half of the sample. In addition, we derive atmospheric parameters and chemical abundance ratios for seven stars beyond 20 kpc. The derived α-abundances of five of these stars follow a Milky Way halo-like trend, while the other two display an underabundance of α-elements for their [Fe/H], indicating an association with accretion events. Furthermore, based on the [Sr/Ba] ratio, we can speculate about the conditions for the formation of a potential chemically peculiar carbon-enhanced metal-poor (CEMP) RR Lyrae star. By analysing the stars’ orbital parameters and abundance ratios, we find hints of association of two of our stars with two massive satellites, namely the Large Magellanic Cloud and Sagittarius. Overall, our results are in line with the suggestion that the accretion of sub-haloes largely contributes to the outer halo stellar populations.
The Impact of Thoracic Ultrasound on Clinical Management of Critically Ill Patients (UltraMan): An International Prospective Observational Study*
Authors: Heldeweg Micah L. A. , Lopez Matta Jorge E. , Pisani Luigi , Slot Stefanie , Haaksma Mark E. , Smit Jasper M. , Mousa Amne , Magnesa Giovanna , Massaro Fabrizia , Touw Hugo R. W. , Schouten Viviane , Elzo Kraemer Carlos V. , van Westerloo David J. , Heunks Leo M. A. , Tuinman Pieter R.
Published: December 2022

Objectives:

To investigate the impact of thoracic ultrasound (TUS) examinations on clinical management in adult ICU patients.

Design:

A prospective international observational study.

Setting:

Four centers in The Netherlands and Italy.

Patients:

Adult ICU patients (> 18 yr) that received a clinically indicated lung ultrasound examination.

Interventions:

None.

Measurements and Main Results:

Clinicians performing TUS completed a pre- and post-examination case report form. Patient characteristics, TUS, and resulting clinical effects were recorded. First, change of management, defined as a TUS-induced change in clinical impression leading to a change in treatment plan, was reported. Second, execution of intended management changes within 8 hours was verified. Third, change in fluid balance after 8 hours was calculated. A total of 725 TUS performed by 111 operators across 534 patients (mean age 63 ± 15.0, 70% male) were included. Almost half of TUS caused a change in clinical impression, which resulted in change of management in 39% of cases. The remainder of TUS confirmed the clinical impression, while a minority (4%) did not contribute. Eighty-nine percent of management changes indicated by TUS were executed within 8 hours. TUS examinations that led to a change in fluid management also led to distinct and appropriate changes in patient’s fluid balance.

Conclusions:

In this international observational study in adult ICU patients, use of TUS had a major impact on clinical management. These results provide grounds for future randomized controlled trials to determine if TUS-induced changes in decision-making also lead to improved health outcomes.
Family Quality of Life in Children with Severe or Profound Disability: Home Versus Residential Care
Authors: Karni-Visel Yael , Nasser Kareem , Manishevitch Hofit , Akrt Sahar , Schertz Mitchell
Published: December 2022

Background:

Most children with severe and profound intellectual disability (SPID) are cared for in their homes, according to current recommendations. Yet, their families face marked emotional, health, and economic challenges.

Aims:

The aim of this study was to examine family quality of life (FQOL) along with psychological and health factors among families who raise children with SPID at home versus those residing in residential care.

Methods:

Sixty caregivers of children aged 2 to 18 years (M = 8.81, SD = 4.62) with SPID (developmental quotient/intellectual quotient <35), living at home (38 caregivers—“home group”) or in residential care (22 caregivers—“residential group”), completed the FQOL Survey, Beck Depression Inventory, Parental Stress Index, Shame and Guilt Scale, and Health and Demographic questionnaires.

Results:

FQOL for most domains and dimensions was rated better among families whose child resides in residential care compared with families who raise their child at home. Similarly, parental stress relating to the child was worse among families who raise their children at home. No significant differences between the 2 groups were noted on other psychological or health measures.

Conclusion:

Family and individual needs for those raising a child with SPID at home should be addressed when planning policy and interventions.
Potential Points of Intervention to Minimize the Impact of Parents' Adverse Childhood Experiences on Child Mental Health
Authors: Buchanan Gretchen J. R. , Tate Allan D. , Barnes Andrew , Trofholz Amanda C. , Berge Jerica M.
Published: December 2022

Objective:

Children of parents who experienced adverse childhood experiences (ACEs) are at elevated risk for mental health (MH) issues. The goal of this study was to explore the relationships between parent ACEs and child MH and to identify potential mediators and points of psychosocial intervention.

Methods:

Participants were 1307 children aged 5 to 9 years from diverse backgrounds and their primary caregivers. Using cross-sectional questionnaire data, we used structural equation modeling to examine the research questions.

Results:

Parent ACEs were directly related to child MH issues (β = 0.189, p < 0.001). This relationship was fully mediated by parent MH (β = 0.374, p < 0.001; β = 0.246, p < 0.001) and positive parenting behaviors (β = −0.237, p < 0.001; β = −0.556, p < 0.001). High parent ACEs were negatively associated with parent MH (β = 0.374, p < 0.001), which was then negatively associated with parenting behaviors (β = −0.500, p < 0.001), which was then negatively associated with child MH (β = −0.600, p < 0.001). Parent MH maintained a significant, though attenuated, direct relationship with child MH (β = 0.102, p < 0.05).

Conclusion:

Parents with high ACEs but who have good mental health and positive parenting behaviors demonstrated no impact of their ACEs on their children's mental health. Providing MH care to parents and parenting programs may be strategies for improving children's MH. Parenting behavior assessment is recommended for clinicians when pediatric patients present with MH concerns.
Food Insecurity and Depressive Symptoms Among Adolescents: Does Federal Nutrition Assistance Act as a Buffer?
Authors: Frank Miranda L. , Sato Amy. F.
Published: December 2022

Objective:

Food insecurity has been associated with a variety of adverse outcomes in adolescents. However, further research is needed to elucidate whether adolescent self-report food insecurity contributes to depressive symptoms. This study examined the (1) association between food insecurity and depressive symptoms and (2) moderating role of federal nutrition assistance in a nonclinical sample of adolescents.

Method:

Adolescents aged 12 to 17 years (N = 141) and one parent/guardian completed self-report questionnaires as part of 2 larger studies examining adolescent stress and eating behaviors. Adolescents (M age = 13.79 years, SD = 1.60, 53.9% female) completed measures of food insecurity and depressive symptoms.

Results:

A bootstrapped linear regression model demonstrated that adolescent food insecurity was significantly, positively associated with depressive symptoms, 95% confidence interval (CI) (0.19–1.64), after controlling for biological sex. Among dyads eligible for federal nutrition assistance (N = 64), the interaction between adolescent food insecurity and National School Lunch Program (NSLP) participation did not reach significance, ΔF(1, 59) = 1.06, 95% CI (−3.80 to 9.29). The interaction between adolescent food insecurity and Supplemental Nutrition Assistance Program (SNAP) participation trended toward significance, ΔF(1, 59) = 2.88, 95% CI (−5.73 to 0.47).

Conclusion:

Adolescents with food insecurity may be at a greater risk for experiencing elevated depressive symptoms. Whereas NSLP participation did not act as a buffer, SNAP participation may attenuate the association between food insecurity and depressive symptoms. Larger longitudinal studies are needed to develop a greater understanding of factors that may alter the relationship between adolescent food insecurity and depressive symptoms.
Return to Sport After Total Shoulder Arthroplasty and Hemiarthroplasty: A Systematic Review
Authors: Franceschetti Edoardo , Gregori Pietro , Giovannetti de Sanctis Edoardo , Palumbo Alessio , Paciotti Michele , Maffulli Nicola , Franceschi Francesco
Published: December 2022

Purpose:

One of the most frequent concerns of the increasing number of patients undergoing shoulder arthroplasty is the possibility to resume sport after surgery. This systematic review determined the rate of return to sport after total shoulder arthroplasty (TSA) and hemiarthroplasty (HA).

Materials and Methods:

The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed to perform this systematic review. A systematic electronic search was performed using the PubMed (MEDLINE), EMBASE, and Cochrane Library databases. All the studies analyzing the rates of reverse shoulder arthroplasties were pooled; data were extracted and statistically analyzed. Only studies with at least 10 adult patients recruited were considered. All studies had to relate return to sport after TSA or HA.

Results:

A total of 76 studies were included for a total of 694 patients. The mean age and average follow-up were, respectively, 64.5 years (range: 24 to 92 y) and 4.5 years (range: 0.5 to 12 y). The mean rate of return to sport ranged from 49.3% to 96.4%. The mean time to resume sports was 8.1 months. The overall rate of return to sport after the procedures, according to a random effect model, was 83%. The mean level of sports at the time of the survey was worsened in 9.4% (±2.82%), improved or reported from good to excellent in 55.6% (±13.6%), and did not change in 40% (±1.4) of patients.

Conclusions:

On the basis of current available data, return to sports after TSA and HA is possible and is highly frequent. The subjective level of practice does not change or improve in most patients. More studies and better designed trials are needed to enrich the evidence on specific sport recovery after the procedure.
Cognitive behavior therapy as dermatological treatment: a narrative review
Authors: Revankar Rishab R. , Revankar Nikita R. , Balogh Esther A. , Patel Heli A. , Kaplan Sebastian G. , Feldman Steven R.
Published: December 2022

Background:

Cognitive behavior therapy (CBT) is efficacious in treating numerous psychological disorders. It is also effective in combination with medication for chronic pain, diabetes, and other diseases. Patients with skin disease report high levels of stress, anxiety, and negative feelings.

Objective:

To summarize the findings on the utility of CBT for the improvement of skin status and quality of life in patients with dermatological conditions.

Methods:

PubMed and Google Scholar databases were searched for relevant articles from database inception to the time of search (October 20, 2021). A total of 30 included studies featured 10 on psoriasis, 11 on atopic dermatitis, 4 on vitiligo, 4 on acne, and 1 study on alopecia areata.

Results:

Several studies, including randomized controlled trials with large study samples, support the effectiveness of CBT and Internet CBT for a number of dermatological conditions. Patients who completed CBT courses were less likely to rely on dermatological healthcare during follow-up.

Limitations:

There are a limited number of studies discussing the implementation of CBT for alopecia, acne, and vitiligo.

Conclusion:

Patients who underwent CBT or Internet CBT in addition to skin care demonstrated improvement with quality of life and severity of skin disease as compared to controls only receiving standard of care treatment.
Strain-Specificity of Probiotics in Pediatrics: A Rapid Review of the Clinical Evidence
Authors: Jankiewicz Mateusz , Łukasik Jan , Kotowska Maja , Kołodziej Maciej , Szajewska Hania
Published: December 2022

Objective:

The dogma of probiotic strain-specificity is widely accepted. However, only the genus- and species-specific effects of probiotics are supported by evidence from clinical trials. The aim of this rapid review was to assess clinical evidence supporting the claim that the efficacy of probiotics in the pediatric population is strain-specific.

Methods:

The Cochrane Library, MEDLINE, and EMBASE databases were searched (up to August 2022) for randomized controlled trials (RCTs) conducted in children aged 0–18 years evaluating the effects of prophylactic or therapeutic administration of probiotics (well-characterized at the strain level) for conditions such as antibiotic-associated diarrhea, acute diarrhea, necrotizing enterocolitis, respiratory tract infections, Helicobacter pylori infection, and atopic dermatitis. To allow evaluation of strain-specificity, a trial could only be included in the review if at least one additional RCT assessed the effect of a different strain of the same species against the same comparator. RCTs without proper strain-level data were excluded. In the absence of identifying head-to-head strain versus strain RCTs, indirect comparisons were made between interventions.

Results:

Twenty-three RCTs were eligible for inclusion. Out of the 11 performed comparisons, with 1 exception (two Lacticaseibacillus paracasei strains in reducing atopic dermatitis symptoms), no significant differences between the clinical effects of different strains of the same probiotic species were found.

Conclusions:

Head-to-head comparison is an optimal study design to compare probiotic strains, but such comparisons are lacking. Based on indirect comparisons, this rapid review demonstrates insufficient clinical evidence to support or refute the claim that probiotic effects in children are strain-specific.
Clinicopathologic Review of Metastatic Breast Cancer to the Gynecologic Tract
Authors: Braun Ankica , Reddy Swathi , Cheng Lin , Gattuso Paolo , Yan Lei
Published: December 2022

Metastatic spread is the single most significant predictor of poor survival in breast cancer. Some of the most common metastatic sites are the bones, lungs, liver, brain, and peritoneal cavity. Clinically metastatic breast cancer to the gynecologic tract is usually asymptomatic and diagnosed as an incidental finding during a histologic examination of gynecologic specimens resected for other reasons. Cases of metastatic breast cancer to gynecologic organs diagnosed from August 1995 to January 2021 were retrieved from our institution’s pathology databases, and their clinicopathologic features were reviewed. The most common site of metastasis was the ovary which was involved in about 79% (22 of 28 cases) of metastases to the gynecologic tract. Clinically, only 8 cases (36%) presented with ovarian mass detected in imaging studies and the rest of the cases were all incidental findings. Among ovarian metastasis, 59% of cases were invasive lobular carcinoma and 41% were invasive ductal carcinoma. In 5 cases, metastatic breast cancer was found in the endometrium, including 2 cases with endometrial metastasis only and 3 cases with multiple gynecologic organs involved. Metastatic breast cancer rarely involved the lower gynecologic tract, with only 7% vaginal metastasis and 4% found in the vulva. The absolute majority of metastatic breast cancer outside of the ovaries were lobular carcinoma (88%). Most of the metastatic breast carcinomas were positive for estrogen receptor on immunohistochemistry (27 of 28 cases, 96%). Her-2/neu immunostaining was positive in 4 cases only (14%). Metastatic breast cancer needs to be distinguished from gynecologic primary neoplasms and metastatic tumors from adjacent urinary and GI tracts. A careful review of the patient’s history and adequate immunohistochemistry panel are helpful to render the diagnosis.
Adult Granulosa Cell Tumour With Heterologous Adipocytic Differentiation: Report of a Unique Case
Authors: Andrade Liliana A.L. De Angelo , Alame Melissa , Truffaux Nathalène , Croce Sabrina , Reis Queiroz Ayla W. , McCluggage W. Glenn
Published: December 2022

Adult granulosa cell tumor is the most common malignant ovarian sex cord-stromal tumor and heterologous elements, in the form of hepatocytes or mucinous epithelium, have rarely been described in these neoplasms. Here, we report an adult granulosa cell tumor in a 61-year-old woman with classic and luteinized elements and exhibiting a previously unreported feature in the form of foci of mature adipocytes. In reporting this case, we review heterologous adipocytic elements and other heterologous elements in ovarian sex cord-stromal tumors and speculate on the pathogenesis of the adipocytic differentiation.
Impact of Neck PET/CT Positivity on Survival Outcomes—Visual and Quantitative Assessment
Authors: Stack Brendan C. , Duan Fenghai , Romanoff Justin , Sicks JoRean D. , Subramaniam Rathan M. , Lowe Val J.
Published: December 2022

Introduction

FDG PET/CT was prospectively studied in 287 cN0 head and neck cancer patients in ACRIN 6685, and additional analysis of neck FDG uptake upon recurrence-free survival (RFS) and overall survival (OS) was performed.

Patients and Methods

Two hundred eight had analyzable data. Survival analysis was performed to compare RFS and OS based on neck FDG visual assessment (VA) and SUVmax. For SUVmax, the optimal thresholds were calculated using conditional inference trees on a randomly selected 70% training data set and validated using the remaining 30% of data. Kaplan-Meier curves with log-rank tests were generated for the patient groups based on VA and optimal SUVmax thresholds, and the hazards ratios (HRs) and 95% confidence intervals (CIs) were also calculated. Hypothesis testing was set at a significance level of 0.05.

Results

A total of 73.9% of bilateral cN0 and 50.0% of unilateral cN0 were alive at the end of the study with the remaining being dead or lost to follow-up. Overall survival median follow-up time was 24.0 months (interquartile range, 15.8–25.3; range, 0–37.0). A total of 63.3% of bilateral cN0 and 42.5% of unilateral cN0 patients remained disease free during the study. Recurrence-free survival median follow-up time was 23.9 months (interquartile range, 12.4–25.2; range, 0–35.6). Visual assessment of necks by our panel of radiologists was significantly associated with RFS (HR [95% CI], 2.30 [1.10–4.79]; P = 0.02), but not with OS (HR [95% CI], 1.64 [0.86–3.14]; P = 0.13). The optimal SUVmax thresholds were 2.5 for RFS and 5.0 for OS. For SUVmax assessment, applying the optimal thresholds to the 30% test data yielded HRs (95% CIs) of 2.09 (0.61–7.14; P = 0.23) for RFS and 3.42 (1.03–11.41; P = 0.03) for OS. The SUVmax threshold of 5.0 was significantly associated with RFS (HR [95% CI], 5.92 [1.79–19.57]; P < 0.001).

Conclusions

Neck FDG uptake by VA is significant for RFS. An SUVmax threshold of 5.0 is significantly associated with OS and RFS.
APOEGenotype-specific Methylation Patterns are Linked to Alzheimer Disease Pathology and Estrogen Response
Authors: Panitch Rebecca , Sahelijo Nathan , Hu Junming ,   the Alzheimer’s Disease Neuroimaging Initiative, Nho Kwangsik , Bennett David A. , Lunetta Kathryn L. , Au Rhoda , Stein Thor D. , Farrer Lindsay A. , Jun Gyungah R.
Published: December 2022

The joint effects ofAPOEgenotype and DNA methylation on Alzheimer disease (AD) risk is relatively unknown. We conducted genome-wide methylation analyses using 2,021 samples in blood (91 AD cases, 329 mild cognitive impairment, 1,391 controls) and 697 samples in brain (417 AD cases, 280 controls). We identified differentially methylated levels in AD compared to controls in anAPOEgenotype-specific manner at 25 cytosine-phosphate-guanine (CpG) sites in brain and 36 CpG sites in blood. Additionally, we identified seven CpG sites in theAPOEregion containingTOMM40, APOE, andAPOC1genes with P<5×10−8betweenAPOEε4 carriers and non-carriers in brain or blood. In brain, the most significant CpG site hypomethylated in ε4 carriers compared to non-carriers) was from theTOMM40in the total sample, while most of the evidence was derived from AD cases. However, the CpG site was not significantly modulating expression of these three genes in brain. Three CpG sites from theAPOEwere hypermethylated inAPOEε4 carriers in brain or blood compared in ε4 non-carriers and nominally significant withAPOEexpression in brain. Three CpG sites from theAPOC1were hypermethylated in blood, which one of the 3 CpG sites significantly loweredAPOC1expression in blood using all subjects or ε4 non-carriers. Co-methylation network analysis in blood and brain detected eight methylation networks associated with AD andAPOEε4 status. Five of the eight networks included genes containing network CpGs that were significantly enriched for estradiol perturbation, where four of the five networks were enriched for the estrogen response pathway. Our findings provide further evidence of the role ofAPOEgenotype on methylation levels associated with AD, especially linked to estrogen response pathway.
Metabolite diversity amongProchlorococcusstrains belonging to divergent ecotypes
Authors: Kujawinski Elizabeth B. , Braakman Rogier , Longnecker Krista , Chisholm Sallie W. , Becker Jamie W. , Dooley Keven , Soule Melissa C. Kido , Swarr Gretchen J. , Halloran Kathryn
Published: December 2022

Primary Abstract

The euphotic zone of the surface ocean contains distinct physical-chemical regimes that vary inversely in light and nutrient concentrations as a function of depth. The most numerous phytoplankter of the mid- and low-latitude ocean is the picocyanobacteriumProchlorococcus,which consists of ecologically distinct subpopulations (i.e., “ecotypes”). Ecotypes have different temperature, light and nutrient optima and display distinct relative abundances along gradients of these niche dimensions. As a primary producer,Prochlorococcusfixes and releases organic carbon to neighboring microbes as part of the microbial loop. However, little is known about the specific moleculesProchlorococcusaccumulates and releases or how these processes vary among its ecotypes. Here we characterize metabolite diversity ofProchlorococcusby profiling three ecologically-distinct cultured strains: MIT9301, representing a high-light adapted ecotype dominating shallow tropical and sub-tropical waters, MIT0801, representing a low-light adapted ecotype found throughout the euphotic zone and MIT9313, representing a low-light adapted ecotype relatively most abundant at the base of the euphotic zone. In both intracellular and extracellular metabolite profiles, we observe striking differences across strains in the accumulation and release of molecules. Some differences reflect variable genome content across the strains, while others likely reflect variable regulation of genetically-conserved pathways. In the extracellular profiles, we identify molecules that may serve as currencies inProchlorococcus’interactions with neighboring microbes and therefore merit further investigation.

Importance

Approximately half of the annual carbon fixation on Earth occurs in the surface ocean through the photosynthetic activities of phytoplankton such as the ubiquitous picocyanobacteriumProchlorococcus.Ecologically-distinct subpopulations ofProchlorococcus(or ecotypes) are central conduits of organic substrates into the ocean microbiome, thus playing important roles in surface ocean production. By measuring the chemical profile of three cultured ecotype strains, we observed striking differences in the likely chemical impact ofProchlorococcussubpopulations on their surroundings. Subpopulations differ along gradients of temperature, light and nutrient concentrations, suggesting that these chemical differences could affect carbon cycling in different ocean strata and should be considered in models ofProchlorococcusphysiology and marine carbon dynamics.
Novel Community-Based Rabies Surveillance (CBRS) In Urban Lilongwe City, Malawi
Authors: Mastala Precious Innocent , Tefera Melaku , Chiweta Edson , Nyamwanza Madeline , Kapalamula Thoko
Published: December 2022

Introduction

Rabies is a neglected tropical disease that is endemic to Malawi, killing almost 500 people every year. Domestic dogs are implicated as the main reservoir for rabies. However, there is limited capacity to detect canine rabies in the country, particularly in urban areas where there are high dog densities. The Lilongwe Society for the Protection and Care of Animals designed and implemented a canine community-based rabies surveillance (CBRS) in Lilongwe city between January and June 2020.

Objectives

This study assessed the effectiveness of the CBRS program in canine rabies detection compared to the traditional passive routine surveillance data of the years between 2015 and 2019. Furthermore, the study determined rabies Post-Exposure Prophylaxis (PEP) issuance trends in emergent cases.

Methods

Suspected rabies cases were recorded and followed. The dogs that were found alive were quarantined for 10 days for observation. Brain samples were collected post-mortem for direct-fluorescent antibody testing for antigen detection.

Results

There were 610 suspected cases, and only 217 (39.2%) were followable. Out of these, 150 (62.8%) were followed. A total of 9 dogs (6%) tested positive, and there were 11 (7.3%) probable cases. This represents a 4.97-fold increase in rabies cases detected compared to the pre-surveillance period, with a resultant of 3.33 cases/month from 0.67 cases/month. The program also helped to initiate PEP treatment in exposed people. There were 141 bite victims and 136 (96.5%) reported for PEP. Out of these, 89 (65.4%) were from healthy bites and 33 (24.4%) from suspect cases indicating a 63.97% to 88.24% rate of irrelevant PEP issuance.

Conclusion

The CBRS program established relevance in increasing canine rabies detection and subsequent prevention of related human infections. It also established a high rate of PEP issuance following healthy bites. Therefore, we recommend enhanced multi-sectoral collaborative efforts aimed at increasing rabies detection and optimizing PEP usage.

One Health Impact Statement

This novel implementation research features a One Health approach, bringing together various stakeholders from the public and private sectors, as well as the community, in the effort to eradicate rabies. This collaboration provides synergy towards accelerating the identification of rabid animals in the community and effectively guides people to take the necessary precautions including prompt Post-Exposure Prophylaxis in cases of exposure, ultimately promoting health at the human-animal interface.
Crowdsourced partner services among men who have sex with men living with HIV: A pilot randomized controlled trial in China
Authors: Yan Xumeng , Tucker Joseph D. , Miller William C. , Tang Weiming
Published: December 2022

Background

To improve the uptake of HIV partner services (HIV PS) among men who have sex with men living with HIV (MLWH) in China, our team used a crowdsourcing approach to develop a tailored intervention package. This study assessed the acceptability, feasibility, and preliminary effectiveness of a crowdsourced HIV PS intervention compared to conventional HIV PS.

Methods

The study conducted a pilot two-arm randomized controlled trial (RCT) to compare the proportion of HIV testing among sexual partners of MLWH. Indexes in the control arm received conventional HIV PS using referral cards. Indexes in the intervention arm received a crowdsourced HIV PS intervention which included HIV self-testing kits for secondary distribution (HIVST-SD), digital education materials, and assisted PS via provider/contract referral. The primary outcomes were (1) intervention feasibility (i.e., the frequency of indexes using crowdsourced intervention components), (2) intervention acceptability (i.e., the evaluation of indexes on intervention components using Likert scales), and (3) the preliminary impact of the intervention (i.e., the proportion of partners getting HIV testing within three months of index enrollment). Descriptive analysis was conducted, and Chi-squared tests were used to test whether the proportional differences were significant.

Results

A total of 121 MSM newly diagnosed with HIV were enrolled between July 2021 and May 2022 in Guangzhou and Zhuhai, China, with 81 in the intervention arm and 40 in the control arm. The 3-month follow-up rates were 93% (75/81) and 83% (33/40), respectively. The crowdsourced intervention components were feasible, as 31 indexes received and 23 indexes used HIVST-SD, 6 indexes used provider-referral to notify 9 sexual partners, and indexes visited the digital educational materials 2.3 times on average. The intervention components also demonstrated acceptability, with HIVST-SD rated 4.4 out of 5 and the digital educational materials rated 4.1 out of 5. The proportion of partners getting HIV testing among all identified partners was 38% (65/171) in the intervention arm, compared to 27% (24/89) in the control arm. The difference was not statistically significant.

Conclusion

The crowdsourced HIV PS intervention components were acceptable and feasible among Chinese MLWH and may improve the proportion of stable partners receiving HIV testing. Further implementation science research is needed to expand PS among key populations in low and middle-income countries.

Clinical trial registration

19-0496
Characterizing proteomic and transcriptomic features of missense variants in amyotrophic lateral sclerosis genes
Authors: Dilliott Allison A. , Rouleau Guy A. , Iqbal Sumaiya , Farhan Sali M.K.
Published: December 2022

Background

Within recent years, there has been a growing number of genes associated with amyotrophic lateral sclerosis (ALS), resulting in an increasing number of novel variants, particularly missense variants, many of which are of unknown clinical significance. Here, we leverage the sequencing efforts of the ALS Knowledge Portal (3,864 individuals with ALS and 7,839 controls) and Project MinE ALS Sequencing Consortium (4,366 individuals with ALS and 1,832 controls) to perform proteomic and transcriptomic characterization of missense variants in 24 ALS-associated genes.

Results

Using predicted human protein structures from AlphaFold, we determined that missense variants carried by individuals with ALS were significantly enriched in β-sheets and α-helices, as well as in core, buried, or moderately buried regions. At the same time, we identified that hydrophobic amino acid residues, compositionally biased protein regions and protein-protein interaction regions are predominantly enriched in missense variants carried by individuals with ALS. Assessment of expression level based on transcriptomics also revealed enrichment of variants of high and medium expression across all tissues and within the brain. We further explored enriched features of interest using burden analyses to determine whether individual genes were driving the enrichment signal. A case study is presented forSOD1to demonstrate proof of concept of how enriched features may aid in defining variant pathogenicity.

Conclusions

Our results present proteomic and transcriptomic features that are important indicators of missense variant pathogenicity in ALS and are distinct from features associated with neurodevelopmental disorders.