bluuebunny/crossref_metadata_2025 huggingface dataset:
Using the Kano model to associate the number of confirmed cases of COVID-19 in a population of 100,000 with case fatality rates: An observational study
Authors: Hsu Sheng-Yao , Chien Tsair-Wei , Yeh Yu-Tsen , Chou Willy
Published: September 2022

Background:

An important factor in understanding the spread of COVID-19 is the case fatality rate (CFR) for each county. However, many of research reported CFRs on total confirmed cases (TCCs) rather than per 100,000 people. The disparate definitions of CFR in COVID-19 result in inconsistent results. It remains uncertain whether the incident rate and CFR can be compared to identify countries affected by COVID-19 that are under (or out of) control. This study aims to develop a diagram for dispersing TCC and CFR on a population of 100,000 (namely, TCC100 and CFR100) using the Kano model, to examine selected countries/regions that have successfully implemented preventative measures to keep COVID-19 under control, and to design an app displaying TCC100 and CFR100 for all infected countries/regions.

Methods:

Data regarding confirmed cases and deaths of COVID-19 in countries/regions were downloaded daily from the GitHub website. For each country/region, 3 values (TCC100, CFR100, and CFR) were calculated and displayed on the Kano diagram. The lower TCC100 and CFR values indicated that the COVID-19 situation was more under control. The app was developed to display both CFR100/CFR against TCC100 on Google Maps.

Results:

Based on 286 countries/regions, the correlation coefficient (CC) between TCC100 and CFR100 was 0.51 (t = 9.76) in comparison to TCC100 and CFR with CC = 0.02 (t = 0.3). As a result of the traditional scatter plot using CFR and TCC100, Andorra was found to have the highest CFR100 (=6.62%), TCC100 (=935.74), and CFR (=5.1%), but lower CFR than New York (CFR = 7.4%) and the UK (CFR = 13.5%). There were 3 representative countries/regions that were compared: Taiwan [TCC100 (=1.65), CFR100 (=2.17), CFR (=1%)], South Korea [TCC100 (=20.34), CFR100 (=39.8), CFR (=2%), and Vietnam [TCC100 (=0.26), CFR100 (=0), CFR (=0%)].

Conclusion:

A Kano diagram was drawn to compare TCC100 against CFT (or CFR100) to gain a better understanding of COVID-19. There is a strong association between a higher TCC100 value and a higher CFR100 value. A dashboard was developed to display both CFR100/CFR against TCC100 for countries/regions.
Effects of goal-oriented nursing intervention on postpartum depression
Authors: Wang Xin-Hui , Zhou Yu , Wang Qing , Yan Xuan , Huang Yan-Hong
Published: September 2022

This retrospective study aimed to explore the effects of goal-oriented nursing intervention (GONI) on postpartum depression (PPD). We retrospectively analyzed the medical records of 72 women with PPD. They were allocated to a treatment group (n = 36, exercise plus GONI) or a control group (n = 36, exercise). Patients in both groups received a total of 3 months of treatment. Outcomes included the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score, HAMD-17 response rate (≥50% score reduction), HAMD-17 remission rate (score ≤ 7), and adverse events. Outcomes were analyzed before and after 3-month of treatment. After treatment, patients in the treatment group achieved more effective outcomes in the HADM-17 total score (P < .01), HADM-17 response rate (P < .01), HADM-17 remission rate (P < .01) than those in the control group. Regarding safety, the medical records of both the groups did not report any adverse events. The results of this study showed that GONI and exercise had more effects in patients with PPD. Further prospective studies are required to validate our findings.
Semi-quantitative evaluation of chest computed tomography for coronavirus disease 2019 in a critical care unit: A case-control study
Authors: Toratani Masayasu , Karasuyama Kana , Kuriyama Keiko , Inoue Atsuo , Hamaguchi Kyoko , Fujiwara Takuya , Kishimoto Kentaro , Ohnishi Mitsuo , Higashi Masahiro
Published: September 2022

The spread of abnormal opacity on chest computed tomography (CT) has been reported as a predictor of coronavirus disease 2019 (COVID-19) severity; however, the relationship between CT findings and prognosis in patients with severe COVID-19 remains unclear. The objective of this study was to evaluate the extent of abnormal opacity on chest CT and its association with prognosis in patients with COVID-19 in a critical care medical center, using a simple semi-quantitative method. This single-center case-control study included patients diagnosed with severe COVID-19 pneumonia who were admitted to a critical care center. The diagnosis of COVID-19 was based on positive results of a reverse transcription polymerase chain reaction test. All patients underwent non-contrast whole-body CT upon admission. Six representative axial chest CT images were selected for each patient to evaluate the extent of lung lesions. The percentage of the area involved in the representative CT images was visually assessed by 2 radiologists and scored on 4-point scale to obtain the bedside CT score, which was compared between patients who survived and those who died using the Mann–Whitney U test. A total of 63 patients were included in this study: 51 survived and 12 died after intensive treatment. The inter-rater reliability of bedside scores between the 2 radiologists was acceptable. The median bedside CT score of the survival group was 12.5 and that of the mortality group was 16.5; the difference between the 2 groups was statistically significant. The degree of opacity can be easily scored using representative CT images in patients with severe COVID-19 pneumonia, without sophisticated software. A greater extent of abnormal opacity is associated with poorer prognosis. Predicting the prognosis of patients with severe COVID-19 could facilitate prompt and appropriate treatment.
Treatment of membranous nephropathy with crescent nephritis by rituximab: A case report
Authors: Zhang Fan , Yang Yiya , Chen Yinyin , Chen Ying , Yin Wei , Liang Yumei , Luo Xun
Published: September 2022

Background:

Crescent formation is rare in primary membranous nephropathy (MN). The mechanism of crescent formation is unknown and the treatments are tentative.

Patient concerns:

A 71-year-old woman presented with nephrotic syndrome, hematuria, and rapidly progressive kidney dysfunction.

Diagnosis:

Kidney biopsy was performed, and the diagnosis was MN in combination with crescentic glomerulonephritis. Circulating anti-PLA2R was detected of a high level.

Interventions:

The patient received rituximab besides corticosteroids.

Outcomes:

The patient achieved complete remission of proteinuria and recovery of kidney function.

Conclusion:

Our case suggests that there is a pathologic feature of MN and crescents in the absence of known immunologic factors as well as rituximab could serve as an effective cure and could be considered in serious MN conditions.
Dedifferentiated liposarcoma found in ovary: A rare case report
Authors: Chen Junyu , Ding Lianying , Wang Taiwei , Wang Mengqi , Zhao Shuhua , Xia Yang
Published: September 2022

Rationale:

Dedifferentiated liposarcoma (DL) of the ovary is a rare mesenchymal tumor which is difficult to diagnose before surgery. The diagnose of DL was depended on the morphology, Immunohistochemical stains, and fluorescence in situ hybridization after the complete surgical resection.

Patient concerns:

We report a case of 63-year-old postmenopausal female who presented with a large pelvic mass and was initially thought to be an original ovarian tumor. However, it was subsequently considered to be a DL arising from the mesentery and developing in ovary.

Diagnosis:

Ovarian DL.

Interventions:

Bilateral salpingo-oophorectomy.

Outcomes:

Until now, there is no recurrence symptoms represented in the patient after surgery for 12 months.

Lessons:

DL happening in ovary is rare. In this case, the exact origin of the mass still remains ambiguous because of the lack of morphological evidence. Although retroperitoneum is the most common area of DL origin, we for long suspect that the mass was initially derived from mesentery and developed in ovary. A long-term may help confirm the exact origin of the tumor. Complete surgical resection plays an important role in the treatment.
Electroacupuncture combined with Qianzhengsan decoction for the treatment of peripheral facial paralysis: A retrospective study
Authors: Chen Wei-Qiang , Li Qiang
Published: September 2022

This study retrospectively explored the effectiveness of electroacupuncture (EA) combined with Qianzhengsan decoction (QZSD) for the treatment of peripheral facial paralysis (PFP). This retrospective study included patients with PFP admitted to a single hospital between July 2018 and June 2020. Ninety patients were included and divided into treatment (n = 45) and control (n = 45) groups. All the patients in both groups received oral prednisone tablets and mecobalamin. In addition, patients in the treatment group received EA and QZSD. The outcomes were the overall response rate, facial nerve function, facial nerve electromyography, and adverse events. All outcome data were analyzed before and after treatment. Patients in the treatment group achieved better outcomes than those in the control group in improving overall response rate (P = .04), facial nerve function (P < .01), and facial nerve electromyography (P < .01). Patients in both groups reported adverse events. The results of this study showed that patients with PFP and QZSD received better outcomes than those who did not. Further studies are required to confirm these results.
Outcomes of lipectomy in patients with advanced unilateral upper extremity lymphedema with regard to the difference in time required for indocyanine green to reach the axilla: A retrospective cohort study in a single center
Authors: Kim Ryuck Seong , Yi Changryul Claud , Lee Jae Woo , Yoon Jin A , Lee Seungbeom , Kim Joo Hyoung
Published: September 2022

This study aimed to compare and analyze the prognosis after lipectomy with respect to the difference in time required for indocyanine green (ICG) to reach the axilla in patients with advanced unilateral upper extremity lymphedema. The study population was divided into 2 groups, according to the time required by ICG to reach the axilla after injection, that is, <1 hour (<1 hour; n = 9) and over 1 hour (>1 hour; n = 8). The patient’s arm volume was examined before surgery and up to 12 months after surgery. The volume difference between the 2 groups was compared using the excess volume ratio. Statistically significant differences were not observed before surgery (P = .847) and 1 month (P = .336), 3 months (P = .630), and 6 months after surgery (P = .124) between the excess volume ratio values of the < 1 hour and > 1 hour groups. A statistically significant difference was confirmed 12 months after surgery (P = .034). The difference in the time when ICG reached the axilla in patients with lymphedema was associated with prognosis after lipectomy. The difference in time could possibly be used as a variable to classify the progress of lymphedema in the future.
Feeding jejunostomy following esophagectomy may increase the occurrence of postoperative small bowel obstruction
Authors: Nakai Tomoki , Kitadani Junya , Ojima Toshiyasu , Hayata Keiji , Katsuda Masahiro , Goda Taro , Takeuchi Akihiro , Tominaga Shinta , Fukuda Naoki , Nagano Shotaro , Yamaue Hiroki
Published: September 2022

This study aimed to clarify the characteristics and treatment of bowel obstruction associated with feeding jejunostomy in patients who underwent esophagectomy for esophageal cancer. In this single-center retrospective study, 363 patients underwent esophagectomy with mediastinal lymph node dissection for esophageal cancer at the Wakayama Medical University Hospital between January 2014 and June 2021. All patients who underwent esophagectomy routinely underwent feeding jejunostomy or gastrostomy. Feeding jejunostomy was used in the cases of gastric tube reconstruction through the posterior mediastinal route or colon reconstruction, while feeding gastrostomy was used in cases of retrosternal route gastric tube reconstruction. Nasogastric feeding tubes and round ligament technique were not used. Postoperative small bowel obstruction occurred in 19 of 197 cases of posterior mediastinal route reconstruction (9.6%), but in no cases of retrosternal route reconstruction because of the feeding gastrostomy (P < .0001). Of the 19 patients who had bowel obstruction after feeding jejunostomy, 10 patients underwent reoperation (53%) and the remaining 9 patients had conservative treatment (47%). The cumulative incidence of bowel obstruction after feeding jejunostomy was 6.7% at 1 year and 8.7% at 2 years. Feeding jejunostomy following esophagectomy is a risk factor for small bowel obstruction. We recommend feeding gastrostomy inserted from the antrum to the jejunum in the cases of gastric tube reconstruction through the retrosternal route or nasogastric feeding tube in the cases of reconstruction through the posterior mediastinal route.
Characteristics of Children With Inflammatory Bowel Disease and Coexisting Celiac Disease Seropositivity
Authors: Cheung Telly , de Zoeten Edwin F. , Hoffenberg Edward J. , Liu Edwin , Pan Zhaoxing , Walker Thomas , Stahl Marisa
Published: September 2022

Objectives:

Celiac disease (CeD) autoimmunity and coexisting inflammatory bowel disease (IBD) present a diagnostic dilemma. Our aims were to describe the phenotype of children with IBD and CeD seropositivity and evaluate provider confidence for diagnosing CeD in this population.

Methods:

We performed a single-center retrospective cohort study of subjects ≤18 years old with IBD and CeD seropositivity between 2006 and 2020. Subjects were considered to have IBD-CeD if they met CeD diagnosis by serology and histology per North American Society For Pediatric Gastroenterology, Hepatology and Nutrition guidelines and if providers suspected CeD as evaluated by a survey. The IBD-only cohort included seropositive participants that did not meet criteria for CeD. Demographic, histologic, gross endoscopic, and laboratory features were compared using Fisher exact test.

Results:

Of 475 children with IBD, 8 had concomitant CeD, 5 had tissue transglutaminase (tTG) immunoglobulin A (IgA) > 10x upper limit of normal (ULN, P = 0.006), and 8 had villous atrophy (VA, P = 0.003) when compared with 17 seropositive participants with IBD-only. No children with IBD-CeD had esophageal eosinophilia, duodenal cryptitis, duodenal ulceration, or fecal calprotectin >250 µg/g. Factors that contributed to provider uncertainty for diagnosing CeD in IBD included the absence of VA and intraepithelial lymphocytes, the presence of neutrophilic and eosinophilic duodenitis, diffuse ulceration, elevated inflammatory markers, and immunosuppression therapy.

Conclusions:

Diagnosing CeD in children with IBD continues to be challenging. Although high titers of tTG IgA and VA increased provider confidence for diagnosing CeD in IBD, development of evidence-based guidelines are needed. They should better assess the importance of features atypical of concomitant CeD that contribute to uncertainty.
Independent and combined associations of depressive symptoms and sleep disturbance with chronic pain in community-dwelling older adults
Authors: Saito Takafumi , Chen Tao , Yatsugi Harukaze , Chu Tianshu , Liu Xin , Kishimoto Hiro
Published: September 2022

Introduction:

There is limited evidence regarding whether depressive symptoms and sleep disturbance are independently or synergistically associated with chronic pain.

Objectives:

We investigated the independent and combined associations of depressive symptoms and sleep disturbance with chronic pain and its severity (and the additive interactions) in community-dwelling older adults.

Methods:

This cross-sectional study analyzed the data of 1374 individuals who were 65 to 75 year old, not in need of long-term care, and completed questionnaires assessing sociodemographic factors, depressive symptoms, sleep disturbance, and chronic pain. The severity of chronic pain was assessed based on pain intensity, pain distribution, and pain type. The participants' status of depressive symptoms and sleep disturbance were categorized in the following 4 groups: neither condition, depressive symptoms alone, sleep disturbance alone, and both conditions.

Results:

Among the 1374 participants, 849 (61.8%) had chronic pain. The multivariable-adjusted odds ratios and 95% confidence intervals of the presence of chronic pain in those with depressive symptoms alone, sleep disturbance alone, and both conditions were 1.40 (0.97–2.03), 1.98 (1.41–2.78), and 2.12 (1.39–2.23), respectively, compared with the neither-condition group. Similar associations were observed for severe chronic pain. However, there were no significant additive interactions. In addition, only sleep disturbance was significantly associated with chronic pain, after adjusting for depressive symptoms.

Conclusions:

Our analyses did not reveal a synergistic effect of depressive symptoms and sleep disturbance on chronic pain and its severity, suggesting that most of the effects of depressive symptoms on chronic pain may be mediated by sleep disturbance.
A multicenter prospective cohort study of endoscopic urethral realignment versus suprapubic cystostomy after complete pelvic fracture urethral injury
Authors: McCormick Benjamin J. , Keihani Sorena , Hagedorn Judith , Selph J. Patrick , Figler Bradley D. , Johnsen Niels V. , da Silva Rodrigo Donalisio , Broghammer Joshua A. , Gupta Shubham , Miller Brandi , Burks Frank N. , Eswara Jairam , Osterberg E. Charles , Carney Kenneth J. , Erickson Bradley A. , Gretzer Matthew B. , Chung Paul H. , Harris Catherine R. , Murphy Gregory P. , Rusilko Paul , Shridharani Anand , Benson Cooper , Alwaal Amjad , Blaschko Sarah D. , Breyer Benjamin N. , Amend Gregory M. , McKibben Maxim , Elliott Sean P. , Schwartz Ian W. , Simhan Jay , Vanni Alex J. , Moses Rachel A. , Myers Jeremy B.
Published: September 2022

BACKGROUND

Pelvic fracture urethral injury (PFUI) occurs in up to 10% of pelvic fractures. There is mixed evidence supporting early endoscopic urethral realignment (EUR) over suprapubic tube (SPT) placement and delayed urethroplasty. Some studies show decreased urethral obstruction with EUR, while others show few differences. We hypothesized that EUR would reduce the rate of urethral obstruction after PFUI.

METHODS

Twenty-six US medical centers contributed patients following either an EUR or SPT protocol from 2015 to 2020. If retrograde cystoscopic catheter placement failed, patients were included and underwent either EUR or SPT placement based on their institution's assigned treatment arm. Endoscopic urethral realignment involved simultaneous antegrade/retrograde cystoscopy to place a catheter across the urethral injury. The primary endpoint was development of urethral obstruction. Fisher's exact test was used to analyze the relationship between PFUI management and development of urethral obstruction.

RESULTS

There were 106 patients with PFUI; 69 (65%) had complete urethral disruption and failure of catheter placement with retrograde cystoscopy. Of the 69 patients, there were 37 (54%) and 32 (46%) in the EUR and SPT arms, respectively. Mean age was 37.0 years (SD, 16.3 years) years, and mean follow-up was 463 days (SD, 280 days) from injury. In the EUR arm, 36 patients (97%) developed urethral obstruction compared with 30 patients (94%) in the SPT arm (p = 0.471). Urethroplasty was performed in 31 (87%) and 29 patients (91%) in the EUR and SPT arms, respectively (p = 0.784).

CONCLUSION

In this prospective multi-institutional study of PFUI, EUR was not associated with a lower rate of urethral obstruction or need for urethroplasty when compared with SPT placement. Given the potential risk of EUR worsening injuries, clinicians should consider SPT placement as initial treatment for PFUI when simple retrograde cystoscopy is not successful in placement of a urethral catheter.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Incidence and Mortality of Emergency General Surgery Conditions Among Solid Organ Transplant Recipients in Ontario, Canada: A Population-based Analysis
Authors: Gomez David , Acuna Sergio A. , Joseph Kim S. , Nantais Jordan , Santiago Robin , Calzavara Andrew , Saskin Refik , Baxter Nancy N.
Published: September 2022

Background.

Emergency general surgery (EGS) conditions and their outcomes are perceived to be disproportionately high among solid organ transplant recipients (SOTRs). However, this has not been adequately investigated at a population level. We characterized the incidence and mortality of EGS conditions among SOTRs compared with nontransplant patients.

Methods.

Data were collected through linked administrative population-based databases in Ontario, Canada. We included all adult SOTRs (kidney, liver, heart, and lung) who underwent transplantation between 2002 and 2017. We then identified posttransplantation emergency department visits for EGS conditions (appendicitis, cholecystitis, choledocolithiasis, perforated diverticulitis, incarcerated/strangulated hernias, small bowel obstruction, and perforated peptic ulcer). Age-, sex-, and year-standardized incidence rate ratios (SIRRs) were generated. Logistic regression models were used to evaluate association between transplantation status and 30 d mortality after adjusting for demographics, year, and comorbidities.

Results.

Ten thousand seventy-three SOTRs and 12 608 135 persons were analyzed. SOTRs developed 881 EGS conditions (non-SOTRs: 552 194 events). The incidence of all EGS conditions among SOTR was significantly higher compared with the nontransplant patients [SIRR 3.56 (95% confidence interval [CI] 3.32-3.82)], even among those with high Aggregated Diagnosis Groups scores (>10) [SIRR 2.76 (95% CI 2.53-3.00)]. SOTRs were 1.4 times more likely to die at 30 d [adjusted odds ratio 1.44 (95% CI 1.08-1.91)] after an EGS event compared with nontransplant patients, predominantly amongst lung transplant recipients [adjusted odds ratio 3.28 (95% CI 1.72-6.24)].

Conclusions.

The incidence of EGS conditions is significantly higher in SOTRs even after stratifying by comorbidity burden. This is of particular importance as SOTRs also have a higher likelihood of death after an EGS condition, especially lung transplant recipients.
Lost in the Forest: Encoding Categorical Variables and the Absent Levels Problem
Authors: Smith Helen L. , Biggs Patrick J. , French Nigel P. , Smith Adam N.H. , Marshall Jonathan C.
Published: September 2022

Levels of a predictor variable that are absent when a classification tree is grown can not be subject to an explicit splitting rule. This is an issue if these absent levels then present in a new observation for prediction. To date, there remains no satisfactory solution for absent levels in random forest models. Unlike missing data, absent levels are fully observed and known. Ordinal encoding of predictors allows absent levels to be integrated and used for prediction. Using a case study on source attribution ofCampylobacterspecies using whole genome sequencing (WGS) data as predictors, we examine how target-agnosticversustarget-based encoding of predictor variables with absent levels affects the accuracy of random forest models. We show that a target-based encoding approach using class probabilities, with absent levels designated the highest rank, is systematically biased, and that this bias is resolved by encoding absent levels according to thea priorihypothesis of equal class probability. We present a novel method of ordinal encoding predictorsviaprincipal coordinates analysis (PCO) which capitalizes on the similarity between pairs of predictor levels. Absent levels are encoded according to their similarity to each of the other levels in the training data. We show that the PCO-encoding method performs at least as well as the target-based approach and is not biased.
Cells in the Polyaneuploid Cancer Cell (PACC) state have increased metastatic potential
Authors: Mallin Mikaela M. , Kim Nicholas , Choudhury Mohammad Ikbal , Lee Se Jong , An Steven S. , Sun Sean X. , Konstantopoulos Konstantinos , Pienta Kenneth J. , Amend Sarah R.
Published: September 2022

Although metastasis is the leading cause of cancer deaths, it is quite rare at the cellular level. Only a rare subset of cancer cells (∼1 in 1.5 billion) can complete the entire metastatic cascade: invasion, intravasation, survival in the circulation, extravasation, and colonization (i.e. are metastasis competent). We propose that cells engaging a Polyaneuploid Cancer Cell (PACC) phenotype are metastasis competent. PACCs are enlarged, non-dividing cells with increased genomic content that form in response to stress. Single-cell tracking using time-lapse microscopy reveals that PACCs are more motile than nonPACCs. Additionally, PACCs exhibit increased capacity for environment-sensing and directional migration in chemotactic environments, predicting successful invasion. Magnetic Twisting Cytometry and Atomic Force Microscopy reveal that cells in the PACC state display hyper-elastic properties like increased peripheral deformability and maintained peri-nuclear cortical integrity that predict successful intravasation and extravasation. Furthermore, four orthogonal methods reveal that PACCs have increased expression of Vimentin, a known hyper-elastic biomolecule. Lastly, anoikis-resistance assays and detection of PACCs in the blood of a patient with metastatic castrate-resistant prostate cancer using a selection- free circulating tumor cell detection platform reveal that PACCs are capable of surviving in the circulation. Taken together with the knowledge that PACCs are capable of eventual depolyploidization and progeny formation (as a potential route to colonization), these data support PACCs as candidate metastasis-competent cells worthy of further analysis.
A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer
Authors: Mayoh Chelsea , Gifford Andrew J , Terry Rachael , Lau Loretta MS , Wong Marie , Rao Padmashree , Shai-Hee Tyler , Saletta Federica , Khuong-Quang Dong-Anh , Qin Vicky , Mateos Marion , Meyran Deborah , Miller Katherine E , Yuksel Aysen , Mould Emily VA , Bowen-James Rachael , Govender Dinisha , Senapati Akanksha , Zhukova Nataliya , Omer Natacha , Dholaria Hetal , Alvaro Frank , Tapp Heather , Diamond Yonatan , Pozza Luciano Dalla , Moore Andrew S , Nicholls Wayne , Gottardo Nicholas G , McCowage Geoffrey , Hansford Jordan R , Khaw Seong-Lin , Wood Paul J , Catchpoole Daniel , Cottrell Catherine E , Mardis Elaine R , Marshall Glenn M , Tyrrell Vanessa , Haber Michelle , Ziegler David S , Vittorio Orazio , Trapani Joseph A , Cowley Mark J , Neeson Paul J , Ekert Paul G
Published: September 2022

Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. We combined immunohistochemistry (IHC) and molecular profiling to develop an alternative, expression-based signature associated with CD8+T-cell infiltration of the TIME in high-risk paediatric tumours. Using this novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.
Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer
Authors: Plattner Christina , Lamberti Giorgia , Blattmann Peter , Kirchmair Alexander , Rieder Dietmar , Loncova Zuzana , Sturm Gregor , Scheidl Stefan , Ijsselsteijn Marieke , Fotakis Georgios , Noureen Asma , Lisandrelli Rebecca , Böck Nina , Nemati Niloofar , Krogsdam Anne , Daum Sophia , Finotello Francesca , Somarakis Antonios , Schäfer Alexander , Wilflingseder Doris , Acera Miguel Gonzalez , Öfner Dietmar , Huber Lukas A. , Clevers Hans , Becker Christoph , Farin Henner F. , Greten Florian R. , Abersold Ruedi , da Cunha Carvalho de Miranda Noel Filipe , Trajanoski Zlatko
Published: September 2022

Background

Despite major advances in the development of targeted therapies, precision (immuno)oncology approaches for patients with colorectal cancer continue to lag behind other solid cancers. Functional precision oncology – a strategy that is based on perturbing primary tumor cells from cancer patients with drugs – could provide an alternate road forward to personalize treatment.

Methods

We extend here the functional precision oncology paradigm to measuring phosphoproteome landscapes using patient-derived organoids (PDOs). We first employed steady-state multi-omics (exome sequencing, RNA sequencing, and proteomics) and single-cell characterization of the PDOs. The PDOs were then perturbed with kinase inhibitors (MEKi, PI3Ki, mTORi, TBKi, BRAFi, and TAKi), and large-scale phosphoproteomics profiling using data-independent acquisition was carried out. Further, we used imaging mass-cytometry-based single-cell proteomic profiling of the primary tumors to characterize cellular composition of the tumor-microenvironment (TME) and to quantify heterocellular signaling crosstalk.

Results

We show that kinase inhibitors induce profound off-target effects resulting in a crosstalk with oncogenic and immune-related pathways. Reconstruction of the topologies of the kinase networks revealed that the patient-specific rewiring of the central EGFR-RAS-MAPK network is unaffected by mutations. Moreover, we show non-genetic heterogeneity of the PDOs and patient- and inhibitor-specific upregulation of stemness and differentiation genes by kinase inhibitors. We complemented our functional profiling by spatial proteomics profiling of the primary tumors using imaging mass cytometry. We quantify spatial heterocellular crosstalk and tumor-immune cell interactions, showing an avoidance of PD1+ immune cells and PD-L1+ tumor cells.

Conclusions

Collectively, we provide a multi-modal framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno)-oncology in colorectal cancer.
Microbiota-stimulated Interleukin-22 regulates brain neurons and protects against stress-induced anxiety
Authors: Ilanges Anoj , Xia Mengyu , Lu Junmei , Chen Lei , Shiao Rani , Wang Changchun , Jin Zheyu , Feng Ru , Qi Qingqing , Yi Han , Li Jixi , Schneeberger Marc , Lu Boxun , Friedman Jeffrey M. , Yu Xiaofei
Published: September 2022

Psychological stress and its sequelae are a major public health problem. While the immune system has been implicated in the development of stress-related disorders, how the immune signals modulate neural responses to stress is poorly understood. Contrary to our expectations, we found that the immune cytokine Interleukin (IL)-22 is the key mediator of an immune-to-brain pathway that diminishes, rather than amplifies, stress-induced anxiety. We showed that stress induced TH17 differentiation and IL-22 production in the intestine following barrier dysfunction and microbiota stimulation. IL-22 then directly signaled to septal neurons in the brain to mitigate anxiety-like behavior. Accordingly, mice treated with exogenous IL-22 showed resilience to chronic stress-induced anxiety disorders. Our study thus reveals a previously-unappreciated immune-to-brain axis that defends against psychological stress, suggesting a potential intervention strategy for stress-related mental diseases.
Analysis of somatic mutations in senescent cells using single-cell whole-genome sequencing
Authors: Zhang Lei , De Cecco Marco , Lee Moonsook , Hao Xiaoxiao , Maslov Alexander Y. , Montagna Cristina , Campisi Judith , Dong Xiao , Sedivy John M. , Vijg Jan
Published: September 2022

Summary

Somatic mutations accumulate in multiple organs and tissues during aging and are a known cause of cancer. Here we tested whether mutations accumulate during replicative senescence. Cellular senescence is also a possible cause of functional decline in aging, yet also acts as an anti-cancer mechanism in vivo. Using single-cell whole-genome sequencing, we compared mutation burdens between early passage and deeply senescent human fibroblasts. The results showed that single-nucleotide variations and small insertions and deletions increased in senescent cells by about two-fold, but have the same spectrum as early passage cells, while it has been known that particular mutational signatures are found in tumor cells. In contrast, aneuploidies were observed in half the senescent cells, but largely absent in early passage cells. Thus, the patterns of mutations among senescent, normal-aged and tumor cells differ significantly.
DRDs and Brain Derived Neurotrophic Factor share a common therapeutic ground: A novel bioinformatic approach sheds new light towards pharmacological treatment of Cognitive and Behavioral Disorders
Authors: Papageorgiou Louis , Kalospyrou Efstathia , Papakonstantinou Eleni , Diakou Io , Pierouli Katerina , Dragoumani Konstantina , Bacopoulou Flora , Chrousos George P , Exarchos Themis P , Vlamos Panagiotis , Eliopoulos Elias , Vlachakis Dimitrios
Published: September 2022

Cognitive and behavioral disorders are subgroups of mental health disorders. Both cognitive and behavioral disorders can occur in people of different ages, genders, and social backgrounds and they can cause serious physical, mental or social problems. The risk factors for these diseases are numerous, with a range from genetic and epigenetic factors to physical factors. In most cases, the appearance of such a disorder in an individual is a combination of his genetic profile and environmental stimuli. To date, researchers have not been able to identify the specific causes of these disorders and as such, there is urgent need for innovative study approaches. The aim of the present study was to identify the genetic factors which seem to be more directly responsible for the occurrence of a cognitive and/or behavioral disorder. More specifically, through bioinformatics tools and software as well as analytical methods such as systemic data and text mining, semantic analysis, and scoring functions, we extracted the most relevant single nucleotide polymorphisms (SNPs) and genes connected to these disorders. All the extracted SNPs were filtered, annotated, classified, and evaluated in order to create the “genomic grammar” of these diseases. The identified SNPs guided the search for top suspected genetic factors, dopamine receptors D and Neurotrophic Factor BDNF, for which regulatory networks were built. The identification of the “genomic grammar” and underlying factors connected to cognitive and behavioral disorders can aid the successful disease profiling, the establishment of novel pharmacological targets and provide the basis for personalized medicine, which takes into account the patient’s genetic background as well as epigenetic factors.
The time to initiate retrieval of a memory depends on recency
Authors: Bright Ian M. , Singh Inder , DiDomenica Rebecca , Oliva Aude , Howard Marc W.
Published: September 2022

Continuous recognition has long been used to study the recency effect in recognition memory. In continuous recognition, response time (RT) increases as a logarithmic function of the lag since a probe was last presented. Although this could simply be due to decaying trace strength, careful examination of response time (RT) distributions showed that the onset of RT distributions changed with the logarithm of the lag since a probe was originally presented. Each doubling of lag resulted in a shift of roughly 20 ms in the rise time of the RT distributions. To test the hypothesis that this increase was simply due to increased facility in processing the probe item, Experiment six repeated items six times. Repetition resulted in faster RTs, but did not change the effect of log lag on RT. In light of recent neurophysio-logical evidence, we consider the hypothesis that memory requires a recovery of temporal context, and the time to retrieve a prior temporal context goes up with the logarithm of the time since it was experienced.
Towards In-Silico CLIP-seq: Predicting Protein-RNA Interaction via Sequence-to-Signal Learning
Authors: Horlacher Marc , Wagner Nils , Moyon Lambert , Kuret Klara , Goedert Nicolas , Salvatore Marco , Ule Jernej , Gagneur Julien , Winther Ole , Marsico Annalisa
Published: September 2022

Abstract

Unraveling sequence determinants which drive protein-RNA interaction is crucial for studying binding mechanisms and the impact of genomic variants. While CLIP-seq allows for transcriptome-wide profiling ofin vivoprotein-RNA interactions, it is limited to expressed transcripts, requiring computational imputation of missing binding information. Existing classification-based methods predict binding with low resolution and depend on prior labeling of transcriptome regions for training. We present RBPNet, a novel deep learning method, which predicts CLIP crosslink count distribution from RNA sequence at single-nucleotide resolution. By training on up to a million regions, RBPNet achieves high generalization on eCLIP, iCLIP and miCLIP assays, outperforming state-of-the-art classifiers. CLIP-seq suffers from various technical biases, complicating downstream interpretation. RBPNet performs bias correction by modeling the raw signal as a mixture of the protein-specific and background signal. Through model interrogation via Integrated Gradients, RBPNet identifies predictive sub-sequences corresponding to known binding motifs and enables variant-impact scoring via in silico mutagenesis. Together, RBPNet improves inference of protein-RNA interaction, as well as mechanistic interpretation of predictions.
Physiological constraints on the rapid dopaminergic modulation of striatal reward activity
Authors: Long Charltien , Lee Kwang , Yang Long , Dafalias Theresia , Wu Alexander K. , Masmanidis Sotiris C.
Published: September 2022

While the contribution of dopaminergic (DA) neurons to associative learning is firmly established, their importance for influencing imminent behavior on short (subsecond) timescales is less clear. Mechanistically, it is thought that DA neurons drive these behavioral changes because of their ability to rapidly alter striatal spiking activity. However, due to limitations of previous approaches, the straightforward prediction that striatal spiking is rapidly influenced by physiologically relevant DA signals has not been rigorously tested. Here, we monitored changes in spiking responses in the ventral striatum while transiently reducing or increasing DA levels. Contrary to the predicted effect, neither spontaneous nor reward-evoked striatal spiking activity was strongly influenced by optogenetic manipulations, except when DA exceeded reward-matched levels. These findings challenge the view that DA plays a major role in rapidly influencing striatal activity. Finally, they suggest a need to distinguish between the modulatory functions of DA under physiological and supra-physiological conditions.
Acute stress impairs target enhancement but not distractor suppression in attention selection: Evidence from the N2pc and Pd
Authors: Luo Yu , Nian Jingqing , Yang Run , Xie Jiao , Zhang Yu
Published: September 2022

Acute stress has a profound impact on attention selection. However, the cognitive mechanism of acute stress on attention selection for neutral stimuli remains unclear. The current study aimed to investigate how acute stress affects target enhancement and distractor suppression in attention selection using a visual search task while EEG was recorded. The Maastricht Acute Stress Test was successfully induced a stress response in the stress group, as indexed by the higher salivary cortisol, state anxiety, and negative emotion. Crucially, the stress group showed significantly smaller N2pc than the control group in the lateral target/midline and contralateral distractor conditions when the distractor salience was high, whereas no significant differences in the Pd were observed in the lateral distractor/midline target condition. These results suggest that acute stress impairs target enhancement rather than distractor suppression in attention selection. This impairment may be due to the impaired function of the prefrontal cortex under acute stress. The present research provides the first insight into the cognitive mechanism of acute stress on attention selection.
Proteogenomic analysis reveals RNA as an important source for tumor-agnostic neoantigen identification correlating with T-cell infiltration
Authors: Tretter Celina , de Andrade Krätzig Niklas , Pecoraro Matteo , Lange Sebastian , Seifert Philipp , von Frankenberg Clara , Untch Johannes , Dreyer Florian S , Bräunlein Eva , Wilhelm Mathias , Zolg Daniel P , Engleitner Thomas , Uhrig Sebastian , Boxberg Melanie , Steiger Katja , Slotta-Huspenina Julia , Ochsenreither Sebastian , von Bubnoff Nikolas , Bauer Sebastian , Boerries Melanie , Jost Philipp J , Schenck Kristina , Dresing Iska , Bassermann Florian , Friess Helmut , Reim Daniel , Grützmann Konrad , Pfütze Katrin , Klink Barbara , Schrock Evelin , Haller Bernhard , Kuster Bernhard , Mann Matthias , Weichert Wilko , Fröhling Stefan , Rad Roland , Hiltensperger Michael , Krackhardt Angela M
Published: September 2022

Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types by combining proteogenomics with phenotypic and functional analyses. By using an optimized computational approach, we discovered a large number of novel tumor-specific and tumor-associated antigens including shared common target candidates. To create a pipeline for the identification of neoantigens in our cohort, we combined deep DNA and RNA sequencing with MS- based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity. In fact, we could detect a broad variety of non-wild type HLA-binding peptides in the majority of patients and confirmed the immunogenicity of 24 neoantigens. Most interestingly, the majority of total and immunogenic neoantigens originated from variants identified in the RNA dataset, illustrating the importance of RNA as a still understudied source of cancer antigens. Moreover, the amount of these mainly RNA-based immunogenic neoantigens correlated positively with overall CD8+ tumor-infiltrating T cells. This study therefore underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.

Statement of significance

The significance of this study lies not only in the potential of our optimized proteogenomic workflow for the discovery of neoantigens (in particular RNA-derived neoantigens) for clinical application, but sheds light on the entity-agnostic prevalence of HLA class I peptide presentation of RNA processing events to be used for tumor targeting.
Cascades of neuronal plasticity in the macaque visual cortex
Authors: Koyano Kenji W. , Esch Elena M. , Hong Julie J. , Waidmann Elena N. , Leopold David A.
Published: September 2022

Primates readily learn new visual objects, with neurons in the inferior temporal cortex exhibiting diminished visual responses to familiar stimuli. The mechanisms of visual plasticity expressed within a neural population are largely unknown. Here we used chronic microwire electrodes in a face-selective cortical area in the macaque to longitudinally track cohorts of neurons across several weeks of exposure to novel faces. Neurons showed gradual adaptation in their late-phase visual responses, with cell-specific time constants ranging from two to twenty days. These time constants were governed by the number of testing days rather than by the cumulative number of stimulus exposures. This gradual buildup of altered visual responses may serve as an internal and graded mark of stimulus familiarity, a central component of visual recognition.
Rigidified Scaffolds for 3 Angstrom Resolution Cryo-EM of Small Therapeutic Protein Targets
Authors: Castells-Graells Roger , Meador Kyle , Arbing Mark A. , Sawaya Michael R. , Gee Morgan , Cascio Duilio , Gleave Emma , Debreczeni Judit É. , Breed Jason , Phillips Chris , Yeates Todd O.
Published: September 2022

Numerous technical advances have made cryo-EM an attractive method for atomic structure determination. Cryo-EM is ideally suited for large macromolecular structures, while problems of low signal-to-noise prevent routine structure determination of proteins smaller than about 50 kDa. This size limitation excludes large numbers of important cellular proteins from structural characterization by this powerful technique, including many cell-signaling proteins of high therapeutic interest. In the present work, we use molecular engineering techniques to rigidify an imaging scaffold, based on a designed protein cage, to the point where 3 Å resolution can be achieved, even for very small proteins. After optimizing the design of the rigidified scaffold on test proteins, we apply this imaging system to the key oncogenic signaling protein KRAS, which represents an outstanding challenge in the area of structure-based drug design. Despite its 19 kDa size, we show that the structure of KRAS, in multiple mutant forms, and bound to its GDP ligand, can be readily interpreted at a resolution slightly better than 3.0 Å. This advance further expands the capability of cryo-EM to become an essentially universal method for protein structure determination, including for applications to small therapeutic protein targets.
Staphylococcus aureus virulence factor expression matters: input from targeted proteomics shows Panton-Valentine leucocidin impact on mortality
Authors: Pivard Mariane , Bastien Sylvere , Macavei Iulia , Mouton Nicolas , Rasigade Jean-Philippe , Couzon Florence , Carrière Romain , Moreau Karen , Lemoine Jérôme , Vandenesch Francois
Published: September 2022

In the case of commensal bacteria such as Staphylococcus aureus, the transition from commensalism to invasion and disease as well as disease severity in the course of an infection remain poorly predictable on the sole basis of virulence gene content. To determine whether variations in the levels of expression of the numerous S. aureus virulence factors could affect disease occurrence and/or severity, we developed a targeted proteomic approach that monitored 149 peptide surrogates targeting 44 proteins. Semi-quantification was achieved by normalization on the signal of ribosomal proteins. We then evaluated this approach on a series of S.aureus strains from 136 patients presenting a severe community-acquired pneumonia, all admitted to an intensive care unit. After adjusting to the Charlson Comorbidity Index score the multivariate analysis of severity parameters found that HlgB, Nuc, and Tsst-1 were positively associated while BlaI and HlgC were negatively associated with leucopenia. BlaZ and HlgB were positively associated with hemoptysis and HlgC was negatively associated with hemoptysis. Regarding mortality, both the multivariate (1.28; 95%CI[1.02;1.60]) and survival (1.15; 95%CI[1.016;1.302]) analyses showed that only PVL was associated with death in a dose-dependent manner. Beyond highlighting the decisive role of PVL in community-acquired pneumonia severity, this study brings the proof of concept that “expression matters” and proposes a method that can be routinely implemented in laboratories, for any Staphylococcal disease, and which could be developed for other commensal bacteria.

One Sentence Summary

A highly multiplexed semi-quantitative mass spectrometry method was developed for 44 Staphylococcus aureus virulence factors; applied to a 136-strain collection from severe community-acquired pneumonia patients, it showed that Panton-Valentine leucocidin was the only factor to impact mortality in a dose-dependent manner.