bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood pressure response during treadmill exercise testing and the risk for future cardiovascular events and new-onset hypertension
Authors: Zafrir Barak , Aker Amir , Asaf Yosi , Saliba Walid 
Published: August 2021

Objective:
The physiologic response to exercise may provide valuable prognostic information. We investigated the association of blood pressure (BP) measurements during exercise stress testing (EST) with long-term risk of myocardial infarction, stroke or death (major adverse cardiovascular event, MACE), as well as the development of new-onset hypertension.

Methods:
A retrospective analysis of treadmill ESTs (years 2005–2019) performed by the Bruce protocol in patients aged 35–75 years without a history of cardiovascular disease (n = 14 792; 48% women). BP was documented at rest, submaximal exercise (Bruce stage-2), peak exercise and recovery (2 min). Association of SBP measures with study outcomes during median follow-up of 6.5 years was investigated.

Results:
Highest vs. lowest SBP quartile at rest (≥140 vs. <120 mmHg), submaximal-exercise (≥170 vs. <130 mmHg), peak-exercise (≥180 vs. ≤145 mmHg) and recovery (≥160 vs. <130 mmHg) was associated with an increase in the adjusted hazard ratio and 95% confidence interval (CI) for MACE: 1.53 (1.23–1.88), 1.33 (1.01–1.76), 1.30 (1.05–1.61), 1.35 (1.09–1.68), respectively. The association between SBP at submaximal exercise and recovery with MACE displayed a J-shaped pattern. Among nonhypertensive patients (n = 8529), excessive SBP response to peak exercise (≥190 mmHg in women and ≥210 mmHg in men) was an independent predictor of hypertension [hazard ratio (95% CI)]: 1.87 (1.41–2.48), as were SBPs during submaximal exercise [>160 vs. ≤130 mmHg: 2.44 (1.97–3.03)] and recovery [≥140 vs. ≤120 mmHg: 1.65 (1.37–1.98)].

Conclusion:
BP measurement during rest, exercise and recovery phases of EST provides incremental prognostic information regarding long-term risk for cardiovascular events and the probability for developing hypertension.
Lens Opacities Classification System III–based artificial intelligence program for automatic cataract grading
Authors: Lu Qiang , Wei Ling , He Wenwen , Zhang Keke , Wang Jinrui , Zhang Yinglei , Rong Xianfang , Zhao Zhennan , Cai Lei , He Xixi , Wu Jun , Ding Dayong , Lu Yi , Zhu Xiangjia 
Published: August 2021

Purpose:
To establish and validate an artificial intelligence (AI)-assisted automatic cataract grading program based on the Lens Opacities Classification System III (LOCS III).

Setting:
Eye and Ear, Nose, and Throat Hospital, Fudan University, Shanghai, China.

Design:
AI training.

Methods:
Advanced deep-learning algorithms, including Faster R-CNN and ResNet, were applied to the localization and analysis of the region of interest. An internal dataset from the EENT Hospital of Fudan University and an external dataset from the Pujiang Eye Study were used for AI training, validation, and testing. The datasets were automatically labeled on the AI platform regarding the capture mode and cataract grading based on the LOCS III.

Results:
The AI program showed reliable capture mode recognition, grading, and referral capability for nuclear and cortical cataract grading. In the internal and external datasets, 99.4% and 100% of automatic nuclear grading, respectively, had an absolute prediction error of ≤1.0, with a satisfactory referral capability (area under the curve [AUC]: 0.983 for the internal dataset; 0.977 for the external dataset); 75.0% (internal dataset) and 93.5% (external dataset) of the automatic cortical grades had an absolute prediction error of ≤1.0, with AUCs of 0.855 and 0.795 for referral, respectively. Good consistency was observed between automatic and manual grading when both nuclear and cortical cataracts were evaluated. However, automatic grading of posterior subcapsular cataracts was impractical.

Conclusions:
The AI program proposed in this study showed robust grading and diagnostic performance for both nuclear and cortical cataracts, based on LOCS III.
Validating a biosignature-predicting placebo pill response in chronic pain in the settings of a randomized controlled trial
Authors: Vachon-Presseau Etienne , Abdullah Taha B. , Berger Sara E. , Huang Lejian , Griffith James W. , Schnitzer Thomas J. , Apkarian A. Vania 
Published: August 2021

Abstract
The objective of this study is to validate a placebo pill response predictive model—a biosignature—that classifies chronic pain patients into placebo responders (predicted-PTxResp) and nonresponders (predicted-PTxNonR) and test whether it can dissociate placebo and active treatment responses. The model, based on psychological and brain functional connectivity, was derived in our previous study and blindly applied to current trial participants. Ninety-four chronic low back pain (CLBP) patients were classified into predicted-PTxResp or predicted-PTxNonR and randomized into no treatment, placebo treatment, or naproxen treatment. To monitor analgesia, back pain intensity was collected twice a day: 3 weeks baseline, 6 weeks of treatment, and 3 weeks of washout. Eighty-nine CLBP patients were included in the intent-to-treat analyses and 77 CLBP patients in the per-protocol analyses. Both analyses showed similar results. At the group level, the predictive model performed remarkably well, dissociating the separate effect sizes of pure placebo response and pure active treatment response and demonstrating that these effects interacted additively. Pain relief was about 15% stronger in the predicted-PTxResp compared with the predicted-PTxNonR receiving either placebo or naproxen, and the predicted-PTxNonR successfully isolated the active drug effect. At a single subject level, the biosignature better predicted placebo nonresponders, with poor accuracy. One component of the biosignature (dorsolateral prefrontal cortex–precentral gyrus functional connectivity) could be generalized across 3 placebo studies and in 2 different cohorts—CLBP and osteoarthritis pain patients. This study shows that a biosignature can predict placebo response at a group level in the setting of a randomized controlled trial.
Remote physical examination for temporomandibular disorders
Authors: Exposto Fernando G. , Castrillon Eduardo E. , Exposto Cristina R. , Costa Dyna Mara F. , Gøkhan Muhammed A. , Svensson Peter , Costa Yuri M. 
Published: August 2021

Abstract
There is a need to further develop telemedicine approaches because of the immediate and perhaps long-term consequences of the coronavirus disease 2019. Thus, a remote protocol for assessment of patients with temporomandibular disorders (TMD) was developed, and the agreement of this protocol was compared with the guidelines of the Diagnostic Criteria for TMD (DC/TMD). A total of 16 individuals were first assessed by a reference standard examination (RSE) and 3 other examinations applied in a random order by 3 examiners: standard physical examination (standard examination), physical examination keeping 2-m distance (physical distanced examination), and examination conducted with the aid of video communication technology (video communication examination). The primary outcomes were the diagnoses of myalgia of the masseter and temporalis muscles and arthralgia. The diagnoses of intra-articular joint disorders were considered secondary outcomes because of a less impact on psychosocial functioning and quality of life when compared with the pain-related diagnoses. The Fleiss kappa coefficient and its 95% confidence interval were computed to determine the level of agreement in diagnoses between each examination protocol and the RSE. There was substantial to almost perfect agreement between the RSE and all the examination protocols for the diagnoses of myalgia (0.86-1.00) and arthralgia (0.74-0.87) (P < 0.001). On the other hand, there was an overall poor agreement (0.30-0.58) between the RSE and all the protocols for the diagnosis of disk displacement with reduction. Remote assessment of patients with pain-related TMD is feasible and presents a high degree of accuracy.
Nerve injury induces transient locus coeruleus activation over time: role of the locus coeruleus–dorsal reticular nucleus pathway
Authors: Camarena-Delgado Carmen , Llorca-Torralba Meritxell , Suárez-Pereira Irene , Bravo Lidia , López‐Martín Carolina , Garcia-Partida Jose A. , Mico Juan A. , Berrocoso Esther 
Published: August 2021

Abstract
The transition from acute to chronic pain results in maladaptive brain remodeling, as characterized by sensorial hypersensitivity and the ensuing appearance of emotional disorders. Using the chronic constriction injury of the sciatic nerve as a model of neuropathic pain in male Sprague–Dawley rats, we identified time-dependent plasticity of locus coeruleus (LC) neurons related to the site of injury, ipsilateral (LCipsi) or contralateral (LCcontra) to the lesion, hypothesizing that the LC→dorsal reticular nucleus (DRt) pathway is involved in the pathological nociception associated with chronic pain. LCipsi inactivation with lidocaine increased cold allodynia 2 days after nerve injury but not later. However, similar blockade of LCcontra reduced cold allodynia 7 and 30 days after inducing neuropathy but not earlier. Furthermore, lidocaine blockade of the LCipsi or LCcontra reversed pain-induced depression 30 days after neuropathy. Long-term pain enhances phosphorylated cAMP-response element binding protein expression in the DRtcontra but not in the DRtipsi. Moreover, inactivation of the LCcontra→DRtcontra pathway using dual viral-mediated gene transfer of designer receptor exclusively activated by designer drugs produced consistent analgesia in evoked and spontaneous pain 30 days postinjury. This analgesia was similar to that produced by spinal activation of α2-adrenoreceptors. Furthermore, chemogenetic inactivation of the LCcontra→DRtcontra pathway induced depressive-like behaviour in naïve animals, but it did not modify long-term pain-induced depression. Overall, nerve damage activates the LCipsi, which temporally dampens the neuropathic phenotype. However, the ensuing activation of a LCcontra→DRtcontra facilitatory pain projection contributes to chronic pain, whereas global bilateral LC activation contributes to associated depressive-like phenotype.
Potential Clinical Utility of a Targeted Circulating Tumor DNA Assay in Esophageal Adenocarcinoma
Authors: Cabalag Carlos S. , Yates Michael , Corrales Mariana Benitez , Yeh Paul , Wong Stephen Q. , Zhang Bonnie Z. , Fujihara Kenji M. , Chong Lynn , Hii Michael W. , Dawson Sarah-Jane , Phillips Wayne A. , Duong Cuong P. , Clemons Nicholas J. 
Published: August 2021

Objective:
To explore the clinical utility of circulating tumor DNA (ctDNA) in esophageal adenocarcinoma (EAC) by developing a cost-effective and rapid technique utilising targeted amplicon sequencing.

Summary of background data:
Emerging evidence suggests that levels of ctDNA in the blood can be used to monitor treatment response and in the detection of disease recurrence in various cancer types. Current staging modalities for EAC such as computerised tomography of the chest/abdomen/pelvis (CT) and positron emission tomography (PET) do not reliably detect occult micro-metastatic disease, the presence of which signifies a poor prognosis. After curative-intent treatment, some patients are still at high risk of recurrent disease, and there is no widely accepted optimal surveillance tool for patients with EAC.

Methods:
Sixty-two patients with EAC were investigated for the presence of ctDNA using a tumor-informed approach. We designed a custom targeted amplicon sequencing panel of target specific primers covering mutational foci in 9 of the most commonly mutated genes in EAC. Serial blood samples were taken before and after neoadjuvant treatment (NAT), and during surveillance.

Results:
Somatic mutations were detected in pre-treatment biopsy samples of 55 out of 62 (89%) EAC patients. Mutations in TP53 (80%) were the most common. Out of these 55 patients, 20 (36%) had detectable ctDNA at baseline. The majority (90%) of patients with detectable ctDNA had either locally advanced tumors, nodal involvement or metastatic disease. In patients with locally advanced tumors, disease free survival (DFS) was more accurately stratified using pre-treatment ctDNA status [HR 4.34 (95% CI 0.93–20.21); P = 0.05] compared to nodal status on PET-CT. In an exploratory subgroup analysis, patients who are node negative but ctDNA positive have inferior DFS [HR 11.71 (95% CI 1.16-118.80) P = 0.04]. In blood samples taken before and following NAT, clearance of ctDNA after NAT was associated with a favourable response to treatment. Furthermore, patients who are ctDNA positive during post-treatment surveillance are at high risk of relapse.

Conclusions:
Our study shows that ctDNA has potential to provide additional prognostication over conventional staging investigation such as CT and PET. It may also have clinical utility in the assessment of response to NAT and as a biomarker for the surveillance of recurrent disease.
American Society of Anesthesiologists-Physical Status Classification As An Independent Risk Factor of Surgical Site Infection After Infra-Inguinal Arterial Bypass
Authors: Tresson Philippe , Quiquandon Samuel , Rivoire Emeraude , Boibieux André , Vanhems Philippe , Bordet Marine , Long Anne 
Published: August 2021

Objectives:
The present study aimed to assess whether high-risk American Society of Anesthesiologists (ASA)-Physical Status was an independent risk factor for the development of surgical site infection (SSI) after infra-inguinal lower extremity bypass (LEB).

Summary of Background Data:
The ASA-Physical Status Classification System assesses the overall physical status preoperatively. ASA-Physical Status is associated with postoperative morbidity and mortality. However, limited data are available on how ASA-Physical Status Class affects the development of SSI after infra-inguinal LEB.

Methods:
Patients who had undergone infra-inguinal LEB from January 1, 2015 to December 31, 2018, for obliterative arteriopathy or popliteal aneurysm at our university hospital were included. SSI risk factors were identified using multivariable logistic regression. The length of hospital stay, major limb events (MALE), major adverse cardiovascular events (MACE), and all-cause mortality were compared for patients with SSI versus those without SSI 3 months and 1- year of follow-up after the index surgery.

Results:
Among the 267 patients included, 30 (11.2%) developed SSI during the 3-month period and 32 (12%) at 1 year. ASA-Physical Status ≥3 [odds ratio (OR): 3.7, 95% confidence interval CI) 1.5–11.1], emergency surgery (OR: 2.7, 95% CI 1.2–6.0), general anesthesia (OR: 2.8, 95% CI 1.3–6.1), and procedure performed by a junior surgeon (OR: 2.7, 95% CI 1.3–6.0) were independently associated with SSI. At 3 months and 1 year, SSI was significantly associated with MALE (including surgical wound debridement, subsequent thrombectomy, major amputation), length of hospital stay, and all-cause mortality.

Conclusion:
The ASA-Physical Status should be considered in medical management when an infra-inguinal LEB is considered in frail patients, to prevent surgical complications.
Prognosis Associated With CA19-9 Response Dynamics and Normalization During Neoadjuvant Therapy in Resected Pancreatic Adenocarcinoma
Authors: Newhook Timothy E. , Vreeland Timothy J. , Griffin James F. , Tidwell Rebecca S. S. , Prakash Laura R. , Koay Eugene J. , Ludmir Ethan B. , Smaglo Brandon G. , Pant Shubham , Overman Michael , Wolff Robert A. , Ikoma Naruhiko , Maxwell Jessica , Kim Michael P. , Lee Jeffrey E. , Katz Matthew H. G. , Tzeng Ching-Wei D. 
Published: August 2021

Objective:
To characterize associations between carbohydrate antigen 19–9 (CA19–9) dynamics during neoadjuvant therapy (NT) and survival for patients with pancreatic ductal adenocarcinoma (PDAC).

Background:
Although normalization of CA19–9 during NT is associated with improved outcomes following PDAC resection, we hypothesize that CA19–9 dynamics during NT can improve prognostication.

Methods:
Characteristics for patients with PDAC undergoing NT (July 2011–October 2018) with ≥3 CA19–9 results (bilirubin<2mg/dL) were collected and grouped by CA19–9 dynamics. Nonproducers (<1 U/ml) were excluded, and normal was ≤35 U/ml. Postresection survival was compared among groups.

Results:
Of 431 patients, 166 had eligible CA19–9 values. Median baseline CA19–9 was 98 U/ml. Overall 2-year postresection recurrence-free survival (RFS) and overall survival (OS) were 37% and 63%, respectively. Patients with normalization (53%) had improved 2-year RFS (47% vs. 28%, P = 0.01) and OS (75% vs. 49%, P = 0.01). CA19–9 dynamics during NT were analyzed by shape, direction, and normalization creating response types (“A-B-C-D-E”). Type A was “Always” decreasing to normalization, B “Bidirectional” with eventual normalization, C “Consistently” normal, D any “Decrease” without normalization, and E “Elevating” without normalization. Types A and B responses were associated with the longest postresection 2-year RFS (51% and 56%) and OS (75% and 92%, respectively) whereas Types D and E had the worst outcomes. After adjusting for node-positivity, perineural invasion, and margin-positivity, CA19–9 response types were independently associated with both RFS and OS, and predicted outcomes are better than CA19–9 normalization alone (likelihood ratio test RFS P < 0.001, OS P = 0.01).

Conclusions:
This novel A-B-C-D-E classification of CA19–9 dynamics during NT was associated with postresection outcomes more precisely than CA19–9 normalization alone.
Retrospective mortality and prevalence of SARS-CoV-2 antibodies in greater Omdurman, Sudan: a population–based cross–sectional survey
Authors: Moser Wendelin , Fahal Mohammed Ahmed Hassan , Abualas Elamin , Bedri Shahinaz , Elsir Mahgoub Taj , Mohamed Mona Fateh El Rahman Omer , Mahmoud Abdelhalim Babiker , Ahmad Amna Ismail Ibrahim , Adam Mohammed A. , Altalib Sami , DafaAllah Ola Adil , Hmed Salahaldin Abdallah , Azman Andrew S. , Ciglenecki Iza , Gignoux Etienne , González Alan , Mwongera Christine , Albela Manuel 
Published: August 2021

SummaryBackgroundEven after adjusting for the expected lower severity due to the younger age of the population, relatively low SARS-CoV-2 incidence and mortality rates have been reported throughout Africa. For investigating whether this is truly the case, we conducted a survey to estimate the COVID-19 related mortality and cumulative incidence of SARS-CoV-2 infections in Omdurman the most populated city of the tripartite metropolis Khartoum in Sudan.MethodsA retrospective, cross–sectional, mortality and seroprevalence survey was conducted in Omdurman, Sudan, from March 1, until April 10 2021. A two–stage cluster sampling method was used to investigate the death rate for the pre–pandemic (January 1, 2019–February 29, 2020) and pandemic (March 1, 2020 – day of the survey) period using questionnaires. The seroprevalence survey was performed in a subset of households and all consenting members were tested with a rapid serological test (SD–Biosensor) and a subgroup additionally with ELISA (EUROIMMUN). Fisher’s exact test was used to assess differences between the pre–and pandemic periods and a random effect and Bayesian latent class model to adjust for test performance.FindingsData from 27315 people (3716 households) for the entire recall period showed a 67% (95% CI 32–110) increase in death rate between the pre–pandemic (0.12 deaths/10000 people/day [95% CI 0.10–0.14]) and pandemic (0.20 [0.16–0.23]) periods. Notably, a 74% (30–133) increase in death was observed among people aged ≥50 years. The adjusted seroprevalence of SARS-CoV-2 was 54.6% (95% CI 51.4–57.8). The seroprevalence was significantly associated with age, increasing up to 80.7% (71.7–89.7) for the oldest age group (≥50 years).InterpretationOur results showed a significant elevated mortality for the pandemic period with a considerable excess mortality in Omdurman, Sudan. The overall high seroprevalence indicated a different age pattern compared to other countries, with a significant increase by age.FundingMedécins Sans Frontières
Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at ER monitoring and regulating fatty acids
Authors: Han Song-iee , Nakakuki Masanori , Nakagawa Yoshimi , Wang Yunong , Araki Masaya , Yamamoto Yuta , Tokiwa Hiroaki , Takeda Hiroyuki , Mizunoe Yuhei , Motomura Kaori , Ohno Hiroshi , Murayama Yuki , Aita Yuichi , Takeuchi Yoshinori , Osaki Yoshinori , Miyamoto Takafumi , Sekiya Motohiro , Matsuzaka Takashi , Yahagi Naoya , Sone Hirohito , Kawano Hiroyuki , Shimano Hitoshi 
Published: August 2021

SummaryThe ER-embedded transcription factors, sterol-regulatory element-binding proteins (SREBPs), master regulators of lipid biosynthesis, are transported to Golgi for proteolytic activation to tune cellular cholesterol levels and regulate lipogenesis. However, mechanisms by which the cell responds to the levels of saturated or unsaturated fatty acids remain underexplored. Here we show that RHBDL4/RHBDD1, a rhomboid family protease, directly cleaves SREBP-1c at ER. The p97/VCP, AAA-ATPase complex then acts as an auxiliary segregase to extract the remaining ER-embedded fragment of SREBP-1c. Importantly, the enzymatic activity of RHBDL4 is enhanced by saturated fatty acids (SFAs), but inhibited by polyunsaturated fatty acids (PUFAs). Genetic deletion of RHBDL4 in mice fed on a Western diet enriched in SFAs and cholesterol prevented SREBP-1c from inducing genes for lipogenesis, particularly for synthesis and incorporation of PUFAs, and secretion of lipoproteins. The RHBDL4–SREBP-1c pathway reveals a regulatory system for monitoring fatty acid composition and maintaining cellular lipid homeostasis.Graphical Abstract
Enhanced circularity in aftermarkets: logistics tradeoffs
Authors: Gatenholm Gabriella , Halldórsson Árni , Bäckstrand Jenny 
Published: August 2021

PurposeThe purpose of this paper is to identify requirements and tradeoffs on logistics services for enhanced circularity of materials and resources.Design/methodology/approachBased on multiple case study design and abductive reasoning, the study investigates 13 different product categories. The data were analyzed based on theoretical,a prioricodes from the literature review. Inductive, emerging codes were added to the coding scheme during the analysis.FindingsRequirements of logistics services to support slowing of resource flows are categorized with respect to initiator, location of the service, single or multiple actors, and transportation of parts, products and people. Moreover, the study identifies new logistics tradeoffs: material and people, knowledge and people, and information and knowledge. Transportation of product, people and parts can be reduced by increasing local knowledge and improve information sharing.Research limitations/implicationsThis review contributes to the understanding of the relationship between logistics services and enhancement of circularity by highlighting requirements on logistics services in the aftermarket supply chain that support slowing of resource flows. To enhance circularity, logistics services must extend the traditional material information flow with the flow of people and knowledge, respectively.Practical implicationsThe categorization provides practitioners and researchers with an overview of requirements and tradeoffs on logistics services to enhance circularity of a particular circular cycle. The implications will provide an opportunity to address environmental impact of transportation and improve the utilization of scarce materials.Social implicationsVariety of tradeoffs in logistics services can enhance slowing and hence circularity of scarce materials.Originality/valueFirst, the authors illustrate how traditional tradeoffs in logistics such as flow of materials, resources and people need to be addressed to enhance circularity through slowing. Second, the authors identify two new tradeoffs in logistics services: knowledge flow and degree of customer involvement.