bluuebunny/crossref_metadata_2025 huggingface dataset:
IDO, TDO, and AHR overexpression is associated with poor outcome in diffuse large B-cell lymphoma patients in the rituximab era
Authors: Chen Xiangli , Zang Yuzhu , Li Dujuan , Guo Jianmin , Wang Yacai , Lin Yuqi , Wei Zhenghong
Published: May 2020

Although Indoleamine 2,3-dioxygenase (IDO), tryptophan-2,3-dioxygenase (TDO), and aryl hydrocarbon receptor (AHR) are involved in cancer immune escape, their prognostic impact on diffuse large B-cell lymphoma (DLBCL) is unknown.

To examine the prognostic impact of IDO, TDO, and AHR on patients with DLBCL.

This was a retrospective study on treatment-naïve patients with newly diagnosed DLBCL at the Henan Province People's Hospital between 01/2012 and 06/2015. Patients with inflammatory reactive lymph nodes were included as controls. All cases were reviewed by 2 pathologists. IDO, TDO, and AHR positivity was determined through immunochemistry. Survival was examined using the Kaplan-Meier method and multivariable Cox analyses.

The positive expression of TDO (50.0% vs 16.7%, P = .005) and AHR (60.0% vs 8.3%, P < .001) were higher in DLBCL than in inflammatory control. The overall survival of IDO, TDO, and AHR positive expression in DLBCL patients was 34.6, 26.7, and 32.2 months, respectively, which is significantly shorter than that of the corresponding negative patients (49.0 months, P = .04; 58.2 months, P < .001; 58.0 months, P < .001; respectively). The multivariable analysis showed that TDO expression and Ann-Arbor stage were independently associated with PFS (TDO: HR = 8.347, 95%CI: 2.992–23.289, P < .001; stage: HR = 2.729, 95%CI: 1.571–4.739, P < .001) and OS (TDO: HR = 9.953, 95%CI: 3.228–30.686, P < .001; stage: HR = 2.681, 95%CI: 1.524–4.719, P = .001) in DLBCL patients.

Overexpression of IDO, TDO, and AHR is associated with poor survival of patients with DLBCL and could be involved in the immune escape of cancer cells. Further studies are necessary to determine whether these proteins can be targeted by treatment regimens.
The computation of case fatality rate for novel coronavirus (COVID-19) based on Bayes theorem
Authors: Chang Chi-Sheng , Yeh Yu-Tsen , Chien Tsair-Wei , Lin Jui-Chung John , Cheng Bor-Wen , Kuo Shu-Chun
Published: May 2020

Background:

When a new disease such starts to spread, the commonly asked questions are how deadly is it? and how many people are likely to die of this outbreak? The World Health Organization (WHO) announced in a press conference on January 29, 2020 that the death rate of COVID-19 was 2% on the case fatality rate (CFR). It was underestimated assuming no lag days from symptom onset to deaths while many CFR formulas have been proposed, the estimation on Bays theorem is worthy of interpretation. Hence, it is hypothesized that the over-loaded burdens of treating patients and capacities to contain the outbreak (LSBHRS) may increase the CFR.

Methods:

We downloaded COVID-19 outbreak numbers from January 21 to February 14, 2020, in countries/regions on a daily basis from Github that contains information on confirmed cases in >30 Chinese locations and other countries/regions. The pros and cons were compared among the 5 formula of CFR, including [A] deaths/confirmed; [B] deaths/(deaths + recovered); [C] deaths/(cases x days ago); [D] Bayes estimation based on [A] and the outbreak (LSBHRS) in each country/region; and [E] Bayes estimation based on [C] deaths/(cases x days ago). The coefficients of variance (CV = the ratio of the standard deviation to the mean) were applied to measure the relative variability for each CFR. A dashboard was developed for daily display of the CFR across each region.

Results:

The Bayes based on (A)[D] has the lowest CV (=0.10) followed by the deaths/confirmed (=0.11) [A], deaths/(deaths + recoveries) (=0.42) [B], Bayes based on (C) (=0.49) [E], and deaths/(cases x days ago) (=0.59) [C]. All final CFRs will be equal using the formula (from, A to E). A dashboard was developed for the daily reporting of the CFR. The CFR (3.7%) greater than the prior CFR of 2.2% was evident in LSBHRS, increasing the CFR. A dashboard was created to present the CFRs on COVID-19.

Conclusion:

We suggest examining both trends of the Bayes based on both deaths/(cases 7 days ago) and deaths/confirmed cases as a reference to the final CFR. An app developed for displaying the provisional CFR with the 2 CFR trends can improve the underestimated CFR reported by WHO and media.
Patient satisfaction in one-stage immediate breast reconstruction after mastectomy
Authors: Lei Chuqi , Xu Lijie , Xu Feng , Li Jie , Jiang Hongchuan , Guan Shan , Wang Xiang , Wen Bing , Li Jinfeng , Li Xiru , Geng Cuizhi , Yin Jian
Published: May 2020

To analyze patient satisfaction and the predictive factors characterizing three types of one-stage immediate breast reconstruction (IBR) after mastectomy, including prosthesis, latissimus dorsi myocutaneous flap (LDMF), transverse rectus abdominis myocutaneous (TRAM) flap techniques.

Data were collected via face-to-face or telephone interviews from eight breast centers in China from January 2012 to December 2016. A standardized questionnaire that evaluated the general satisfaction and aesthetic satisfaction was sent to patients who had undergone IBR. Logistic regression analysis was performed to identify risk factors associated with patient satisfaction among the three types of breast reconstruction.

A total of 412 questionnaires were sent out, and 309 copies were collected including 226 prosthesis, 46 LDMF, and 37 pedicle TRAM reconstruction. Logistic regression analysis showed that general satisfaction and aesthetic satisfaction were significantly correlated with radiotherapy (P < .001, P = .018), respectively. Besides, the aesthetic satisfaction was also associated with nipple-areola complex (NAC) preservation (P < .001).

Our multi-center study identified factors of higher patient satisfaction, like NAC preservation and absence of radiotherapy, in order to help breast surgeons make better decisions about individualized reconstruction plan.
Can cervical vascular ultrasound combined with transcranial Doppler ultrasound accurately diagnose cerebral infarction?
Authors: Qin Li-wei , Wang Chen , Feng Xiu-juan , Wang Xiao-hui , Qin Li-hong , Weeks Christina
Published: May 2020

Background:

The purpose of this study is to investigate the impact of cervical vascular ultrasound (CVU) combined transcranial Doppler ultrasound (TDU) in the diagnosis of cerebral infarction (CI).

Methods:

The following electronic databases will be sought from PUBMED, EMBASE, Cochrane Library, PSYCINFO, Web of Science, Allied and Complementary Medicine Database, WANGFANG, VIP database, and China National Knowledge Infrastructure. The search period will cover from the initial indexing to March 1, 2020 without restrictions of language and publication status. All case-controlled studies which identifying the impact of CVU combined TDU in the diagnosis of CI will be considered. Two authors will independently perform the whole process of study selection, data extraction, and quality assessment, respectively. If any disagreements occur between two authors, we will invite a third experienced author to help solve them through discussion. Quality Assessment of Diagnostic Accuracy Studies tool will be used to check study quality, and RevMan V.5.3 software and Stata V.12.0 software will be utilized to carry out statistical analysis.

Results:

This study will summarize the most recent evidence that focusing on the impact of CVU combined TDU in the diagnosis of CI.

Conclusion:

This study will provide helpful evidence to determine whether CVU combined TDU is an accurate diagnosis tool for CI or not.

Systematic review registration:

PROSPERO CRD42020171367.
The effect of Shexiang Tongxin Dropping Pills on coronary microvascular dysfunction (CMVD) among those with a mental disorder and non-obstructive coronary artery disease based on stress cardiac magnetic resonance images
Authors: Tian Jinfan , Zhang Lijun , Yang Xueyao , Zuo Huijuan , Zhao Xin , Yong Jingwen , He Yi , Song Xiantao
Published: May 2020

Introduction:

Coronary microvascular dysfunction (CMVD), highly prevalent among patients with a mental disorder (anxiety or depression), is closely related to adverse cardiac events, including hospitalization, sudden cardiac death, and myocardial infarction. Shexiang Tongxin Dropping Pills (STDP), a traditional Chinese medicine, exerts endothelial protective function by anti-inflammation, anti-oxidative stress, and promoting blood circulation. STDP protects against CMVD in previous fundamental studies. The present trial is aiming at evaluating the effect of STDP on CMVD among depressed or anxious patients with non-obstructive coronary artery disease (NOCAD).

Methods and analysis:

Seventy-two depressed or anxious patients diagnosed with NOCAD combined with CMVD utilizing coronary artery angiography and stress cardiac magnetic resonance (CMR) will be recruited in the present study. These patients will be randomized into two groups, namely, Nicorandil group (Nicorandil combined with routine medicine), and STDP groups (STDP combined with routine medicine). The change of CMVD status by assessing absolute myocardial blood flow and myocardial reperfusion using stress CMR 3-month after discharge is defined as the primary endpoint. Major adverse cardiac events (MACEs), quality of life (QOL), and metal disorder improvement are defined as the secondary endpoints. Seattle angina questionnaire (SAQ) which is used to assess angina pectoris and QOL will be recorded at 1-, 3-, 6-, 9-, 12-month of follow-up. Seven-item Generalized Anxiety Disorder Scale (GAD-7) and 9-item depression module from the Patient Health Questionnaire (PHQ9) which utilized to evaluate anxiety and depression, respectively, will be recorded at 1-, 3-, 6-, 9-, 12-month of follow-up. This study will first evaluate the efficacy of STDP on CMVD among patients with a mental disorder and NOCAD, and discuss the potential mechanisms, providing therapeutic evidence for the STDP for these patients.
Single-port endoscopic mastectomy via the lateral chest approach for the treatment of grade II gynecomastia
Authors: Jian Chenxing , Wu Limin , Lin Lisheng , Liu Wei , Zheng Zifang , Yang Chunkang
Published: May 2020

To investigate the feasibility of single-port endoscopic mastectomy via the lateral chest approach in the treatment of Simon grade II gynecomastia.

Data from 12 patients with grade II gynecomastia admitted from January 2017 to November 2018 were retrospectively analyzed, and related satisfaction surveys were conducted 6 months after the operation.

All surgeries were successfully performed under single-port endoscopy, and no patients were converted to open surgery. There were no serious complications related to the surgery, and all the patients were satisfied with the postoperative appearance.

The application of single-port endoscopy in the surgical treatment of grade II gynecomastia is safe and reliable.
A systematic review and meta-analysis to compare the efficacy of conbercept with ranibizumab in patients with macular edema secondary to retinal vein occlusion
Authors: Liu Weishai , Li Yanjie , Cao Rongxia , Bai Zichao , Liu Weiqin
Published: May 2020

Background:

The objective of this review and meta-analysis is to investigate the efficacy of conbercept and ranibizumab, combined with or without laser photocoagulation, in patients with macular edema secondary to retinal vein occlusion (RVO-ME).

Methods:

Several databases have been used to identify relevant publications. After screening, a meta-analysis was conducted to compare conbercept and ranibizumab with the support of RevMan 5.3 (Cochrane Library Software, Oxford, UK).

Results:

In this study, 9 randomized controlled trials and 6 retrospective trials were included with a total of 1180 patients. No significant difference was found in best corrected visual acuity (BCVA) or central macular thickness (CMT) in the baseline parameters [BCVA (weighted mean difference (WMD): –0.01; 95% confidence interval CI: –0.03 to 0.01; P = .17), CMT (WMD: 20.14; 95% CI: –26.70 to 66.97; P = .40). No significant differences were found in the improvements of BCVA and adverse events (AEs) between the 2 groups after injection of loading dosage [the 1st month BCVA (WMD: –0.01; 95% CI: –0.04 to 0.02; P = .54),the 3rd month BCVA (WMD: –0.02; 95% CI: -–0.05 to 0.01; P = .23), the 6th month BCVA (WMD: –0.02; 95% CI: –0.05 to 0.01; P = .27), AEs (odds ratio: 0.84; 95% CI: 0.38 to 1.84; P = .66)]. However, there were significant differences between conbercept and ranibizumab treatment in terms of CMT [1st month CMT (WMD: –11.70; 95% CI: –19.71 to –3.68; P < .01), 3rd month CMT (WMD: –10.08; 95% CI: –15.62 to –4.53; P < .01), 6th month CMT (WMD: –15.83; 95% CI: –22.88 to –8.78; P < .01)] and the number of injections (WMD, –0.36; 95% CI: –0.68 to –0.04; P = .03).

Conclusion:

The current pooled evidence suggested that both therapies of intravitreal conbercept and intravitreal ranibizumab with or without laser photocoagulation are effective in vision function in RVO-ME patients, and confirmed that conbercept has advantages over ranibizumab in terms of CMT and the number of injections for treating RVO-ME. In addition, conbercept has the statistically same visual gains and safety as ranibizumab in RVO-ME patients. Longer-term follow-up surveys on the safety and effectiveness of these 2 treatment regimens are required.
Isolated left bronchial isomerism that was incidentally detected as a severe obstructive ventilatory disturbance in an asymptomatic adult patient
Authors: Heo Manbong , Jeong Jong Hwan , You Jung Wan , Kim Ju-Young , Park Mi Jung , Jeon Kyung Nyeo , Lee Jong Deog , Lee Seung Jun
Published: May 2020

Rationale:

Left bronchial isomerism is generally associated with abnormal arrangement of the atrium and abdominal viscera; therefore, its diagnosis is confirmed in early childhood.

Patient concerns:

Here we report a rare case involving a 36-year-old man with isolated left bronchial isomerism that presented as an asymptomatic severe obstructive ventilatory disturbance during pulmonary function tests performed as part of routine assessments for an orbital wall fracture. The patient was a current smoker and did not show any respiratory symptoms.

Diagnosis:

Chest computed tomography revealed left bronchial isomerism, and further tests showed that there was no involvement of other organs.

Interventions:

We recommended smoking cessation and the long-term use of an inhaled long-acting bronchodilator.

Outcomes:

The findings from this case highlight the causative role of left bronchial isomerism in asymptomatic adults with chronic obstructive pulmonary disease.

Lessons:

Physicians should consider this condition as a cause of obstructive ventilatory disturbances in asymptomatic adult patients.
Motor recovery by the aberrant pyramidal pathway in a patient with cerebral infarct
Authors: Jang Sung Ho , Lee Jun , Seo You Sung
Published: May 2020

Introduction:

The aberrant pyramidal tract (APT) refers to the collateral pathway of the pyramidal tract (PT) descending through the medial lemniscus in the midbrain and pons. We report on a patient who showed changes of the APT from the early stage to the chronic stage concurrent with motor recovery following an infarct in the cerebral peduncle.

Patient concerns:

An 84-year-old female patient presented with moderate motor weakness of her upper and lower extremities (2+/2+) due to cerebral infarct on the right cerebral peduncle of midbrain. One week after her stroke, her motor weakness was similar to that at the onset (2+/2+). During 5 weeks’ rehabilitation, her motor weakness recovered to the point that she was able to move upper and lower extremities against gravity with some resistance (4-/4-).

Diagnosis:

Cerebral infarct on the right cerebral peduncle of midbrain

Interventions:

She participated in a comprehensive rehabilitative management program, including movement therapy, neurotrophic drugs, and neuromuscular electrical stimulation therapy of the left finger extensor and ankle dorsiflexor muscles.

Outcomes:

On 1-week and 6-week diffusion tensor tractographys (DTTs), the right PT was not reconstructed, but the right APT, which descended through the medial lemniscus pathway at the midbrain and pons and the pyramid at the medulla, was observed. The right APT became thicker on six-week DTT compared with 1-week DTT. On 1-week transcranial magnetic stimulation study, an motor evoked potential with delayed latency and decreased amplitude was evoked from the affected (right) hemisphere (latency: 24.4 msec and amplitude: 0.2uV). In contrast, its latency was decreased and amplitude was increased on six-week transcranial magnetic stimulation study (latency: 21.8 msec, amplitude: 0.8 uV)

Conclusions:

We demonstrated changes in the APT from the early stage to the chronic stage concurrent with motor recovery in a patient with an infarct in the cerebral peduncle. Our findings have important implications that a spared APT could contribute to the motor recovery in patients with cerebral infarct when the PTis completely injured at the onset of cerebral infarct,.
The start of gastrectomy at different time-of-day influences postoperative outcomes
Authors: Wang Bin , Yao Yizhou , Wang Xuchao , Li Hao , Qian Huan , Jiang Linhua , Zhu Xinguo
Published: May 2020

Gastric cancer (GC) continues to be 1 of the malignant tumors with high morbidity and mortality worldwide. Although the improvements in targeted inhibitor therapy have promoted survival, the first choice for GC patients is still surgery. However, prolonged surgery may tire surgeons and affect surgical outcomes.

To detect whether different time-of-day radical gastrectomy influenced short-term and long-term surgical outcomes.

This study included 117 patients between 2008 and 2012 who underwent a radical gastrectomy. These patients were grouped into the morning (before 13:00) and afternoon (after 13:00) groups or divided into 2 groups according to the median operation start time (before or after 11:23). Then, the relevant influence of the surgical start time was analyzed.

The morning group (before 13:00) and the front median group (before 11:23) showed longer operative time (P = .008 and P = .016, respectively), lower estimated blood loss (P < .001 and P = .158, respectively), and longer time before resuming oral intake (P < .001 and P < .173, respectively) than the afternoon group (after 13:00) or latter median group (after 11:23). Starting the operation in the morning had no effect on the rate of postoperative complications. The operation start time had no significant influence on the overall survival of patients who underwent a radical gastrectomy. However, in subgroup analysis, patients who underwent a distal gastrectomy faced poor prognosis when their surgery started after 13:00 (P = .030).

The results suggest that the operation start time might be an indicator of total operative time, estimated blood loss, and the time to resuming oral intake. The operation start time may also influence the prognosis of radical gastrectomy in patients with GC.
Standardization of rehabilitation program for post-apoplectic limb spasm treated by Tongjing Tiaoxing tuina and scalp acupuncture with physical therapy
Authors: Zhang Qiongshuai , Wang Yufeng , Ji Guangcheng , Cao Fang , Hu Guanyu , Cong Deyu , Xu Xiaohong , Song Bailin
Published: May 2020

Background:

Tong Jing Tiao Xing tuina (TJTX) is a Chinese massage method. Excising with scalp acupuncture (ESA) is a treatment combining scalp electroacupuncture with physical therapy (PT), and yinao fujian formula (YNFJ) is a Chinese oral herbal granule medicine. The combination of the 3 methods is called the “Zhishen Tiaoxing” (ZSTX) rehabilitation program, which is used as an alternative of limb spasm after stroke. There is little available evidence demonstrating its safety and efficacy.

Methods:

This will be a subject-blind, randomized controlled trial conducted in 3 medical centers. It will strictly follow the Standards for Reporting Interventions in Clinical Trials of Acupuncture, 2010. We will recruit 316 patients with limb spasm after stroke, 200 from the Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China, 80 from the Second Affiliated Hospital of Heilongjiang University of Chinese medicine, Harbin, China, and 36 from Huashan Hospital of Fudan University, Shanghai, China. A block randomization sequence stratified by centers will be generated using SAS Version 9.2 software (SAS Institute, Cary, NC, USA), which was performed at the Guangdong Provincial Hospital of Chinese Medicine's Key Unit of Methodology in Clinical Research. The treatment group is treated with TJTX (once a day), ESA (once a day), and oral YNFJ (twice a day). The control group will be treated with PT. Two groups of patients will be treated 5 sessions a week for 4 weeks, and there will be 6-month follow-up. The outcome evaluators will be blinded to patient grouping. The primary outcome will be modified Ashworth scales. The secondary outcome indexes will be the simplified Fugl–Meyer assessment scale, surface electromyogram root mean square value, modified Barthel index, stroke-specific quality of life scale, health scale of traditional Chinese medicine, visual analogue scale (VAS), and the Hamilton depression scale.

Discussion:

The Randomized Controlled Trial (RCT) mainly aim to evaluate the effectiveness and safety of traditional Chinese medicine rehabilitation program, by comparing the treatment of ZSTX with the PT for the treatment of limb spasm after stroke.

Trial registration:

Chinese Clinical Trial Registry: ChiCTR 1900024255. Registered on July 3, 2019.
Appraisal and recommendation synthesis of guidelines and consensuses for interventions of pressure ulcers
Authors: Geng Jie , Yang Ke-Lu , Cai Yi-Tong , Shi Ji-Yuan , Yin Min , Wang Xiao-Ping
Published: May 2020

Background:

Pressure ulcers (PU) bring a considerable physical and mental burden on patients and their families, and have put families and government under tremendous pressure to cover the cost for treatment. Therefore, this protocol proposes to evaluate the quality of existing PU clinical practice guidelines (CPGs) and compare the similarities and differences between its recommendations in order to improve the treatment efficacy and reduce the PU treatment cost.

Methods:

Electronic databases and specific databases of CPGs will be searched. Study selection and data collection will be performed independently by two reviewers. The Appraisal of Guidelines for Research & Evaluation II (AGREE II) Instrument and Reporting Items for Practice Guidelines in Healthcare (RIGHT) will be used to assess the methodological quality and reporting quality of included CPGs. Bubble plot will be used to describe the difference of the quality, and mind mapping will be plotted to illustrate the comparison of recommendations of a guideline when needed. R software, MindMaster and Excel will be used.

Results:

The results of this study will be submitted to a peer-reviewed journal for publication.

Conclusion:

This systematic review will provide comprehensive evidence of CPGs of PU.

PROSPERO registration number:

CRD42020149176.
The study on the risk of other endocrine glands autoimmune diseases in patients with type 1 diabetes mellitus
Authors: Liu Yang , Chen Shuchun , Zhang Dongmei , Li Zelin , Wang Xing , Xie Xing , Zhu Haijiao , Ren Luping , Wang Liqin
Published: May 2020

To study the changes of pancreas, thyroid, adrenal, parathyroid and gonadal organ-specific antibodies in patients with type 1 diabetic patients and to explore the risk of development to other endocrine gland autoimmune diseases.

Fifty one patients with type 1 diabetes mellitus were selected. ELISA was used to detect islet, adrenal gland, Parathyroid, gonadal organ-specific antibody levels, the level of thyroid-related antibodies by lectrochemiluminescence.

Compared with the healthy control group, the levels of the 17-α-OHAb, 21-OHAb, NALP5Ab, P450sccAb, and CaSRAb in the T1DM group were significantly higher. GADAb-positive patients were more likely to have TPOAb-positive patients than GADAb-negative patients, and the positive rate of 2 thyroid antibodies in GADAb-positive patients was significantly higher than that in GADAb-negative patients. The presence of these antibodies is related to the age of onset of type 1 diabetes or Patient age. In combination with 1 or 2 islet antibody-positive patients, the combined non-islet antibody positive rate was higher than that of islet antibody-negative patients.

Patients with type 1 diabetes with other autoimmune diseases at risk significantly increased compared with normal, of which the most common thyroid autoimmune disease, thyroid antibodies and hormone levels should be routinely detected at the first visit and long-term follow-up.
Characteristics of diffusion tensor imaging of central nervous system in children with tourette's disease
Authors: Xia Xianwu , Lin Yeqing , Lang Boxu , Yuan Jianjun , Sheng Liang , Yang Dengfa , Shen Jianmin
Published: May 2020

To investigate the characteristics of diffusion tensor imaging (DTI) of the central nervous system in children with Tourette syndrome (TS).

Fifteen children with TS (TS group) and 15 normal children (control group) were studied, and all of them underwent DTI. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) parameters were calculated using the DTIStudio software. The region of interest was delineated manually. The ADC and FA values of the bilateral caudate nucleus, bilateral globus pallidus, bilateral putamen, bilateral thalamus, and bilateral frontal lobe white matter were measured using the region of interest editor software. The differences of FA values and ADC values between the same brain areas were compared. The associations between ADC, FA values and Yale Global Tic Severity Scale (YGTSS) scores were evaluated by Pearson correlation analyses.

The FA values of left globus pallidus and left thalamus were significantly lower in the TS group than in the control group (P < .05), while the ADC values of the right caudate nucleus and bilateral thalamus were significantly higher in the TS group than in the control group (P < .05). The decrease in FA in the left thalamus significantly correlated with the YGTSS score (r = 0.692; P < .05). No correlation was found between FA and ADC values in other brain regions and the YGTSS score (P > .05).

After the DTI analyses, abnormalities were found in the left globus pallidus, right caudate nucleus, and bilateral thalamus in children with TS. Especially the changes in the left thalamus structure was crucial in the pathophysiological clock of TS.
Congenital microcephaly with early onset epileptic encephalopathy caused by ASNS gene mutation
Authors: Chen Chen , Hao Yunpeng , Liang Jianmin , Liu Xuncan
Published: May 2020

Rationale:

Asparagine synthetase deficiency (ASNSD) refers to a congenital metabolic abnormality caused by mutation in the asparagine synthetase (ASNS) gene encoded by chromosome 7q21. Herein, we report the first case of ASNSD in China, in which novel ASNS mutations were identified.

Patient concerns:

A 6-month-old boy presented with a 4-month history of microcephaly and psychomotor developmental retardation and a 2-month history of epilepsy. Four months after birth, magnetic resonance imaging demonstrated a giant cyst in the right lateral ventricle, and a ventriculoperitoneal shunt was placed. Video electroencephalography showed a hypsarrhythmia pattern with a string of tonic-clonic and myoclonic seizures. On admission, physical examination showed microcephaly. Neurologic examination showed a decreased tension in the trunk muscles and an increased tension in the extremity muscles; tendon hyperreflexia was noted, and bilateral pathologic reflexes were positive.

Diagnosis:

A diagnosed of congenital microcephaly was made. Whole-exome sequencing revealed a heterozygous deletion mutation c.666_667delCT (p.L2221Lfs∗5) in exon 6 of the ASNS gene and a heterozygous missense mutation c.1424C>T (p.T457I) in exon 13 of the ASNS gene.

Interventions:

After admission, intravenous adrenocorticotropic hormone and oral topiramate was administrated for 4 weeks, while the seizures persisted. Then, levetiracetam and clonazepam were added.

Outcomes:

After the follow-up period of 18 months, video electroencephalography showed that complex episodes disappeared with changes in multiple focal spike and sharp waves; 1 focal attack arising from the left occipital region and 2 focal attacks arising from the right middle temporal and the right occipital region were recorded.

Lessons:

This is the first case of ASNSD in China. We identified 2 novel mutations (c.666_667delCT and c.1424C>T) in the ASNS gene, which expands the ASNS gene mutation profile and will be beneficial for genetic diagnosis.
Clinical Application of Image Analysis in Pathology
Authors: Cornish Toby C.
Published: May 2020

Quantitative biomarkers are key prognostic and predictive factors in the diagnosis and treatment of cancer. In the clinical laboratory, the majority of biomarker quantitation is still performed manually, but digital image analysis (DIA) methods have been steadily growing and account for around 25% of all quantitative immunohistochemistry (IHC) testing performed today. Quantitative DIA is primarily employed in the analysis of breast cancer IHC biomarkers, including estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2/neu; more recently clinical applications have expanded to include human epidermal growth factor receptor 2/neu in gastroesophageal adenocarcinomas and Ki-67 in both breast cancer and gastrointestinal and pancreatic neuroendocrine tumors. Evidence in the literature suggests that DIA has significant benefits over manual quantitation of IHC biomarkers, such as increased objectivity, accuracy, and reproducibility. Despite this fact, a number of barriers to the adoption of DIA in the clinical laboratory persist. These include difficulties in integrating DIA into clinical workflows, lack of standards for integrating DIA software with laboratory information systems and digital pathology systems, costs of implementing DIA, inadequate reimbursement relative to those costs, and other factors. These barriers to adoption may be overcome with international standards such as Digital Imaging and Communications in Medicine (DICOM), increased adoption of routine digital pathology workflows, the application of artificial intelligence to DIA, and the emergence of new clinical applications for DIA.
Hemostatic potential of cold-stored non-leukoreduced whole blood over time: An assessment of platelet function and thrombin generation for optimal shelf life
Authors: Assen Scott , Cardenas Jessica , George Mitchell , Wang Yao-Wei , Wade Charles E. , Meyer David , Cotton Bryan A.
Published: May 2020

OBJECTIVES

Cold-stored low-titer whole blood (WB) is becoming increasingly used as the preferred product for initial hemorrhagic shock resuscitation. The purpose of this study was to identify whether the current 21-day shelf life is the optimal duration for storage of WB, maintaining hemostatic efficacy.

METHODS

Five units of fresh low-titer group O WB (non-leukoreduced) were acquired from our regional blood center. These units were stored at 4°C for up to 21 days as per current clinical storage guidelines in our emergency department. Hemostatic parameters were measured in vitro at 0 days, 7 days, 14 days, and 21 days. Assessments of hemostatic potential included cell count, rapid thrombelastography (r-TEG) and kaolin thrombelastography (TEG), multiplate impedance aggregometry, and calibrated automated thrombogram (CAT). Univariate analysis, including one-way analysis of variance with repeated measures, was performed (STATA 12.1).

RESULTS

Compared with baseline product (0 days), both platelet count and platelet function of WB showed sharp decreases at 7 days and again at 14 days. Platelet function deterioration was noted by r-TEG c (MA), TEG-MA, and multiplate arachidonic acid and adenosine diphosphate (all p < 0.001). With respect to clot initiation, r-TEG ACT and TEG R-time were similar over the 21-day shelf life (p = 0.058 and p = 0.620, respectively). Thrombin generation assessed by CAT demonstrated stable endogenous thrombin potential over the course of storage (p = 0.162), but increased peak thrombin generation and quicker time to peak generation after 7 days.

CONCLUSION

While the platelet function of WB degrades significantly at 7 days (and again at 14 days), clot initiation remains stable over time, and thrombin generation appears to be improved at 7 days. This study supports a current storage limit for cold-stored, low-titer WB of 14 days.
Graft-versus-host Disease Prophylaxis With Abatacept Reduces Severe Acute Graft-versus-host Disease in Allogeneic Hematopoietic Stem Cell Transplant for Beta-thalassemia Major With Busulfan, Fludarabine, and Thiotepa
Authors: Khandelwal Pooja , Yeh Rosa F. , Yu Louie , Lane Adam , Dandoy Christopher E. , El-Bietar Javier , Davies Stella M. , Grimley Michael S.
Published: May 2020

Background.

We hypothesized that the addition of 4 doses of abatacept to our standard acute graft-versus-host disease (GVHD) prophylaxis would reduce the incidence of day +100 severe acute GVHD in children with transfusion-dependent beta-thalassemia major undergoing a myeloablative allogeneic hematopoietic stem cell transplant (HSCT), without impacting engraftment.

Methods.

Twenty-four children with beta-thalassemia major received abatacept at a dose of 10 mg/kg intravenously on days –1, +5, +14, and +28 after HSCT in addition to calcineurin inhibitors and methylprednisolone. Outcomes were compared to 8 beta-thalassemia patients who received standard acute GVHD prophylaxis.

Results.

There was no difference in engraftment between the 2 groups. No patient had grades III–IV acute GVHD by day +100 in the abatacept cohort compared with 50% in the standard acute GVHD prophylaxis group (P = 0.001). Viral reactivation occurred in 5 children in the standard acute GVHD cohort and in 20 children in the abatacept cohort (P = 0.2). Thalassemia-free survival after HSCT was 100% in the abatacept cohort compared to 62.5% in the standard cohort at last follow-up (P = 0.007).

Conclusions.

Adding abatacept to our routine GVHD prophylaxis reduced the incidence of day +100 severe acute GVHD without impacting engraftment or survival.
The Meaning Behind the Scar: Anonymous Live Liver Donors’ Perceptions of Their Surgical Scars
Authors: Krause Sandra , Pritlove Cheryl , Abbey Susan , Jung Judy
Published: May 2020

Background.

Scarring can greatly impact quality of life for individuals (ie, causing depression posttraumatic stress disorder and body image issues). Those who wish to be anonymous live liver donors are warned of the potential negative psychological impacts associated with the large scar left from liver donation surgery. Given the unique degree of autonomy that these patients have over their surgery, we explore whether a sample of 26 anonymous live liver donors experience a unique relationship with their scar.

Methods.

Anonymous donors participated in a semistructured qualitative interview examining their experience with donation. Interviews were audio-recorded, transcribed, and analyzed using the constant comparison method for themes pertaining, to participants’ perception of their scar.

Results.

Five main themes were identified—a marker of satisfaction about the donation experience, a physical reminder of donation, a trigger for recipient-related thoughts, an awareness tool, and a potential threat to anonymity. Donors did not voice any body image or cosmetic concerns due to their scars. Instead, discussions about the negative aspects of scarring centered around the identifying nature of their scar.

Conclusions.

These findings help underscore the distinctiveness of anonymous living liver donors as a patient population. Preparing anonymous living liver donors for different types of cosmetic issues relating to their scar (ie, as a possible threat to their desired anonymity) may be more appropriate than preparing them in the same way as other donor populations.
Evaluation of Renal Anionic Secretion Following Living-donor and Deceased-donor Renal Transplantation: A Clinical Pharmacokinetic Study of Cefoxitin Microdosing
Authors: Kalluri Hari V. , Sood Puneet , Zhao Wenchen , Randhawa Parmjeet S. , Tevar Amit D. , Hariharan Sundaram , Humar Abhinav , Venkataramanan Raman
Published: May 2020

Background.

Renal transplantation is the treatment of choice for patients with end-stage renal disease. Because kidneys are the primary excretory organs for various drugs/drug metabolites, changes in renal graft function would significantly alter the clearance and exposure of renally secreted drugs. Renal allografts from living and deceased donors normally undergo numerous insults, including injuries associated with prolonged cold ischemic time, reperfusion, and nephrotoxicity due to calcineurin inhibitors. These physiologic and pharmacologic stresses can alter the expression and functional capacity of renal organic anionic transporters (OATs).

Methods.

The objectives of this study were to assess the longitudinal changes in renal anionic secretion in kidney transplant patients, to study the effect of prolonged cold ischemic time on OAT secretion in kidney transplant patients (living- versus deceased-donor recipients), and to compare OAT secretory capacity of renal transplant recipients with healthy volunteers. Cefoxitin was used as a probe drug to assess OAT secretion. Cefoxitin pharmacokinetics was studied in 15 de novo renal transplant recipients following intravenous administration of 200 mg cefoxitin within 14 d and beyond 90 d posttransplantation.

Results.

No longitudinal changes in real OAT secretion in early posttransplant period were observed, and there were no differences in renal OAT secretion between living- and deceased-donor renal transplant recipients. Overall, cefoxitin exposure was 2.6-fold higher and half-life increased by 2.2-fold in renal transplant recipients when compared with historical healthy controls.

Conclusions.

These results suggest that OAT system is functioning well, but renal transplant recipients would need significantly lower dosage of drugs that are primarily secreted via the OAT system compared with normal subjects.
MatchMaker: A Deep Learning Framework for Drug Synergy Prediction
Authors: Kuru Halil Ibrahim , Tastan Oznur , Cicek A. Ercument
Published: May 2020

Drug combination therapies have been a viable strategy for the treatment of complex diseases such as cancer due to increased efficacy and reduced side effects. However, experimentally validating all possible combinations for synergistic interaction even with high-throughout screens is intractable due to vast combinatorial search space. Computational techniques can reduce the number of combinations to be evaluated experimentally by prioritizing promising candidates. We present MatchMaker that predicts drug synergy scores using drug chemical structure information and gene expression profiles of cell lines in a deep learning framework. For the first time, our model utilizes the largest known drug combination dataset to date, DrugComb. We compare the performance of MatchMaker with the state-of-the-art models and observe up to ~ 20% correlation and ~ 40% mean squared error (MSE) improvements over the next best method. We investigate the cell types and drug pairs that are relatively harder to predict and present novel candidate pairs. MatchMaker is built and available athttps://github.com/tastanlab/matchmaker
Dynamic Loading of Human Engineered Heart Tissue Enhances Contractile Function and Drives Desmosome-linked Disease Phenotype
Authors: Bliley Jacqueline M. , Vermeer Mathilde C.S.C , Duffy Rebecca M. , Batalov Ivan , Kramer Duco , Tashman Joshua W. , Shiwarski Daniel J. , Lee Andrew , Teplenin Alexander S. , Volkers Linda , Coffin Brian , Hoes Martijn F. , Kalmykov Anna , Palchesko Rachelle N. , Sun Yan , Jongbloed Jan D.H. , Bomer Nils , de Boer Rudolf. A. , Suurmeijer Albert J.H. , Pijnappels Daniel A. , Bolling Maria C. , van der Meer Peter , Feinberg Adam W.
Published: May 2020

The role mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes in the heart. However, most EHT systems are unable to model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained fractional shortening of >10%. To do this, 3D EHTs are integrated with an elastic polydimethylsiloxane (PDMS) strip that provides mechanical pre- and afterload to the tissue in addition to enabling contractile force measurements based on strip bending. Our results demonstrate in wild-type EHTs that dynamic loading is beneficial based on the magnitude of the forces, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we use hiPSC–derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy (ACM) due to mutations in desmoplakin. We demonstrate that manifestation of this desmosome-linked disease state requires the dyn-EHT conditioning and that it cannot be induced using 2D or standard 3D EHT approaches. Thus, dynamic loading strategy is necessary to provoke a disease phenotype (diastolic lengthening, reduction of desmosome counts, and reduced contractility), which are akin to primary endpoints of clinical disease, such as chamber thinning and reduced cardiac output.

Single Sentence Summary

Development of a dynamic mechanical loading platform to improve contractile function of engineered heart tissues and study cardiac disease progression.
Chromosome-scale assembly and annotation of the macadamia genome (Macadamia integrifoliaHAES 741)
Authors: Nock Catherine J. , Baten Abdul , Mauleon Ramil , Langdon Kirsty S. , Topp Bruce , Hardner Craig , Furtado Agnelo , Henry Robert J. , King Graham J.
Published: May 2020

Macadamia integrifoliais a representative of the large basal eudicot family Proteaceae and the main progenitor species of the Australian native nut crop macadamia. Since its commercialisation in Hawaii fewer than 100 years ago, global production has expanded rapidly. However, genomic resources are limited in comparison to other horticultural crops. The first draft assembly ofM. integrifoliahad good coverage of the functional gene space but its high fragmentation has restricted its use in comparative genomics and association studies. Here we have generated an improved assembly of cultivar HAES 741 (4,094 scaffolds, 745 Mb, N50 413 kb) using a combination of Illumina paired and PacBio long read sequences. Scaffolds were anchored to 14 pseudo-chromosomes using seven genetic linkage maps. This assembly has improved contiguity and coverage, with >120 Gb of additional sequence. Following annotation, 34,274 protein-coding genes were predicted, representing 92% of the expected gene content. Our results indicate that the macadamia genome is repetitive and heterozygous. The total repeat content was 55% and genome-wide heterozygosity, estimated by read mapping, was 0.98% or one SNP per 102 bp. This is the first chromosome-scale genome assembly for macadamia and the Proteaceae. It is expected to be a valuable resource for breeding, gene discovery, conservation and evolutionary genomics.
Marriage in the Melting Pot: An evolutionary approach to European ancestry, homogamy and fertility in the United States
Authors: Schahbasi Alexander , Huber Susanne , Fieder Martin
Published: May 2020

Objective

To understand marriage patterns, homogamy and fertility of women of European ancestry in the United States from an evolutionary perspective we aim to investigate if a prevalence for ancestral homogamy exists, the factors influencing a female preference for an ancestral homogamous vs. an heterogamous marriage, if an ancestral homogamous vs. heterogamous marriages influences fertility and if there is an inherted component of the tendency to marry homogamously vs. heterogamously. Furthermore we aim to determine the heritability of homogamous vs. heterogamous marriage behaviour.

Methods

We used the census data of 369,121 US women married only once and aged between 46 and 60 years, provided by IPUMS USA (https://usa.ipums.org/usa/). We used linear mixed models to determine associations of the probability of a homogamous vs. heterogamous marriage and the individual fertility of a women. We aimed to estimate the heritability (in our case genetic & parental environment) of marriage behaviour using a linear mixed model.

Results

We found, that ancestral heterogamous marriages are more frequent (56.5%), compared to homogamous marriages (43.5%). Most of the variance in inter- ancestry marriage and fertility is explained by ancestry per se, followed by the ratio of individuals of a certain ancestral background in a county: the more individuals of a certain ancestry live in a county the lower is the tendency to marry someone of a different ancestral background. Furthermore we found that about 11.8% of the marriage behaviour is heritable. Being in a homogamous marriage as well as the income of the spouse are both significantly positively associated with the number of children a women has and the probability that a women has at least one child.

Discussion

The most important explaining factor (in terms of variance explained) for being in an ancestral homogamous vs. heterogamous marriage, for number of children, as well as childlessness is the ancestry of the women. Albeit we are not able to distinguish the genetic and social heritability on basis of our data, with a total value of 11.8% variance explained, only a small heritability for in-group vs, out-group marriage behaviour is indicated.
DeepGraphMol, a multi-objective, computational strategy for generating molecules with desirable properties: a graph convolution and reinforcement learning approach
Authors: Khemchandani Yash , O’Hagan Stephen , Samanta Soumitra , Swainston Neil , Roberts Timothy J. , Bollegala Danushka , Kell Douglas B.
Published: May 2020

We address the problem of generating novel molecules with desired interaction properties as a multi-objective optimization problem. Interaction binding models are learned from binding data using graph convolution networks (GCNs). Since the experimentally obtained property scores are recognised as having potentially gross errors, we adopted a robust loss for the model. Combinations of these terms, including drug likeness and synthetic accessibility, are then optimized using reinforcement learning based on a graph convolution policy approach. Some of the molecules generated, while legitimate chemically, can have excellent drug-likeness scores but appear unusual. We provide an example based on the binding potency of small molecules to dopamine transporters. We extend our method successfully to use a multi-objective reward function, in this case for generating novel molecules that bind with dopamine transporters but not with those for norepinephrine. Our method should be generally applicable to the generationin silicoof molecules with desirable properties.