bluuebunny/crossref_metadata_2025 huggingface dataset:
Mean platelet volume and mean platelet volume/platelet count ratio in nonvalvular atrial fibrillation stroke and large artery atherosclerosis stroke
Authors: Zhu Ning , Shu Hao , Jiang Wenbing , Wang Yi , Zhang Shunkai
Published: July 2020

Ischemic stroke subtypes such as patients with large artery atherosclerosis, cardioembolism, and embolic stroke of undetermined source were investigated. This study was performed aimed to determine mean platelet volume (MPV) and mean platelet volume/platelet count (MPV/Plt) ratio in nonvalvular atrial fibrillation (AF) stroke and large artery atherosclerosis (LAA) stroke.

We conducted a retrospective study of consecutive patients for treatment of acute ischemic stroke at Ruian People's Hospital from March 2017 to October 2018. The patients with ischemic stroke caused by AF and LAA were recruited to this study. Ischemic stroke was confirmed by magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), ischemic lesions on diffusion-weighted imaging were measured in terms of size, composition, and pattern. MPV and platelet count were examined and (MPV/Plt) ratio was calculated.

Three hundred seventy one patients were enrolled composing of 177 (47.7%) nonvalvular AF and 194 (52.2%) with LAA. The MPV (11.3 ± 1.3 vs 10.8 ± 1.0, P < .001) and MPV/Plt ratio (0.066 ± 0.025 vs 0.055 ± 0.20, P < .001) were much higher in AF group than LAA group. Receiver-operating characteristic (ROC) analysis showed MPV (AUC: 0.624, confidence interval: 0.567–0.68, P < .001) and MPV/Plt (AUC: 0.657, confidence interval: 0.601–0.713, P < .001) predicted AF between the 2 groups. MPV/Plt ratio was negatively associated with lesion volume (r = –0.161, P = .033) in AF. The analyses of subtypes of composition of infarcts and infarct pattern showed that MPV/Plt ratio was almost higher in AF than LAA except for subcortical-only pattern. Multivariable regression analyses demonstrated National Institutes of Health Stroke Scale (NIHSS) score (r = 2.74; P < .001), LAD (r = –1.15; P = .025) and MPV/Plt ratio (r = –180.64; P = .021) were correlated with lesion volume.

Our results indicated elevated MPV and MPV/Plt ratio for the identification of difference between AF and LAA in patients with ischemic stroke.
Acupuncture plus rehabilitation for post-stroke depression
Authors: Hou Yonghui , Zhang Ning , Hao Jieming , Wang Xiangzhi , Wen Zehuai , Luo Ding , Ning Baile , Fu Wenbin , Liu Ying
Published: July 2020

Background:

Post-stroke depression (PSD) is a common stroke complication that is characterized by hopelessness, anxiety, disordered sleep, and lowered responsiveness. Rehabilitation and acupuncture treatments are often combined to treat PSD; however, there has been no meta-analysis on their synergistic effect. Therefore, we aim to perform a systematic review and meta-analysis to estimate the effectiveness of acupuncture and rehabilitation in PSD treatment.

Methods:

We will search the following electronic databases: PubMed, the Cochrane Library, EMBASE, the China National Knowledge Infrastructure, the Chinese Biomedical Literature Database, China Science and Technology Journal Database, and Wan Fang databases. We will include studies published between the database initiation and May 2020. Two reviewers will separately conduct study selection, data extraction, and risk of bias assessment. Disputes will be settled by consulting a third reviewer. Review Manager Software 5.3 will be employed for this meta-analysis.

Results:

This systematic review will assess whether acupuncture combined with rehabilitation treatment is more effective than rehabilitation alone in the management of PSD.

Conclusion:

This systematic review will provide evidence regarding the synergistic effect of acupuncture and rehabilitation treatment for PSD.
Feasibility of measuring urethral pressure during female midurethral slings
Authors: Meng Ling-Feng , Wang Miao , Zhang Wei , Liu Xiao-Dong , Zhang Yao-Guang
Published: July 2020

Rationale:

Stress urinary incontinence (SUI) refers to the involuntary leakage of urine when abdominal pressure increases. Midurethral slings (MUS) have become the main surgical method for treating SUI, but no quantitative standard for the degree of sling tightness during operation exists. We achieved this quantitative measurement using ambulatory urodynamic equipment.

Patient concerns:

A 49-year-old woman presented to our hospital with intermittent urine leakage. Five pads were used daily to keep the vulva dry. The preoperative urethral pressure profilometry (UPP) showed that maximum urethral pressure (MUP) was 54 cmH2O and maximum urethral closure pressure (MUCP) was 53 cmH2O.

Diagnosis:

According to the medical history and examination findings, the patient was diagnosed as SUI.

Interventions:

The MUS and UPP were performed.

Outcomes:

The intraoperative UPP showed that MUP was 29 cmH2O and MUCP was 17 cmH2O. Three months after the operation, the patient was followed up by telephone. The amount of urine pad usage decreased from 5 pads/d to 0 pads/d, reaching the social control standard (0–1 pads/d). The patient's international consultation on incontinence questionnaire short form score decreased from 18 to 5, and their incontinence quality of life score increased from 12.5 to 78.4. The effect of urine control was satisfactory, and no complications occurred.

Five months after operation, the patient was reexamined in the outpatient department. The UPP showed that the MUP was 98 cmH2O and the MUCP was 72 cmH2O. The patient still uses 1 pad/day. The international consultation on incontinence questionnaire short form score is 6 and incontinence quality of life score is 79.5. The curative effect is stable.

Lessons:

MUS has become an effective surgical method for SUI, and the tightness of the sling directly affects the surgical outcome. We have achieved the measurement of urethral pressure during MUS. However, although we found that there is no obvious clinical significance of urethral pressure measurement in MUS operation, future research will benefit from our findings by improving upon our study design to help standardize the clinical diagnosis and treatment of MUS.
A case report of ectopic pregnancy arising in a unicornuate uterus, accompanied by the undescended tube and ovary with double inferior vena cava
Authors: Jang Y.S. , Kim Y.S.
Published: July 2020

Rationale:

The incidence of a unicornuate uterus is 0.2% to 0.3% of the whole population. A unicornuate uterus is closely associated with obstetrical complications such as early miscarriages, ectopic pregnancy, and malpresentation.

Patient concerns:

A 32-year-old patient developed a rare ectopic pregnancy arising at a distal, fimbriated end of the undescended fallopian tube.

Diagnoses:

A transvaginal ultrasound scan revealed hemoperitoneum and no gestational sac in the uterine endometrium. A laparoscopic finding showed that high up in the right abdomen, just below the liver, an ectopic mass could be seen arising at a distal, fimbriated end of the fallopian tube, which was developed adjacent to the undescended right ectopic ovary.

Interventions:

After laparoscopic removal of the right salpinx, we removed it with a bag.

Outcomes:

One day after the operation, she was discharged without problems. Postoperative hysterosalpingography showed the unicornuate uterus with patent left and some right salpinx. Magnetic resonance imaging revealed a unicornuate uterus, right ovary at the right inferior hepatic area, a bilateral normal kidney, and double inferior vena cava.

Lessons:

This is the first reported case of its type. It demonstrated that ectopic pregnancy may occur in the upper abdomen, not in the pelvic cavity, in uterine anomaly, and double inferior vena cava; hence, we must thoroughly check the whole abdominal cavity. Additional imaging tests are needed after treatment to see if there are any abnormalities.
Emphysematous osteomyelitis of the spine
Authors: Sung Sahyun , Lee Byung Ho , Kim Jung-Hwan , Park Yung , Ha Joong Won , Moon Seong-Hwan , Lee Hwan-Mo , Kwon Ji-Won
Published: July 2020

Rationale:

Emphysematous osteomyelitis is a rare disease caused by gas-forming bacteria. But only 45 cases have been reported in the literature since then.

Patient concerns:

A 72-year-old female presented to our hospital with severe lower back pain that aggravated 4 days ago.

Diagnoses:

Computed tomography (CT) revealed intraosseous mottled air in the T12 and L1 vertebral bodies and epidural space. The enhanced T1 and T2 magnetic resonance imaging scans showed heterogeneous signal intensity of vertebral bodies, suggestive of emphysematous osteomyelitis.

Interventions:

Surgery was performed to identify culture strains and to remove emphysematous lesions of the vertebral body using extensive transpedicular irrigation.

Outcomes:

Escherichia coli (E coli) was identified in the surgical specimen, and intravenous antibiotic therapy was continued with cefotaxime. The patient had a significant decrease in lower back pain after the surgery and the final CT scan before discharge revealed significantly decreased air at T12 and L1 vertebral bodies and no air density in the epidural space.

Lessons:

We present a patient diagnosed with emphysematous osteomyelitis in vertebral bodies caused by E coli and successfully treated with surgical intervention.
A randomized double-blind placebo-controlled multicenter trial of Bushen Yisui and Ziyin Jiangzhuo formula for constipation in Parkinson disease
Authors: Jin Zhaohui , Liu Zhengtang , Kang Lei , Yang Aoran , Zhao Hongbo , Yan XiaoYan , Zhang Tianqing , Gao Lei , Liu Aixian , Fang Boyan
Published: July 2020

Introduction:

Constipation is a common nonmotor symptom of Parkinson disease (PD). Constipation can also impact patient's quality of life. Chinese herbal medicines have been used for the treatment of constipation in PD. This trial will evaluate the efficacy and safety of a Chinese herbal formula Bushen Yisui and Ziyin Jiangzhuo (BYZJ) for the treatment of constipation in PD.

Methods and analysis:

This randomized, double-blind, placebo-controlled, multicenter clinical trial will involve 4 hospitals in Beijing, China. The study will aim to recruit 90 PD patients with constipation between 30 and 80 years-of age with a score of 1 – 4 on the Hoehn and Yahr scale. Once recruited, Patients will be randomized into a BYZJ group or a placebo group in a 2:1 ratio. The trial will include a 1-week run-in period, a 4-week double-blind treatment period, a 4-week and a 12-week follow-up period. All patients will be educated about PD-related constipation during the run-in period. BYZJ granules and simulated granules will be administered twice daily for 4 weeks to the BYZJ group and the placebo group respectively. Assessments will be performed during run-in period, before the start of treatment (baseline, week 0), and at 4, 8, and 16 weeks. The primary outcome will be measured with the Constipation Severity Instrument, and secondary outcomes will be evaluated with the Patient Assessment of Constipation Quality of Life questionnaire, Bristol Stool Form Scale, Movement Disorders–Unified Parkinson Disease Rating Scale, Nonmotor Symptoms Scale, PD Sleep Scale, Parkinson Fatigue Scale-16. Laxative use (dose and frequency) will also be recorded. Intention-to-treat and per-protocol set analyses will be used to compare symptom improvement between the 2 groups. Any adverse events will be recorded.

Discussion:

If found effective and safe, BYZJ formula will be one of Chinese herb to treat constipation and even other nonmotor or motor symptoms in PD patients. The results will sustain the broader use of BYZJ formula in PD.
Analysis of factors related to preterm birth: a retrospective study at Nanjing Maternity and Child Health Care Hospital in China
Authors: Huang Jin , Qian Yating , Gao Mingming , Ding Hongjuan , Zhang Lei , Jia Ruizhe
Published: July 2020

Preterm birth is the most important cause of neonatal mortality and morbidity worldwide. The aim of this study was to identify factors associated with preterm birth and examine the heterogeneity and interactions between these factors.

We collected data from 1607 pregnant women treated at Nanjing Maternity and Child Health Care Hospital in China. The women included in the study were divided into the full-term group and the preterm-birth group. We used t-tests to compare the characteristics of age and body mass index, Chi-square tests for the other variables, and we used the Wald test to calculate the interaction between factors that may affect preterm birth. The heterogeneity test was used to study the relationship between subgroups. Multivariable logistic regression analysis was used to explore the associations between risk factors and preterm birth, which included all risk factors. All tests were 2-tailed, P < 0.05 was considered significant, and 95% confidence intervals were estimated for percentages.

There was no statistical difference in basic characteristics such as age between the full-term and preterm groups. We found 6 independent risk factors that were associated with preterm birth (P < .05): preeclampsia (PE), intrahepatic cholestasis, premature rupture of the membranes (PROM), placenta previa, chorioamnionitis, and scarred uterus. Five combinations of these factors were statistically significant (P < .05) in terms of heterogeneity: PE and PROM; placenta previa and polyhydramnios; chorioamnionitis and PE; PROM and maternal body mass index; and PROM and gestational diabetes mellitus. Ultimately, the 2 subgroups that showed interactions were PE and PROM and chorioamnionitis and PE.

The interaction between different factors over the course of preterm birth cannot be ignored. When independent risk factors are combined with other diseases, such as PE combined with PROM or chorioamnionitis in this study, it may more likely result in preterm birth. Thus, this situation deserves particular clinical attention.
The Usefulness of Maximum Standardized Uptake Value at the Delayed Phase of Tc-99m sestamibi single-photon emission computed tomography/computed tomography for Identification of Parathyroid Adenoma and Hyperplasia
Authors: Suh Hoon Young , Na Hee Young , Park So Yeon , Choi June Young , So Young , Lee Won Woo
Published: July 2020

Tc-99m sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) has been used to help surgeons explore the location of parathyroid diseases, but quantitative parameters have not been systemically investigated for this purpose. We aimed to establish objective criteria for adenoma and hyperplasia using the standardized uptake value (SUV) in patients with hyperparathyroidism.

Thirty-nine hyperparathyroid patients (male/female: 17/22, age: 58.33 ± 11.69 years) with at least 1 uptake-positive lesion of any degree by visual assessment in preoperative Tc-99m sestamibi quantitative SPECT/CT were included from Oct 2015 to Oct 2017. Pathologically, 44 lesions (32 adenomas and 12 hyperplasia) were identified. All patients experienced normalized levels of intact parathyroid hormone immediately after surgery. Quantitative SPECT/CT was performed at 10 minute and 2 hour post injection of Tc-99m sestabmibi (dose = 740 MBq), and maximum SUV (SUVmax) was measured for the parathyroid lesions. Experienced pathologists evaluated the percentage cellular proportions of chief cells, oxyphil cells, and clear cells.

SUVmax (g/mL) of adenomas, hyperplasia, and reference thyroid tissue were 12.92 ± 6.68, 7.90 ± 5.49, and 7.01 ± 2.62 at 10min (early phase), decreasing to 7.46 ± 5.66, 4.65 ± 3.14, and 2.21 ± 1.07 at 2 hour (delayed phase), respectively. The adenomas showed significantly higher SUVmax than both the hyperplasia (P = .0131) and reference thyroid tissue (P < .0001) along the early and delayed phases, but the SUVmax of the hyperplasia did not differ from that of the reference thyroid tissue (P = .4196). The adenomas and hyperplasia were discriminated from the reference thyroid tissue using a cutoff SUVmax of 3.26 at the delayed phase. The adenomas had lower %proportions of oxyphil cells than the hyperplasia (P = .0054), but its SUVmax at the delayed phase was positively correlated with the %proportions of mitochondria-abundant oxyphil cells (rho = 0.418, P = .0173). The hyperplasia showed no correlation between SUVmax and cellular proportions.

SUVmax at the delayed phase in the Tc-99m sestamibi quantitative SPECT/CT was useful for the identification and differentiation of parathyroid lesions causing hyperparathyroidism.
A comparison of the efficacy and safety of complementary and alternative therapies for ulcerative colitis
Authors: Lu Meiqi , Zhang Ting , Lu Zhen , Wang Wei , Chen Ting , Cao Zhiqun
Published: July 2020

Background:

The incidence of ulcerative colitis (UC) is increasing year by year worldwide, and it is listed as one of the refractory diseases by World Health Organization. In addition to typical intestinal manifestations such as abdominal pain, diarrhea, mucus, pus, and bloody stool, it can also accompany multiorgan and multisystem extraintestinal manifestations, seriously affecting the life and work of patients. Furthermore, UC patients with a tremendous psychological pressure and affects their physical and mental health. In recent years, many complementary and alternative therapies have been used for treatment of UC, but only pair-wised drugs have been evaluated in the traditional meta-analyses and some results are inconsistent. Consequently, it is essential to propose a protocol for systematic review and meta-analysis to discuss the efficacy and safety of complementary and alternative therapies in the treatment of UC.

Methods:

We will search Chinese and English databases comprehensively and systematically from the establishment of databases to May 2020, free of language or publication restrictions. All randomized controlled trials on complementary and alternative therapies for UC will be included. Two researchers will independently screen titles, abstracts, full texts, and extract data, then assess the bias risk of each study. We will conduct pairwise meta-analyses and Bayesian network meta-analyses to the relative outcomes of the efficacy and safety. Data analysis will use STATA and WinBUGs 1.4.3 software in this meta-analysis.

Results:

This study will evaluate the efficacy and safety of complementary and alternative therapies for UC based on changes in symptoms, clinical efficacy, quality of life and adverse events.

Conclusion:

This study will provide evidence for whether complementary and alternative therapies are beneficial to the treatment of UC. In order to provide reliable evidence-based medicine for clinical practice.

INPLASY registration number:

INPLASY202060015
Tibial intramedullary nailing in the lateral decubitus position
Authors: Xu Lei , Zhu Wanbo , Xie Kai , Liu Lei , Zhang Xianzuo , Yang Jiazhao , Wang Xujin , Fang Shiyuan
Published: July 2020

Background:

Traditional intramedullary nailing (IMN) for tibial shaft fractures through an infrapatellar approach is typically performed in the supine position and requires a specially designed operative table and an experienced assistant throughout the surgery. We attempted to perform IMN for tibial fractures in the lateral decubitus position to make the process easier both for surgeons and radiographers.

Methods:

A total of 36 tibial IMN procedures were performed with the patient in the lateral position from May 1, 2014 to April 30, 2016. The technical feasibility and early results were evaluated.

Results:

The mean time to complete the nailing procedure during surgery was 78.4 ± 1.1 min. The mean intraoperative time for fluoroscopy was 36.7 ± 1.1 min. No radiographic angular malalignment or bone non-union was reported. No surgical site infections or other surgery-related complications occurred in our series.

Conclusion:

Tibial IMN through an infrapatellar approach in the lateral decubitus position may be a valuable alternative as it simplifies the procedure for both surgeons and radiographers. This technique is highly effective for surgical operation and fluoroscopy compared to traditional supine position. This technique also seems to provide satisfactory clinical and radiographic outcomes in our preliminary clinical outcomes.
An uncommon manifestation of COVID-19 pneumonia on CT scan with small cavities in the lungs
Authors: Chen Jinqing , Peng Song , Zhang Bangjun , Liu Zhifeng , Liu Lang , Zhang Wendy
Published: July 2020

Rationale:

Chest computed tomography (CT) scans play a key role in diagnosing and managing of COVID-19 pneumonia. The typical manifestations of COVID-19 pneumonia on a chest CT scan are ground glass opacities, consolidation, nodules, and linear opacities. It can be accompanied by a “crazy-paving” pattern, air bronchograms, pleural hypertrophy, and pleural effusion. However, no literature has reported a case with cavities in the lungs.

Patient concerns:

A 34-year-old male patient complained of fever, cough, fatigue, myalgia, diarrhea, headache, and dizziness for 2 weeks. This patient is living in Xiaogan, a city around Wuhan, and he had contact with a patient with COVID-19 pneumonia from Wuhan <14 days before he had fever.

Diagnosis:

A nucleic acid test by rRT-PCR returned positive on a pharyngeal swab, confirming the diagnosis of COVID-19 pneumonia.

Interventions:

Isolation antiviral treatment.

Outcomes:

After 19 days of isolation and antiviral treatment, his temperature returned to normal and the symptoms were relieved. The laboratory results also were returning to normal levels. The chest CT scan showed that the acute inflammation had subsided significantly. With 2 consecutive novel coronavirus nucleic acid tests had returned negative, the patient was discharged from the hospital and sent to a government designated hotel for quarantine observation. The unique chest CT manifestation in this case was the small cavities in both lungs during the absorption phase of this disease. These small cavities developed into consolidated nodules with clear edges and gradually shrank or disappeared.

Lessons:

Although 2 consecutive nucleic acid tests returned negative in this patient, the small cavity changes in the lungs were observed, so the patient was quarantined for 14 days. However, follow-up CT after the first 14 days’ quarantine showed new small cavity changes on the lungs, a further 14 days of quarantine was recommended. Therefore, in some COVID-19 cases, even if the nucleic acid tests turns negative, the disappearance of lung lesions may take a long time. The repeated chest CT scan plays an important role in the diagnosis and evaluation of the recovery of COVID-19.
Defining the “Tipping Point” to Success as a Surgeon–scientist
Authors: Emamaullee Juliet , Lian Tiffany , Moroz Stacy , Zuckerbraun Brian , Matthews Jeffrey , Gosain Ankush
Published: July 2020

Background:

Since 2005, the American College of Surgeons has administered the Jacobson Promising Investigator Award (JPIA), which recognizes surgeon-scientists at the “tipping point” of their research careers.

Objective:

We retrospectively reviewed JPIA applicants to identify factors associated with selection for the award and future research success.

Methods:

Profiles were reviewed for all applicants between 2008 and 2018, at the time of application and as of 2019. Web of Science and NIH Reporter metrics were also reviewed for each applicant.

Results:

Eleven of 97 applicants were selected for the JPIA. At the time of application, awardees were more likely to have extramural (NIH K-award) versus intramural (KL2) or other career development award funding (55% vs 33%, P = 0.03) and more publications [median 70 (interquartile range, IQR 55–100) vs 40 (IQR 22–67), P = 0.03]. Post-application, JPIA awardees were more likely to achieve a higher h-Index and m-quotient compared to nonawardees (P < 0.001 for both). All JPIA recipients received new NIH funding post-award, including 82% with R01 funding, compared to 23% of nonselected applicants (P < 0.0001). Over $48 million from NIH was awarded to JPIA recipients since 2008, representing a 147-fold return on investment.

Conclusions:

Selection for the JPIA is associated with previous extramural NIH K award and, on average, 70 peer-reviewed publications at the time of application. Receipt of the JPIA is associated with a high rate of subsequent NIH R01 funding and publication metrics. The JPIA is an excellent indicator of “tipping point” success in academic surgery and demonstrates the huge potential impact of philanthropic support on early career surgeon-investigators.
Biophysical modeling of the neural origin of EEG and MEG signals
Authors: Næss Solveig , Halnes Geir , Hagen Espen , Hagler Donald J. , Dale Anders M. , Einevoll Gaute T. , Ness Torbjørn V.
Published: July 2020

Electroencephalography (EEG) and magnetoencephalography (MEG) are among the most important techniques for non-invasively studying cognition and disease in the human brain. These signals are known to originate from cortical neural activity, typically described in terms of current dipoles. While the link between cortical current dipoles and EEG/MEG signals is relatively well understood, surprisingly little is known about the link between different kinds of neural activity and the current dipoles themselves. Detailed biophysical modeling has played an important role in exploring the neural origin of intracranial electric signals, like extracellular spikes and local field potentials. However, this approach has not yet been taken full advantage of in the context of exploring the neural origin of the cortical current dipoles that are causing EEG/MEG signals.

Here, we present a method for reducing arbitrary simulated neural activity to single current dipoles. We find that the method is applicable for calculating extracranial signals, but less suited for calculating intracranial electrocorticography (ECoG) signals. We demonstrate that this approach can serve as a powerful tool for investigating the neural origin of EEG/MEG signals. This is done through example studies of the single-neuron EEG contribution, the putative EEG contribution from calcium spikes, and from calculating EEG signals from large-scale neural network simulations. We also demonstrate how the simulated current dipoles can be used directly in combination with detailed head models, allowing for simulated EEG signals with an unprecedented level of biophysical details.

In conclusion, this paper presents a framework for biophysically detailed modeling of EEG and MEG signals, which can be used to better our understanding of non-inasively measured neural activity in humans.

Graphical abstract

Highlights

Current dipoles are computed from biophysically detailed simulated neuron and network activity

Extracted current dipoles allow for accurate computation of EEG and MEG signals in simplified and detailed head models

Current-diplole approximation generally not suitable for accurate calculations of ECoG signals

Method provides biophysics-based link between detailed neural activity and systems-level signals
DNA methylation analysis of amplicons from individuals exposed to maternal tobacco use during pregnancy, and offspring conduct problems in childhood and adolescence
Authors: Noble Alexandra J. , Pearson John F. , Noble Alasdair D. , Boden Joseph M. , Horwood L. John , Kennedy Martin A. , Osborne Amy J.
Published: July 2020

Maternal tobacco smoking during pregnancy is a large driver of health inequalities and a higher prevalence of conduct problem has been observed in exposed offspring. Further, maternal tobacco use during pregnancy can also alter offspring DNA methylation. However, currently, limited molecular evidence have been found to support this observation. Thus we aim to examine the association between maternal tobacco use in pregnancy and whether offspring Conduct problems is mediated by tobacco exposure-induced via DNA methylation differences. Understanding the etiology of the causal link will be crucial in the early identification and treatment of CP in children and adolescents. DNA was sourced from the Christchurch Health and Development Study, a longitudinal birth cohort studied for over 40 years in New Zealand. Bisulfite-based amplicon sequencing of 10 loci known to play a role in neurodevelopment, or with associations with CP phenotypes, was undertaken. We identified nominally significant differential DNA methylation at specific CpG sites inCYP1A1, ASH2LandMEF2Cin individuals with Conduct problems who were exposed to tobaccoin utero.We conclude that environmentally-induced DNA methylation differences could play a role in the observed link between maternal tobacco use during pregnancy and childhood/adolescent Conduct problems However, larger sample sizes are needed to produce an adequate amount of power to investigate this interaction further.
Stability of the pH-Dependent Parallel-Stranded d(CGA) Motif
Authors: Luteran E. M. , Kahn J. D. , Paukstelis P. J.
Published: July 2020

Non-canonical DNA structures that retain programmability and structural predictability are increasingly being used in DNA nanotechnology applications, where they offer versatility beyond traditional Watson-Crick interactions. The d(CGA) triplet repeat motif is structurally dynamic and can transition between parallel-stranded homo-base paired duplex and anti-parallel unimolecular hairpin in a pH-dependent manner. Here, we evaluate the thermodynamic stability and nuclease sensitivity of oligonucleotides composed of the d(CGA) motif and several structurally related sequence variants. These results show that the structural transition resulting from decreasing the pH is accompanied by both a significant energetic stabilization and decreased nuclease sensitivity as unimolecular hairpin structures are converted to parallel-stranded homo-base paired duplexes. Furthermore, the stability of the parallel-stranded duplex form can be altered by changing the 5′-nucleobase of the d(CGA) triplet and the frequency and position of the altered triplets within long stretches of d(CGA) triplets. This work offers insight into the stability and versatility of the d(CGA) triplet repeat motif and provides constraints for using this pH-adaptive structural motif for creating DNA-based nanomaterials.

STATEMENT OF SIGNIFICANCE

This article addresses the stability of the d(CGA) triplet motif and variants in solution. Our study reveals changes in thermodynamic stability and nuclease resistance in response to pH. The identity of the 5′-nucleobase within each triplet and the position and frequency of different triplets within stretches of d(CGA) triplets can tune parallel-stranded duplex stability. This tunability can be used for nanotechnological applications where the specificity of the 5′-nucleobase pairing interaction is used to order of long stretches of d(CGA) triplets. These results can inform the rational design of pH-sensitive structurally switchable DNA-based nanomaterials.
Heart Snapshot: a broadly validated smartphone measure of VO2max for collection of real world data
Authors: Webster Dan E. , Tummalacherla Meghasyam , Higgins Michael , Wing David , Ashley Euan , Kelly Valerie E. , McConnell Michael V. , Muse Evan D. , Olgin Jeff , Mangravite Lara , Godino Job , Kellen Michael , Omberg Larsson
Published: July 2020

Expanding access to precision medicine will increasingly require that patient biometrics can be measured in remote care settings. VO2max, the maximum volume of oxygen usable during intense exercise, is one of the most predictive biometric risk factors for cardiovascular disease, frailty, and overall mortality.1,2However, VO2max measurements are rarely performed in clinical care or large-scale epidemiologic studies due to the high cost, participant burden, and need for specialized laboratory equipment and staff.3,4To overcome these barriers, we developed two smartphone sensor-based protocols for estimating VO2max: a generalization of a 12-minute run test (12-MRT) and a submaximal 3-minute step test (3-MST). In laboratory settings, Lins concordance for these two tests relative to gold standard VO2max testing waspc=0.66 for 12-MRT andpc=0.61 for 3-MST. Relative to “silver standards”5(Cooper/Tecumseh protocols), concordance waspc=0.96 andpc=0.94, respectively. However, in remote settings, 12-MRT was significantly less concordant with gold standard (pc=0.25) compared to 3-MST (pc=0.61), though both had high test-retest reliability (ICC=0.88 and 0.86, respectively). These results demonstrate the importance of real-world evidence for validation of digital health measurements. In order to validate 3-MST in a broadly representative population in accordance with theAll of UsResearch Program6for which this measurement was developed, the camera-based heart rate measurement was investigated for potential bias. No systematic measurement error was observed that corresponded to skin pigmentation level, operating system, or cost of the phone used. The smartphone-based 3-MST protocol, here termedHeart Snapshot, maintained fidelity across demographic variation in age and sex, across diverse skin pigmentation, and between iOS and Android implementations of various smartphone models. The source code for these smartphone measurements, along with the data used to validate them,6are openly available to the research community.
Simultaneous quantification of mRNA and protein in single cells reveals post-transcriptional effects of genetic variation
Authors: Brion Christian , Lutz Sheila , Albert Frank W.
Published: July 2020

Trans-acting DNA variants may specifically affect mRNA or protein levels of genes located throughout the genome. However, prior work comparedtrans-acting loci mapped in studies performed separately or with limited statistical power. Here, we developed a CRISPR-based system for simultaneous quantification of mRNA and protein of a given gene via dual fluorescent reporters in single, live cells of the yeastSaccharomyces cerevisiae. In large populations of recombinant cells from a cross between two genetically divergent strains, we mapped 86trans-acting loci affecting the expression of ten genes. Less than 20% of these loci had concordant effects on mRNA and protein of the same gene. Most loci influenced protein but not mRNA of a given gene. One such locus harbored a premature stop variant in theYAK1kinase gene that had specific effects on protein or mRNA of dozens of genes. These results demonstrate complex, post-transcriptional genetic effects on gene expression.

One sentence summary

A CRISPR-based dual reporter assay enables genetic mapping of DNA variants that specifically affect mRNA or protein levels intrans.
A free boundary mechanobiological model of epithelial tissues
Authors: Tambyah Tamara A. , Murphy Ryan J. , Buenzli Pascal R. , Simpson Matthew J.
Published: July 2020

In this study, we couple intracellular signalling and cell–based mechanical properties to develop a novel free boundary mechanobiological model of epithelial tissue dynamics. Mechanobiological coupling is introduced at the cell level in a discrete modelling framework, and new reaction–diffusion equations are derived to describe tissue–level outcomes. The free boundary evolves as a result of the underlying biological mechanisms included in the discrete model. To demonstrate the accuracy of the continuum model, we compare numerical solutions of the discrete and continuum models for two different signalling pathways. First, we study the Rac–Rho pathway where cell– and tissue–level mechanics are directly related to intracellular signalling. Second, we study an activator–inhibitor system which gives rise to spatial and temporal patterning related to Turing patterns. In all cases, the continuum model and free boundary condition accurately reflect the cell–level processes included in the discrete model.
A combined microphysiological-computational omics approach in dietary protein evaluation
Authors: Jochems Paulus G.M. , Keusters Willem R. , America Antoine H.P. , Rietveld Pascale C.S. , Bastiaan-Net Shanna , Ariëns Renata M.C. , Tomassen Monic M.M. , Lewis Fraser , Li Yang , Westphal Koen G.C. , Garssen Johan , Wichers Harry J. , van Bergenhenegouwen Jeroen , Masereeuw Rosalinde
Published: July 2020

The ever-growing world population puts pressure on food security. To tackle this, waste stream proteins and novel protein sources need to be evaluated for nutritional value, which requires information on digesta peptide composition in comparison to established protein sources and coupling to biological parameters. Here, we present a novel combined experimental and computational approach comparing seventeen protein sources with cow’s whey protein (WPC) as benchmark.In vitrodigestion was followed by proteomics analysis and statistical model clustering based on Bayesian Information Criterion. Next, we incorporated functional protein data after evaluating the effects of eighteen protein digests on intestinal barrier integrity, viability, brush border enzyme activity and immune parameters using a bioengineered intestine. Our data show that a holistic approach allows evaluating a dietary protein’s potential for delivery of bioactive peptides, where protein source (animal, plant or novel source-derived) does not seem to be the driving force for clustering.
Highly Sensitive Detection ofCampylobacter spp.in Chicken Meat using a Silica Nanoparticle Enhanced Dot Blot DNA Biosensor
Authors: Vizzini Priya , Manzano Marisa , Farre Carole , Meylheuc Thierry , Chaix Carole , Ramarao Nalini , Vidic Jasmina
Published: July 2020

Paper-based DNA biosensors are powerful tools in point-of-care diagnostics since they are affordable, portable, user-friendly, rapid and robust. However, their sensitivity is not always as high as required to enable DNA quantification. To improve the response of standard dot blots, we have applied a new enhancement strategy that increases the sensitivity of assays based on the use of biotinylated silica-nanoparticles (biotin-Si-NPs). After immobilization of a genomicCampylobacterDNA onto a paper membrane, and addition of a biotinylated-DNA detection probe, hybridization was evidenced using streptavidin-conjugated to horseradish peroxidase (HRP) in the presence of luminol and H2O2. Replacement of the single biotin by the biotin-Si-NPs boosted on average a 30 fold chemiluminescent read-out of the biosensor. Characterization of biotin-Si-NPs onto a paper with immobilized DNA was done using a scanning electron microscope. A limit of detection of 3 pg/μL of DNA, similar to the available qPCR kits, is achieved, but it is cheaper, easier and avoids inhibition of DNA polymerase by molecules from the food matrices. We demonstrated that the new dot blot coupled to biotin-Si-NPs successfully detectedCampylobacterfrom naturally contaminated chicken meat, without needing a PCR step. Hence, such an enhanced dot blot paves the path to the development of a portable and multiplex paper based platform for point-of-care screening of chicken carcasses forCampylobacter.

Graphical abstract
Peopling of Tibet Plateau and multiple waves of admixture of Tibetans inferred from both modern and ancient genome-wide data
Authors: Wang Mengge , Zou Xing , Ye Hui-Yuan , Wang Zheng , Liu Yan , Liu Jing , Wang Fei , Yao Hongbin , Chen Pengyu , Tao Ruiyang , Wang Shouyu , Wei Lan-Hai , Tang Renkuan , Wang Chuan-Chao , He Guanglin
Published: July 2020

Archeologically attested human occupation on the Tibet Plateau (TP) can be traced back to 160 thousand years ago (kya, Xiahe) via archaic people and 30~40 kya via anatomically modern human in Nwya Devu. However, the past human movements and peopling of the TP keep in its infancy in the modern/ancient DNA studies. Here, we performed the first modern/ancient genomic meta-analysis among 3,017 Paleolithic to present-day eastern Eurasian genomes (2,444 modern individuals from 183 populations (including 98 Ü-Tsang/Ando/Kham Tibetans) and 573 ancients (including 161 Chinese ancients first meta-analyzed here)). Closer genetic connection between ancient-modern highland Tibetans and lowland island/coastal Neolithic northern East Asians was identified, reflecting the main ancestry of high-altitude Tibeto-Burman speakers originated from the ancestors of Houli/Yangshao/Longshan ancients in the middle and lower Yellow River basin, consistent with the common North-China origin of Sino-Tibetan language and dispersal pattern of millet farmers. Although the shared common northern East Asian lineage between Tibetans and lowland East Asians, we still identified genetic differentiation between Highlanders and lowland northern East Asians, the former harboring more deeply diverged Hoabinhian/Onge ancestry and the latter possessing more modern Neolithic southern East Asian and Siberian ancestry, which suggested the co-existence of Paleolithic and Neolithic ancestries in modern and Neolithic East Asian Highlanders. Tibetans from Ü-Tsang/Ando/Kham Tibetan regions showed strong population stratifications consistent with their cultural backgrounds and geographic terrains (showed as barriers for human movements): stronger Chokhopani affinity in Ü-Tsang Tibetans, more western Eurasian ancestry in Ando and greater Neolithic southern East Asian ancestry in Kham Tibetan. Modern combined ancient genomes documented multiple waves of human migrations in TP past: the first layer of local Hunter-Gatherer mixed with Qijia Farmer arose the Chokhopani-associated Proto-Tibetan-Burman, admixture with the additional genetic materials from the western Eurasian steppe, Yellow River and Yangtze River respectively gave rise to modern Ando, Ü-Tsang and Kham Tibetans.
Can we improve slow learning in cerebellar patients?
Authors: Hulst Thomas , Mamlins Ariels , Frens Maarten , Chang Dae-In , Göricke Sophia L. , Timmann Dagmar , Donchin Opher
Published: July 2020

Cerebellar patients are impaired in motor adaptation. Further, motor adaptation can be divided into a fast component and a slow component, and the cerebellum is known to be especially crucial for the slow component. We tested whether the cerebellar deficit in motor adaptation can be ameliorated by training paradigms targeting slow learning using four visuomotor tasks: standard, gradual, overlearning and long intertrial intervals. We measured slow learning in patients and age-matched controls using a standard paradigm developed for reaching movements by Smith in 2006. The paradigm quantifies slow learning as the magnitude of spontaneous recovery of a previously learned and washed-out adaptation. Cerebellar patients had slower learning and reached a lower level of final adaptation, as seen in previous studies. Nevertheless, both groups had robust spontaneous recovery. Moreover, spontaneous recovery was increased in both groups in the overlearning paradigm with no significant difference between them. Computational modeling suggested that increased spontaneous recovery in the Control group reflects a changed slow adaptation system. That is, in the overlearning in controls, the slow system forgot more slowly and had a slower response to errors. In contrast, the same modeling suggests that no such change in the slow system occurred in the Cerebellar group. Rather, increased spontaneous recovery in this group seems to be the result of greater accumulated slow adaptation in the overlearning. We used our modeling results to predict that overlearning should have slower adaptation in the counterperturbation. Modeling further suggested we would not see these difference in the cerebellar patients. Follow-up analysis confirmed these model predictions. Taken together, our results imply that residual slow learning in cerebellar patients is expressed during increased training trials, but the primary cerebellar deficit is not improved.
From Chemoproteomic-Detected Amino Acids to Genomic Coordinates: Insights into Precise Multi-omic Data Integration
Authors: Palafox Maria F. , Arboleda Valerie A. , Backus Keriann M.
Published: July 2020

The integration of proteomic, transcriptomic, and genetic-variant annotation data will improve our understanding genotype-phenotype associations. Due, in part, to challenges associated with accurate inter-database mapping, such multi-omic studies have not extended to chemoproteomics, a method that measure the intrinsic reactivity and potential ‘druggability’ of nucleophilic amino acid side chains. Here, we evaluated two mapping approaches to match chemoproteomic-detected cysteine and lysine residues with their genetic coordinates. Our analysis reveals that databases update cycles and reliance on stable identifiers can lead to pervasive misidentification of labeled residues. Enabled by this examination of mapping strategies, we then integrated our chemoproteomic data within silicogenerated predictions of genetic variant pathogenicity, which revealed that codons of highly reactive cysteines are enriched for genetic variants that are predicted to be more deleterious. Our study provides a roadmap for more precise inter-database comparisons and points to untapped opportunities to improve the predictive power of pathogenicity scores and to advance prioritization of putative druggable sites through integration of predictions of pathogenicity with chemoproteomic datasets.
Low cell number proteomic analysis using in-cell protease digests reveals a robust signature for cell cycle state classification
Authors: Van Kelly , al-Rawi Aymen , Lewis David , Kustatscher Georg , Ly Tony
Published: July 2020

Comprehensive proteome analysis of rare cell phenotypes remains a significant challenge. We report a method for low cell number mass spectrometry (MS)-based proteomics using protease digestion of mildly formaldehyde-fixed cellsin cellulo, which we call the ‘in-cell digest’. We combined this with AMPL (Averaged MS1 Precursor Library Matching) to quantitatively characterise proteomes from low cell numbers of human lymphoblasts. 4,500 proteins were detected from 2,000 cells and 2,500 proteins were quantitated from 200 lymphoblasts. The ease of sample processing and high sensitivity makes this method exceptionally suited for the proteomic analysis of rare cell states, including immune cell subsets and cell cycle subphases.

To demonstrate the method, we characterised the proteome changes across 16 cell cycle states isolated from an asynchronous TK6 human lymphoblast culture, avoiding synchronization. States included late mitotic cells present at extremely low frequency. We identified 119 pseudoperiodic proteins (PsPs) that vary across the cell cycle. Clustering of the PsPs showed abundance patterns consistent with ‘waves’ of protein degradation in late S, at the G2&M border, mid-mitosis and at mitotic exit. These clusters were distinguished by significant differences in predicted nuclear localization and interaction with the APC/C. The dataset also identifies putative APC/C substrates in mitosis and the temporal order in which they are targeted for degradation.

We demonstrate that a protein signature made of these 119 high confidence cell cycle regulated proteins can be used to perform unbiased classification of proteomes into cell cycle states. We applied this signature to 296 proteomes that encompass a range of quantitation methods, cell types, and experimental conditions. The analysis confidently assigns a cell cycle state for 49 proteomes, including correct classification for proteomes from synchronized cells. We anticipate this robust cell cycle protein signature will be crucial for classifying cell states in single cell proteomes.