bluuebunny/crossref_metadata_2025 huggingface dataset:
Acupuncture for postoperative pain of lumbar disc herniation: A systematic review and meta-analysis
Authors: Zhang Weidong , Liu Huan , Le Xuezhen , Song Kunyu , Yang Fo , Cui Zhenhai , Zhao Wenhai
Published: January 2023

Background:

Evidence for the effects of acupuncture on postoperative pain of Lumbar disc herniation (LDH) is inconsistent. We conducted this systematic review and meta-analysis to evaluate the efficacy of acupuncture for postoperative pain of LDH.

Methods:

We performed a comprehensive search on PubMed, Embase, Web of Science, Cochrane Central, and four Chinese databases (CNKI, Wan Fang, CBMdisc, and VIP) for articles published before September 2021. The data extraction table was made for the ten included studies, and the risk of bias was assessed using the Cochrane collaboration tool, followed by statistical analysis using RevMan 5.3.

Results:

A total of ten studies involving 838patients were included. The statistical meta-analysis showed that acupuncture treatment was significantly better than drugs in improving cure rate (OR = 2.24, 95% CI = [1.58, 3.19], P < .00001) and the total effectiveness rate (OR = 4.85, 95% CI = [2.59, 9.08], P < .00001). And the results from the meta-analysis showed that acupuncture group was superior to control group in debasing visual analog scale score (MD = −1.26, 95% CI = [−1.72, −0.79], P < .00001) and improving Japanese Orthopaedic Association score (MD = 4.21, 95% CI = [1.53, 6.90], P < .00001). In addition, acupuncture was statistically significantly better than drugs (OR = 0.27, 95% CI = [0.11, 0.62], P = .002) in the incidence of adverse events, However, there was no statistically significant difference between acupuncture and rehabilitation (OR = 0.36, 95% CI = [0.07, 1.98], P = .24).

Conclusion:

Acupuncture is an effective and safe treatment for postoperative pain of LDH. It can be recommended to manage patients with postoperative pain of LDH. However, considering the unsatisfactory quality of the included studies, more high-quality randomized controlled trials with a large sample size are needed to elucidate this issue.
Risk factors for new vertebral compression fracture after kyphoplasty and efficacy of osteoporosis treatment: A STROBE-compliant retrospective study
Authors: Choi Sang Sik , Kim Heezoo , Choung Yoo Jin , Jeong Sung Jin , Lee Chung Hun
Published: January 2023

Kyphoplasty (KP) has been widely used to treat vertebral compression fractures (VCFs). However, the issue of new VCFs after KP remains controversial. Identification of risk factors for new VCF after KP may help prevent their occurrence in patients. This study aimed to retrospectively determine the major risk factors for new VCF after KP, including those associated with osteoporosis drugs used after kyphoplasty. We reviewed 117 patients who underwent single-level KP. During the follow-up period of 1 year after KP, the demographic data of these patients were compared by dividing them into two groups: those with new fractures (n = 19) and those without new fractures (n = 98). We investigated the age, sex, fracture location, medical history, steroid use history, bone mineral density (BMD), type of osteoporosis treatment, period from fracture to KP, KP method (unilateral or bilateral), bone cement dose, intradiscal cement leakage, preoperative and postoperative compression ratio, kyphotic angle (KA), and lowest vertebral body height in the fractured vertebrae. Based on these data, the factors related to new VCFs after KP were investigated using univariate and multivariate logistic regression analyses. We also investigated whether there were differences in new VCFs according to the type of osteoporosis treatment. During the 1-year follow-up period after KP, the rate of new VCFs was 16.2%. Factors related to new VCFs were BMD, intradiscal cement leakage, KA recovery rate after 1 day, and baseline height in the univariate and multivariate logistic regression analyses. The group treated with zoledronate after KP tended to show a lower frequency of developing new VCFs than the groups treated with alendronate (P = .07), calcium (P = .05), selective estrogen receptor modulator (SERM) (P = .15), and risendronate (P = .02). This study showed that for patients with new VCFs after KP, lower BMD, greater intradiscal cement leakage, greater KA recovery rate, and lower baseline vertebral height were likely risk factors for the development of new VCFs. Additionally, among the drugs used for the treatment of osteoporosis after KP, zoledronate tends to reduce the development of new VCFs compared with other bisphosphonates, SERMs, or calcium.
TCM syndrome differentiation and treatment of narcolepsy based on neurobiological mechanism: A review
Authors: Liu Zhao , Guan Ruiqian , Pan Limin
Published: January 2023

Narcolepsy is a relatively rare brain disorder caused by the selective loss of orexin neurons. Narcolepsy is divided into Narcolepsy Type 1 (NT1) and Narcolepsis Type 2 (NT2). The pathogenesis of NT1 has been well established due to the severe loss of orexin neurons, while NT2 is still poorly understood, and little is known about its underlying neurobiological mechanisms. human leukocyte antigen alleles have been found to strongly influence the development of narcolepsy, with more than 90% of NT1 patients carrying the human leukocyte antigen II allele DQB1*06:02. In addition to the genetic evidence for the DQBI*06:02 allele, some other evidence suggests that a T cell-mediated immune mechanism destroys the orexin neurons of NT1, with CD4 + T cells being key. For this disease, traditional Chinese medicine (TCM) therapy has its own characteristics and advantages, especially the combination of acupuncture and medicine in the treatment of this disease in TCM, which has made considerable and gratifying progress. The purpose of this review is to introduce the frontier progress of neurobiology of narcolepsy, and to explore the syndrome differentiation and treatment of narcolepsy with the combined use of TCM and Western medicine combined with TCM.
Mediating effects of self-esteem on the relationship between mindful parenting and social anxiety level in Chinese adolescents
Authors: Chong-Wen Wu , Sha-Sha Li , Xu E
Published: January 2023

This study aimed to investigate the relationship between mindful parenting and social anxiety level in Chinese adolescents and to explore the mediating roles of self-esteem between mindful parenting and social anxiety level. A total of 302 adolescents and their main caregivers were investigated by using the Chinese version of the Mindful Parenting Scale, Self-Esteem Scale and the Center for Epidemiological Studies Depression Scale and the Social Anxiety Scale. Related analysis was used to investigate the relationship between mindful parenting, self-esteem and social anxiety level. Mindful parenting and self-esteem were significantly associated with social anxiety level. Self-esteem mediated the relationship between mindful parenting and social anxiety level. Both mindful discipline and being in the moment influenced adolescents’ social anxiety level through self-esteem. Self-esteem completely mediated the association between mindful parenting and social anxiety level. Longitudinal research is needed to better understand the relationship between mindful parenting and social anxiety level in adolescents.
A case report of maturity-onset diabetes of the young (MODY12) in a Chinese Han patient with a novel ABCC8 gene mutation
Authors: Wang Yuan , Kang Chao , Tong Qiang , Wang Hui , Zhang Rui , Qiao Qiao , Sang Qian , Wang Xiaocui , Wang Jian , Xu Jing
Published: January 2023

Rationale:

Maturity onset diabetes of the young (MODY) is the most common type of monogenic diabetes, characterized by autosomal dominant inheritance, the age of onset is often <25 years old, and the clinical manifestations are atypical. MODY12 is caused by a rare missense mutation of adenosine triphosphate (ATP)-binding cassette transporter subfamily C member 8 (ABCC8) gene and more than 50 ABCC8 variants were associated with MODY12.

Patient concerns:

The patient was a 30-year-old Chinese Han man. He was overweight with a poor control of blood glucose.

Diagnoses:

The patient was diagnosed with MODY12.

Interventions:

The patient was given glimepiride (4 mg/d) with diet and exercise therapy to reduce blood glucose and weight.

Outcomes:

The level of fasting blood glucose and C-peptide was improved after 1 year treatment as well as body weight.

Lessons:

A Chinese Han adult with a heterozygous missense mutation c.3976G > A (p.Glu1326Lys) was diagnosed with MODY12, which was the new pathogenic mutation for the disease. This report expands the spectrum of variants causing MODY12 and reduces misdiagnosis.
Treatment of Alzheimer’s disease by combination of acupuncture and Chinese medicine based on pathophysiological mechanism: A review
Authors: Liu Zhao , Guan Ruiqian , Bu Fan , Pan Limin
Published: January 2023

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by neurodegeneration, nerve loss, neurofibrillary tangles, and Aβ plaques. In modern medical science, there has been a serious obstacle to the effective treatment of AD. At present, there is no clinically proven and effective western medicine treatment for AD. The reason is that the etiology of AD is not yet fully understood. In 2018, the international community put forward a purely biological definition of AD, but soon this view of biomarkers was widely questioned, because the so-called AD biomarkers are shared with other neurological diseases, the diagnostic accuracy is low, and they face various challenges in the process of clinical diagnosis and treatment. Nowadays, scholars increasingly regard AD as the result of multimechanism and multicenter interaction. Because there is no exact Western medicine treatment for AD, the times call for the comprehensive treatment of AD in traditional Chinese medicine (TCM). AD belongs to the category of “dull disease” in TCM. For thousands of years, TCM has accumulated a lot of relevant treatment experience in the process of diagnosis and treatment. TCM, acupuncture, and the combination of acupuncture and medicine all play an important role in the treatment of AD. Based on the research progress of modern medicine on the pathophysiology of AD, this paper discusses the treatment of this disease with the combination of acupuncture and medicine.
Effectiveness of interleukin-17A inhibitors in patients with ankylosing spondylitis: A protocol for systematic review and meta-analysis
Authors: Yan Mingguang , Fang Xiao , Guo Jianjun , Yin Weibing
Published: January 2023

Background:

Ankylosing spondylitis is a chronic immune-mediated inflammatory arthritis. Interleukin-17A (IL-17A) inhibitors is recognized as a novel therapeutic target for ankylosing spondylitis. However, there is still a lack of high-quality research evidence regarding the issues. Therefore, we performed a protocol for systematic review and meta-analysis to evaluate the efficacy and safety of IL-17A inhibitors in patients with ankylosing spondylitis.

Methods:

This protocol will be conducted under the preferred reporting items for systematic reviews and meta-analyses protocols (PRISMA-P) guidelines. Furthermore, the study has been registered on PROSPERO (CRD42022375885). The following electronic databases will be searched regardless of language and publication status: Pubmed, MEDLINE, EMBASE, China Biomedical Database, China National Knowledge Infrastructure, VIP Database, and Wanfang Database. Cochrane “bias risk” tool is used to assess the bias risk of the quality of the included literature. Data synthesis and statistical analysis will be performed using the RevMan 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) software.

Results:

A synthesis of current evidence of IL-17A inhibitors for ankylosing spondylitis will be shown in this protocol.

Conclusion:

This review can provide convincing evidence to help clinicians make decisions when dealing with ankylosing spondylitis.
Effects of subarachnoid extension following intracerebral hemorrhage: A systematic review and meta-analysis
Authors: Liu Tingzhi , Mai Jilin , Pang Linlin , Huang Ya , Han Jing , Su Weixiang , Chen Kaichang , Qin Peiying
Published: January 2023

Background:

The effects of subarachnoid extension (SAHE) following intracerebral hemorrhage (ICH) have not yet been fully understood. We conducted a systematic review and meta-analysis of published literature on this topic to better understand the effects of SAHE.

Methods:

PubMed, Embase, and Cochrane databases were thoroughly searched from inception to October 16, 2022 to identify studies that evaluated the association between SAHE and mortality and worse functional outcomes in primary ICH. Crude odds ratios (cOR) and adjusted odds ratios (aOR) with 95% confidence interval (CI) were calculated to compare the endpoints.

Results:

Three studies with 3368 participants were eventually included in the analysis. In the short-term follow-up of the primary endpoint, no association was observed between SAHE and mortality (cOR: 0.51, 95% CI: 0.01–28.19; aOR: 2.31, 95% CI: 0.72–7.45). In the long-term follow-up of the primary endpoint, SAHE was associated with a significantly increased mortality of patients with primary ICH (cOR: 3.00, 95% CI: 2.27–3.98); however, only 1 study provided the values of aOR and 95% CI and showed that SAHE was not associated with increased mortality (aOR: 1.14, 95% CI: 0.71–1.83). For the secondary endpoint, the data of only 1 study on major disability (modified Rankin Scale = 3–5) were available, and the results revealed that SAHE increased the probability of major disability, but not after adjusting for baseline hematoma volume.

Conclusion:

There is insufficient evidence to demonstrate the correlation between SAHE and mortality and worse functional outcomes in primary ICH. The validation of this correlation requires further studies as the potential effect and mechanisms of SAHE remain unclear.
A study on the assessment and scoring standard of badminton course in colleges and universities: A review
Authors: Hu Xiaofeng , Jiang Qiaolin
Published: January 2023

With the continuous promotion of quality education, the importance of physical education in college teaching is increasingly prominent. In order to meet the sports needs of different students, badminton courses are introduced in colleges and universities. Badminton not only has a strong entertainment, but also a good physical exercise, loved by students. However, due to the existing badminton class evaluation standard is not scientific and reasonable, which is not conducive to the smooth implementation of physical education, this paper studies the current situation of badminton assessment and scoring standards, points out the existing problems in the teaching process, and gives a new way to improve the assessment and scoring standards of badminton in colleges and universities, in order to provide reference for the assessment system of badminton in colleges and universities, and then improve the teaching effect of badminton.
Clinical pregnancy outcomes prediction in vitro fertilization women based on random forest prediction model: A nested case-control study
Authors: Yang Hongya , Liu Fang , Ma Yuan , Di Man
Published: January 2023

The present study aimed to analyze the risk factors influencing the in vitro fertilization embryo transfer (IVF-ET) pregnancy and to construct a prediction model for clinical pregnancy outcome in patients receiving IVF-ET based on the predictors. In this nested case-control study, the data of 369 women receiving IVF-ET were enrolled. Univariate and multivariate Logistic regression analyses were conducted to identify the potential predictors. Ten-fold cross validation method was used to validate the random forest model for predicting the clinical pregnancy. The receiver operating characteristic curve was drawn to evaluate the prediction ability of the model. The importance of variables was shown according to Mean Decrease Gini. The data delineated that age (odds ratio [OR]= 1.093, 95% confidence interval [CI]: 1.036–1.156, P = .0010), body mass index (BMI) (OR = 1.094, 95%CI: 1.021–1.176, P = .012), 3 cycles (OR = 0.144, 95%CI: 0.028–0.534, P = .008), hematocrit (HCT) (OR = 0.865, 95% CI: 0.791–0.943, P = .001), luteinizing hormone (LH) (OR = 0.678, 95%CI: 0.549–0.823, P < .001), progesterone (P) (OR = 2.126, 95%CI: 1.112–4.141, P = .024), endometrial thickness (OR = 0.132, 95%CI: 0.034–0.496, P = .003) and FSH (OR = 1.151, 95%CI: 1.043–1.275, P = .006) were predictors associated with the clinical pregnancy outcome of patients receiving IVF-ET. The results might provide a novel method to identify patients receiving IVF-ET with a high risk of poor pregnancy outcomes and provide interventions in those patients to prevent the occurrence of poor pregnancy outcomes.
Clinical features and outcome of influenza pneumonia in critically-ill immunocompromised patients
Authors: Raymond Matthieu , Martin Maëlle , Lamouche-Wilquin Pauline , Blonz Gauthier , Decamps Paul , Agbakou Maïté , Desmedt Luc , Reignier Jean , Lascarrou Jean-Baptiste , Canet Emmanuel
Published: January 2023

Immunocompromised subjects are at risk of severe viral infections which may require intensive care unit (ICU) admission. Data on the outcome of influenza pneumonia in critically-ill immunocompromised subjects are limited. We conducted a single-center observational study. All subjects admitted to the ICU for influenza pneumonia between 2016 and 2020 were included. The main objective was to compare the clinical features and outcome of critically-ill subjects with flu according to their immune status. 137 subjects (age 60 years-old, 58.4% male) were included, of whom 58 (42.34%) were intubated during the ICU stay. Forty-three (31.4%) subjects were immunocompromised. Immunocompromised subjects had a higher Charlson comorbidity index. In contrast, severity scores and hypoxemia at ICU admission, and ventilatory support during ICU stay were similar between the 2 groups. There was no difference in the rate of co-infections and ventilator-associated pneumonia between the 2 groups. Among intubated subjects, 10 (23.26%) immunocompromised subjects developed severe acute respiratory distress syndrome compared to 13 (13.83%) non-immunocompromised (P = .218). ICU mortality was 13.97%, with mortality being 3-times higher in immunocompromised subjects (25.58% vs 8.6%, P = .015). On multivariable analysis, immunocompromised status, higher age and lower arterial oxygen partial pressure/fraction of inspired oxygen were associated with an increased ICU mortality. Immunocompromised subjects with severe influenza pneumonia were more likely to develop severe acute respiratory distress syndrome and had a 3-fold increase in ICU mortality compared to non-immunocompromised subjects. Such difference was not explained by an increased rate of co-infections or nosocomial pneumonia, suggesting that influenza virus was by itself responsible of a more severe form of pulmonary disease in immunocompromised subjects.
The effect of vitamin D supplementation on glycemic status and C-reactive protein levels in type 2 diabetic patients with ischemic heart disease: A protocol for systematic review and meta-analysis
Authors: Chai Xuxia , Jin Yonghe , Wei Yongmei , Yang Rong
Published: January 2023

Background:

Vitamin D might be beneficial in diabetic patients with ischemic heart disease through its favorable effect on metabolic profiles and biomarkers of inflammation and oxidative stress. We performed a protocol for systematic review and meta-analysis to assess whether vitamin D supplementation could improve glucose control and inflammation in type 2 diabetic patients with ischemic heart disease.

Methods:

The proposed systematic review and meta-analysis will conform to the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols. Seven electronic databases including Web of Science, Embase, PubMed, Wanfang Data, Scopus, Science Direct, Cochrane Library were searched in October 2022 by 2 independent reviewers. The risk of bias assessment of the included studies was assessed using the tool recommended in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0). Data analysis was performed with Review Manager Software (RevMan Version 5.4, The Cochrane Collaboration, Copenhagen, Denmark).

Results:

This study will provide a high-quality synthesis to assess the effectiveness and safety of vitamin D supplementation on type 2 diabetic patients with ischemic heart disease.

Conclusion:

This systematic review may lead to several recommendations, for both patients and researchers, as which is the best therapy for type 2 diabetic patients with ischemic heart disease and how future studies need to be designed, considering what is available now and what is the reality of the patient.
INSR novel mutations identified in a Chinese family with severe INSR-related insulin resistance syndromes: A case report
Authors: Yu Lu , Yu Fang , Ma Zongrui , Lu Huilin , Luo Jian , Sun Ting , Liu Qin , Gan Shenglian
Published: January 2023

Rationale:

Severe insulin receptor gene (INSR)-related insulin resistance syndromes (SIR) include Donohue syndrome (DS), Rabson–Mendenhall syndrome (RMS), and type A insulin resistance. The incidence of DS is about 1 in 4 million births. We identified novel INSR mutations (c.2246delG and c.2646 + 5G > A) in a patient with SIR, which expanded the variant spectrum and helped to improve the understanding of the diagnosis and treatment of this condition.

Patient concerns:

A 10-year-old Chinese boy was admitted to the hospital for deepening skin color. He presented with growth retardation, peculiar facial features, acanthosis nigricans, hypertrichosis, extremely high insulin levels, fasting hypoglycemia, and postprandial hyperglycemia, Whole-exome gene testing suggested compound heterozygous mutations in INSR (c.2246delG and c.2646 + 5G > A).

Diagnosis:

The diagnosis was SIR. What’s more, based on the phenotypic and biographical results, this child did not present typical RMS and DS but rather an intermediate phenotype between the 2 conditions.

Interventions:

On the basis of a sensible diet and exercise, the patient was prescribed metformin (250 mg) at breakfast and lunch, which was increased to 500 mg after 1 month.

Outcomes:

After 2 months of treatment, the patient’s glycated hemoglobin (HbA1c) levels decreased to 6% but his insulin resistance did not improve significantly.

Lessons:

In children who are not obese but with severe insulin resistance, growth retardation, hirsutism, and hyperglycemia, genetic testing should be performed for early diagnosis, active treatment, and follow-up.
Predictive model of hypoxemia after shoulder arthroscopy: A retrospective observational study
Authors: Lin Fei , Gong Xue , Lei Guangchun , Wang Xiong , Chen Cheng , Zhang Lan
Published: January 2023

The study is aimed to establish a predictive model of hypoxemia after shoulder arthroscopy. The predictive model was based on a retrospective study with 756 patients who underwent shoulder arthroscopic surgery in Sichuan Orthopaedic Hospital from June 2019 to December 2020. Independent risk factors of hypoxemia in the post-anesthesia care unit (PACU) were screened out by the binary logistics regression and the primary predictive model was completed, which was evaluated by the receiver operating characteristic (ROC) curve and Hosmer–Lemeshow goodness-of-fit test. A separate cohort of 324 patients in the PACU from January 2021 to June 2021 was enrolled to validate the predictive model. Seven hundred fifty-six patients and 19 variables were enrolled in the binary logistics regression and 324 patients were validated by the primary predictive model. Logistics regression showed that application of irrigating solution ≥20 L, age, body mass index, and number of B-lines were independent risk factors of hypoxemia in the PACU (P < .05). The risk predictive model of hypoxemia in the PACU was established according to those factors. The model was validated by the Hosmer–Lemeshow test and the area under the curve of ROC was 0.823. The model area under the curve of external effect subject ROC was 0.870. The risk predictive model established in our study can predict the risk of hypoxemia in the PACU well and have good efficacy.
Maximizing opportunities for kidney transplantation in older adults
Authors: Fleetwood Vidya A. , Caliskan Yasar , Rub Fadee Abu Al , Axelrod David , Lentine Krista L.
Published: January 2023

Purpose of review

To summarize the current state of evidence related to the outcomes of older adults who need and receive kidney transplants, and strategies to facilitate appropriate transplant access in this at-risk group.

Recent findings

Older adults are a rapidly growing subgroup of the kidney transplant waitlist. Compared to younger adults, older kidney transplant recipients have increased mortality after kidney transplant and lower death-censored graft survival. In determining suitability for transplantation in older patients, clinicians must balance procedural and immunosuppression-related risk with incremental survival when compared with dialysis. To appropriately increase access to transplantation in this population, clinicians and policy makers consider candidates’ chronological age and frailty, as well as the quality of and waiting time for a donated allograft. Given risk of deterioration prior to transplant, candidates should be rapidly evaluated, listed, and transplanted using living donor and or less than ideal deceased donor organs when available.

Access to transplantation for older adults can be increased through targeted interventions to address frailty and reduce waiting times through optimized organ use. Focused study and educational interventions for patients and providers are needed to improve the outcomes of this vulnerable group.
Opportunities for Improving Motor Assessment and Rehabilitation After Stroke by Leveraging Video-Based Pose Estimation
Authors: Cherry-Allen Kendra M. , French Margaret A. , Stenum Jan , Xu Jing , Roemmich Ryan T.
Published: January 2023

Stroke is a leading cause of long-term disability in adults in the United States. As the healthcare system moves further into an era of digital medicine and remote monitoring, technology continues to play an increasingly important role in post-stroke care. In this Analysis and Perspective article, opportunities for using human pose estimation—an emerging technology that uses artificial intelligence to track human movement kinematics from simple videos recorded using household devices (e.g., smartphones, tablets)—to improve motor assessment and rehabilitation after stroke are discussed. The focus is on the potential of two key applications: (1) improving access to quantitative, objective motor assessment and (2) advancing telerehabilitation for persons post-stroke.
Factors Associated With Diagnostic Error: An Analysis of Closed Medical Malpractice Claims
Authors: Grenon Véronique , Szymonifka Jackie , Adler-Milstein Julia , Ross Jacqueline , Sarkar Urmimala
Published: January 2023

Introduction

Missed and delayed diagnoses have received substantial attention as a quality and patient safety priority. To the extent that electronic health records, team-based care, and other mitigation strategies have been successful in improving diagnosis since the last large-scale study, we would expect that the contributing factors to diagnostic claims may have changed.

Methods

This study sought to examine paid medical malpractice claims as a proxy to identify contributing factors that reflect a clear diagnostic error. Diagnostic error cases with indemnity payments (2009–2020) were identified using the Candello (formerly known as CRICO) proprietary taxonomy. Factors associated with indemnity payments were analyzed using a multivariable logistic regression model.

Results

Of 5367 included claims, 2161 (40%) had indemnity payments. A majority of claims had multiple contributing factors on the diagnostic pathway. In multivariable analysis, factors independently associated with an indemnity payment included the insurer (odds ratio and 95% confidence interval, 2.8 [2.4–3.3]), high injury severity (1.9 [1.3–2.8]) or death (1.5 [0.99–2.1]), and case setting (inpatient (0.77 [0.65–0.91]) or emergency department (0.67 [0.49–0.92])). Importantly, cases with contributing factors outside of Candello’s diagnostic pathway were more likely to lead to indemnity payment.

Conclusions

The digital transformation and acceleration of team-based care in medicine have not mitigated the malpractice risks of complex cases with severe injuries and multiple missteps.
Acute Care Surgery and Surgical Rescue: Expanding the Definition
Authors: Diaz Jose J , Barnes Stephen , O’Meara Lindsay , Sawyer Robert , May Addison , Cullinane Daniel , Schroeppel Thomas , Chipman Amanda , Kufera Joseph , Vesselinov Roumen , Zielinski Martin ,   for the Meridian Study Group
Published: January 2023

Background:

Surgical Rescue (SR) is the recovery of patients with surgical complications. Patients transferred (TP) for surgical diagnoses to higher-level care or inpatients (IP) admitted to nonsurgical services may develop intra-abdominal infection (IAI) and require emergency surgery (ES). The aims were to characterize the SR population by the site of ES consultation, open abdomen (OA), and risk of mortality.

Study Design:

Secondary analysis of an international, multi-institutional prospective observational study of patients requiring ES for IAI. Laparotomy before the transfer was an exclusion criterion. Patients were divided into groups: Clinic/ED (C/ED), IP, or TP. Data collected included demographics, the severity of illness (SOI), procedures, OA, and # of laparotomies. The primary outcome was mortality. Multivariable logistic regression models were constructed.

Results:

There were 752 study patients [C/ED (63.8%), vs. TP (23.4%), & IP (12.8%)], with mean age of 59 and 43.6% female. IP had worse SOI scores (CCI, ASA, and SOFA). The most common procedures were small and large bowel (77.3%). IP and TP had similar rates of OA (IP 52.1% & TP 52.3 %) vs. C/ED (37.7%) (p<0.001) and IP had more relaparotomies (3-4). The unadjusted mortality rate was as highest in IP (n=24,25.0%) vs TP (n=29, 16.5%), and C/ED (n=68, 14.2%) (p=0.03). Adjusting for age and SOI, only SOI had an impact on the risk of mortality. [AUC of 86%]

Conclusions:

IP had the highest unadjusted mortality after ES for IAI and was followed by the TP; SOI drove the risk of mortality. SR must be extended to IP for timely recognition of the IAI.
Reactivity and mechanism in chemical and synthetic biology
Authors: Richards Nigel G. J. , Bearne Stephen L. , Goto Yuki , Parker Emily J.
Published: January 2023

Physical organic chemistry and mechanistic thinking provide a strong intellectual framework for understanding the chemical logic of evolvable informational macromolecules and metabolic transformations in living organisms. These concepts have also led to numerous successes in designing and applying tools to delineate biological function in health and disease, chemical ecology and possible alternative chemistries employed by extraterrestrial life. A symposium at the 2020 Pacifichem meeting was scheduled in December 2020 to discuss designing and exploiting expanded genetic alphabets, methods to understand the biosynthesis of natural products and re-engineering primary metabolism in bacteria. The COVID-19 pandemic led to postponement of in-person discussions, with the symposium eventually being held on 20–21 December 2021 as an online event. This issue is a written record of work presented on biosynthetic pathways and enzyme catalysis, engineering microorganisms with new metabolic capabilities, and the synthesis of non-canonical, nucleobases for medical applications and for studies of alternate chemistries for living organisms. The variety of opinion pieces, reviews and original research articles provide a starting point for innovations that clarify how complex biological systems emerge from the rules of chemical reactivity and mechanism.

This article is part of the themed issue ‘Reactivity and mechanism in chemical and synthetic biology’.
Exploring a chemical scaffold for rapid and selective photoaffinity labelling of non-ribosomal peptide synthetases in living bacterial cells
Authors: Ishikawa Fumihiro , Konno Sho , Uchiyama Yuko , Kakeya Hideaki , Tanabe Genzoh
Published: January 2023

Non-ribosomal peptide synthetases (NRPSs) biosynthesize many pharmaceuticals and virulence factors. The biosynthesis of these natural peptide products from biosynthetic gene clusters depends on complex regulations in bacteria. However, our current knowledge of NRPSs is based on enzymological studies using full NRPS systems and/or a single NRPS domain in heterologous hosts. Chemical and/or biochemical strategies to capture the endogenous activities of NRPSs facilitate studies on NRPS cell biology in bacterial cells. Here, we describe a chemical scaffold for the rapid and selective photoaffinity labelling of NRPSs in purified systems, crude biological samples and living bacterial cells. We synthesized photoaffinity labelling probes coupled with 5′-
O-N
-(phenylalanyl)sulfamoyladenosine with clickable alkyl diazirine or trifluoromethyl phenyl diazirine. We found that a trifluoromethyl phenyl diazirine-based probe cross-linked the Phe-activating domain of a GrsA-NRPS with high selectivity and sensitivity at shorter ultraviolet (UV) irradiation times (less than 5 min) relative to a prototypical benzophenone-based probe. Our results demonstrated that this quick labelling protocol can prevent damage to proteins and cells caused by long UV irradiation times, providing a mild photoaffinity labelling method for biological samples.

This article is part of the theme issue ‘Reactivity and mechanism in chemical and synthetic biology’.
Crystal structures of ‘ALternative Isoinformational ENgineered’ DNA in B-form
Authors: Shukla Madhura S. , Hoshika Shuichi , Benner Steven A. , Georgiadis Millie M.
Published: January 2023

The first structural model of duplex DNA reported in 1953 by Watson & Crick presented the double helix in B-form, the form that genomic DNA exists in much of the time. Thus, artificial DNA seeking to mimic the properties of natural DNA should also be able to adopt B-form. Using a host–guest system in which Moloney murine leukemia virus reverse transcriptase serves as the host and DNA as the guests, we determined high-resolution crystal structures of three complexes including 5′-CTT
BPPBBSSZZS
AAG, 5′-CTT
SSPBZPSZBB
AAG and 5′-CTT
ZZPBSBSZPP
AAG with 10 consecutive unnatural nucleobase pairs in B-form within self-complementary 16 bp duplex oligonucleotides. We refer to this ALternative Isoinformational ENgineered (ALIEN) genetic system containing two nucleobase pairs (
P:Z
, pairing 2-amino-imidazo-[1,2-
a
]-1,3,5-triazin-(8
H
)-4-one with 6-amino-5-nitro-(1
H
)-pyridin-2-one, and
B:S
, 6-amino-4-hydroxy-5-(1
H
)-purin-2-one with 3-methyl-6-amino-pyrimidin-2-one) as ALIEN DNA. We characterized both position- and sequence-specific helical, nucleobase pair and dinucleotide step parameters of
P:Z
and
B:S
pairs in the context of B-form DNA. We conclude that ALIEN DNA exhibits structural features that vary with sequence. Further,
Z
can participate in alternative stacking modes within a similar sequence context as captured in two different structures. This finding suggests that ALIEN DNA may have a larger repertoire of B-form structures than natural DNA.

This article is part of the theme issue ‘Reactivity and mechanism in chemical and synthetic biology’.
Success probability of high-affinity DNA aptamer generation by genetic alphabet expansion
Authors: Kimoto Michiko , Tan Hui Pen , Tan Yaw Sing , Mislan Nur Afiqah Binte Mohd , Hirao Ichiro
Published: January 2023

Nucleic acid aptamers as antibody alternatives bind specifically to target molecules. These aptamers are generated by isolating candidates from libraries with random sequence fragments, through an evolutionary engineering system. We recently reported a high-affinity DNA aptamer generation method that introduces unnatural bases (UBs) as a fifth letter into the library, by genetic alphabet expansion. By incorporating hydrophobic UBs, the affinities of DNA aptamers to target proteins are increased over 100-fold, as compared with those of conventional aptamers with only the natural four letters. However, there is still plenty of room for improvement of the methods for routinely generating high-affinity UB-containing DNA (UB-DNA) aptamers. The success probabilities of the high-affinity aptamer generation depend on the existence of the aptamer candidate sequences in the initial library. We estimated the success probabilities by analysing several UB-DNA aptamers that we generated, as examples. In addition, we investigated the possible improvement of conventional aptamer affinities by introducing one UB at specific positions. Our data revealed that UB-DNA aptamers adopt specific tertiary structures, in which many bases including UBs interact with target proteins for high affinity, suggesting the importance of the UB-DNA library design.

This article is part of the theme issue ‘Reactivity and mechanism in chemical and synthetic biology’.
Allosteric inhibition of
Staphylococcus aureus
MenD by 1,4-dihydroxy naphthoic acid: a feedback inhibition mechanism of the menaquinone biosynthesis pathway
Authors: Stanborough Tamsyn , Ho Ngoc Anh Thu , Bulloch Esther M. M. , Bashiri Ghader , Dawes Stephanie S. , Akazong Etheline W. , Titterington James , Allison Timothy M. , Jiao Wanting , Johnston Jodie M.
Published: January 2023

Menaquinones (MKs) are electron carriers in bacterial respiratory chains. In
Staphylococcus aureus
(
Sau
), MKs are essential for aerobic and anaerobic respiration. As MKs are redox-active, their biosynthesis likely requires tight regulation to prevent disruption of cellular redox balance. We recently found that the
Mycobacterium tuberculosis
MenD, the first committed enzyme of the MK biosynthesis pathway, is allosterically inhibited by the downstream metabolite 1,4-dihydroxy-2-naphthoic acid (DHNA). To understand if this is a conserved mechanism in phylogenetically distant genera that also use MK, we investigated whether the
Sau-
MenD is allosterically inhibited by DHNA. Our results show that DHNA binds to and inhibits the SEPHCHC synthase activity of
Sau
-MenD enzymes. We identified residues in the DHNA binding pocket that are important for catalysis (Arg98, Lys283, Lys309) and inhibition (Arg98, Lys283). Furthermore, we showed that exogenous DHNA inhibits the growth of
Sau
, an effect that can be rescued by supplementing the growth medium with MK-4. Our results demonstrate that, despite a lack of strict conservation of the DHNA binding pocket between
Mtb
-MenD and
Sau
-MenD, feedback inhibition by DHNA is a conserved mechanism in
Sau
-MenD and hence the
Sau
MK biosynthesis pathway. These findings may have implications for the development of anti-staphylococcal agents targeting MK biosynthesis.

This article is part of the theme issue ‘Reactivity and mechanism in chemical and synthetic biology’.
MVMRmode: Introducing an R package for plurality valid estimators for multivariable Mendelian randomisation
Authors: Woolf Benjamin , Gill Dipender , Grant Andrew J , Burgess Stephen
Published: January 2023

Background

Mendelian randomisation (MR) is the use of genetic variants as instrumental variables. Mode-based estimators (MBE) are one of the most popular types of estimators used in univariable-MR studies. However, because there are no plurality valid regression estimators, there are no existent modal estimators for multivariable-MR.

Methods

We use the residual method for multivariable-MR to introduce two multivariable modal estimators: multivariable-MBE, which uses IVW to create residuals fed into a traditional plurality valid estimator, and multivariable-CM which instead has the residuals fed into the contamination mixture method. We then use Monte-Carlo simulations to explore the performance of these estimators when compared to existing ones and re-analyse the data used by Grant and Burgess (2021) looking at the causal effect of intelligence, education, and household income on Alzheimer’s disease as an applied example.

Results

In our simulation, we found that multivariable-MBE was generally too variable to be much use. Multivariable-CM produced more precise estimates on the other hand. Multivariable-CM performed better than MR-Egger in almost all settings, and Weighted Median under balanced pleiotropy. However, it underperformed Weighted Median when there was a moderate amount of directional pleiotropy. Our re-analysis supported the conclusion of Grant and Burgess (2021), that intelligence had a protective effect on Alzheimer’s disease, while education, and household income do not have a causal effect.

Conclusions

Here we introduced two, non-regression-based, plurality valid estimators for multivariable MR. Of these, “multivariable-CM” which uses IVW to create residuals fed into a contamination-mixture model, performed the best. This method uses a plurality of variants valid assumption, and appears to provided precise and unbiased estimates in the presence of balanced pleiotropy and small amounts of directional pleiotropy. We developed the MVMRmode R package (available fromhttps://github.com/bar-woolf/MVMRmode/wiki) to facilitate the use of this estimator. We hope this will further enable the future triangulation of univariable MR studies which have used plurality valid estimators with multivariable MR designs.
The genetic architecture of changes in adiposity during adulthood
Authors: Venkatesh Samvida S. , Ganjgahi Habib , Palmer Duncan S. , Coley Kayesha , Wittemans Laura B. L. , Nellaker Christoffer , Holmes Chris , Lindgren Cecilia M. , Nicholson George
Published: January 2023

Obesity is a heritable disease, characterised by excess adiposity that is measured by body mass index (BMI). While over 1,000 genetic loci are associated with BMI, less is known about the genetic contribution to adiposity trajectories over adulthood. We derive adiposity-change phenotypes from 1.5 million primary-care health records in over 177,000 individuals in UK Biobank to study the genetic architecture of weight-change. Using multiple BMI measurements over time increases power to identify genetic factors affecting baseline BMI. In the largest reported genome-wide study of adiposity-change in adulthood, we identify novel associations with BMI-change at six independent loci, including rs429358 (a missense variant inAPOE). The SNP-based heritability of BMI-change (1.98%) is 9-fold lower than that of BMI, and higher in women than in men. The modest genetic correlation between BMI-change and BMI (45.2%) indicates that genetic studies of longitudinal trajectories could uncover novel biology driving quantitative trait values in adulthood.
Dermal microdialysis: a method to determine drug levels in the skin of patients with Post Kala-azar Dermal Leishmaniasis (PKDL)
Authors: Wijnant Gert-Jan , Moulik Srija , Chatterjee Kingshuk , Das Nilay K , de la Flor Raúl , Van Bocxlaer Katrien , Croft Simon L. , Chatterjee Mitali
Published: January 2023

Objectives

Post-kala-azar-dermal leishmaniasis (PKDL) is an infectious skin disease that occurs after apparent cure from visceral leishmaniasis (VL) and causes stigmatizing lesions on the face and other exposed body parts. While the first-line drug miltefosine is typically used for 28 days to treat VL, 12 weeks of therapy is required for PKDL, highlighting the need to evaluate the extent of drug penetration at the dermal site of infection. In this proof-of-concept study, we demonstrate the use of a minimally invasive sampling technique called microdialysis to measure dermal drug exposure in a PKDL patient, providing a tool for the optimisation of treatment regimens.

Methods and Materials

Three PKDL patients receiving miltefosine (50 mg twice daily for 12 weeks) were recruited to the study. Conventional blood samples and skin biopsies were collected to determine drug content. One patient consented to undergo dermal microdialysis. Briefly, a µDialysis Linear Catheter 66 for skin and muscle, a probe with a semi-permeable membrane, was inserted in the dermis. A perfusate (a drug-free physiological solution) was pumped through the probe at a low flow rate, allowing miltefosine present in the dermis to cross the membrane and be collected in the dialysates over time. Protein-free (dialysates) and total (blood and skin biopsies) drug concentrations were analysed using LC-MS/MS.

Results and conclusions

After confirming the presence of miltefosine in skin lesions of PKDL patients via traditional biopsy sampling, protein-free drug concentrations over time (Cmax≈ 1 µg/ml) could be detected in the infected dermis via microdialysis. This clinical proof-of-concept study thus illustrates the potential of dermal microdialysis as a minimally invasive alternative to invasive skin biopsies to quantify drug concentrations directly at the pharmacological site of action in PKDL.
Mechanistic modeling of brain metastases in NSCLC provides computational markers for personalized prediction of outcome
Authors: Benzekry Sébastien , Schlicke Pirmin , Tomasini Pascale , Simon Eléonore
Published: January 2023

Background

Intracranial progression after curative treatment of early-stage non-small cell lung cancer (NSCLC) occurs from 10 to 50% and is difficult to manage, given the heterogeneity of clinical presentations and the variability of treatments available.

The objective of this study was to develop a mechanistic model of intracranial progression to predict survival following a first brain metastasis (BM) event.

Methods

Data included early-stage NSCLC patients treated with a curative intent who had a BM as the first and single relapse site (N=31).

We propose a mechanistic mathematical model to estimate the amount and sizes of (visible and invisible) BMs. The two key parameters of the model areα, the proliferation rate of a single tumor cell; andμ, the per day, per cell, probability to metastasize. The predictive value of these individual computational biomarkers was evaluated.

Findings

The model was able to correctly describe the number and size of metastases at the time of first BM relapse for 20 patients. Parametersαandμwere significantly associated with overall survival (OS) (HR 1.65 (1.07-2.53) p=0.0029 and HR 1.95 (1.31-2.91) p=0.0109, respectively). Adding the computational markers to the clinical ones significantly improved the predictive value of OS (c-index increased from 0.585 (95% CI 0.569-0.602) to 0.713 (95% CI 0.700-0.726), p<0.0001).

Interpretation

We demonstrated that our model was applicable to brain oligoprogressive patients in NSCLC and that the resulting computational markers had predictive potential. This may help lung cancer physicians to guide and personalize the management of NSCLC patients with intracranial oligoprogression.

SIGNIFICANCE STATEMENT

Non-small cell lung cancer is difficult to manage when brain metastases are present. This study presents a mathematical model that can be calibrated on individual patients’ data early in the treatment course to explain the growth dynamics of brain metastases and demonstrates that the mathematically derived parameters can serve as predictive tool in clinical routine care.

Highlights

-

Mechanistic mathematical modeling allows individualized prognosis for lung cancer patients at first brain metastatic relapse

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Individual model-derived computational parameters identifies high-risk patients in terms of brain metastasis progression and survival

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Prognostic features include quantification of the number and sizes of both clinically visible and invisible brain metastases