bluuebunny/crossref_metadata_2025 huggingface dataset:
An improvement on the technique of transosseous tunnels for the fixation of lower pole patella fracture
Authors: Hu Jialang , Guo Xin
Published: March 2022

The technique of transosseous tunnels is widely used in lower pole patella fracture (LPP). Though the extensor mechanism can be restored, distal avulsion fragments are usually unstable. The subsequent fracture gap and nonunion impair the extensor mechanism in turn. Cerclage is a promising method for treating the condition. The aim of this prospective cohort study is to determine if cerclage around the patella combined with the technique of transosseous tunnels stabilizes the avulsion fragments and brings out improved outcomes on LPP.

Twenty two patients with LPP were treated with the hybrid technique. The patients were followed up and evaluated clinically and radiographically. The functional outcome was assessed by the average range of knee movement and Lysholm knee rating system at 6 months after surgery, as well as the final follow-up. Radiologically, Insall-Salvati ratio and the time from surgery to bone union were assessed.

Postoperatively, with a mean followed-up of 12 months. All of the patients regained stability of the knee with an average range of movements of 131.8 degrees at 6 months after operation and 138.2 degrees at the final follow-up. On the Lysholm knee rating system, all cases were classified as excellent. The average score was 93.2 at 6 months after operation and 95.9 at the final follow-up. In radiological assessment, no fracture gap or nonunion occurred. The average Insall-Salvati ratio (I-S ratio) was 1.03.

The hybrid technique offers further stabilization for the avulsion fragments and strengthens attachment of the patellar tendon, which brings forward time of rehabilitation and achieves good clinical outcomes.
A comparative study of a nerve block therapy with and without a deeply inserted acupotomy applied to hyeopcheok points for lumbosacral radiculopathy
Authors: Choi Sooil , Park Sukhee , Lim Young-Soo , Park Tae-Yong , Do Kwang-Sun , Byun Sang Hyun , Yoon Sang-Hoon , Lee Jin-Hyun
Published: March 2022

Introduction:

The prevalence of lumbosacral radiculopathy is estimated to be approximately 3% to 5% in patient populations. Lumbosacral radiculopathy is largely caused by a complex interaction between biomechanical and biochemical factors. Nerve block therapy (NBT) mainly treats lumbosacral radiculopathy by improving the biochemical factors, whereas acupotomy mainly focuses on improving the biomechanical factors. Therefore, it is thought that synergistic effects may be obtained for the treatment of lumbosacral radiculopathy when both NBT and acupotomy are combined. However, no study in China and Korea, where acupotomy is majorly provided, has reported the effects of such a combination treatment. Therefore, this study aimed to evaluate the safety, effectiveness, and cost-effectiveness of the concurrent use of a deeply inserted acupotomy and NBT for the treatment of lumbosacral radiculopathy.

Methods/design:

This is an open-label, parallel, assessor-blinded, randomized controlled trial, which will include 50 patients with lumbosacral radiculopathy. After patients voluntarily agree to participate in the study, they will be screened, and will undergo necessary examinations and tests according to the protocol. Those who satisfy the selection criteria will be randomly assigned to either the NBT + acupotomy or NBT groups in a 1:1 ratio. Both groups will undergo 2 NBTs once every 2 weeks from 1 week after the screening test. The treatment group will receive additional acupotomy twice a week for 4 weeks. The primary endpoint is the Oswestry Disability Index, whereas the secondary endpoints are the Numeral Rating Scale, European Quality of Life 5-dimension, McGill pain Questionnaire, Roland-Morris Disability Questionnaire, safety assessment, and economic feasibility evaluation. The measurements will be made at 0, 2, 4, and 8 weeks.

Ethics and dissemination:

This trial has received complete ethical approval from the Ethics Committee of Catholic Kwandong University International St. Mary's Hospital (IS20OISE0085). We intend to submit the results of the trial to a peer-reviewed journal and/or conferences.
Combination therapy of ursodeoxycholic acid and glucocorticoid and (or) immunosuppressant in patients with primary biliary cholangitis
Authors: Wang Zi-Long , Song Kai-Min , Jin Rui , Xie Yan-Di , Wang Yu-Qiong , Liu Zhi-Cheng , Feng Bo
Published: March 2022

Background/objectives:

Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune cholestasis liver disease. There were many studies comparing a combination of glucocorticoids and/or immunosuppressants to a single UDCA therapy in PBC patients, while the literature demonstrated divergent finds. To evaluate the effectiveness of ursodeoxycholic acid (UDCA) combined with glucocorticoids and (or) immunosuppressants on biochemistry, immunology, histology, clinical symptoms, and adverse reactions of PBC from the perspective of evidence-based medicine.

Materials and methods:

PubMed, web of science, the Cochrane Library, EMBASE databases were searched to collect clinical randomized trials and self-control studies of UDCA combined with glucocorticoids and (or) immunosuppressants and UDCA monotherapy in the treatment of PBC. The retrieval time is from the establishment of the database to August 2020. Two reviewers independently screened literature, extracted data and evaluated the bias of included studies. Revman 5.3 software was used for meta-analysis.

Results:

Six studies including 201 patients were included. The meta-analysis found that the combination therapy can improve some biochemical indexes, immunological indexes, and clinical symptoms of patients with PBC. However, combination therapy has no significant improvement in other biochemical indicators which respond to liver and bile duct damage, such as ALT, GGT, and ALB. Besides, the improvement of liver histology is limited, and the incidence of adverse events is higher.

Conclusion:

Overall, the combination therapy showed no improvement in key biochemical parameters and limited improvement in liver pathology. Besides, the side effects were more serious. Therefore, in the current treatment regimen, it is not recommended for PBC patients.
Personal protective equipment and adverse dermatological reactions among healthcare workers
Authors: Nguyen Chrystie , Young Fletcher Graham , McElroy Doug , Singh Aniruddha
Published: March 2022

The pandemic of the 2019 novel coronavirus disease (COVID-19) has caused an unprecedented mobilization of the United States’ healthcare workforce. In addition to working extended hours under increased duress, healthcare professionals (HCP) of all stations have been making use of various types of personal protective equipment (PPE) with greatly increased frequency and duration. Current data regarding adverse skin reactions as a possible consequence of PPE use are, particularly in the United States, largely insufficient for policy-makers to make informed decisions regarding daily PPE use among HCP.

The research vehicle employed by this study is a cross-sectional 25-item survey distributed via email to workers currently employed by a five-hospital system in southcentral Kentucky. This survey was used to collect information from hospital workers of all professional roles about their experiences during the COVID-19 pandemic, focusing on reports of adverse dermatological reactions and associated risk factors.

Out of 879 respondents, 54.4% reported some type of skin irritation reaction. Skin irritation was significantly more prevalent among medical and medical support staff than non-medical hospital workers, with the highest prevalence among Certified Nurse Assistant (CNAs). Among clinical workers, those in dedicated COVID-19 units reported the highest prevalence of adverse skin reaction. The most common complaint was dryness/scaling of the skin (306 out of 439, 69.7%), and the most common location was the facial cheeks (305 out of 516, 59.1%). Among those who reported skin irritation, the average self-reported severity of skin reaction (on a scale of 1–5) was 2.00 ± 0.05, and the mean total days of skin reaction per month was 11.70 ± 0.39 days. Total days of irritation per month was found to be significantly related to “total days of PPE use per month,” “hours of PPE use per day,” “frequency of hand washing,” and“use of disinfecting UV irradiation.” Severity of skin reaction was found to be significantly related to “hours per day of PPE use,” “consecutive days of PPE use,” and “female sex.”

Clinical workers that put in the most face-to-face time with patients, and those in dedicated COVID-19 units, had the highest risk of adverse skin reaction. Overall, skin reactions were found to be mild, even in those hospital workers with the heaviest PPE use. Because the widespread and consistent use of facial masks in public settings has become a key tool in our protracted struggle with SARS-CoV-2, these findings may help to ameliorate concerns that everyday facial mask and/or other PPE usage contributes to significant dermatologic morbidity among both medical professionals and public citizens.
ANCA-associated vasculitis in idiopathic pulmonary fibrosis
Authors: Traila Daniel , Marc Monica Steluta , Pescaru Camelia , Manolescu Diana , Fira-Mladinescu Ovidiu
Published: March 2022

Rationale:

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. Patients with IPF represent a heterogeneous population with several described clinical phenotypes. More recently, the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in IPF patients, with an incidence higher than that in the general population, has drawn attention.

Patient concerns:

A 64-year-old woman previously diagnosed with IPF presented to the emergency department with hemoptysis and hypoxemic respiratory failure.

Diagnoses:

High-resolution chest computed tomography revealed bilateral ground-glass opacities associated with areas of consolidation superimposed on the patient's fibrotic background pattern. Diffuse alveolar hemorrhage was confirmed by the presence of hemorrhagic bronchoalveolar lavage fluid. Hematological and biochemical investigations revealed an inflammatory syndrome, moderate anemia, and rapidly progressive glomerulonephritis. Serological analysis revealed perinuclear antineutrophil cytoplasmic antibody positivity and high levels of antimyeloperoxidase antibodies antibodies. The patient underwent kidney biopsy, which revealed necrotizing glomerulonephritis. Clinical and laboratory findings were diagnostic of microscopic polyangiitis with lung and renal involvement.

Interventions:

Cyclophosphamide in combination with methylprednisolone was administered as remission induction therapy. The maintenance therapy consisted of mycophenolate mofetil and prednisone.

Outcomes:

The patient achieved clinical, radiological, and serological remission within six weeks of treatment.

Lessons:

The association between IPF and ANCA-associated vasculitis may represent a distinct clinical phenotype. Autoimmune testing for ANCAs should be considered part of the diagnostic work-up and follow-up of patients with IPF because of the clinical and therapeutic implications of developing vasculitis in an already vulnerable patient.
Disparities in Comorbidities in Lung Cancer: Findings From the Behavioral Risk Factor Surveillance System
Authors: Johnson Lee Ann , Briley Patrick , Bolin Linda P. , Kitko Lisa , Ellis Charles
Published: March 2022

Background

In persons with lung cancer, sex and race are independent predictors of comorbidities and are associated survival. It is unclear how comorbidity profiles differ across sex and race.

Objective

The objective was to examine comorbidity differences between men and women and Blacks and Whites.

Methods

Data from the 2014, 2016, 2017, and 2018 Behavioral Risk Factor Surveillance System were analyzed using descriptive statistics, χ
2 test of independence, and multiple logistic regression. Variables included sociodemographics and comorbidities.

Results

Among individuals with lung cancer (N = 594), men were more likely to experience a heart attack (odds ratio [OR], 3.59; 95% confidence interval [CI], 1.62–7.96) and diabetes (OR, 2.83; 95% CI, 1.57–5.10) and less likely to experience depressive disorder (OR, 0.360; 95% CI, 0203–0.637). Black men (OR, 28.57; 95% CI, 9.22–88.55) and women (OR, 2.48; 95% CI, 1.02–6.05) were more likely to have a history of stroke.

Conclusion

Findings show that there may be differences in patterns of comorbidities among individuals with lung cancer. As we continue to move toward individualized medicine in cancer care, future work in this area should examine social determinants of health and how they may influence the patterns of comorbidities.

Implication for Nurses

Although nurses may be aware that certain groups have an increased risk for certain comorbid conditions, this study highlights what groups with lung cancer may be more likely to have certain comorbidities. Nurses can assess individuals for comorbidities and provide education on how to manage comorbidities during cancer treatment.
The Relationship Between Sexual Satisfaction and Marital Satisfaction in Women With Ovarian Cancer and Their Spouses
Authors: Aktaş Demet , Bahar Arzu
Published: March 2022

Background

Ovarian cancer can have long-term physical and psychosexual effects on survivors. The post–ovarian cancer sexuality concerns of women can cause sadness and anxiety and negatively impact sexual and marital satisfaction in these women and their spouses.

Objective

The aim of this study was to investigate the relationship between sexual satisfaction and marital satisfaction of women with ovarian cancer and their spouses.

Methods

This study was designed retrospectively. This study was conducted with 172 participants: 86 women with ovarian cancer and 86 spouses. Data were collected over 6 months from July 2019 to December 2019. Sexual satisfaction levels were assessed using the Golombok Rust Inventory of Sexual Satisfaction. Marital satisfaction levels were assessed using the Golombok Rust Inventory of Marital State.

Results

Spouses’ sexual satisfaction (mean, 8.10) was worse than that of the women (mean, 5.60). The women’s marital satisfaction (mean, 47.39) was worse than that of their spouses (mean, 40.75).

Conclusions

As the sexual satisfaction of the women increased, the marital satisfaction of the women (r = 0.346, P = .001) and spouses (r = 0.308, P = .001) increased. As the sexual satisfaction of the spouses increased, the marital satisfaction of the women (r = 0.512, P = .001) and spouses (r = 0.409, P = .001) increased.

Implications for Practice

Nurses and healthcare teams need to be aware of post–ovarian cancer sexual and marital satisfaction problems of women and their spouses and organize activities at education and couple counseling on these problems.
Distinct Nausea Profiles Are Associated With Gastrointestinal Symptoms in Oncology Patients Receiving Chemotherapy
Authors: Singh Komal , Pituch Keenan , Zhu Qiyun , Gu Haiwei , Ernst Brenda , Tofthagen Cindy , Brewer Melanie , Kober Kord M. , Cooper Bruce A. , Paul Steven M. , Conley Yvette P. , Hammer Marilyn , Levine Jon D. , Miaskowski Christine
Published: March 2022

Background

Unrelieved chemotherapy-induced nausea (CIN) occurs 48% of patients undergoing chemotherapy and is one of the most debilitating symptoms that patients report.

Objective

The aims of this study were to identify subgroups of patients with distinct CIN profiles and determine how these subgroups differed on demographic and clinical characteristics; severity, frequency, and distress of CIN; and the co-occurrence of common gastrointestinal symptoms.

Methods

Patients (n = 1343) completed demographic questionnaire and Memorial Symptom Assessment Scale 6 times over 2 cycles of chemotherapy. Latent class analysis was used to identify subgroups of patients with distinct CIN profiles. Differences among these subgroups were evaluated using parametric and nonparametric statistics.

Results

Four distinct CIN profiles were identified: none (40.8%), increasing-decreasing (21.5%), decreasing (8.9%), and high (28.8%). Compared with the none class, patients in the high class were younger, had a lower annual household income, had child care responsibilities, had a lower Karnofsky Performance Status score and a higher Self-administered Comorbidity Questionnaire score, and were more likely to have received chemotherapy on a 14-day cycle and a highly emetogenic chemotherapy regimen. In addition, patients in the high class reported high occurrence rates for dry mouth, feeling bloated, diarrhea, lack of appetite, abdominal cramps, difficulty swallowing, mouth sores, weight loss, and change in the way food tastes.

Conclusions

That 60% of the patients reported moderate to high CIN occurrence rates confirms that this unrelieved symptom is a significant clinical problem.

Implications for Practice

Nurses need to evaluate patients’ level of adherence to their antiemetic regimen and make appropriate referrals for physical therapy, psychological services, and dietary counseling.
“Less time committed to care”
Authors: Sage Rayna , Mashinchi Genna M. , Lissau Ari , Standley Krys , Ender Justice
Published: March 2022

In 2016, the federal government mandated that all Medicaid-funded personal assistance services be documented through an Electronic Visit Verification (EVV) program by January 2020. Most states have asked for extensions due to difficulties in implementation and strong opposition from consumer advocacy groups. Qualitative research has documented various concerns of consumers and consumer advocates. In 2020 (prepandemic), we conducted a mail survey of consumers which included questions regarding familiarity with, and attitudes toward, EVV. Respondents could also write in qualitative comments. This paper explores consumers' perceptions of EVV using four survey items related to fraud, benefits, concerns, and protection and 25 qualitative comments related to these topics. We found that respondents agreed most with statements focused on both concerns with EVV interfering with their care and help in reducing fraud. In general, the most common quantitative response to the statements was indifference. Qualitative comments centered on concerns about EVV interfering with services in a variety of ways, although there were also comments related to EVV being protective, beneficial, or helpful in reducing fraud. We also identified a new category in the qualitative comments about consumers' beliefs that the work done by their personal assistance service workers is underrecognized. We recommend that policy makers and service organizations continue to collect information from consumers as EVV is implemented and altered to both meet the expectations of the legislation and the needs of consumers and workers.
Administration of Subcutaneous Injections
Authors: Sexson Kathryn , Lindauer Allison , Harvath Theresa A.
Published: March 2022

This article is part of a series, Supporting Family Caregivers: No Longer Home Alone, published in collaboration with the AARP Foundation. Results of focus groups conducted as part of the AARP Foundation's No Longer Home Alone video project supported evidence that family caregivers aren't being given the information they need to manage the complex care regimens of their family members. This series of articles and accompanying videos aims to help nurses provide caregivers with the tools they need to manage their family member's medications. Each article explains the principles nurses should consider and reinforce with caregivers and is accompanied by a video for the caregiver to watch. The second video can be accessed at http://links.lww.com/AJN/A75.
Combining Breast and Ovarian Operations Increases Complications
Authors: Henn Dominic , Barrera Janos A. , Sivaraj Dharshan , Lin John Q. , Rizk Nada M. , Ma Irene , Gurtner Geoffrey C. , Lee Gordon K. , Nazerali Rahim S.
Published: March 2022

Background:

Breast cancer resulting from a genetic mutations, such as BRCA1 or BRCA2, is seen in 5 to 10 percent of patients. More widespread genetic testing has increased the number of affected women undergoing prophylactic mastectomy and oophorectomy. Recent studies have yielded mixed results regarding complication rates after combined breast and ovarian operations. The authors compared surgical outcomes of breast operations performed in combination with salpingo-oophorectomies or as separate procedures.

Methods:

The authors retrospectively analyzed surgical complications and length of hospital stay in 145 female patients, from which 87 had undergone combined breast surgery and salpingo-oophorectomy, and 58 had undergone these procedures separately. Multivariate logistic regression models were used to calculate odds ratios and 95 percent confidence intervals.

Results:

Patients undergoing combined breast and ovarian operations experienced higher rates of overall complications (46.5 percent versus 19 percent; p < 0.001), infections (22.2 percent versus 8.6 percent; p < 0.05), and delayed wound healing (13.2 percent versus 0 percent; p < 0.05) related to the breast surgery, when compared with patients undergoing separate procedures. Multivariate logistic regression analysis confirmed a significant association between combined surgery and overall postoperative complications (OR, 5.87; 95 percent CI, 2.03 to 16.91; p = 0.02). Patients undergoing tissue expander–based breast reconstruction combined with ovarian surgery had significantly longer hospital stays compared to patients undergoing separate procedures (3.5 days versus 1.8 days; p < 0.001).

Conclusions:

The authors’ data indicate that combining breast and ovarian operations is associated with a higher risk of postoperative complications related to the breast procedure and increases the duration of hospital stay in patients with tissue expander–based reconstructions. The authors’ study provides valuable information for preoperative counseling of patients considering both breast and ovarian surgery.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Prospective Longitudinal Patient-Reported Satisfaction and Health-Related Quality of Life following DIEP Flap Breast Reconstruction: Effects of Reconstruction Timing
Authors: Ochoa Oscar , Garza Ramon , Pisano Steven , Chrysopoulo Minas , Ledoux Peter , Arishita Gary , Ketchum Norma , Michalek Joel E. , Nastala Chet
Published: March 2022

Background:

Without reconstruction, mastectomy alone can produce significant detrimental effects on health-related quality of life. The magnitude of quality-of-life benefits following breast reconstruction may be unique based on timing of reconstruction. Facilitated by the BREAST-Q questionnaire, characterization of how reconstruction timing differentially affects patient-reported quality of life is essential for improved evidence-based clinical practice.

Methods:

Consecutive DIEP flap breast reconstruction patients prospectively completed BREAST-Q questionnaires preoperatively and at two different time intervals postoperatively. The first (postoperative time point A) and second (postoperative time point B) postoperative questionnaires were completed 1 month postoperatively and following breast revision/symmetry procedures, respectively. Postoperative flap and donor-site complications were recorded prospectively. Stratified by timing (immediate versus delayed) of reconstruction, preoperative clinical data, operative morbidity, and BREAST-Q scores were compared at all time points.

Results:

Between July of 2012 and August of 2016, 73 patients underwent 130 DIEP flap breast reconstructions. Collectively, breast satisfaction, psychosocial well-being, and sexual well-being scores significantly (p < 0.001) increased postoperatively versus baseline. Chest and abdominal physical well-being scores returned to baseline levels by postoperative time point B. Preoperatively, patients undergoing delayed breast reconstruction reported significantly (p < 0.05) lower breast satisfaction, psychosocial well-being, and sexual well-being scores compared to immediate reconstruction patients. Postoperatively, delayed and immediate reconstruction patients reported similar quality-of-life scores. Outcome satisfaction and flap and donor-site morbidity were similar between groups irrespective of timing of reconstruction.

Conclusions:

In this prospective study, patient-reported outcomes demonstrate significant improvements in breast satisfaction, psychosocial well-being, and sexual well-being among patients following DIEP flap reconstruction. Moreover, preoperative differences in quality-of-life scores among delayed/immediate reconstruction patients were eliminated postoperatively.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
Ultrarare missense and frameshift variants in the TECTA gene may involve tectorial membrane in familial Meniere disease
Authors: Román-Naranjo Pablo , Parra-Perez Alberto M. , Escalera-Balsera Alba , Soto-Varela Andrés , Gallego-Martinez Alvaro , Aran Ismael , Perez-Fernandez Nicolas , Bächinger David , Eckhard Andreas H. , Gonzalez-Aguado Rocio , Frejo Lidia , Lopez-Escamez Jose A.
Published: March 2022

Background

Meniere’s disease (MD) is an inner ear disease defined by episodes of vertigo associated with sensorineural hearing loss initially affecting low- to medium frequencies, tinnitus, and aural fullness. Familial aggregation has been reported in 9-10% of MD patients showing, mostly, an autosomal dominant inheritance pattern with incomplete penetrance. However, familial MD is a genetically heterogeneous disorder and other inheritance patterns have been recently proposed, such as recessive and digenic inheritance involving rare variants in OTOG and MYO7A genes, respectively. In this study, a familial MD cohort was recruited to identify new candidate genes.

Methods

Exome sequencing was performed in 99 individuals (from 77 families) diagnosed with MD according to the diagnostic criteria defined by the Barany Society. Candidate variants were classified based on the ACMG/AMP guidelines, and their effects were evaluated by protein modeling. Standard audiometric evaluations were retrieved, and a case report was made of each family to assess the genotype-phenotype correlations.

Results

The TECTA gene, which encodes α-tectorin, was highlighted as a candidate for four multicase MD families carrying rare missense heterozygous variants and a short deletion in this gene. Variants in α-tectorin were also found in two additional families with one MD patient and relatives with partial syndromes carrying a missense heterozygous variant and a short deletion. According to the predicted protein model, these variants could affect the stability of α-tectorin.

Conclusions

Several MD families were identified carrying rare variants and deletions in the TECTA gene, which encodes one of the main proteins of the tectorial membrane (TM). The TM is an extracellular matrix localized over the sensory epithelium mediating the mechanical stimulation of cochlear hair cells, a critical role in the process of hearing. Modifications on the TM stability and the micromechanics involved in the sound-evoked motion of stereocilia might be involved in familial MD.
A Progeroid Syndrome Caused by RAF1 deficiency Underscores the importance of RTK signaling for Human Development
Authors: Wong Samantha , Tan Yu Xuan , Tan Kiat Yi , Loh Abigail , Aziz Zainab , Özkan Engin , Kayserili Hülya , Escande-Beillard Nathalie , Reversade Bruno
Published: March 2022

Somatic and germline gain-of-function point mutations in RAF, the first oncogene to be discovered in humans, delineate a group of tumor-prone syndromes known as RASopathies. In this study, we document the first human phenotype resulting from the germline loss of function of the proto-oncogene RAF1 (a.k.a. CRAF). In a consanguineous family, we uncovered a homozygous p.Thr543Met mutation segregating with a neonatal lethal progeroid syndrome with cutaneous, craniofacial, cardiac and limb anomalies. Structure-based prediction and functional tests using human knock-in cells showed that threonine 543 is essential to: 1) ensure RAF1’s stability and phosphorylation, 2) maintain its kinase activity towards substrates of the MAPK pathway and 3) protect from stress-induced apoptosis. When injected in Xenopus embryos mutant RAF1T543M failed to phenocopy the effects of overactive FGF/MAPK signaling confirming its hypomorphic activity. Collectively, our data disclose the genetic and molecular etiology of a novel segmental progeroid syndrome which highlights the importance of RTK signaling for human development and homeostasis.

Short summary

A germline homozygous recessive loss-of-function mutation p.T453M in RAF1 causes a neonatal lethal progeroid syndrome. In vitro and in vivo tests demonstrate that Thr543 is necessary for RAF1’s protein stability, to transduce signaling to the MAPK pathway and to respond to stress-induced apoptosis.
Deep learning based electrocardiographic screening for chronic kidney disease
Authors: Holmstrom Lauri , Christensen Matthew , Yuan Neal , Hughes J. Weston , Theurer John , Jujjavarapu Melvin , Fatehi Pedram , Kwan Alan , Sandhu Roopinder K. , Ebinger Joseph , Cheng Susan , Zou James , Chugh Sumeet S. , Ouyang David
Published: March 2022

Background

Undiagnosed chronic kidney disease (CKD) is a common and usually asymptomatic disorder that causes a high burden of morbidity and early mortality worldwide. We developed a deep learning model for CKD screening from routinely acquired ECGs.

Methods

We collected data from a primary cohort with 111,370 patients which had 247,655 ECGs between 2005 and 2019. Using this data, we developed, trained, validated, and tested a deep learning model to predict whether an ECG was taken within one year of the patient receiving a CKD diagnosis. The model was additionally validated using an external cohort from another healthcare system which had 312,145 patients with 896,620 ECGs from between 2005 and 2018.

Results

Using 12-lead ECG waveforms, our deep learning algorithm achieved discrimination for CKD of any stage with an AUC of 0.77 (95% CI 0.76-0.77) in a held-out test set and an AUC of 0.71 (0.71-0.71) in the external cohort. Our 12-lead ECG-based model performance was consistent across the severity of CKD, with an AUC of 0.75 (0.0.74-0.77) for mild CKD, AUC of 0.76 (0.75-0.77) for moderate-severe CKD, and an AUC of 0.78 (0.77-0.79) for ESRD. In our internal health system with 1-lead ECG waveform data, our model achieved an AUC of 0.74 (0.74-0.75) in detecting any stage CKD. In the external cohort, our 1-lead ECG-based model achieved an AUC of 0.70 (0.70-0.70). In patients under 60 years old, our model achieved high performance in detecting any stage CKD with both 12-lead (AUC 0.84 [0.84-0.85]) and 1-lead ECG waveform (0.82 [0.81-0.83]).

Conclusions

Our deep learning algorithm was able to detect CKD using ECG waveforms, with particularly strong performance in younger patients and patients with more severe stages of CKD. Given the high global burden of undiagnosed CKD, further studies are warranted to evaluate the clinical utility of ECG-based CKD screening.
An antisense oligonucleotide-based strategy to ameliorate cognitive dysfunction in the 22q11.2 Deletion Syndrome
Authors: Thakur Pratibha , Lackinger Martin , Diamantopoulou Anastasia , Rao Sneha , Chen Yijing , Khalizova Khakima , Ferng Annie , Mazur Curt , Kordasiewicz Holly , Shprintzen Robert J. , Markx Sander , Xu Bin , Gogos Joseph A.
Published: March 2022

Adults and children with the 22q11.2 Deletion Syndrome demonstrate cognitive, social and emotional impairments and high risk for schizophrenia. Work in mouse model of the 22q11.2 deletion provided compelling evidence for abnormal expression and processing of microRNAs. A major transcriptional effect of the microRNA dysregulation is up-regulation ofEmc10,a component of the ER membrane complex, which promotes membrane insertion of a subset of polytopic and tail-anchored membrane proteins. We previously uncovered a key contribution of EMC10 in mediating the behavioral phenotypes observed in 22q11.2 deletion mouse models. Here we show that expression and processing of miRNAs is abnormal andEMC10expression is elevated in neurons derived from 22q11.2 deletion carriers. Reduction ofEMC10 levelsrestores defects in neurite outgrowth and calcium signaling in patient neurons. Furthermore, antisense oligonucleotide administration and normalization ofEmc10in the adult mouse brain not only alleviates cognitive deficits in social and spatial memory but remarkably sustains these improvements for over two months post injection, indicating its therapeutic potential. Broadly, our study integrates findings from both animal models and human neurons to elucidate the translational potential of modulatingEMC10levels and downstream targets as a specific venue to ameliorate disease progression in 22q11.2 Deletion Syndrome.
Early life pain experience changes adult functional pain connectivity in the rat somatosensory and the medial prefrontal cortex
Authors: Chang Pishan , Fabrizi Lorenzo , Fitzgerald Maria
Published: March 2022

Early life pain experience (ELP) alters adult pain behaviour and increases injury induced pain hypersensitivity, but the effect of ELP upon adult functional brain connectivity is not known. We have performed continuous local field potential (LFP) recording in the awake adult male rats to test the effect of ELP upon functional cortical connectivity related to pain behaviour. Somatosensory cortex (S1) and medial prefrontal cortex (mPFC) LFPs evoked by mechanical hindpaw stimulation were recorded simultaneously with pain reflex behaviour for 10 days after adult skin injury. We show that, post adult injury, S1 LFP delta and gamma energy and S1 LFP delta/gamma frequency modulation are significantly increased in ELP rats compared to controls. Adult injury also induces increases in S1-mPFC functional connectivity which is significantly prolonged in ELP rats, lasting 4 days compared to 1 day in controls. Importantly, the increases in LFP energy and connectivity in ELP rats were directly correlated with increased behavioural pain hypersensitivity. Thus, early life pain (ELP) alters adult brain functional connectivity, both within and between cortical areas involved in sensory and affective dimensions of pain. The results reveal altered brain connectivity as a mechanism underlying the effects of early life pain upon adult pain perception.

Significance Statement

Pain and stress in early life has a lasting impact upon pain behaviour and may increase vulnerability to chronic pain in adults. Here we record pain-related cortical activity and simultaneous pain behaviour in awake adult male rats previously exposed to pain in early life. We show that functional connectivity within and between the somatosensory cortex and the medial prefrontal cortex is increased in these rats and that these increases are correlated with their behavioural pain hypersensitivity. The results reveal that early life pain alters adult brain connectivity, which may explain the impact of childhood pain upon adult chronic pain vulnerability.
Multiple sclerosis cortical lesion detection with deep learning at ultra-high-field MRI
Authors: Rosa Francesco La , Beck Erin S. , Maranzano Josefina , Todea Ramona-Alexandra , van Gelderen Peter , de Zwart Jacco A. , Luciano Nicholas J. , Duyn Jeff H. , Thiran Jean-Philippe , Granziera Cristina , Reich Daniel S. , Sati Pascal , Cuadra Meritxell Bach
Published: March 2022

Manually segmenting multiple sclerosis (MS) cortical lesions (CL) is extremely time-consuming, and past studies have shown only moderate inter-rater reliability. To accelerate this task, we developed a deep learning-based framework (CLAIMS: Cortical Lesion Artificial Intelligence-based assessment in Multiple Sclerosis) for the automated detection and classification of MS CL with 7T MRI.

Two 7T datasets, acquired at different sites, were considered. The first consisted of 60 scans that include 0.5mm isotropic MP2RAGE acquired 4 times (MP2RAGEx4), 0.7mm MP2RAGE, 0.5mm T2*-weighted GRE, and 0.5mm T2*-weighted EPI. The second dataset consisted of 20 scans including only 0.75×0.75×0.9 mm MP2RAGE. CLAIMS was first evaluated using 6-fold cross-validation with single and multi-contrast 0.5mm MRI input. Second, performance of the model was tested on 0.7mm MP2RAGE images after training with either 0.5mm MP2RAGEx4, 0.7mm MP2RAGE, or alternating the two. Third, its generalizability was evaluated on the second external dataset and compared with a state-of-the-art technique based on partial volume estimation and topological constraints (MSLAST). CLAIMS trained only with MP2RAGEx4 achieved comparable results to the multi-contrast model, reaching a CL true positive rate of 74% with a false positive rate of 30%. Detection rate was excellent for leukocortical and subpial lesions (83%, and 70%, respectively), whereas it reached 53% for intracortical lesions. The correlation between disability measures and CL count was similar for manual and CLAIMS lesion counts. Applying a domain-scanner adaptation approach and testing CLAIMS on the second dataset, the performance was superior to MSLAST when considering a minimum lesion volume of 6μL (lesion-wise detection rate of 71% vs 48%).

The proposed framework outperforms previous state-of-the-art methods for automated CL detection across scanners and protocols. In the future, CLAIMS may be useful to support clinical decisions at 7T MRI, especially in the field of diagnosis and differential diagnosis of multiple sclerosis patients.
Altered brain reward response to monetary incentives in fibromyalgia: A replication study
Authors: Park Su Hyoun , Deng Eden Z. , Baker Anne K. , MacNiven Kelly H. , Knutson Brian , Martucci Katherine T.
Published: March 2022

Dysregulated brain reward systems have been observed in chronic pain. Using functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task, Martucci et al. (2018) showed that neural responses to reward anticipation and outcome are altered in patients with fibromyalgia. The current study aimed to replicate these results in a separate cohort of patients with fibromyalgia recruited at a new location using a similar study design. Twenty patients with fibromyalgia and 20 healthy controls were included in the replication study. Group fMRI analyses revealed a solid and consistent trend of main findings similar to the previous results. Specifically, in the replication cohort of patients with fibromyalgia, medial prefrontal cortex (MPFC) activity was reduced during gain anticipation and increased during no-loss (non-punishment) outcomes, as compared to controls. Similar to the Martucci et al. results, again in the replication cohort, nucleus accumbens activity during gain anticipation did not differ in patients compared to controls. The same behavioral, correlational, and exploratory analyses that were conducted in the Martucci et al. study were conducted in the present replication study, with prior results largely replicated here. Thus, the present replication study results solidify observations of altered cortico-striatal processing to monetary rewards in chronic pain, which underscore relevance of altered brain reward circuits, particularly as related to the MPFC in patients with fibromyalgia.
Differences in Genetic Correlations between Posttraumatic Stress Disorder and Alcohol Use Disorder-Related Phenotypes Compared to Alcohol Consumption-Related Phenotypes
Authors: Bountress Kaitlin E. , Bustamante Daniel , de Viteri Stacey Subbie-Saenz , Chatzinakos Chris , Sheerin Christina , Peterson Roseann E. , Webb Bradley T. , Daskalakis Nikolaos P. , Edenberg Howard ,   The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group, Meyers Jackie , Amstadter Ananda
Published: March 2022

Background

Posttraumatic Stress Disorder (PTSD) tends to co-occur with greater alcohol consumption as well as alcohol use disorder (AUD). However, it is unknown whether the same etiologic factors that underlie PTSD-AUD comorbidity also contribute to PTSD-alcohol consumption.

Methods

We used summary statistics from large-scale genome-wide association studies (GWAS) of European-ancestry (EA) and African-ancestry (AA) participants to estimate genetic correlations between PTSD (both the diagnosis and re-experiencing symptoms) and a range of alcohol consumption-related and AUD-related phenotypes (e.g., drinks per week, max drinks, consumption, AUD).

Results

In EAs, there were positive genetic correlations between PTSD phenotypes and AUD-related phenotypes (i.e., Alcohol Use Disorders Identification Test (AUDIT) problem score, maximum alcohol intake, AUD, and alcohol dependence) (rGs: .132-.533, all FDR adjusted p<.05). However, the genetic correlations between PTSD phenotypes and alcohol consumption -related phenotypes (i.e., drinks per week, AUDIT consumption score, AUDIT total score, and a combination of consumption and problems) were negatively associated or non-significant (rGs: -.417- -.042, FDR adjusted p: <.05-NS). For AAs, the direction of correlations was sometimes consistent and sometimes inconsistent with that in EAs, and the ranges were larger (rGs for AUD--related: -.275 -.266, FDR adjusted p: NS, alcohol consumption-related: .145-.699, FDR adjusted p: NS).

Conclusions

These findings illustrate that the genetic associations between consumption and problem alcohol phenotypes and PTSD differ in both strength and direction. Thus, the genetic factors that may lead someone to develop PTSD and consume large quantities of alcohol are not the same as those that lead someone to develop PTSD-AUD.
A predictive model for hospitalization and survival to COVID-19 in a retrospective population-based study
Authors: Cisterna-García Alejandro , Guillén-Teruel Antonio , Caracena Marcos , Pérez Enrique , Jiménez Fernando , Francisco-Verdú Francisco J. , Reina Gabriel , González-Billalabeitia Enrique , Palma José T. , Sánchez Álvaro , Botía Juan A.
Published: March 2022

The severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) is highly transmissible and has been responsible for a pandemic associated with a high number of deaths. The clinical management of patients and the optimal use of resources are two important factors in reducing this mortality, especially in scenarios of high incidence. To this end, it is necessary to develop tools that allow early triage of patients with the minimal use of diagnostic tests and based on readily accessible data, such as electronic medical records. This work proposes the use of a machine learning model that allows the prediction of mortality and risk of hospitalization using simple demographic characteristics and comorbidities, using a COVID-19 dataset of 86867 patients. In addition, we developed a new method designed to deal with data imbalance problems. The model was able to predict with high accuracy (89-93%, ROC-AUC = 0.94) the patient’s final status (expired/discharged) and with medium accuracy the risk of hospitalization (71-73%, ROC-AUC = 0.75). These models were obtained by assembling and using easily obtainable clinical characteristics (2 demographic characteristics and 19 predictors of comorbidities). The most relevant features of these models were the following patient characteristics: age, sex, number of comorbidities, osteoarthritis, obesity, depression, and renal failure.
Cost-effectiveness of digital therapeutics for essential hypertension
Authors: Nomura Akihiro , Tanigawa Tomoyuki , Kario Kazuomi , Igarashi Ataru
Published: March 2022

Background

Hypertension increases the risk of cardiovascular and other diseases. Lifestyle modification is a significant component of nonpharmacological treatments for hypertension. We previously reported the clinical efficacy of digital therapeutics (DTx) in the HERB-DH1 trial. However, there is still a lack of cost-effectiveness assessments evaluating the impact of prescription DTx. This study aimed to analyze the cost-effectiveness of using prescription DTx in treating hypertension.

Methods

We developed a monthly cycle Markov model and conducted Monte Carlo simulations using the HERB-DH1 trial data to investigate quality-adjusted life-years (QALYs) and the cost of DTx for hypertension plus guideline-based lifestyle modification consultation treatment as usual (TAU), comparing DTx+TAU and TAU-only groups with a lifetime horizon. The model inputs were obtained from the HERB-DH1 trial, published or publicly available data, and expert assumptions. The incremental cost-effectiveness ratio (ICER) per QALY was used as the benchmark for cost-effectiveness. We performed probabilistic sensitivity analyses (PSAs) using the Monte Carlo simulation with 2 million sets.

Results

The DTx+TAU strategy produced 18.778 QALY and was associated with ¥3,924,075 ($34,122) expected costs, compared with 18.686 QALY and ¥3,813,358 ($33,160) generated by the TAU-only strategy over a lifetime horizon, resulting in an ICER of ¥1,199,880 ($10,434)/QALY gained for DTx+TAU. The monthly cost and attrition rate of DTx for hypertension have a significant impact on ICERs. In the PSA, the probability of the DTx arm being a cost-effective option was 87.8% at a threshold value of ¥5 million ($43,478)/QALY gained.

Conclusions

The DTx+TAU strategy was more cost-effective than the TAU-only strategy.
Faster post-malnutrition weight gain during childhood is associated with risk of non-communicable disease in adult survivors of severe malnutrition
Authors: Thompson Debbie S. , McKenzie Kimberley , Opondo Charles , Boyne Michael S. , Lelijveld Natasha , Wells Jonathan , Cole Tim J. , Anujuo Kenneth , Abera Mubarek , Berhane Melkamu , Kerac Marko ,   CHANGE Study Collaborators Group, Badaloo Asha
Published: March 2022

Background

Nutritional rehabilitation during severe malnutrition (SM) aims to rapidly restore body size and minimize poor short-term outcomes. We hypothesized that too rapid weight gain during and after treatment might however predispose to cardiometabolic risk in adult life.

Methods

Weight and height during hospitalization and one year post-hospitalization were abstracted from hospital records of children who survived SM. Six definitions of post-malnutrition weight gain/growth were analysed as continuous variables, quintiles and latent classes in age-sex and minimum weight-for-age z-scores-adjusted regression models against adult anthropometry, body composition (DEXA), blood pressure, blood glucose, insulin, and lipids.

Results

60% of 278 participants were male, mean (SD) age 28.2 (7.7) years, mean (SD) BMI 23.6 (5.2) kg/m2. Mean admission age for SM was 10.9 months (range 0.3-36.3 months) and 207/270 (77%) were wasted (weight-for-height z-score<-2). During childhood, mean rehabilitation weight gain (SD) was 10.1(3.8) g/kg/day and 0.8(0.5) g/kg/day in the first year post-hospitalization. Rehabilitation weight gain >12.9 g/kg/day was associated with higher adult BMI (difference=0.5kg/m2, 95%CI: 0.1-0.9,p= 0.02), waist circumference (difference=1.4cm, 95%CI: 0.4-2.4,p=0.005), fat mass (difference = 1.1kg, 95%CI: 0.2-2,p=0.02), fat mass index (difference=0.32, 95%CI: -0.0001-0,p=0.05), and android fat mass (difference=0.09 kg, 95%CI: 0.01-0.2,p=0.03). Rehabilitation (g/month) and post-hospitalization (g/kg/month) weight gain were associated with greater lean mass (difference = 0.7 kg, 95% CI: 0.1, 1.3,p= 0.02) (difference=1.3kg, 95% CI: 0.3-2.4,p=0.015) respectively.

Conclusion

Rehabilitation weight gain exceeding 13g/kg/day was associated with adult adiposity in young, normal-weight adult SM survivors. This raises questions around existing malnutrition weight gain targets and warrants further studies exploring optimal post-malnutrition growth.