bluuebunny/crossref_metadata_2025 huggingface dataset:
Among Patients Taking Beta-Adrenergic Blockade Therapy, Use Measured (Not Predicted) Maximal Heart Rate to Calculate a Target Heart Rate for Cardiac Rehabilitation
Authors: Keteyian Steven J. , Steenson Katherina , Grimshaw Crystal , Mandel Noah , Koester-Qualters Wanda , Berry Robert , Kerrigan Dennis J. , Ehrman Jonathon K. , Peterson Edward L. , Brawner Clinton A.
Published: June 2023

Purpose:

Among patients in cardiac rehabilitation (CR) on beta-adrenergic blockade (βB) therapy, this study describes the frequency for which target heart rate (THR) values computed using a predicted maximal heart rate (HRmax), correspond to a THR computed using a measured HRmax in the guideline-based heart rate reserve (HRreserve) method.

Methods:

Before CR, patients completed a cardiopulmonary exercise test to measure HRmax, with the data used to determine THR via the HRreserve method. Additionally, predicted HRmax was computed for all patients using the 220 − age equation and two disease-specific equations, with the predicted values used to calculate THR via the straight percent and HRreserve methods. The THR was also computed using resting heart rate (HR) +20 and +30 bpm.

Results:

Mean predicted HRmax using the 220 − age equation (161 ± 11 bpm) and the disease-specific equations (123 ± 9 bpm) differed (P < .001) from measured HRmax (133 ± 21 bpm). Also, THR computed using predicted HRmax resulted in values that were infrequently within the guideline-based HRreserve range calculated using measured HRmax. Specifically, 0 to ≤61% of patients would have had an exercise training HR that fell within the guideline-based range of 50-80% of measured HRreserve. Use of standing resting HR +20 or +30 bpm would have resulted in 100% and 48%, respectively, of patients exercising below 50% of HRreserve.

Conclusions:

A THR computed using either predicted HRmax or resting HR +20 or +30 bpm seldom results in a prescribed exercise intensity that is consistent with guideline recommendations for patients in CR.
Placebo effects contribute to brief online mindfulness interventions for chronic pain: results from an online randomized sham-controlled trial
Authors: Davies Jonathan N. , Colagiuri Ben , Sharpe Louise , Day Melissa A.
Published: June 2023

Mindfulness apps are becoming popular treatments for chronic pain and mental health, despite mixed evidence supporting their efficacy. Furthermore, it is unclear whether improvements in pain are due to mindfulness-specific effects or placebo effects because no trials have compared mindfulness against a sham control. The objective of this study was to compare mindfulness against 2 sham conditions with differing proximity to mindfulness to characterize the relative contributions of mindfulness-specific and nonspecific processes on chronic pain. We assessed changes in pain intensity and unpleasantness and mindfulness-specific and nonspecific pain-related processes in 169 adults with chronic or recurrent pain randomized to receive a single 20-minute online session of mindfulness, specific sham mindfulness, general sham mindfulness, or audiobook control. Mindfulness was not superior to shams for reducing pain intensity or unpleasantness, and no differential engagement of theorized mindfulness-specific processes was observed. However, mindfulness and both shams reduced pain unpleasantness relative to audiobook control, with expectancy most strongly associated with this effect. Sham specificity had no influence on expectancy or credibility ratings, pain catastrophizing, or pain effects. These findings suggest that improvements in chronic pain unpleasantness following a single session of online-delivered mindfulness meditation may be driven by placebo effects. Nonspecific treatment effects including placebo expectancy and pain catastrophizing may drive immediate pain attenuation rather than theorized mindfulness-specific processes themselves. Further research is needed to understand whether mindfulness-specific effects emerge after longer durations of online training.
Preclinical effects of cannabidiol in an experimental model of migraine
Authors: Sturaro Chiara , Fakhoury Bianca , Targowska-Duda Katarzyna M. , Zribi Gilles , Schoch Jennifer , Ruzza Chiara , Calò Girolamo , Toll Lawrence , Cippitelli Andrea
Published: June 2023

Migraine is a disabling disorder characterized by recurrent headaches, accompanied by abnormal sensory sensitivity and anxiety. Despite extensive historical use of cannabis in headache disorders, there is limited research on the nonpsychoactive cannabidiol (CBD) for migraine and there is no scientific evidence to prove that CBD is an effective treatment. The effects of CBD are examined here using a calcitonin gene-related peptide (CGRP)-induced migraine model that provides measures of cephalic allodynia, spontaneous pain, altered light sensitivity (photophobia), and anxiety-like behavior in C57BL/6J mice. A single administration of CGRP induced facial hypersensitivity in both female and male mice. Repeated CGRP treatment produced progressively decreased levels in basal thresholds of allodynia in females, but not in males. A single CBD administration protected both females and males from periorbital allodynia induced by a single CGRP injection. Repeated CBD administration prevented increased levels of basal allodynia induced by repeated CGRP treatment in female mice and did not lead to responses consistent with migraine headache as occurs with triptans. Cannabidiol, injected after CGRP, reversed CGRP-evoked allodynia. Cannabidiol also reduced spontaneous pain traits induced by CGRP administration in female mice. Finally, CBD blocked CGRP-induced anxiety in male mice, but failed in providing protection from CGRP-induced photophobia in females. These results demonstrate the efficacy of CBD in preventing episodic and chronic migraine-like states with reduced risk of causing medication overuse headache. Cannabidiol also shows potential as an abortive agent for treating migraine attacks and headache-related conditions such as spontaneous pain and anxiety.
Additive Manufacturing and Upper-Limb Orthoses: A Scoping Review
Authors: Gehner Amy , Lunsford Dianna
Published: June 2023

Introduction

Additive manufacturing has the potential to revolutionize the orthotic fabrication process for health professionals. Although there is evidence to suggest the benefits of additive manufacturing in rehabilitation-related fields, there is still fairly limited evidence supporting the use of 3D-printed orthoses as an effective and feasible alternative to manually fabricated devices used for the upper limb (UL). The purpose of this scoping review was to examine how 3D printers are currently being used in UL orthotic fabrication within the scope of rehabilitation professionals.

Methods

A literature search was conducted using five databases from 2011 to 2021. Two independent researchers reviewed the abstracts and full text of the articles. The PRISMA process was used to report findings, and data extraction and charting were completed according to the JBI-suggested scoping review protocol.

Results

Thirty-three studies were reviewed as determined by inclusion criteria from various disciplines and countries. Eight diagnostic categories identifying indications for use were derived from the studies including arthritic conditions, burns/contractures and wound care, finger deformities, neurological and neuromuscular disorders, and traumatic, strain, and nerve injuries. Both benefits and challenges are identified with the use of 3D-printed orthoses.

Conclusions

The scope of the 3D-printed orthoses produced in this review is broad and internationally widespread. More evidence is needed to determine the effectiveness of 3D-printed orthoses for each of the identified conditions, but the benefits outside of healing are obvious. The current state of the evidence suggests that this technology remains exploratory in respect to UL orthoses and is therefore not yet ready to be implemented in clinics. With appropriate supports and more evidence, 3D printing still has the potential to revolutionize the UL orthotic fabrication process.

Clinical Relevance

It may be unrealistic for rehabilitation professionals to design and fabricate 3D-printed orthoses without the proper education or time, but it is important for health care professionals to have an emphasized presence in this conversation, as it is their responsibility to treat the patients. This suggests that co-design, combining professionals' expertise, might be the best approach to fabricating these devices for patients.
Risk Selection and Care Fragmentation at Medicare Accountable Care Organizations for Patients With Dementia
Authors: Johnston Kenton J. , Loux Travis , Joynt Maddox Karen E.
Published: June 2023

Background:

Patients with dementia are a growing and vulnerable population within Medicare. Accountable care organizations (ACOs) are becoming Medicare’s dominant care model, but ACO enrollment and care patterns for patients with dementia are unknown.

Objective:

The aim of this study was to compare differences in ACO enrollment for patients with versus without dementia, and in risk profiles and ambulatory care among patients with dementia by ACO enrollment status.

Research Design:

Cohort study assessing the relationships between patient dementia, following-year ACO enrollment, and ambulatory care patterns.

Subjects:

A total of 13,362 (weighted: 45, 499,049) person-years for patients [2761 (weighted: 6,312,304) for dementia patients] ages 65 years and above in the 2015–2019 Medicare Current Beneficiary Survey.

Measures:

We assessed differences in ACO enrollment rates for patients with versus without dementia, and in dementia-relevant ambulatory care visit rates and validated care fragmentation indices among patients with dementia by ACO enrollment status.

Results:

Patients with versus without dementia were less likely to be enrolled in (38.3% vs. 44.6%, P<0.001), and more likely to exit (21.1% vs. 13.7%, P<0.01) ACOs. Among patients with dementia, those enrolled versus not enrolled in ACOs had a more favorable social and health risk profile on 6 of 16 measures (P<0.05). There were no differences in rates of dementia-relevant, primary, or specialty care visits. ACO enrollment was associated with 45.7% higher wellness visit rates (P<0.001), and 13.4% more fragmented primary care (P<0.01) spread across 8.7% more distinct physicians (P<0.05).

Conclusion:

Medicare ACOs are less likely to enroll and retain patients with dementia than other patients and provide more fragmented primary care without providing additional dementia-relevant ambulatory care visits.
Delivery of Cervical and Colorectal Cancer Screenings During the Pandemic in Community Health Centers
Authors: Huguet Nathalie , Danna Maria , Baron Andrea , Hall Jennifer , Hodes Tahlia , O’Malley Jean , Holderness Heather , Marino Miguel , DeVoe Jennifer E. , Cohen Deborah J.
Published: June 2023

Background:

The coronavirus disease 2019 pandemic led to clinical practice changes, which affected cancer preventive care delivery.

Objectives:

To investigate the impact of the coronavirus disease 2019 pandemic on the delivery of colorectal cancer (CRC) and cervical cancer (CVC) screenings.

Research Design:

Parallel mixed methods design using electronic health record data (extracted between January 2019 and July 2021). Study results focused on 3 pandemic-related periods: March–May 2020, June–October 2020, and November 2020–September 2021.

Subjects:

Two hundred seventeen community health centers located in 13 states and 29 semistructured interviews from 13 community health centers.

Measures:

Monthly up-to-date CRC and CVC screening rates and monthly rates of completed colonoscopies, fecal immunochemical test (FIT)/fecal occult blood test (FOBT) procedures, Papanicolaou tests among age and sex-eligible patients. Analysis used generalized estimating equations Poisson modeling. Qualitative analysts developed case summaries and created a cross-case data display for comparison.

Results:

The results showed a reduction of 75% for colonoscopy [rate ratio (RR) = 0.250, 95% CI: 0.224–0.279], 78% for FIT/FOBT (RR = 0.218, 95% CI: 0.208–0.230), and 87% for Papanicolaou (RR = 0.130, 95% CI: 0.125–0.136) rates after the start of the pandemic. During this early pandemic period, CRC screening was impacted by hospitals halting services. Clinic staff moved toward FIT/FOBT screenings. CVC screening was impacted by guidelines encouraging pausing CVC screening, patient reluctance, and concerns about exposure. During the recovery period, leadership-driven preventive care prioritization and quality improvement capacity influenced CRC and CVC screening maintenance and recovery.

Conclusions:

Efforts supporting quality improvement capacity could be key actionable elements for these health centers to endure major disruptions to their care delivery system and to drive rapid recovery.
Shared Decision-making Lowers Medical Expenditures and the Effect Is Amplified in Racially-Ethnically Concordant Relationships
Authors: Brown Timothy T. , Hurley Vanessa B. , Rodriguez Hector P. , Lee Jadyn , Gupta Neel , Toolsie Grace , Markarian Sione , Valenzuela Sofia
Published: June 2023

Background:

Racial-ethnic disparities are pervasive in health care. One mechanism that may underlie disparities is variation in shared decision-making (SDM), which encompasses high-quality clinician-patient communication, including deliberative discussions about treatment options.

Objectives:

To determine whether SDM has causal effects on outcomes and whether these effects are stronger within racial-ethnic concordant clinician-patient relationships.

Research Design:

We use instrumental variables to estimate the causal effect of SDM on outcomes.

Subjects:

A total of 60,584 patients from the 2003–2017 Integrated Public Use Microdata Series Medical Expenditure Panel Survey. Years 2018 and 2019 were excluded due to changes in the Medical Expenditure Panel Survey that omitted essential parts of the SDM index.

Measures:

Our key variable of interest is the SDM index. Outcomes included total, outpatient, and drug expenditures; physical and mental health; and the utilization of inpatient and emergency services.

Results:

SDM lowers annual total health expenditures for all racial-ethnic groups, but this effect is only moderated among Black patients seen by Black clinicians, more than doubling in size relative to Whites. A similar SDM moderation effect also occurs for both Black patients seen by Black clinicians and Hispanic patients seen by Hispanic clinicians with regard to annual outpatient expenditures. There was no significant effect of SDM on self-reported physical or mental health.

Conclusions:

High-quality SDM can reduce health expenditures without negatively impacting overall physical or mental health, supporting a business case for health care organizations and systems to improve racial-ethnic clinician-patient concordance for Black and Hispanic patients.
Nurse Disrespect and Abuse Toward Laboring and Child-Birthing Women
Authors: Alzyoud Fatima A. , McCurry Mary K. , Hunter Revell Susan M. , Kellogg Marni
Published: June 2023

Background

Disrespect and abuse of laboring and child-birthing women in healthcare is a global problem that violates a woman’s right to respectful care. The abuse can be life-threatening and jeopardizes their rights to health, bodily integrity, and freedom from discrimination. This study aimed to understand the factors influencing nurse and midwife disrespect and abuse of child-birthing women in healthcare settings.

Methods

An exploratory, nonexperimental, cross-sectional design was used to identify correlates and predictors of disrespect and abuse of child-birthing women by nurses/midwives. Pearson product–moment correlation and hierarchical multiple regression analyses were used to explore the relationships between nurse intrapersonal, interpersonal (Nursing Incivility Scale), organizational/structural factors (Professional Practice Work Environment Inventory), and disrespect and abuse (Disrespect and Abuse Scale) toward women during labor and childbirth.

An online electronic survey was used to collect data from an international nursing and midwifery population from May 2021 to September 2021. Data were collected from 231 nurses and midwives.

Results

The standardized regression coefficients showed that gender, number of hours worked per week, and organizational/structural factors were all predictors of disrespect and abuse. Organizational/structural factors were the strongest predictor of disrespect and abuse, accounting for 20% of the variance in the regression model.

Discussion

These findings support the patient abuse in healthcare model, where researchers hypothesized that nurse/midwife intrapersonal, interpersonal, and organizational/structural factors contribute to patient abuse in healthcare settings. Work environment, gender, and number of hours worked per week were significant predictors of disrespect and abuse. The results of this study support future research that addresses unhealthy work environments and develops policies to transform the values and norms of labor and delivery.
Psychological distress in a Portuguese sample of cancer patients during the COVID-19 pandemic: a cross-sectional study
Authors: Paredes Tiago F. , Silva Sonia M. , Pacheco Ana F. , de Sousa Bruno C. , Pires Carlos A. , Dias Albina S. , Costa Ana L. , Mesquita Ana R. , Fernandes Eloisa E. , Marques Graciete F. , Vieira Marla S. , Leal Monick B. , Amaral Natalia J. , Rodrigues Vitor J.
Published: June 2023

Objective:

Considering the lack of studies exploring the psychological impact of COVID-19 on patients living with and beyond cancer, this study aimed to explore the levels of emotional distress, anxiety, and depression in patients with cancer and survivors during the COVID-19 pandemic and to identify psychological risk factors.

Methods:

Data for this cross-sectional study were collected through an online questionnaire comprised a self-report questionnaire and the Hospital Anxiety and Depression Scale (HADS). Descriptive statistics and linear regression models were used to characterize the sample and identify the determinants of emotional distress, depression, and anxiety. Statistical analyses were performed using R, version 4.1.1.

Results:

The sample included 940 patients with cancer and survivors, mostly female (87.1%), with a mean age of 49.7 years. More than half of the patients were survivors (55.1%); 56.7% were diagnosed with breast cancer, and 35.0% had other chronic diseases. Most participants believed that they were more likely to be infected with COVID-19 (53.9%) and that they may have more complications if they were infected (76.7%). Approximately half of the participants revealed significant emotional distress (49.3%), 18.1% revealed significant depression, and 29.2% revealed significant anxiety. Female patients, participants with lower education levels, unemployed/lay-off, or in a medical leave with a chronic disease, taking care of someone with a chronic disease, or perceiving a higher risk of being infected with COVID-19 had higher levels of emotional distress, depression, and anxiety.

Conclusions:

This study provides useful information regarding the impact of the COVID-19 pandemic on the mental health of patients with cancer and survivors, showing that an increased number of patients experienced significant emotional distress during the pandemic.
Combined Therapeutic Plasma Exchange and Continuous Renal Replacement Therapy in Children With Dengue-Associated Acute Liver Failure and Shock Syndrome: Single-Center Cohort From Vietnam*
Authors: Vo Luan Thanh , Do Viet Chau , Trinh Tung Huu , Vu Thien , Nguyen Thanh Tat
Published: June 2023

OBJECTIVES:

Pediatric acute liver failure (PALF) is a fatal complication in patients with severe dengue. To date, clinical data on the combination of therapeutic plasma exchange (TPE) and continuous renal replacement therapy (CRRT) for managing dengue-associated PALF concomitant with shock syndrome are limited.

DESIGN:

Retrospective cohort study (January 2013 to June 2022).

PATIENTS:

Thirty-four children.

SETTING:

PICU of tertiary Children’s Hospital No. 2 in Vietnam.

INTERVENTIONS:

We assessed a before-versus-after practice change at our center of using combined TPE and CRRT (2018 to 2022) versus CRRT alone (2013 to 2017) in managing children with dengue-associated acute liver failure and shock syndrome. Clinical and laboratory data were reviewed from PICU admission, before and 24 h after CRRT and TPE treatments. The main study outcomes were 28-day in-hospital mortality, hemodynamics, clinical hepatoencephalopathy, and liver function normalization.

MEASUREMENTS AND MAIN RESULTS:

A total of 34 children with a median age of 10 years (interquartile range: 7–11 yr) underwent standard-volume TPE and/or CRRT treatments. Combined TPE and CRRT (n = 19), versus CRRT alone (n = 15), was associated with lower proportion of mortality 7 of 19 (37%) versus 13 of 15 (87%), difference 50% (95% CI, 22–78; p < 0.01). Use of combined TPE and CRRT was associated with substantial advancements in clinical hepatoencephalopathy, liver transaminases, coagulation profiles, and blood lactate and ammonia levels (all p values < 0.001).

CONCLUSIONS:

In our experience of children with dengue-associated PALF and shock syndrome, combined use of TPE and CRRT, versus CRRT alone, is associated with better outcomes. Such combination intervention was associated with normalization of liver function, neurological status, and biochemistry. In our center we continue to use combined TPE and CRRT rather than CRRT alone.
The Surgical Management of Migraines and Chronic Headaches
Authors: Zhu Kevin , Ha Michael , Finkelstein Emily R. , Chaudry Salman , Hricz Nicholas , Ngaage Ledibabari M. , Rasko Yvonne
Published: June 2023

Background

Migraine headache can be an extremely debilitating condition, with pharmacotherapy for prophylaxis or treatment of acute symptoms being unsuccessful in a large proportion of patients. Surgical management of migraine has recently gained popularity as an alternative to pharmacotherapy for severe disease. However, the novel nature of these procedures may lead to variable insurance coverage, limiting access to care.

Methods

A cross-sectional analysis of 101 US insurance companies was conducted. Companies were chosen based on greatest market share and enrollment per state. A Web-based search or phone call identified whether each company had a publicly available policy on nonsurgical or surgical management of migraine or headache. For companies with an available policy, coverage was categorized into covered, covered on a case-by-case basis, or never covered, with criteria required for coverage collected and categorized.

Results

Of the 101 evaluated insurers, significantly fewer companies had a policy on surgical treatment for migraine or headache (n = 52 [52%]) compared with nonsurgical treatment (n = 78 [78%]) (P < 0.001). For companies with a policy, the most frequently covered nonsurgical treatments were biofeedback (n = 23 [92%]) and botulism toxin injections (n = 61 [88%]). Headaches were an approved indication for occipital nerve stimulation in 4% (n = 2) of company policies and nerve decompression in 2% (n = 1) of policies. Migraines were never offered preauthorized coverage for surgical procedures.

Conclusion

Approximately half of US insurance companies have a publicly available policy on surgical management of migraine or headache. Surgical treatment was seldom covered for the indication of headache and would never receive preauthorized coverage for migraine. Lack of coverage may create challenges in accessing surgical treatment. Additional prospective, controlled studies are necessary to further support the efficacy of surgical treatment.
Outcomes of Laparoscopic Versus Open Liver Resection: A Case-control Study With Propensity Score Matching
Authors: Kirimker Elvan Onur , Ozgu Kerem , Ersoz Siyar , Tuzuner Acar
Published: June 2023

Background:

This study aimed to evaluate the perioperative outcomes of patients with benign and malignant liver lesions scheduled for laparoscopic and open surgery using a propensity score-matched approach to analyze additional cofactors influencing outcomes.

Patients and Methods:

In this study, we retrospectively reviewed 270 patients who underwent laparoscopic or open liver resection at our institute between October 2016 and November 2021. Patients were divided into open and laparoscopic liver resection groups and compared according to the intention to treat principle. In the purification process for the nonrandom nature of the study, a matching analysis was performed at a 1:1 case-control ratio. The PS model included selected data on body mass index, additional data on the American Society of Anesthesiology score, cirrhosis, lesion <2 cm from the hilum, lesion <2 cm from the hepatic vein or inferior vena cava, and type of neoadjuvant chemotherapy.

Results:

The operation time and 30- and 90-day mortality rates were similar between the groups. The average length of hospital stay was 11 days in the open surgery group and 9 days in the laparoscopic surgery group after matching (P=0.011). The 30-day morbidity rate was statistically different between the groups before and after matching, favoring the laparoscopic group (P=0.001 and 0.006, respectively). After the propensity score-matched approch, the open group’s Pringle time was shorter than that of the laparoscopic group. The total operative time was longer in the laparoscopic than in the open surgery group. This did not change after matching (300 vs. 240 min).

Conclusions:

Laparoscopic surgery is a feasible and safe treatment option for patients with liver tumors, with promising results in terms of morbidity and hospital stay.
Application of a New Retraction Method in Laparoscopic Gastrectomy for Gastric Cancer
Authors: Zhang Shun , Cui Xi-mao , Du Tao , Ma Chi-ye , Hu Ren-hao , Yuan Biao , Yan Dong-yi , Song Chun , Jiang Xiao-hua
Published: June 2023

Background:

Better exposition is important for lymph node dissection in the suprapancreatic region and lesser curvature region of the stomach, and digestive tract reconstruction, especially without excellent assistants.

Patients and Methods:

We developed a new laparoscopic retraction method with the use of two internal retractors (TIRs) punctured along with suture. Clinicopathological data, surgical data, and postoperative outcomes were assessed.

Results:

Of the 143 patients included, 51 underwent surgery with the double-sling suture method and 92 underwent surgery with the TIRs method. Laparoscopic radical gastrectomy was successfully performed in all patients. There were no significant differences in patient characteristics or preoperative data in the 2 groups. The operative time was significantly shorter in the TIR group, but the amount of bleeding did not differ. No retraction-related complications both in clipped tissue and liver occurred in all patients.

Conclusions:

Our new retraction technique provided an optimal surgical field and make surgery lower requirements for assistants.
Group size rather than social status influences personal immune efficacy in a socially polymorphic bee
Authors: Nguyen Thi Thu Ha , Asano Tsukani , Cronin Adam L.
Published: June 2023

The evolution of group living is associated with increased pressure from parasites and pathogens. This can be offset by greater investment in personal immune defences and/or the development of cooperative immune defences (social immunity). An enduring question in evolutionary biology is whether social-immune benefits arose in response to an increased need in more complex societies, or arose early in group living and helped facilitate the evolution of more complex societies. In this study, we shed light on this question through investigating how immunity varies intraspecifically in a socially polymorphic bee. Using a novel immune assay, we show that personal antibacterial efficacy in individuals from social nests is higher than that of solitary individuals, but that this can be explained by higher densities in social nests. We conclude that personal immune effects are likely to play a role in the social/solitary transition in this species. These patterns are consistent with the idea that social immunity evolved secondarily, following the evolution of group living. The flexibility of the individual immune system may have favoured a reliance on its use during the facultative phase early in social evolution.
Neuroanatomical characterization of the Nmu-Cre knock-in mice reveals an interconnected network of unique neuropeptidergic cells
Authors: Medrano Mireia , Allaoui Wissal , Van Bulck Mathias , Thys Sofie , Makrini-Maleville Leila , Seuntjens Eve , De Vos Winnok H. , Valjent Emmanuel , Gaszner Bálazs , Van Eeckhaut Ann , Smolders Ilse , De Bundel Dimitri
Published: June 2023

Neuromedin U (NMU) is an evolutionary conserved neuropeptide that has been implicated in multiple processes, such as circadian regulation, energy homeostasis, reward processing and stress coping. Although the central expression of NMU has been addressed previously, the lack of specific and sensitive tools has prevented a comprehensive characterization of NMU-expressing neurons in the brain. We have generated a knock-in mouse model constitutively expressing Cre recombinase under the
Nmu
promoter. We have validated the model using a multi-level approach based on quantitative reverse-transcription polymerase chain reactions,
in situ
hybridization, a reporter mouse line and an adenoviral vector driving Cre-dependent expression of a fluorescent protein. Using the Nmu-Cre mouse, we performed a complete characterization of NMU expression in adult mouse brain, unveiling a potential midline NMU modulatory circuit with the ventromedial hypothalamic nucleus (VMH) as a key node. Moreover, immunohistochemical analysis suggested that NMU neurons in the VMH mainly constitute a unique population of hypothalamic cells. Taken together, our results suggest that Cre expression in the Nmu-Cre mouse model largely reflects NMU expression in the adult mouse brain, without altering endogenous NMU expression. Thus, the Nmu-Cre mouse model is a powerful and sensitive tool to explore the role of NMU neurons in mice.
A temperature-dependent virus-binding assay reveals the presence of neutralizing antibodies in human cytomegalovirus gB vaccine recipients’ sera
Authors: Gomes Ariane C. , Baraniak Ilona A. , McIntosh Megan R. , Sodi Isabella , Langstone Toby , Siddiqui Saima , Atkinson Claire , McLean Gary R. , Griffiths Paul D. , Reeves Matthew B.
Published: June 2023

Human cytomegalovirus (HCMV) remains an important cause of mortality in immune-compromised transplant patients and following congenital infection. Such is the burden, an effective vaccine strategy is considered to be of the highest priority. The most successful vaccines to date have focused on generating immune responses against glycoprotein B (gB) – a protein essential for HCMV fusion and entry. We have previously reported that an important component of the humoral immune response elicited by gB/MF59 vaccination of patients awaiting transplant is the induction of non-neutralizing antibodies that target cell-associated virus with little evidence of concomitant classical neutralizing antibodies. Here we report that a modified neutralization assay that promotes prolonged binding of HCMV to the cell surface reveals the presence of neutralizing antibodies in sera taken from gB-vaccinated patients that cannot be detected using standard assays. We go on to show that this is not a general feature of gB-neutralizing antibodies, suggesting that specific antibody responses induced by vaccination could be important. Although we can find no evidence that these neutralizing antibody responses are a correlate of protection in vivo in transplant recipients their identification demonstrates the utility of the approach in identifying these responses. We hypothesize that further characterization has the potential to aid the identification of functions within gB that are important during the entry process and could potentially improve future vaccine strategies directed against gB if they prove to be effective against HCMV at higher concentrations.
36-h Total Sleep Deprivation Induced Aberrant Insula Sub-regional Functional Connectivity
Authors: Chen Xiangling , Zhang Kaiming , Lei Shiyu , Yang Hai , Zheng Yue , Wu Xuemei , Ma Xinuo , Weng Xiechuan
Published: June 2023

Total sleep deprivation (TSD) induces aberrant insula functional connectivity (FC). The insula comprises at least three functionally distinct subregions: anterior dorsal (dAI), anterior ventral (vAI), and posterior insula (PI). Biased attention toward the anterior insula (AI) has limited our complete understanding of the TSD impact. We aimed to investigate TSD-induced functional connectivity and lateralization across the insula subregions. A total of 54 healthy young men completed 36-h TSD. Two sessions of psychomotor vigilance task (PVT) and 3T resting-state functional magnetic resonance imaging (rs-fMRI) scanning were carried out. A seed-based FC was conducted using bilateral insula subregions. Impaired vigilance, altered functional connectivity and lateralization were observed after TSD. The AI showed enhanced connectivity with the cerebellum, middle frontal gyrus, putamen, and postcentral gyrus but decreased connectivity with the temporal lobes, angular gyrus, calcarine sulcus, anterior cingulum, and medial orbitofrontal gyrus. The PI had increased connectivity with the middle frontal, inferior temporal, and inferior parietal gyrus but showed an anti-correlation with the middle temporal regions, posterior cingulum, and angular gyrus. All the seeds showed ipsilateral connections with specific brain regions, excluding the cerebellum. Both the vAI and PI displayed FC with the insula. The correlation analysis between PVT and brain signal changes did not survive Bonferroni correction. This study provided information about potential functional asymmetries of insula subregions caused by 36-h TSD. These findings provided new insights into the neural mechanisms of inter-hemispheric communication and coordination, which is essential for understanding the overall brain function.
The MIND diet, brain transcriptomic alterations, and dementia
Authors: Li Jun , Capuano Ana W. , Agarwal Puja , Arvanitakis Zoe , Wang Yanling , De Jager Philip L. , Schneider Julie A. , Tasaki Shinya , de Paiva Lopes Katia , Hu Frank B. , Bennett David A , Liang Liming , Grodstein Francine
Published: June 2023

Identifying novel mechanisms underlying dementia is critical to improving prevention and treatment. As an approach to mechanistic discovery, we investigated whether MIND diet (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), a consistent risk factor for dementia, is correlated with a specific profile of cortical gene expression, and whether such a transcriptomic profile is associated with dementia, in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). RNA sequencing (RNA-Seq) was conducted in postmortem dorsolateral prefrontal cortex tissue from 1,204 deceased participants; neuropsychological assessments were performed annually prior to death. In a subset of 482 participants, diet was assessed ~6 years before death using a validated food-frequency questionnaire; in these participants, using elastic net regression, we identified a transcriptomic profile, consisting of 50 genes, significantly correlated with MIND diet score (P=0.001). In multivariable analysis of the remaining 722 individuals, higher transcriptomic score of MIND diet was associated with slower annual rate of decline in global cognition (β=0.011 per standard deviation increment in transcriptomic profile score,P=0.003) and lower odds of dementia (odds ratio [OR] =0.76,P=0.0002). Cortical expression of several genes appeared to mediate the association between MIND diet and dementia, includingTCIM, whose expression in inhibitory neurons and oligodendrocytes was associated with dementia in a subset of 424 individuals with single-nuclei RNA-seq data. In a secondary Mendelian randomization analysis, genetically predicted transcriptomic profile score was associated with dementia (OR=0.93,P=0.04). Our study suggests that associations between diet and cognitive health may involve brain molecular alterations at the transcriptomic level. Investigating brain molecular alterations related to diet may inform the identification of novel pathways underlying dementia.
KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss
Authors: Kauwe Grant , Pareja-Navarro Kristeen A. , Yao Lei , Chen Jackson H. , Wong Ivy , Saloner Rowan , Cifuentes Helen , Nana Alissa L. , Shah Samah , Li Yaqiao , Le David , Spina Salvatore , Grinberg Lea T. , Seeley William W. , Kramer Joel H. , Sacktor Todd C. , Schilling Birgit , Gan Li , Casaletto Kaitlin B. , Tracy Tara E.
Published: June 2023

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer’s disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.
Co-aggregation and parallel aggregation of specific proteins in major mental illness
Authors: Samardžija Bobana , Juković Maja , Zaharija Beti , Renner Éva , Palkovits Miklós , Bradshaw Nicholas J.
Published: June 2023

Background

Disrupted proteostasis is an emerging area of research into major depressive disorder. Several proteins have been implicated as specifically forming aggregates in the brains of subsets of patients with psychiatric illnesses, these proteins include CRMP1, DISC1, NPAS3 and TRIOBP-1. It is unclear, however, whether these normally aggregate together in the same individuals, and, if so, whether each protein aggregates independently of each other (“parallel aggregation”) or if the proteins physically interact and aggregate together (“co-aggregation”).

Materials and methods

Post mortem insular cortex samples from major depressive disorder and Alzheimer’s disease patients, suicide victims and control individuals had their insoluble fractions isolated and tested by Western blotting to determine which of these proteins are insoluble, and therefore likely aggregating. The ability of the proteins to co-aggregate (directly interact and form common aggregate structures) was tested by systematic pairwise expression in SH-SY5Y neuroblastoma cells, examined by immunofluorescent microscopy.

Results

Many individuals displayed multiple insoluble proteins in the brain, although not enough to imply interaction between the proteins. Cell culture analysis revealed that only a few of the proteins analyzed can consistently co-aggregate with each other: DISC1 with CRMP1 and TRIOBP-1. DISC1 was able to induce aggregation of full length TRIOBP-1, but not its domains expressed individually.

Conclusions

While specific proteins are capable of co-aggregating, and appear to do so in the brains of individuals with mental illness, and potentially also with suicidal tendency, it is more common for such proteins to aggregate in a parallel manner, through independent mechanisms.
Megafauna diversity and functional declines in Europe from the Last Interglacial (LIG) to the present
Authors: Davoli Marco , Monsarrat Sophie , Pedersen Rasmus , Scussolini Paolo , Karger Dirk Nikolaus , Normand Signe , Svenning Jens-Christian
Published: June 2023

Aim:to estimate European megafauna diversity and functional declines in the present compared to the nearest in time modern-analogue climate period prior to the worldwide diffusion ofHomo sapiens.

Location:Europe.

Time period:Last Interglacial (LIG; ca. 127,000 years ago) to present.

Major taxa studied:wild, large (≥10 kg) terrestrial mammals.

Methods:we assessed the distribution of 48 European megafauna species during the LIG using hindcasting modelling and fossil records. Then, we estimated the decline in megafauna community diversity and potential trait-based functional effects from the LIG to the present, accounting for climate differences between the two periods.

Results:from the LIG to the present, species richness and community biomass across Europe dropped by 74.3% (± 9.9% SD) and 96.7% (± 4.1% SD), respectively. Functional diversity dropped by 59.1% (± 11.8% SD) for herbivores and by 48.2% (± 25.0% SD) for carnivores, while trait-informed potential vegetation and meat consumptions dropped by 91.1% (± 7.4% SD) and 61.2% (± 17.2% SD), respectively. The loss in megafauna diversity and associated ecological processes were high everywhere, but particularly in western Europe for carnivores and in the East European Plain for herbivores. We found that potential megafauna richness and functional patterns in the two periods were near identical if only climate-driven differences were considered.

Main conclusions:severe, size-biased defaunation has degraded megafauna assemblages and megafauna-mediated ecological processes across Europe from the LIG to the present. These patterns cannot be explained by climate differences between the two periods, thus were likely driven by the impact of prehistoric Homo sapiens. The results suggest that the structure of wild ecosystems of the present strongly deviates from the evolutionary norm, notably with decreased functional heterogeneity and decreased fluxes of biogeochemical compounds across the trophic networks, highlighting the importance of ambitious policies of megafauna community restoration to support ecosystems functioning.
Genetic background influences the 5XFAD Alzheimer’s disease mouse model brain proteome
Authors: Hurst Cheyenne D. , Dunn Amy R. , Dammer Eric B. , Duong Duc M. , Seyfried Nicholas T. , Kaczorowski Catherine C. , Johnson Erik C. B.
Published: June 2023

There is a pressing need to improve the translational validity of Alzheimer’s disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. Here we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in hippocampus and cortex (n=3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across hippocampus and cortex in 5XFAD and non-transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress response and neuronal synapse/signaling. The modules with the strongest relationship to human disease—neuronal synapse/signaling and lysosome/stress response—were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated to AD genotype in hippocampus compared to cortex. Our findings suggest that genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD.
Multivariate classification of multichannel long-term electrophysiology data identifies different sleep stages in fruit flies
Authors: Jagannathan Sridhar R. , Jeans Rhiannon , Van De Poll Matthew N. , van Swinderen Bruno
Published: June 2023

Sleep is observed in most animals, which suggests it subserves a fundamental process associated with adaptive biological functions. However, the evidence to directly associate sleep with a specific function is lacking, in part because sleep is not a single process in many animals. In humans and other mammals, different sleep stages have traditionally been identified using electroencephalograms (EEGs), but such an approach is not feasible in different animals such as insects. Here, we perform long-term multichannel local field potential (LFP) recordings in the brains of behaving flies undergoing spontaneous sleep bouts. We developed protocols to allow for consistent spatial recordings of LFPs across multiple flies, allowing us to compare the LFP activity across awake and sleep periods and further compare the same to induced sleep. Using machine learning, we uncover the existence of distinct temporal stages of sleep and explore the associated spatial and spectral features across the fly brain. Further, we analyze the electrophysiological correlates of micro-behaviours associated with certain sleep stages. We confirm the existence of a distinct sleep stage associated with rhythmic proboscis extensions and show that spectral features of this sleep-related behavior differ significantly from those associated with the same behavior during wakefulness, indicating a dissociation between behavior and the brain states wherein these behaviors reside.
Stimulation of VTA dopamine inputs to LH upregulates orexin neuronal activity in a DRD2-dependent manner
Authors: Harada Masaya , Capdevila Laia Serratosa , Wilhelm Maria , Burdakov Denis , Patriarchi Tommaso
Published: June 2023

Dopamine and orexins (hypocretins) play important roles in regulating reward-seeking behaviors. It is known that hypothalamic orexinergic neurons project to dopamine neurons in the ventral tegmental area (VTA), where they can stimulate dopaminergic neuronal activity. Although there are reciprocal connections between dopaminergic and orexinergic systems, whether and how dopamine regulates the activity of orexin neurons is currently not known. Here we implemented an opto-Pavlovian task in which mice learn to associate a sensory cue with optogenetic dopamine neuron stimulation to investigate the relationship between dopamine release and orexin neuron activity in the LH. We found that dopamine release can be evoked in LH upon optogenetic stimulation of VTA dopamine neurons, and is also naturally evoked by cue presentation after opto-Pavlovian learning. Furthermore, orexin neuron activity could also be upregulated by local stimulation of dopaminergic terminals in the LH in a way that is partially dependent on dopamine D2 receptors (DRD2). Our results reveal previously unknown orexinergic coding of reward expectation and unveil an orexin-regulatory axis mediated by local dopamine inputs in the LH.

Highlights

Optical VTA DA neuron stimulation is sufficient to elicit a Pavlovian-like dopamine transient in the NAc

Dopamine in the LH encodes both negative and positive reward prediction errors

Dopamine in the LH positively modulates orexin neuronal activity locally in a D2R dependent way