bluuebunny/crossref_metadata_2025 huggingface dataset:
The changing landscape for patients with relapsed/refractory acute myeloid leukaemia
Authors: Isidori Alessandro , Ferrara Felicetto
Published: September 2021

Purpose of review

The treatment of patients with relapsed or refractory (R/R) acute myeloid leukaemia (AML) has been an unequal challenge for many decades. Although significant progress has been made in the discovery of the mechanisms underlying the molecular pathogenesis of the disease, more than 50% of AML patients still die, mostly from relapsed disease. Currently, the only potential curative option for patients with R/R AML remains allogeneic bone marrow transplantation in second complete remission, which is far being easy to achieve, mainly for patients with primary induction failure or older than 65 years. The purpose of this review is to discuss recent advances in the management of patients with R/R AML, with particular emphasis to new therapeutic options that are replacing conventional salvage chemotherapy.

Recent findings

The development of new agents selectively targeting molecular abnormalities offer more effective and less toxic alternative to chemotherapy, potentially useful as a bridge to allogeneic stem cell transplantation in second complete remission.

The recent approval of new drugs for R/R is transforming the paradigm of care we have relied on for the past 50 years. Ongoing clinical trials will tell us how bright is the future for R/R AML patients.
Reducing the Negative Impact of Social Distancing Through Intentional Connectedness
Authors: Akers Shanna W. , Joseph Rachel A.
Published: September 2021

Social distancing during the COVID-19 pandemic resulted in both positive and negative effects. Nursing education was significantly impacted by the necessity of remote learning and absence of clinical experiences. The purpose of this article is to discuss how intentionality in social connectedness can combat the negative impact of social distancing in nursing education. Lessons learned and strategies employed by nursing educators during the intentional application of social connectedness are presented.
The Educator's Art of Prayer and Caring
Authors: Mingo Sharon
Published: September 2021

Baccalaureate nursing students often encounter significant academic and personal hardships that produce stress-induced anxiety. Nursing educators can foster the practice of prayer and caring with struggling nursing students as a means of helping students manage anxiety and stress. Christian educators can offer prayer when guiding and counseling students who are struggling with academics or other situations that negatively influence their progress toward professional practice. Three case studies illustrate an educator's use of prayer with students.
The Pain of Infertility
Authors: Schoonover-Shoffner Kathy
Published: September 2021

Infertility, the inability to conceive and/or carry a baby to term, is an agonizing experience for many. Both the experience and pain of infertility are ancient, shared by women and men of the Bible and by couples today. An insider's look into infertility can help nurses understand the suffering that occurs, suggest what can be said and done that can be helpful as well as hurtful, and offer insight into what can be gained personally and spiritually through the experience of infertility.
The impact of bolus versus continuous infusion of intravenous ketamine on bispectral index variations and desflurane administration during major surgery
Authors: Carrara Lucie , Nault Mathieu , Morisson Louis , Godin Nadia , Idrissi Moulay , Fortier Annik , Guertin Marie Claude , Brulotte Véronique , Fortier Louis-Philippe , Verdonck Olivier , Richebe Philippe
Published: September 2021

BACKGROUND

Although ketamine, a NMDA-receptor antagonist, tends to increase the bispectral index (BIS), it remains a widely used analgesic whenever administered in low doses during major surgery.

OBJECTIVE

The objective of this study was to compare the impact of intravenous ketamine (given either as a continuous infusion or as a bolus) on BIS and to compare desflurane administration and postoperative outcomes between the groups.

DESIGN

Prospective, randomised, parallel-group, open-label study.

SETTING

University hospital, operating room.

PARTICIPANTS

Fifty patients, scheduled for major abdominal surgery.

INTERVENTIONS AND MAIN OUTCOMES MEASURES

Patients were randomised into two groups: ketamine by intravenous continuous infusion – group (KI) and ketamine by i.v. bolus – group (KB). In the KI group, ketamine at a rate of 0.25 mg kg−1 h−1 was commenced at skin incision (T0) and maintained at this rate for the duration of surgery. In group KB, a ketamine bolus of 0.25 mg kg−1was administered at T0 and repeated every hour. The difference in BIS between the groups was compared from T0 onwards. The amount of desflurane administered to keep BIS within the usual recommended range (40–60) was compared, as were the doses of phenylephrine and remifentanil. Postoperative pain and recovery outcomes were also assessed.

RESULTS

After T0, the BIS increased significantly from baseline in group KB compared with group KI: the rise in BIS was 20 ± 8 vs. 11 ± 6, respectively (P = 0.0001). The between-group mean difference (95% confidence interval (CI), was 9 (5 to 13). In group KB, desflurane administration significantly increased for the first 15 min after T0: 6.3 ± 1.8 vs. 3.8 ± 1.3 ml (P < 0.0001) with a mean intergroup group difference (95% CI) of 2.4 (1.5 to 3.4) ml. There was no difference in desflurane administration when considering the full hour from T0 to T60 min: 16 ± 9 vs. 15 ± 5 ml (P = 0.63) with a mean intergroup difference (95% CI) of 1 (−3 to 5) ml. After surgery, pain scores, opioid consumption, incidence of nausea and vomiting and recovery scores were similar between groups.

CONCLUSION

Compared with a continuous ketamine infusion, a ketamine bolus significantly increased the BIS after T0. In order to keep the BIS below 60, significantly more desflurane was administered from T0 to T15 min in group KB. To prevent such higher desflurane administration and its related atmospheric pollution, our results suggest administering intra-operative intravenous ketamine as an infusion rather than a bolus.

TRIAL REGISTRATION

Clinicaltrials.gov registration identifier: NCT03781635.
The bladder microbiome and interstitial cystitis: is there a connection?
Authors: Abernethy Melinda G. , Tsuei Angie
Published: September 2021

Purpose of review

Interstitial cystitis/painful bladder syndrome (PBS) is a debilitating condition, the etiology of which remains unclear and for which there are variable and often unsatisfactory treatment options. Within the last decade, evolving knowledge regarding the presence and role of the urinary microbiome has led to investigations regarding its impact on symptoms and severity of interstitial cystitis PBS.

Recent findings

Since 2017, five studies have investigated differences between the microbiome of female patients with interstitial cystitis /PBS to asymptomatic controls. While varied in methodology, specifically with regard to urine collection processing and microbial detection, the majority of studies (4/5) found no association between urinary microbiota and interstitial cystitis /PBS.

Research regarding the role of the urinary microbiome and lower urinary tract function and dysfunction, including interstitial cystitis /BPS, remains in preliminary stages. While data regarding the role of lactobacillus in lower urinary tract homeostasis is inconclusive, further research is warranted.
Incidence and correlates of high blood pressure from childhood to adulthood: the Birth to Twenty study
Authors: Meer Romain , Boateng Daniel , Klipstein-Grobusch Kerstin , Norris Shane A. , Kagura Juliana
Published: September 2021

Background:

There is growing evidence from high-income countries suggesting that hypertension developed in childhood and adolescence persists into adulthood. The objective of this study was to investigate the incidence and risk factors of high blood pressure (BP) in urban black children.

Methods:

We used data from the Birth to Twenty (BT20+) cohort in Johannesburg, South Africa constituting of children born in 1990 and who had their growth, development and blood pressure measured at six follow-up periods over the course of 13 years. High BP was classified as at least 95th percentile for age, sex and height. Incidence rate of high BP was calculated using survival analysis and risk factors were determined by use of Cox proportional hazard regression.

Results:

Over a follow-up period of 13 years, the overall incidence rate of high BP was 57 cases per 1000 person-years (95% CI 53.2–61.1). Risk for incident high BP increased with rapid relative weight gain in early childhood (hazard ratio =1.11, 95% CI 1.00–1.22), mid-childhood (hazard ratio = 1.13, 95% CI 1.03–1.24) and adolescence (hazard ratio = 1.21, 95% CI 0.99–1.47). Maternal parity significantly increased the risk for incident high BP (hazard ratio = 1.08, 95% CI 1.01–1.15).

Conclusion:

Maternal parity and relative weight gain were determinants for incident high blood pressure in urban black South African children and adolescents. To reduce the high incidence and the disease burden of high BP, national programs should focus on promoting healthy lifestyle in early stages of life to prevent rapid weight gain and later cardiovascular disease risk. Further research is required to investigate whether incident high BP in childhood predict clinical outcomes in adulthood.
Comparison of the 2017 American Academy of Pediatrics with the fourth report and the 2016 European Society of Hypertension guidelines for the diagnosis of hypertension and the detection of left ventricular hypertrophy in children and adolescents: a systematic review and meta-analysis
Authors: Goulas Ioannis , Farmakis Ioannis , Doundoulakis Ioannis , Antza Christina , Kollios Konstantinos , Economou Marina , Kotsis Vasilios , Stabouli Stella
Published: September 2021

Background and objectives:

In 2017, the American Academy of Pediatrics (AAP) recommended new blood pressure (BP) thresholds for the diagnosis of hypertension in children and adolescents. We assessed the impact of the AAP guideline, as compared to the Fourth Report and the 2016 European Society of Hypertension guidelines (ESH), on the prevalence of hypertension and the detection of left ventricular hypertrophy (LVH).

Methods:

We systematically searched for studies evaluating the impact of the 2017 AAP guidelines on the prevalence of hypertension and LVH compared with the Fourth Report or the 2016 ESH guidelines. Meta-analysis was performed to compare the overall risk of LVH between the guidelines. We used a random-effects model to synthesize quantitative data.

Results:

We included 18 observational studies in the systematic review with an overall moderate to high risk of bias. The AAP guideline identified more children with hypertension than the Fourth Report and the ESH guidelines. In the meta-analysis of three observational studies, the guidelines revealed similar associations with LVH [odds ratio (OR) = 3.89, 95% confidence interval (95% CI) 1.68–8.99 for AAP and OR = 3.19, 95% CI 1.14–8.88 for Fourth Report/ESH guidelines]. Qualitative analysis of two observational studies revealed similar predictive value of the guidelines for LVH in adult life.

Conclusion:

Despite the higher prevalence of hypertension frequently reported by the adoption of AAP guideline BP thresholds compared with Fourth Report and the ESH guidelines, the new thresholds have not been proved to advance assessment of cardiovascular risk in terms of LVH currently the most accepted subclinical marker in youth.
C-reactive protein and hypertension among Ghanaian migrants and their homeland counterparts: the Research on Obesity and Diabetes among African Migrants study
Authors: van Apeldoorn Joshua A.N. , van der Linden Eva L. , Bahendeka Silver , Beune Erik , Meeks Karlijn A.C. , Klipstein-Grobusch Kerstin , van den Born Bert-Jan , Agyemang Charles
Published: September 2021

Background:

Hypertension (HTN) is a growing public health problem in sub-Saharan Africa (SSA) and SSA migrants in Europe. Elevated levels of inflammatory marker C-reactive protein (CRP) have been linked to HTN but the relationship of CRP and HTN among SSA populations has not been studied. To address this knowledge gap, we studied the association between CRP and HTN in migrant and nonmigrant SSA populations residing in different settings.

Methods:

Cross-sectional data from the multicentre Research on Obesity and Diabetes among African Migrants (RODAM) study were analysed including 5683 Ghanaians aged at least 18 years, residing in rural and urban Ghana, and Europe. Multivariate logistic regression analyses were used to assess the association between high levels of CRP (≥3 mg/l) and HTN (SBP ≥140 mmHg and/or DBP ≥90 mmHg and/or use of antihypertensive medication) per geographical site and sex.

Results:

The association between CRP levels and HTN varied by sex and geographical location. In age-adjusted models, there was an association between high CRP levels and HTN in urban-Ghanaian women (odds ratio 1.50, 95% confidence interval 1.10–2.03), and European-Ghanaian men (1.68, 1.16–2.43) and women (1.63, 1.28–2.07). However, these associations were attenuated after adjustment for conventional risk factors, especially BMI. No association was found in rural-Ghanaians or urban-Ghanaian men.

Conclusion:

Our findings show an association between CRP and HTN among Ghanaian migrants and urban-Ghanaian women, however, this was largely explained by conventional risk factors. Thus, prevention of conventional risk factors, in particular obesity, may help to reduce the potentially low-grade inflammatory mechanism underlying HTN.
Glaucoma Health Coaching: A Survey of Eye Drop Instillation Education
Authors: Taribagil Priyal , Thomas Sarah , Mathew Rashmi G.
Published: September 2021

Précis:

Health coaching is an effective strategy in supporting glaucoma patients to become champions of their own health. A personalized program should be implemented at the point of diagnosis.

Purpose:

Glaucoma is the leading cause of irreversible blindness worldwide. Its mainstay of treatment is intraocular pressure–lowering eye drops. Yet, many patients do not receive education regarding their condition, the importance of their eye drops, and how to instil them. The purpose of this audit was to assess what proportion of glaucoma patients had received any education regarding eye drop usage and whether a health coaching intervention would be beneficial.

Materials and Methods:

This prospective audit was conducted during World Glaucoma Week at Moorfields Eye Hospital. Patients diagnosed with glaucoma were given a 6-part questionnaire. Subsequently, they received a coaching session with a pharmacy team member, focusing on eye drop instillation. Patient feedback was recorded.

Results:

The sample size was 262. Overall, 92% of patients who had received teaching found it useful. Approximately half the patients had never been shown how to use eye drops before. In all, 79% of those who had never received a demonstration thought that further coaching would be helpful. When experiencing difficulties with eye drop instillation; 29% of patients felt comfortable asking a relative; 26% would not ask for help, and 16% would consult their glaucoma doctor. Almost 30% of patients had poked themselves in the eye at least once, during self-administration.

Conclusions:

Experienced and inexperienced patients found glaucoma health coaching beneficial. Health coaching empowers patients with long-term conditions to be champions of their own health condition, and it is important for patients to receive this training from the onset of their treatment.
Prevalence of Anxiety and Depression in Patients With Primary Glaucoma in Western India
Authors: Dayal Ashutosh , Sodimalla Kalyani V.K. , Chelerkar Vidya , Deshpande Madan
Published: September 2021

Précis:

Glaucoma can cause disturbance in psychological and emotional functioning of patients, leading to anxiety and depression, even early in the disease. Identification and management of these problems should be included as a part of the holistic approach for patient care.

Purpose:

The purpose of this study was to assess the prevalence of anxiety and depression in patients with primary glaucoma using a standard validated questionnaire.

Methodology:

A cross-sectional prevalence study was carried out on 200 patients attending the glaucoma outpatient clinic at a tertiary care eye hospital in Pune, India. After obtaining written consent, all patients underwent a thorough ophthalmic examination. Those with primary glaucoma were included in the study and classified on the basis of the Hodapp-Parrish-Anderson criteria. Participants were asked to respond to the Hospital Anxiety and Depression Scale (HADS) questionnaire, and responses were analyzed statistically.

Results:

The mean HADS-Anxiety score was 4.5 (SD=3.4), while HADS-Depression was 4.1 (SD=3.8). The severity of the disease was associated with significantly higher HADS scores. Mean HADS-Anxiety scores were 3.1 (SD=2.9) for mild glaucoma, 4.4 (SD=2.6) for moderate, and 7.7 (SD=3.0) for advanced disease (P<0.001). Similarly, mean HADS-Depression scores were 2.0 (SD=2.6), 4.2 (SD=3.0), and 8.3 (SD=3.3), respectively for mild, moderate, and severe glaucoma (P<0.001). Based on HADS scores, a third of patients (34.5%) were symptomatic for anxiety or depression, out of which 25 (12.5%) could be classified as definite cases. Duration of treatment had no association with HADS scores.

Conclusions:

An association exists between the amount of visual loss among patients with glaucoma and symptoms of anxiety and depression, irrespective of disease duration. This information may help to choose treatment approaches most likely to be beneficial to the patients.
Cerebral monitoring in surgical ICU patients
Authors: Massari Dario , de Keijzer Ilonka N. , Scheeren Thomas W.L.
Published: September 2021

Purpose of review

To give an overview of cerebral monitoring techniques for surgical ICU patients.

Recent findings

As the burden of postsurgical neurological and neurocognitive complications becomes increasingly recognized, cerebral monitoring in the surgical ICU might gain a relevant role in detecting and possibly preventing adverse outcomes. However, identifying neurological alterations in surgical ICU patients, who are often sedated and mechanically ventilated, can be challenging. Various noninvasive and invasive techniques are available for cerebral monitoring, providing an assessment of cortical electrical activity, cerebral oxygenation, blood flow autoregulation, intracranial pressure, and cerebral metabolism. These techniques can be used for the diagnosis of subclinical seizures, the assessment of sedation depth and delirium, the detection of an impaired cerebral blood flow, and the diagnosis of neurosurgical complications.

Cerebral monitoring can be a valuable tool in the early detection of adverse outcomes in surgical ICU patients, but the evidence is limited, and clear clinical indications are still lacking.
Evaluating a Multicomponent Strategy to Address Burnout, Job Engagement, and Job Satisfaction Among Telepsychiatrists
Authors: Mahmoud Hossam , Naal Hady , Mitchell Bridget
Published: September 2021

Introduction:

Preventing and managing burnout among psychiatrists in the United States is a national priority. Telepsychiatry is a promising web-based modality for the delivery of psychiatric services that has the potential for reducing burnout rates. However, it may also be associated with certain occupational challenges such as social and professional isolation, which may impact telepsychiatrists’ performance and well-being. Therefore, it is important to develop ways to enhance retention rates of telepsychiatrists and reduce their risk of burnout.

Methods:

In this study, we examine approaches implemented by a telepsychiatry organization between 2018 and 2019, as part of a strategy to enhance the job satisfaction, engagement, and well-being of telepsychiatrists. This article describes the development, implementation, and outcomes associated with this strategy.

Results:

Individual and organizational-level outcomes showed overall higher job satisfaction, higher retention rates, and higher output rates over the period in which the strategy was implemented compared with previously, which translate to increased access to mental health care services for patients and imply a reduced risk of burnout among telepsychiatrists.

Conclusions:

Given the risk for social, professional, and academic isolation among telepsychiatrists, organizational engagement efforts are advisable, feasible, and may be associated with significant improvement in satisfaction and retention among telepsychiatrists. Our findings have important implications for enhancing the performance and job satisfaction of telepsychiatrists and potentially reducing burnout rates in this population of providers.

Practical Applications:

Effective strategy efforts included: (1) enhancing and standardizing recruitment efforts to ensure proper matching of the psychiatrist with organization, site, and patient population; (2) ensuring congruence between the individual’s and the organization’s values; (3) providing support for nonclinical administrative tasks; (4) maintaining professional and social communication, support, and supervision via multiple channels.
Exercise Prescription Practices to Improve Mental Health
Authors: Escobar-Roldan Ivan D. , Babyak Michael A. , Blumenthal James A.
Published: September 2021

Objective:

There is growing evidence that higher levels of physical activity are associated with better mental health. Furthermore, interventional studies have shown that exercise may improve symptoms in a number of psychiatric conditions. Despite this evidence, relatively little information is available about how these findings have been translated into clinical practice. The goal of this study was to characterize the exercise prescribing practices of health care providers from different subspecialties and evaluate factors that may influence their prescribing practices.

Methods:

We conducted a cross-sectional survey among faculty and staff from a large academic tertiary care medical center in the southeastern United States. Participants were invited to complete the survey via email or departmental newsletters. Descriptive statistics were used to characterize the sample and ordered logistic regression was used to analyze practices about exercise as a therapy for psychiatric illness.

Results:

A total of 185 respondents completed the survey. More than half of the providers (58%) reported that they regularly recommend exercise as part of the treatment for patients with psychiatric conditions; however, few providers offered specific exercise instructions (24%) or followed national guidelines (30%). Depression (84.9%) and anxiety (69.2%) were the most common indications for exercise prescription, while insufficient knowledge or training was the most common barrier to prescribing exercise. We also found significant differences in prescription practices depending on the providers’ formal clinical degree and their reported personal exercise habits.

Conclusions:

Exercise is recognized by most clinicians as a therapeutic option for psychiatric conditions. Despite this recognition, only a small proportion provide recommendations consistent with national guidelines or empirical research.
Periodic Catatonia: Long-term Treatment With Lamotrigine: A Case Report
Authors: Konstantinou Gerasimos , Papageorgiou Charalabos C. , Angelopoulos Elias
Published: September 2021

Periodic catatonia is a rare form of catatonia, characterized by episodes occurring in a cyclic pattern with clinical features of combined stupor and excitement, with intervals of remission. Although periodic catatonia is not common, it is an urgent condition, requiring hospitalization for evaluation and treatment. The management of periodic catatonia is quite challenging, mainly because of the unknown pathophysiological mechanisms involved in the onset of this clinical entity, which are less clear than in other forms of catatonia. Although positive trials of several medications in the acute phase of periodic catatonia have been published, available literature concerning the prevention of recurrent catatonic episodes is scarce. Here, we present the case of a patient with periodic catatonia in which long-term treatment with lamotrigine appears to have acted prophylactically in reducing the occurrence and severity of new catatonic episodes. A better understanding of the mechanisms involved in the pathophysiology of periodic catatonia and increasing psychiatrists’ and physicians’ awareness of the presentation of this clinical entity could be of benefit in shedding light on the most appropriate treatment approach. However, further clinical studies are needed before any firm recommendations can be made.
Mental Health and COVID-19: Challenges and Multimodal Clinical Solutions
Authors: Masand Prakash , Patkar Ahaan , Tew Christine , Hoerner Alissa , Szabo Steven T. , Gupta Sanjay
Published: September 2021

The Coronavirus Disease 2019 (COVID-19) pandemic has led to an exponential rise in mental health issues. Studies have shown that, in times of increased unemployment rates and economic downturn, rates of mental health issues, suicide, substance use, and domestic violence tend to increase. Barriers to care, including stigma and decreased access to providers, contribute to morbidity and mortality. Telehealth services are being utilized to help increase access to care, and economic stimulus packages have been created to help with the financial burden that is often associated with increased mental health stressors. Efforts to prevent burnout and other policy recommendations can help decrease mental health issues in first responders and health care professionals, who are at an increased risk for these problems. Increasing the ability to provide wellness screenings to the general population, to educate the public about preventive measures and practices, and to provide mental health and substance use treatment, such as medication management and therapy services, are among top priorities to further reduce the socioeconomic impact of COVID-19 on mental illness.
Can Nonoffending Pedophiles Be Reached for the Primary Prevention of Child Sexual Abuse by Addressing Nonoffending Individuals Who Are Attracted to Minors in the United States? New Strategies With The Global Prevention Project
Authors: Tenbergen Gilian , Martinez-Dettamanti Meg , Christiansen Candice
Published: September 2021

This paper introduces a new prevention strategy against child sexual abuse (both offline and online) in the United States. The Global Prevention Project is a supportive treatment program designed for nonoffending minor-attracted persons who reside in the community. Attraction to minors and the underlying scientific terms (pedophilia/hebephilia) are discussed and a framework is provided for how to implement such a program in the United States. Our treatment modality is described to provide transparency in our clinical work. We discuss challenges encountered in this domain with possible solutions and the legal ramifications of preventing child sexual abuse behaviors by targeting nonoffending individuals.
Commentary: Diagnostic and Treatment Issues in Psychosis
Authors: Garakani Amir
Published: September 2021

The 3 cases presented in this issue highlight challenges in evaluating and treating patients with psychotic symptoms. The first case involved the rare but debilitating condition of periodic catatonia, the second case involved the use of intranasal oxytocin to augment an antipsychotic for a patient with worsening psychotic symptoms (and a prior diagnosis of schizophrenia) in the postpartum period, and the third case involved auto-enucleation (often referred to as “Oedipism”), a violent form of self-mutilation, in a patient presenting with first-episode schizophrenia. These case reports reinforce the need to consider a wide differential diagnosis before initiating treatment. Understanding the broad spectrum with which psychotic symptoms can present, or rare presentations of more common conditions, can help clarify the diagnosis and guide treatment, and hopefully help prevent or reduce future self-harm or violence, psychotic episodes, and hospitalizations.
Therapeutic Risk Management for Violence: Safety Planning for Other-directed Violence
Authors: McGarity Suzanne , Stacy Stephanie , Borges Lauren M. , Barnes Sean M. , Nazem Sarra , Gerard Georgia R. , Clark Kaily , Matarazzo Bridget B. , Bahraini Nazanin H. , Wortzel Hal S.
Published: September 2021

Therapeutic management of risk for other-directed violence (ODV) involves screening, assessment, and clinically appropriate intervention. In this 5-part series, effective screening and assessment for ODV have been described as a combination of clinical interviewing and the use of structured tools to inform clinical impressions of both acute and chronic risk for violence. Once risk of violence is identified, therapeutic management of the risk throughout the course of treatment is best achieved by determining the function of the violent ideation and behavior. This can be achieved through the use of functional chain analysis. Chain analysis not only serves the purpose of providing insight into the contingencies of violent behavior but also helps to identify target areas of intervention where other skills, strategies, and means to access resources for support can be applied. In this fifth and final column of the series, we describe an intervention with all of these outcomes as its goals. A safety plan for ODV assists both clients and mental health professionals in disrupting patterns of violent ideation or behavior that would otherwise continue causing not only harm to others but prolonged negative consequences for those engaging in such behaviors.
Organizing a Rational Approach to Treatments of Disorders of Consciousness Using the Anterior Forebrain Mesocircuit Model
Authors: Fridman Esteban A. , Schiff Nicholas D.
Published: September 2021

Organizing a rational treatment strategy for patients with multifocal structural brain injuries and disorders of consciousness (DOC) is an important and challenging clinical goal. Among potential clinical end points, restoring elements of communication to DOC patients can support improved patient care, caregiver satisfaction, and patients' quality of life. Over the past decade, several studies have considered the use of the anterior forebrain mesocircuit model to approach this problem because this model proposes a supervening circuit-level impairment arising across DOC of varying etiologies. We review both the conceptual foundation of the mesocircuit model and studies of mechanisms underlying DOC that test predictions of this model. We consider how this model can guide therapeutic interventions and discuss a proposed treatment algorithm based on these ideas. Although the approach reviewed originates in the evaluation of patients with chronic DOC, we consider some emerging implications for patients in acute and subacute settings.
Evoked and Event-Related Potentials as Biomarkers of Consciousness State and Recovery
Authors: Pruvost-Robieux Estelle , Marchi Angela , Martinelli Ilaria , Bouchereau Eléonore , Gavaret Martine
Published: September 2021

The definition of consciousness has been the subject of great interest for many scientists and philosophers. To better understand how evoked potentials may be identified as biomarkers of consciousness and recovery, the different theoretical models sustaining neural correlates of consciousness are reviewed. A multimodal approach can help to better predict clinical outcome in patients presenting with disorders of consciousness. Evoked potentials are inexpensive and easy-to-implement bedside examination techniques. Evoked potentials are an integral part of prognostic evaluation, particularly in cases of cognitive motor dissociation. Prognostic criteria are well established in postanoxic disorders of consciousness, especially postcardiac arrest but are less well determined in other etiologies. In the early examination, bilateral absence of N20 in disorder of consciousness patients is strongly associated with unfavorable outcome (i.e., death or unresponsive wakefulness syndrome) especially in postanoxic etiologies. This predictive value is lower in other etiologies and probably also in children. Both N20 and mismatch negativity are proven outcome predictors for acute coma. Many studies have shown that mismatch negativity and P3a are characterized by a high prognostic value for awakening, but some patients presenting unresponsive wakefulness syndrome also process a P3a. The presence of long-latency event-related potential components in response to stimuli is indicative of a better recovery. All neurophysiological data must be integrated within a multimodal approach combining repeated clinical evaluation, neuroimaging, functional imaging, biology, and neurophysiology combining passive and active paradigms.
Sparse canonical correlation to identify breast cancer related genes regulated by copy number aberrations
Authors: Dutta Diptavo , Sen Ananda , Satagopan Jaya
Published: September 2021

Background

Copy number aberrations (CNAs) in cancer affect disease outcomes by regulating molecular phenotypes, such as gene expressions, that drive important biological processes. To gain comprehensive insights into molecular biomarkers for cancer, it is critical to identify key groups of CNAs, the associated gene networks, regulatory modules, and their downstream effect on outcomes.

Methods

In this paper, we demonstrate an innovative use of sparse canonical correlation analysis (sCCA) to effectively identify the ensemble of CNAs, gene networks and regulatory modules in the context of binary and censored disease endpoints. Our approach detects potentially orthogonal gene expression modules which are highly correlated with sets of CNA and then identifies the genes within these modules that are associated with the outcome.

Results

Analyzing clinical and genomic data on 1,904 breast cancer patients from the METABRIC study, we found 14 gene modules to be regulated by groups of proximally located CNA sites. We validated this finding using an independent set of 1,077 breast invasive carcinoma samples from The Cancer Genome Atlas (TCGA). Our analysis on 7 clinical endpoints identified several novel and interpretable regulatory associations, highlighting the role of CNAs in key biological pathways and processes for breast cancer. Genes significantly associated with the outcomes were enriched for early estrogen response pathway, DNA repair pathways as well as targets of transcription factors such as E2F4, MYC and ETS1 that have recognized roles in tumor characteristics and survival. Subsequent meta-analysis across the endpoints further identified several genes through aggregation of weaker associations.

Conclusions

Our findings suggest that sCCA analysis can aggregate weaker associations to identify interpretable and important genes, networks and pathways that are clinically consequential.
The impact of mental health and substance use issues on COVID-19 vaccine readiness: a cross sectional community-based survey in Ontario, Canada
Authors: Mehra Kamna , Markoulakis Roula , Kodeeswaran Sugy , Redelmeier Donald A. , Sinyor Mark , MacKillop James , Cheung Amy , Levitt Emily E. , Addison Tracey , Levitt Anthony
Published: September 2021

Background

COVID-19 vaccines have been approved for use in Canada since December 2020. However, data about factors associated with vaccine hesitancy and the impact of mental health and/or substance use (MHSU) issues on vaccine uptake are currently not available. The goal of this study was to explore factors, particularly MHSU factors, that impact COVID-19 vaccination intentions in Ontario, Canada.

Methods

A community-based cross-sectional survey with recruitment based on age, gender, and geographical location (to ensure a representative population of Ontario), was conducted in February 2021. Multinomial logistic regression was used to test the relationship between COVID-19 vaccination status and plans and sociodemographic background, social support, anxiety about contracting COVID-19, and MHSU concerns.

Results

Of the total sample of 2528 respondents, 1932 (76.4%) were vaccine ready, 381 (15.1%) were hesitant, and 181 (7.1%) were resistant. Significant independent predictors of vaccine hesitancy compared with vaccine readiness included younger age (OR=2.11, 95%CI=1.62-2.74), female gender (OR=1.36, 95%CI=1.06-1.74), Black ethnicity (OR=2.11, 95%CI=1.19-3.75), lower education (OR=1.69, 95%CI=1.30-2.20), lower SES status (OR=.88, 95%CI=.84-.93), lower anxiety about self or someone close contracting COVID-19 (OR=2.06, 95%CI=1.50-2.82), and lower depression score (OR=.90, 95%CI=.82-.98). Significant independent predictors of vaccine resistance compared with readiness included younger age (OR=1.72, 95%CI=1.19-2.50), female gender (OR=1.57, 95%CI=1.10-2.24), being married (OR=1.50, 95%CI=1.04-2.16), lower SES (OR=.80, 95%CI=.74-.86), lower satisfaction with social support (OR=.78, 95%CI=.70-.88), lower anxiety about contracting COVID-19 (OR=7.51, 95%CI=5.18-10.91), and lower depression score (OR=.85, 95%CI=.76-.96).

Interpretation

COVID-19 vaccination intention is affected by sociodemographic factors, anxiety about contracting COVID-19, and select mental health issues.
Sleep spindles track cortical learning patterns for memory consolidation
Authors: Petzka Marit , Chatburn Alex , Charest Ian , Balanos George M. , Staresina Bernhard P.
Published: September 2021

Memory consolidation, the transformation of labile memory traces into stable long-term representations, is facilitated by post-learning sleep. Computational and biophysical models suggest that sleep spindles may play a key mechanistic role for consolidation, igniting structural changes at cortical sites involved in prior learning. Here we tested the resulting prediction that spindles are most pronounced over learning-related cortical areas and that the extent of this learning-spindle overlap predicts behavioural measures of memory consolidation. Using high-density scalp Electroencephalography (EEG) and Polysomnography (PSG) in healthy volunteers, we first identified cortical areas engaged during a temporospatial associative memory task (power decreases in the alpha/beta frequency range, 6-20 Hz). Critically, we found that participant-specific topographies (i.e., spatial distributions) of post-learning sleep spindle amplitude correlated with participant-specific learning topographies. Importantly, the extent to which spindles tracked learning patterns further predicted memory consolidation across participants. Our results provide empirical evidence for a role of post-learning sleep spindles in tracking learning networks, thereby facilitating memory consolidation.
Multiplex spatial systems analysis of local nanodose drug responses predicts effective treatment combinations of immunotherapies and targeted agents in mammary carcinoma
Authors: Tatarova Zuzana , Blumberg Dylan C. , Korkola James E. , Heiser Laura M. , Muschler John L. , Schedin Pepper J. , Ahn Sebastian W. , Mills Gordon B. , Coussens Lisa M. , Jonas Oliver , Gray Joe W.
Published: September 2021

Better methods are needed to identify effective combinations of immunotherapies with chemotherapies and targeted anti-cancer agents. Here we present a Multiplex Implantable Microdevice Assay (MIMA) system for rapid in vivo assessment of the effects of multiple, spatially separate anticancer drugs directly in the complex tumor microenvironment. In prototypic experiments, olaparib, lenvatinib, palbociclib, venetoclax, panobinostat, doxorubicin, and paclitaxel and combinations thereof were administered simultaneously to murine mammary tumor models. Quantitative multiplex immunohistochemistry and spatial systems analyses of each local drug response defined cellular relations of fibroblasts, endothelial cells, immune lineages, immunogenic cell death, tumor proliferation and/or cancer stem cells that were used to predict effective drug combinations. A predicted combination of panobinostat, venetoclax and anti-CD40 showed long-term anti-tumor efficacy in multiple mouse models with no observable toxicity when administered systemically. Future MIMA use promises to design effective drug combinations for tumor cell control and immune activation on a personalized basis.
Nanomolar, noncovalent antagonism of hedgehog cholesterolysis: exception to the “irreversibility rule” for protein autoprocessing inhibition
Authors: Wagner Andrew G , Stagnitta Robert T , Xu Zihan , Pezzullo John L , Kandel Nabin , Giner José-Luis , Covey Douglas F , Wang Chunyu , Callahan Brian P
Published: September 2021

Hedgehog (Hh) signaling ligands undergo carboxy terminal sterylation through specialized autoprocessing, called cholesterolysis. Sterylation is brought about intramolecularly in a single turn-over by an enzymatic domain, called HhC. HhC is found in precursor Hh proteins only. Through cholesterolysis, HhC is cleaved from the precursor. Attempts to identify molecules that inhibit intramolecular cleavage/sterylation activity of HhC have resulted in antagonists that bind HhC irreversibly through covalent mechanisms, as is commonplace for protein autoprocessing inhibitors. Here we report an exception to the “irreversibility rule” for protein autoprocessing inhibition. Using a FRET-based activity assay for HhC, we screened a focused library of sterol-like analogs for HhC cholesterolysis inhibitors. We identified and validated four structurally related noncovalent inhibitors, which were then used for SAR studies. The most effective derivative, tBT-HBT, binds HhC reversibly with an IC50 of 300 nM. An allosteric binding site for tBT-HBT, encompassing interactions from the two subdomains of HhC, is suggested by kinetic analysis, mutagenesis studies, and photoaffinity labeling. A striking resemblance is found between the inhibitors described here and a family of noncovalent, allosteric activators of HhC, which we described previously. The inhibitor/activator duality appears to be mediated by the same allosteric site, which displays sensitivity to subtle differences in the structure of a heterocycle substituent on the effector molecule.
Molecular Organization of the Early Stages of Nucleosome Phase Separation Visualized by Cryo-Electron Tomography
Authors: Zhang Meng , Díaz-Celis César , Onoa Bibiana , Cañari-Chumpitaz Cristhian , Requejo Katherinne I. , Liu Jianfang , Vien Michael , Nogales Eva , Ren Gang , Bustamante Carlos
Published: September 2021

It has been proposed that the intrinsic property of nucleosome arrays to undergo liquid-liquid phase separation (LLPS) in vitro is responsible for chromatin domain organization in vivo. However, understanding nucleosomal LLPS has been hindered by the challenge to characterize the structure of resulting heterogeneous condensates. We used cryo-electron tomography and deep learning-based 3D reconstruction/segmentation to determine the molecular organization of condensates at various stages of LLPS. We show that nucleosomal LLPS involves a two-step process: a spinodal decomposition process yielding irregular condensates, followed by their unfavorable conversion into more compact, spherical nuclei that grow into larger spherical aggregates through accretion of spinodal material or by fusion with other spherical condensates. Histone H1 catalyzes more than 10-fold the spinodal-to-spherical conversion. We propose that this transition involves exposure of nucleosome hydrophobic surfaces resulting in modified inter-nucleosome interactions. These results suggest a physical mechanism by which chromatin may transition from interphase to metaphase structures.
The eyes have it: The pupillary light response as a physiological index of aphantasia, sensory and phenomenological imagery strength
Authors: Kay Lachlan , Keogh Rebecca , Andrillion Thomas , Pearson Joel
Published: September 2021

The pupillary light response is an important automatic physiological response that optimises light reaching the retina. Recent work has shown that the pupil also adjusts in response to illusory brightness and a range of cognitive functions, however, it remains unclear what exactly drives these endogenous changes. Here we show that the imagery pupillary light response correlates with objective measures of sensory imagery strength. Further, the trial-by-trial phenomenological vividness of visual imagery is tracked by the imagery pupillary light response. We also demonstrated that there was no evidence for an imagery pupillary light response in a group of individuals without visual imagery (aphantasia), however, they did show perceptual pupil light responses and pupil dilation with larger cognitive load. Our results provide evidence that the pupillary light response indexes the sensory strength of visual imagery and also provides the first physiological validation of aphantasia.
Genomic Signatures of Sexual Selection on Pollen-Expressed Genes in Arabis alpina
Authors: Gutiérrez-Valencia Juanita , Fracassetti Marco , Horvath Robert , Laenen Benjamin , Désamore Aurélie , Drouzas Andreas D. , Friberg Magne , Kolář Filip , Slotte Tanja
Published: September 2021

Fertilization in angiosperms involves the germination of pollen on the stigma, followed by the extrusion of a pollen tube that elongates through the style and delivers two sperm cells to the embryo sac. Sexual selection could occur throughout this process when male gametophytes compete for fertilization. The strength of sexual selection during pollen competition should be affected by the number of genotypes deposited on the stigma. As increased self-fertilization reduces the number of mating partners, and the genetic diversity and heterozygosity of populations, it should thereby reduce the intensity of sexual selection during pollen competition. Despite the prevalence of mating system shifts, few studies have directly compared the molecular signatures of sexual selection during pollen competition in populations with different mating systems. Here we analyzed whole-genome sequences from natural populations of Arabis alpina, a species showing mating system variation across its distribution, to test whether shifts from cross- to self-fertilization result in molecular signatures consistent with sexual selection on genes involved in pollen competition. We found evidence for efficient purifying selection on genes expressed in vegetative pollen, and overall weaker selection on sperm-expressed genes. This pattern was robust when controlling for gene expression level and specificity. In agreement with the expectation that sexual selection intensifies under cross-fertilization, we found that the efficacy of purifying selection on male gametophyte-expressed genes was significantly stronger in genetically more diverse and outbred populations. Our results show that intra-sexual competition shapes the evolution of pollen-expressed genes, and that its strength fades with increasing self-fertilization rates.