Improving Conversations about Parkinson's Dementia.

BACKGROUND: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. OBJECTIVES: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia. METHODS: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. RESULTS: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals. CONCLUSION: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.

Rapid Whole-Genome Sequencing and Clinical Management in the PICU: A Multicenter Cohort, 2016-2023.

OBJECTIVES: Analysis of the clinical utility of rapid whole-genome sequencing (rWGS) outside of the neonatal period is lacking. We describe the use of rWGS in PICU and cardiovascular ICU (CICU) patients across four institutions. DESIGN: Ambidirectional multisite cohort study. SETTING: Four tertiary children's hospitals. PATIENTS: Children 0-18 years old in the PICU or CICU who underwent rWGS analysis, from May 2016 to June 2023. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 133 patients underwent clinical, phenotype-driven rWGS analysis, 36 prospectively. A molecular diagnosis was identified in 79 patients (59%). Median (interquartile range [IQR]) age was 6 months (IQR 1.2 mo-4.6 yr). Median time for return of preliminary results was 3 days (IQR 2-4). In 79 patients with a molecular diagnosis, there was a change in ICU management in 19 patients (24%); and some change in clinical management in 63 patients (80%). Nondiagnosis changed management in 5 of 54 patients (9%). The clinical specialty ordering rWGS did not affect diagnostic rate. Factors associated with greater odds ratio (OR [95% CI]; OR [95% CI]) of diagnosis included dysmorphic features (OR 10.9 [95% CI, 1.8-105]) and congenital heart disease (OR 4.2 [95% CI, 1.3-16.8]). Variables associated with greater odds of changes in management included obtaining a genetic diagnosis (OR 16.6 [95% CI, 5.5-62]) and a shorter time to genetic result (OR 0.8 [95% CI, 0.76-0.9]). Surveys of pediatric intensivists indicated that rWGS-enhanced clinical prognostication (p < 0.0001) and contributed to a decision to consult palliative care (p < 0.02). CONCLUSIONS: In this 2016-2023 multiple-PICU/CICU cohort, we have shown that timely genetic diagnosis is feasible across institutions. Application of rWGS had a 59% (95% CI, 51-67%) rate of diagnostic yield and was associated with changes in critical care management and long-term patient management.

Application of cell-free plasma next-generation sequencing technology in the diagnosis and management of pediatric meningitis.

This retrospective study evaluates the clinical utility of CFPNGS in the diagnosis and management of pediatric meningitis. CFPNGS identified a causative pathogen in 36% of 28 subjects, compared to 50% for diverse conventional testing (57% combined). CFPNGS may be considered as an adjunct to standard testing.

Preventing and Controlling Zinc Deficiency Across the Life Course: A Call to Action.

Through diverse roles, zinc determines a greater number of critical life functions than any other single micronutrient. Beyond the well-recognized importance of zinc for child growth and resistance to infections, zinc has numerous specific roles covering the regulation of glucose metabolism, and growing evidence links zinc deficiency with increased risk of diabetes and cardiometabolic disorders. Zinc nutriture is, thus, vitally important to health across the life course. Zinc deficiency is also one of the most common forms of micronutrient malnutrition globally. A clearer estimate of the burden of health disparity attributable to zinc deficiency in adulthood and later life emerges when accounting for its contribution to global elevated fasting blood glucose and related noncommunicable diseases (NCDs). Yet progress attenuating its prevalence has been limited due, in part, to the lack of sensitive and specific methods to assess human zinc status. This narrative review covers recent developments in our understanding of zinc's role in health, the impact of the changing climate and global context on zinc intake, novel functional biomarkers showing promise for monitoring population-level interventions, and solutions for improving population zinc intake. It aims to spur on implementation of evidence-based interventions for preventing and controlling zinc deficiency across the life course. Increasing zinc intake and combating global zinc deficiency requires context-specific strategies and a combination of complementary, evidence-based interventions, including supplementation, food fortification, and food and agricultural solutions such as biofortification, alongside efforts to improve zinc bioavailability. Enhancing dietary zinc content and bioavailability through zinc biofortification is an inclusive nutrition solution that can benefit the most vulnerable individuals and populations affected by inadequate diets to the greatest extent.

The influence of working memory and processing speed on other aspects of cognitive functioning in de novo Parkinson's disease: Initial findings from network modelling and graph theory.

Deficits in working memory (WM) and processing speed (PS) are thought to undermine other cognitive functions in de novo Parkinson's disease (dnPD). However, these interrelationships are only partially understood. This study investigated whether there are stronger relationships between verbal WM and verbal episodic memory encoding and retrieval, whether verbal WM and PS have a greater influence on other aspects of cognitive functioning, and whether the overall strength of interrelationships among several cognitive functions differs in dnPD compared to health. Data for 198 healthy controls (HCs) and 293 dnPD patients were analysed. Participants completed a neuropsychological battery probing verbal WM, PS, verbal episodic memory, semantic memory, language and visuospatial functioning. Deficit analysis, network modelling and graph theory were combined to compare the groups. Results suggested that verbal WM performance, while slightly impaired, was more strongly associated with measures of verbal episodic memory encoding and retrieval, as well as other measured cognitive functions in the dnPD network model compared to the HC network model. PS task performance was impaired and more strongly associated with other neuropsychological task scores in the dnPD model. Associations among task scores were stronger overall in the dnPD model. Together, these results provide further evidence that WM and PS are important influences on the other aspects of cognitive functioning measured in this study in dnPD. Moreover, they provide novel evidence that verbal WM and PS might bear greater influence on the other measured cognitive functions and that these functions are more strongly intertwined in dnPD compared to health.

Neuropsychological correlates of visual hallucinatory phenomena in Lewy body disease.

OBJECTIVES: Visual hallucinations (VH) ranging from minor to complex, are the most common psychiatric feature of Lewy Body Disease (LBD). Despite their high prevalence and poor prognostic implications instigating extensive research, the precise mechanisms underlying VH remain unclear. Cognitive impairment (CI) is a risk factor and a consistent correlate of VH in LBD. To help shed light on their underlying mechanisms, this study investigates the pattern of CI across the spectrum of VH in LBD. METHODS: 30 LBD patients with minor VH (MVH), 13 with complex VH (CVH) and 32 without VH were retrospectively compared on the domains of higher-order visual processing, memory, language and executive functioning. The VH groups were further stratified to investigate whether phenomenological subtypes have distinct cognitive correlates. RESULTS: LBD patients with CVH were impaired on the visuo-spatial and executive functioning domains relative to controls. LBD patients with MVH were also impaired on the visuo-spatial domain. No differences emerged in cognitive domains affected between patient groups endorsing specific hallucinatory phenomena. CONCLUSION: A pattern of CI indicating fronto-subcortical dysfunction in combination with posterior cortical involvement is implicated in the genesis of CVH. Moreover, this posterior cortical dysfunction may precede the occurrence of CVH as indicated by selective visuo-spatial deficits in LBD patients with MVH.

A Bayesian predictive processing account of Othello syndrome in Parkinson's disease.

Introduction: Although delusions in Parkinson's disease (PD) are rare, when they occur they frequently take the form of "Othello syndrome": the irrational belief that a spouse or partner is being unfaithful. Hitherto dismissed as either a by-product of dopamine therapy or cognitive impairment, there are still no convincing theoretical accounts to explain why only some patients fall prey to this delusion, or why it persists despite clear disconfirmatory evidence.Methods: We discuss the limitations of existing explanations of this delusion, namely hyperdopaminergia-induced anomalous perceptual experiences and cognitive impairment, before describing how Bayesian predictive processing accounts can provide a more comprehensive explanation by foregrounding the importance of prior experience and its impact upon computation of probability. We illustrate this new conceptualisation with three case vignettes.Results: We suggest that in those with prior experience of romantic betrayal, hyperdominergic-induced aberrant prediction errors enable anomalous perceptual experiences to accrue greater prominence, which is then maintained through Bayes-optimal inferencing to confirm cognitive distortions, eliciting and shaping this dangerous delusion.Conclusions: We propose the first comprehensive mechanistic account of Othello syndrome in PD and discuss implications for clinical interventions.

Lifespan normative data (18-89 years) for Raven's Advanced Progressive Matrices Set I.

Raven's Advanced Progressive Matrices (APM) Set I is a validated and brief test of fluid intelligence, ideal for use in busy clinical settings. However, there is a dearth of normative data allowing an accurate interpretation of APM scores. To address this, we present normative data from across the adult lifespan (18-89 years) for the APM Set I. Data are presented in five age cohorts (total N = 352), including two older adult cohorts (65-79 years and 80-89 years), which allows age-standardized assessment. We also present data from a validated measure of premorbid intellectual ability, which was absent from previous standardizations of longer forms of the APM. In line with previous findings, a striking age-related decline was noted, beginning relatively early in adulthood and most marked amongst lower-scoring individuals. Older adults did not demonstrate difficulty with specific test items or make an increased proportion of specific errors. Sex was not a significant predictor of performance. The data set is of particular use in the neuropsychological assessment of older adults, given the known susceptibility of fluid intelligence to both the effects of normal ageing and acquired brain injury in older age. The results are discussed in light of theories of neurological ageing.

Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients.

Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with COVID-19 susceptibility genetic variants. More broadly, we demonstrate how capturing acute, disease-mediated changes in transcription initiation can provide insight into the underlying molecular mechanisms and stratify patient disease severity.

Transforming Nigerian Food Systems Through Their Backbones: Lessons From a Decade of Staple Crop Biofortification Programing.

This article presents the evolution of the biofortification program in Nigeria over the last decade and the role of interdisciplinary research in informing cost-effective, efficient, and inclusive development; implementation; and scaling of this program. Launched in 2011 to improve Nigeria's food systems to deliver accessible and affordable nutrients through commonly consumed staples, the Nigeria biofortification program was implemented through an effective partnership between the CGIAR and public, private, and civil society sectors at federal, state, and local levels. By the end of 2021, several biofortified varieties of Nigeria's 2 main staples, namely cassava and maize, were officially released for production by smallholders, with several biofortified varieties of other key staples (including pearl millet, rice, and sorghum) either under testing or in the release pipeline. In 2021, the program was estimated to benefit 13 million Nigerians consuming biofortified cassava and maize varieties. The evidence on the nutritional impact, consumer and farmer acceptance, and cost-effective scalability of biofortified crops documented by the program resulted in the integration of biofortified crops in several key national public policies and social protection programs; private seed and food company products/investments, as well as in humanitarian aid.

Mind the 'GAPP': a pre-graduation assessment of preparedness for practice amid a pandemic.

Introduction 'Preparedness for practice' refers to a multifaceted concept, encompassing not only clinical skills, but also broader, non-clinical skills, such as communication and professionalism. Previous graduates have reported feeling less prepared for complex procedures, such as molar endodontics and surgical extractions. Dental students typically utilise their final year to refine their clinical skills, however, the COVID-19 pandemic has meant that newly qualified dentists will have had around six months where they have not performed clinical dentistry before beginning dental foundation training (DFT).Aims This study aimed to explore final year students' self-reported preparedness for practice, identify areas of relative weakness that may influence future training needs and to highlight any perceived impact of the pandemic on final year experience and potential impact on DFT.Materials and methods The current Graduate Assessment of Preparedness for Practice (GAPP) questionnaire was adapted for our specific research aims and piloted and the PreGAPP questionnaire distributed via the social media channels of dental school student societies. Analysis was carried out using IBM Statistical Package for the Social Sciences software using descriptive statistics and the Mann-Whitney U test for two unrelated variables.Results Responses were received from final year students across all 16 UK dental schools. Students reported increased preparedness across domains in which they had the most experience; for example, providing preventative advice and administering local anaesthesia. Male students reported feeling significantly more prepared than female students, mature students significantly more than younger students, and students on four-year courses significantly more than traditional five-year courses. The COVID-19 pandemic was expected to have a major-to-severe impact on undergraduate experience and future DFT prospects.Conclusion Dental graduates in the COVID-19 era may have significantly different training needs to those before them. Complex clinical procedures remain the areas where students feel they are least prepared for practice. The importance of a clinical passport to highlight current experience level to trainers, alongside the creation of a personal development plan at the beginning of DFT, will ensure that targeted and personalised training can be implemented where required.

Peripheral IV Administration of Hypertonic Saline: Single-Center Retrospective PICU Study.

OBJECTIVES: To determine the frequency and characteristics of complications of peripherally administered hypertonic saline (HTS) through assessment of infiltration and extravasation. DESIGN: Retrospective cross-sectional study. SETTING: Freestanding tertiary care pediatric hospital. PATIENTS: Children who received HTS through a peripheral IV catheter (PIVC). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We conducted a single-center retrospective review from January 2012 to 2019. A total of 526 patients with 1,020 unique administrations of HTS through a PIVC met inclusion criteria. The primary endpoint was PIVC failure due to infiltration or extravasation. The indication for the administration of HTS infusion was collected. Catheter data was captured, including the setting of catheter placement, anatomical location on the patient, gauge size, length of time from catheter insertion to HTS infusion, in situ duration of catheter lifespan, and removal rationale. The administration data for HTS was reviewed and included volume of administration, bolus versus continuous infusion, infusion rate, infusion duration, and vesicant medications administered through the PIVC. There were 843 bolus infusions of HTS and 172 continuous infusions. Of the bolus administrations, there were eight infiltrations (0.9%). The continuous infusion group had 13 infiltrations (7.6%). There were no extravasations in either group, and no patients required medical therapy or intervention by the wound care or plastic surgery teams. There was no significant morbidity attributed to HTS administration in either group. CONCLUSIONS: HTS administered through a PIVC infrequently infiltrates in critically ill pediatric patients. The infiltration rate was low when HTS is administered as a bolus but higher when given as a continuous infusion. However, no patient suffered an extravasation injury or long-term morbidity from any infiltration.

Apathy in Parkinson's Disease: A Retrospective Study of Its Prevalence and Relationship With Mood, Anxiety, and Cognitive Function.

Apathy is thought to be an important clinical feature of Parkinson's disease (PD). However, its prevalence ranges greatly across studies because of differing definitions, assessment tools, and patient inclusion criteria. Furthermore, it remains unclear how the presentation of apathy in PD is related to mood disorder and/or cognitive impairment. This study sought to examine the prevalence of a pure apathy syndrome in PD, distinct from both depression and anxiety, and reveal its associated cognitive profile. A retrospective study was performed on 177 PD patients who had completed measures of apathy [Apathy Evaluation Scale (AES)] and mood functioning [Hospital Anxiety and Depression Scale (HADS)] and had undergone extensive neuropsychological assessment, using measures of intellectual functioning, memory, executive function, attention, language, visual processing, and cognitive speed; 14.7% of the sample indicated clinically significant levels of apathy, but this nearly always co-presented with depression and/or anxiety, with cases of "pure" apathy very rare (2.8%). On extensive cognitive assessment, patients with mood disorder performed worse on a measure of non-verbal intellectual functioning, but patients with additional apathy or apathy only demonstrated no further losses. The syndrome of apathy in PD greatly overlaps with that of depression and anxiety, suggesting that apathy in PD may be in large an epiphenomenon of mood disorder, with no specific neuropsychological features.

The Arthur App: Designing an Augmentative and Alternative Communication Method for Use With Hospitalized Patients.

An innovative augmentative and alternative communication method consisting of a mobile application (app) on an Apple iPad®, such as the Arthur app, can provide patients with barriers to verbal communication an easy means to express their needs, feelings, and questions. When using this technology, it is important to consider the right patient population at the right time, as well as the proper quantity and quality of information.

Long-term success of low-frequency subthalamic nucleus stimulation for Parkinson's disease depends on tremor severity and symptom duration.

Patients with Parkinson's disease can develop axial symptoms, including speech, gait and balance difficulties. Chronic high-frequency (>100 Hz) deep brain stimulation can contribute to these impairments while low-frequency stimulation (<100 Hz) may improve symptoms but only in some individuals. Factors predicting which patients benefit from low-frequency stimulation in the long term remain unclear. This study aims to confirm that low-frequency stimulation improves axial symptoms, and to go further to also explore which factors predict the durability of its effects. We recruited patients who developed axial motor symptoms while using high-frequency stimulation and objectively assessed the short-term impact of low-frequency stimulation on axial symptoms, other aspects of motor function and quality of life. A retrospective chart review was then conducted on a larger cohort to identify which patient characteristics were associated with not only the need to trial low-frequency stimulation, but also those which predicted its sustained use. Among 20 prospective patients, low-frequency stimulation objectively improved mean motor and axial symptom severity and quality of life in the short term. Among a retrospective cohort of 168 patients, those with less severe tremor and those in whom axial symptoms had emerged sooner after subthalamic nucleus deep brain stimulation were more likely to be switched to and remain on long-term low-frequency stimulation. These data suggest that low-frequency stimulation results in objective mean improvements in overall motor function and axial symptoms among a group of patients, while individual patient characteristics can predict sustained long-term benefits. Longer follow-up in the context of a larger, controlled, double-blinded study would be required to provide definitive evidence of the role of low-frequency deep brain stimulation.

Profiling Transcription Initiation in Peripheral Leukocytes Reveals Severity-Associated Cis-Regulatory Elements in Critical COVID-19.

The contribution of transcription factors (TFs) and gene regulatory programs in the immune response to COVID-19 and their relationship to disease outcome is not fully understood. Analysis of genome-wide changes in transcription at both promoter-proximal and distal cis-regulatory DNA elements, collectively termed the 'active cistrome,' offers an unbiased assessment of TF activity identifying key pathways regulated in homeostasis or disease. Here, we profiled the active cistrome from peripheral leukocytes of critically ill COVID-19 patients to identify major regulatory programs and their dynamics during SARS-CoV-2 associated acute respiratory distress syndrome (ARDS). We identified TF motifs that track the severity of COVID- 19 lung injury, disease resolution, and outcome. We used unbiased clustering to reveal distinct cistrome subsets delineating the regulation of pathways, cell types, and the combinatorial activity of TFs. We found critical roles for regulatory networks driven by stimulus and lineage determining TFs, showing that STAT and E2F/MYB regulatory programs targeting myeloid cells are activated in patients with poor disease outcomes and associated with single nucleotide genetic variants implicated in COVID-19 susceptibility. Integration with single-cell RNA-seq found that STAT and E2F/MYB activation converged in specific neutrophils subset found in patients with severe disease. Collectively we demonstrate that cistrome analysis facilitates insight into disease mechanisms and provides an unbiased approach to evaluate global changes in transcription factor activity and stratify patient disease severity.

Dental foundation training in the COVID-19 era - the national recruitment lottery.

National recruitment has radically transformed the selection and allocation of dental graduates to dental foundation training (DFT) schemes across England, Wales and Northern Ireland, with recruitment in Scotland via a separate, independent process. It has been reported as a mostly positive change to the previous deanery-led model, in which nepotism allegedly featured too widely. A candidate's ranking is typically based on performance across two face-to-face assessments and a situational judgement test (SJT). The COVID-19 pandemic, however, has created a recruitment 'lottery' of sorts, in which ranking for 2021 is now solely based on the SJT. Subject matter experts assert that neither preparation nor revision for the SJT is required; yet, following the announcement of the adaptation to DFT recruitment for September 2021, a rapid rise of exorbitantly priced SJT question banks, mock papers, workshops and courses has ensued - a shameless monetisation of the collective angst and increased pressure faced by dental students. Preparation courses present a conceivable risk of SJT 'coaching' and 'faking'. Where medicine leads, dentistry usually follows and future selection to DFT needs to strongly consider the introduction of academic performance measures. SJTs remain one of the most well-accepted, reliable and cost-effective means of selection into healthcare roles, however, only when part of a wider selection process.

Metagenomic Next-Generation Sequencing for Pathogen Detection and Transcriptomic Analysis in Pediatric Central Nervous System Infections.

BACKGROUND: Pediatric central nervous system (CNS) infections are potentially life-threatening and may incur significant morbidity. Identifying a pathogen is important, both in terms of guiding therapeutic management and in characterizing prognosis. Usual care testing by culture and polymerase chain reaction is often unable to identify a pathogen. We examined the systematic application of metagenomic next-generation sequencing (mNGS) for detecting organisms and transcriptomic analysis of cerebrospinal fluid (CSF) in children with central nervous system (CNS) infections. METHODS: We conducted a prospective multisite study that aimed to enroll all children with a CSF pleocytosis and suspected CNS infection admitted to 1 of 3 tertiary pediatric hospitals during the study timeframe. After usual care testing had been performed, the remaining CSF was sent for mNGS and transcriptomic analysis. RESULTS: We screened 221 and enrolled 70 subjects over a 12-month recruitment period. A putative organism was isolated from CSF in 25 (35.7%) subjects by any diagnostic modality. Metagenomic next-generation sequencing of the CSF samples identified a pathogen in 20 (28.6%) subjects, which were also all identified by usual care testing. The median time to result was 38 hours. CONCLUSIONS: Metagenomic sequencing of CSF has the potential to rapidly identify pathogens in children with CNS infections.