Onabotulinum toxin injections for shoulder and chest wall muscle pain in breast cancer survivors: retrospective study - preliminary report.

OBJECTIVES: The primary objective of this retrospective review is to describe patient-reported improvement in muscular pain after initial treatment with onabotulinum toxin. A secondary objective was to determine other physiatry (physical medicine & rehabilitation (PM&R)) interventions ordered. METHODS: Preliminary retrospective review of physiatry interventions for 47 patients referred by breast radiation oncology to PM&R at a tertiary referral-based academic cancer centre clinic from 1 January 2018 to 31 December 2021 for muscular shoulder/chest wall pain. RESULTS: Patients were most commonly diagnosed with muscle spasm 27/47 (58%), lymphedema 21/47 (45%), myalgia/myofascial pain 16/47 (34%), radiation fibrosis 14/47 (30%), fatigue/deconditioning 13/47 (28%), neurological impairment 11/47 (23%) and joint pathology 3/47 (6%). The top three physiatric interventions were home exercise programme education (17/47, 36%), botulinum toxin injection (17/47, 36%) and physical or occupational therapy referral (15/47, 32%). Patients who had muscle spasms documented were more likely to have botulinum toxin recommended by physiatry (24/24) compared with those with questionable spasms (4/7) and those without spasms(0/16) (p=0.0005). 17/28 (60.7%) received botulinum toxin injection, and a total of 35 injections were performed during the study period. 94% (16/17) of patients who received botulinum toxin injection voiced improvement in pain after injection. CONCLUSION: Botulinum toxin injections may play a role in the treatment of muscle spasm-related pain in breast cancer survivors. Additional blinded controlled research on the effectiveness of botulinum toxin injection after breast cancer treatment with spastic muscular shoulder/chest wall pain is needed.

Performance of Large Language Models on Medical Oncology Examination Questions.

Importance: Large language models (LLMs) recently developed an unprecedented ability to answer questions. Studies of LLMs from other fields may not generalize to medical oncology, a high-stakes clinical setting requiring rapid integration of new information. Objective: To evaluate the accuracy and safety of LLM answers on medical oncology examination questions. Design, Setting, and Participants: This cross-sectional study was conducted between May 28 and October 11, 2023. The American Society of Clinical Oncology (ASCO) Oncology Self-Assessment Series on ASCO Connection, the European Society of Medical Oncology (ESMO) Examination Trial questions, and an original set of board-style medical oncology multiple-choice questions were presented to 8 LLMs. Main Outcomes and Measures: The primary outcome was the percentage of correct answers. Medical oncologists evaluated the explanations provided by the best LLM for accuracy, classified the types of errors, and estimated the likelihood and extent of potential clinical harm. Results: Proprietary LLM 2 correctly answered 125 of 147 questions (85.0%; 95% CI, 78.2%-90.4%; P < .001 vs random answering). Proprietary LLM 2 outperformed an earlier version, proprietary LLM 1, which correctly answered 89 of 147 questions (60.5%; 95% CI, 52.2%-68.5%; P < .001), and the best open-source LLM, Mixtral-8x7B-v0.1, which correctly answered 87 of 147 questions (59.2%; 95% CI, 50.0%-66.4%; P < .001). The explanations provided by proprietary LLM 2 contained no or minor errors for 138 of 147 questions (93.9%; 95% CI, 88.7%-97.2%). Incorrect responses were most commonly associated with errors in information retrieval, particularly with recent publications, followed by erroneous reasoning and reading comprehension. If acted upon in clinical practice, 18 of 22 incorrect answers (81.8%; 95% CI, 59.7%-94.8%) would have a medium or high likelihood of moderate to severe harm. Conclusions and Relevance: In this cross-sectional study of the performance of LLMs on medical oncology examination questions, the best LLM answered questions with remarkable performance, although errors raised safety concerns. These results demonstrated an opportunity to develop and evaluate LLMs to improve health care clinician experiences and patient care, considering the potential impact on capabilities and safety.

GNN Codon Adjacency Tunes Protein Translation.

The central dogma treats the ribosome as a molecular machine that reads one mRNA codon at a time as it adds each amino acid to its growing peptide chain. However, this and previous studies suggest that ribosomes actually perceive pairs of adjacent codons as they take three-nucleotide steps along the mRNA. We examined GNN codons, which we find are surprisingly overrepresented in eukaryote protein-coding open reading frames (ORFs), especially immediately after NNU codons. Ribosome profiling experiments in yeast revealed that ribosomes with NNU at their aminoacyl (A) site have particularly elevated densities when NNU is immediately followed (3') by a GNN codon, indicating slower mRNA threading of the NNU codon from the ribosome's A to peptidyl (P) sites. Moreover, if the assessment was limited to ribosomes that have only recently arrived at the next codon, by examining 21-nucleotide ribosome footprints (21-nt RFPs), elevated densities were observed for multiple codon classes when followed by GNN. This striking translation slowdown at adjacent 5'-NNN GNN codon pairs is likely mediated, in part, by the ribosome's CAR surface, which acts as an extension of the A-site tRNA anticodon during ribosome translocation and interacts through hydrogen bonding and pi stacking with the GNN codon. The functional consequences of 5'-NNN GNN codon adjacency are expected to influence the evolution of protein coding sequences.

Outcomes of isolated medial tibial plateau fractures by fracture morphology.

PURPOSE: To identify a cohort of isolated medial tibial plateau fractures treated with surgical fixation and to categorize them by Moore and Wahlquist classifications in order to determine the rate of complications with each fracture morphology and the predictive value of each classification system. We hypothesized there would be high rates of neurovascular injury, compartment syndrome, and complications overall with a higher incidence of neurovascular injury in Moore type III rim avulsion fractures and Wahlquist type C fractures that enter the plateau lateral to the tibial spines. METHODS: Patients who presented to six Level I trauma centers between 2010 and 2021 who underwent surgical fixation for isolated medial tibial plateau fractures were retrospectively reviewed. Data including demographics, radiographs, complications, and functional outcomes were collected. RESULTS: One hundred and fifty isolated medial tibial plateau fractures were included. All patients were classified by the Wahlquist classification of medial tibial plateau fractures, and 139 patients were classifiable by the Moore classification of tibial plateau fracture-dislocations. Nine percent of fractures presented with neurovascular injury: 5 % with isolated vascular injury and 6 % with isolated nerve injury. There were no significant differences in neurovascular injury by fracture type (Wahlquist p = 0.16, Moore p = 0.33). Compartment syndrome developed in two patients (1.3 %). The average final range of motion was 0.8-122° with no difference by Wahlquist or Moore classifications (p = 0.11, p = 0.52). The overall complication rate was 32 % without differences by fracture morphology. The overall rate of return to the operating room (OR) was 25 %. CONCLUSIONS: Isolated medial tibial plateau fractures often represent fracture-dislocations of the knee and should receive a meticulous neurovascular exam on presentation with a high suspicion for neurovascular injury. No specific fracture pattern was found to be predictive of neurovascular injuries, complications, or final knee range of motion. Patients should be counseled pre-operatively regarding high rates of return to the OR after the index surgery.

Comparative physiological effects of antipsychotic drugs in children and young people: a network meta-analysis.

BACKGROUND: The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the effects of various antipsychotic medications on physiological variables in children and adolescents with neuropsychiatric and neurodevelopmental conditions. METHODS: For this network meta-analysis, we searched Medline, EMBASE, PsycINFO, Web of Science, and Scopus from database inception until Dec 22, 2023, and included randomised controlled trials comparing antipsychotics with placebo in children or adolescents younger than 18 years with any neuropsychiatric and neurodevelopmental condition. Primary outcomes were mean change from baseline to end of acute treatment in bodyweight, BMI, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, prolactin, heart rate, systolic blood pressure (SBP), and QT interval corrected for heart rate (QTc) for patients receiving either active treatment or placebo. For multigroup trials reporting several doses, we calculated a summary value for each physiological variable for all doses. After transitivity assessment, we fitted frequentist random-effects network meta-analyses for all comparisons in the network. A Kilim plot was used to summarise the results for all treatments and outcomes, providing information regarding the strength of the statistical evidence of treatment effects, using p values. Network heterogeneity was assessed with τ, risk of bias of individual trials was assessed with the Cochrane Collaboration's Tool for Assessing Risk of Bias, and the credibility of findings from each network meta-analysis was assessed with the Confidence in Network Meta-Analysis (CINEMA) app. This study is registered on PROSPERO (CRD42021274393). FINDINGS: Of 6676 studies screened, 47 randomised controlled trials were included, which included 6500 children (mean age 13·29 years, SD 2·14) who received treatment for a median of 7 weeks (IQR 6-8) with either placebo (n=2134) or one of aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, pimozide, quetiapine, risperidone, or ziprasidone (n=4366). Mean differences for bodyweight change gain compared with placebo ranged from -2·00 kg (95% CI -3·61 to -0·39) with molindone to 5·60 kg (0·27 to 10·94) with haloperidol; BMI -0·70 kg/m2 (-1·21 to -0·19) with molindone to 2·03 kg/m2 (0·51 to 3·55) with quetiapine; total cholesterol -0·04 mmol/L (-0·39 to 0·31) with blonanserin to 0·35 mmol/L (0·17 to 0·53) with quetiapine; LDL cholesterol -0·12 mmol/L (-0·31 to 0·07) with risperidone or paliperidone to 0·17 mmol/L (-0·06 to 0·40) with olanzapine; HDL cholesterol 0·05 mmol/L (-0·19 to 0·30) with quetiapine to 0·48 mmol/L (0·18 to 0·78) with risperidone or paliperidone; triglycerides -0·03 mmol/L (-0·12 to 0·06) with lurasidone to 0·29 mmol/L (0·14 to 0·44) with olanzapine; fasting glucose from -0·09 mmol/L (-1·45 to 1·28) with blonanserin to 0·74 mmol/L (0·04 to 1·43) with quetiapine; prolactin from -2·83 ng/mL (-8·42 to 2·75) with aripiprazole to 26·40 ng/mL (21·13 to 31·67) with risperidone or paliperidone; heart rate from -0·20 bpm (-8·11 to 7·71) with ziprasidone to 12·42 bpm (3·83 to 21·01) with quetiapine; SBP from -3·40 mm Hg (-6·25 to -0·55) with ziprasidone to 10·04 mm Hg (5·56 to 14·51) with quetiapine; QTc from -0·61 ms (-1·47 to 0·26) with pimozide to 0·30 ms (-0·05 to 0·65) with ziprasidone. INTERPRETATION: Children and adolescents show varied but clinically significant physiological responses to individual antipsychotic drugs. Treatment guidelines for children and adolescents with a range of neuropsychiatric and neurodevelopmental conditions should be updated to reflect each antipsychotic drug's distinct profile for associated metabolic changes, alterations in prolactin, and haemodynamic alterations. FUNDING: UK Academy of Medical Sciences, Brain and Behaviour Research Foundation, UK National Institute of Health Research, Maudsley Charity, the Wellcome Trust, Medical Research Council, National Institute of Health and Care Research Biomedical Centre at King's College London and South London and Maudsley NHS Foundation Trust, the Italian Ministry of University and Research, the Italian National Recovery and Resilience Plan, and Swiss National Science Foundation.

Transcutaneous Ablation of Lung Tissue in a Porcine Model Using Magnetic-Resonance-Guided Focused Ultrasound (MRgFUS).

Focused ultrasound (FUS) is a minimally invasive treatment that utilizes high-energy ultrasound waves to thermally ablate tissue. Magnetic resonance imaging (MRI) guidance may be combined with FUS (MRgFUS) to increase its accuracy and has been proposed for lung tumor ablation/debulking. However, the lungs are predominantly filled with air, which attenuates the strength of the FUS beam. This investigation aimed to test the feasibility of a new approach using an intentional lung collapse to reduce the amount of air inside the lung and a controlled hydrothorax to create an acoustic window for transcutaneous MRgFUS lung ablation. Eleven pigs had one lung mechanically ventilated while the other lung underwent a controlled collapse and subsequent hydrothorax of that hemisphere. The MRgFUS lung ablations were then conducted via the intercostal space. All the animals recovered well and remained healthy in the week following the FUS treatment. The location and size of the ablations were confirmed one week post-treatment via MRI, necropsy, and histological analysis. The animals had almost no side effects and the skin burns were completely eliminated after the first two animal studies, following technique refinement. This study introduces a novel methodology of MRgFUS that can be used to treat deep lung parenchyma in a safe and viable manner.

Imaging the top of the Earth's inner core: a present-day flow model.

Despite considerable progress in seismology, mineral physics, geodynamics, paleomagnetism, and mathematical geophysics, Earth's inner core structure and evolution remain enigmatic. One of the most significant issues is its thermal history and the current thermal state. Several hypotheses involving a thermally-convecting inner core have been proposed: a simple, high-viscosity, translational mode, or a classical, lower-viscosity, plume-style convection. Here, we use state-of-the-art seismic imaging to probe the outermost shell of the inner core for its isotropic compressional speed and compare it with recently developed attenuation maps. The pattern emerging in the resulting tomograms is interpreted with recent data on the viscosity of iron as the inner core surface manifestation of a thermally-driven flow, with a positive correlation among compressional speed and attenuation and temperature. Although the outer-core convection controls the heat flux across the inner core boundary, the internally driven inner-core convection is a plausible model that explains a range of observations for the inner core, including distinct anisotropy in the innermost inner core.

Specific isoforms of the ubiquitin ligase gene WWP2 are targets of osteoarthritis genetic risk via a differentially methylated DNA sequence.

BACKGROUND: Transitioning from a genetic association signal to an effector gene and a targetable molecular mechanism requires the application of functional fine-mapping tools such as reporter assays and genome editing. In this report, we undertook such studies on the osteoarthritis (OA) risk that is marked by single nucleotide polymorphism (SNP) rs34195470 (A > G). The OA risk-conferring G allele of this SNP associates with increased DNA methylation (DNAm) at two CpG dinucleotides within WWP2. This gene encodes a ubiquitin ligase and is the host gene of microRNA-140 (miR-140). WWP2 and miR-140 are both regulators of TGFß signaling. METHODS: Nucleic acids were extracted from adult OA (arthroplasty) and foetal cartilage. Samples were genotyped and DNAm quantified by pyrosequencing at the two CpGs plus 14 flanking CpGs. CpGs were tested for transcriptional regulatory effects using a chondrocyte cell line and reporter gene assay. DNAm was altered using epigenetic editing, with the impact on gene expression determined using RT-qPCR. In silico analysis complemented laboratory experiments. RESULTS: rs34195470 genotype associates with differential methylation at 14 of the 16 CpGs in OA cartilage, forming a methylation quantitative trait locus (mQTL). The mQTL is less pronounced in foetal cartilage (5/16 CpGs). The reporter assay revealed that the CpGs reside within a transcriptional regulator. Epigenetic editing to increase their DNAm resulted in altered expression of the full-length and N-terminal transcript isoforms of WWP2. No changes in expression were observed for the C-terminal isoform of WWP2 or for miR-140. CONCLUSIONS: As far as we are aware, this is the first experimental demonstration of an OA association signal targeting specific transcript isoforms of a gene. The WWP2 isoforms encode proteins with varying substrate specificities for the components of the TGFß signaling pathway. Future analysis should focus on the substrates regulated by the two WWP2 isoforms that are the targets of this genetic risk.

Prognostic value of different discretization parameters in 18fluorodeoxyglucose positron emission tomography radiomics of oropharyngeal squamous cell carcinoma.

Purpose: We aim to interrogate the role of positron emission tomography (PET) image discretization parameters on the prognostic value of radiomic features in patients with oropharyngeal cancer. Approach: A prospective clinical trial (NCT01908504) enrolled patients with oropharyngeal squamous cell carcinoma (N=69; mixed HPV status) undergoing definitive radiotherapy and evaluated intra-treatment 18fluorodeoxyglucose PET as a potential imaging biomarker of early metabolic response. The primary tumor volume was manually segmented by a radiation oncologist on PET/CT images acquired two weeks into treatment (20 Gy). From this, 54 radiomic texture features were extracted. Two image discretization techniques-fixed bin number (FBN) and fixed bin size (FBS)-were considered to evaluate systematic changes in the bin number ({32, 64, 128, 256} gray levels) and bin size ({0.10, 0.15, 0.22, 0.25} bin-widths). For each discretization-specific radiomic feature space, an LASSO-regularized logistic regression model was independently trained to predict residual and/or recurrent disease. The model training was based on Monte Carlo cross-validation with a 20% testing hold-out, 50 permutations, and minor-class up-sampling to account for imbalanced outcomes data. Performance differences among the discretization-specific models were quantified via receiver operating characteristic curve analysis. A final parameter-optimized logistic regression model was developed by incorporating different settings parameterizations into the same model. Results: FBN outperformed FBS in predicting residual and/or recurrent disease. The four FBN models achieved AUC values of 0.63, 0.61, 0.65, and 0.62 for 32, 64, 128, and 256 gray levels, respectively. By contrast, the average AUC of the four FBS models was 0.53. The parameter-optimized model, comprising features joint entropy (FBN = 64) and information measure correlation 1 (FBN = 128), achieved an AUC of 0.70. Kaplan-Meier analyses identified these features to be associated with disease-free survival (p=0.0158 and p=0.0180, respectively; log-rank test). Conclusions: Our findings suggest that the prognostic value of individual radiomic features may depend on feature-specific discretization parameter settings.

Osteoarthritis as an Enhanceropathy: Gene Regulation in Complex Musculoskeletal Disease.

PURPOSE OF REVIEW: Osteoarthritis is a complex and highly polygenic disease. Over 100 reported osteoarthritis risk variants fall in non-coding regions of the genome, ostensibly conferring functional effects through the disruption of regulatory elements impacting target gene expression. In this review, we summarise the progress that has advanced our knowledge of gene enhancers both within the field of osteoarthritis and more broadly in complex diseases. RECENT FINDINGS: Advances in technologies such as ATAC-seq have facilitated our understanding of chromatin states in specific cell types, bolstering the interpretation of GWAS and the identification of effector genes. Their application to osteoarthritis research has revealed enhancers as the principal regulatory element driving disease-associated changes in gene expression. However, tissue-specific effects in gene regulatory mechanisms can contribute added complexity to biological interpretation. Understanding gene enhancers and their altered activity in specific cell and tissue types is the key to unlocking the genetic complexity of osteoarthritis. The use of single-cell technologies in osteoarthritis research is still in its infancy. However, such tools offer great promise in improving our functional interpretation of osteoarthritis GWAS and the identification of druggable targets. Large-scale collaborative efforts will be imperative to understand tissue and cell-type specific molecular mechanisms underlying enhancer function in disease.

Focal Neurotoxicity Associated With Topical 5-Fluorouracil.

Topical 5-Fluorouracil (5-FU) is an antineoplastic chemotherapy drug used to treat precancerous and cancerous skin growths, such as actinic keratoses (AKs), squamous cell carcinoma in situ, and superficial basal cell carcinoma. The topical agent may rarely cause neurotoxic adverse effects. Multiple cases of systemic 5-FU and capecitabine chemotherapy-induced neuropathies have been reported. However, until now, the topical administration of the drug has not been reported to cause neurotoxicity. We present a case of an 83-year-old male who was prescribed topical 5-FU 5% cream to treat AKs on the left anterior scalp and returned weeks later with the development of focal neurotoxicity in the treatment area. He presented with focal paralysis of the left medial frontalis muscle, with initial loss of sensation followed by intermittent pain and paresthesias, persisting four months after the cessation of therapy. He was referred to a neurologist and received a diagnosis of supraorbital neuralgia. The temporal relationship of symptom onset and the localization of symptoms to the treated area strongly suggests that the medication contributed to the observed neurologic effects. These effects are more likely to be observed in patients with a genetic deficiency of dihydropyrimidine dehydrogenase (DPD), which is responsible for the majority of 5-FU degradation (80%), therefore potentially leading to toxic levels of unmetabolized 5-FU. Providers should be aware of the potentially neurotoxic effects of topical 5-FU in order to properly counsel patients and to consider this as a possible etiology of neurologic deficits in patients using this drug.

Cellular Pre-Adaptation to the High O2 Concentration Used in Standard Cell Culture Confers Resistance to Subsequent H2O2-Induced Cell Death.

The addition of hydrogen peroxide (H2O2) to cultured cells is widely used as a method to modulate redox-regulated cellular pathways, including the induction of programmed cell death in cell culture experiments and the testing of pro- and antioxidant compounds. Here, we assessed the effect on the cellular response to H2O2 of pre-adapting squamous cell carcinoma cells (A431) to the standard cell culture oxygenation of 18.6% O2, compared to cells pre-adapted to a physiological skin O2 concentration (3.0% O2). We showed that cells pre-adapted to 18.6% O2 resisted H2O2-induced cell death compared to cells pre-adapted to 3.0% O2 for 96 h prior to treatment with H2O2. Moreover, the enzymatic activities of catalase and glutathione reductase, as well as the protein expression levels of catalase, were higher in cells pre-adapted to 18.6% O2 compared to cells pre-adapted to 3.0% O2. H2O2-resistant cells, pre-adapted to 18.6% O2, exhibited increased nuclear Nrf-2 levels. It is concluded that A431 cells pre-adapted to standard cell culture oxygenation conditions resist H2O2-induced cell death. This effect may be related to their heightened activation of Nrf-2.

Predictors of a Preference for Telemedicine Virtual Visits in Patients Undergoing Cancer Rehabilitation.

ABSTRACT: The purpose of this retrospective study was to examine the use of virtual visits (telemedicine) at our cancer rehabilitation outpatient clinics from March 2020 to August 2021, when virtual visits became more widely available, and to identify any demographic and clinical variables making patients more likely to favor virtual over in-person visits. There were 3971 outpatient encounters (2020 virtual and 1951 in-person visits from a total of 1638 patients) in our cancer rehabilitation outpatient clinics during this time frame. Significant findings in both the univariate and multivariate analyses were race (P < .001 and P = .006, respectively), cancer type (P < .001 for both), and distance to the clinic (P < .001 for both). Our research showed that virtual visits were accepted by patients with cancer, and that younger age (62 compared to 65), non-White race/ethnicity, solid tumor, and shorter distance to the clinic were associated with a preference for virtual over in-person visits.

Combining machine learning with structure-based protein design to predict and engineer post-translational modifications of proteins.

Post-translational modifications (PTMs) of proteins play a vital role in their function and stability. These modifications influence protein folding, signaling, protein-protein interactions, enzyme activity, binding affinity, aggregation, degradation, and much more. To date, over 400 types of PTMs have been described, representing chemical diversity well beyond the genetically encoded amino acids. Such modifications pose a challenge to the successful design of proteins, but also represent a major opportunity to diversify the protein engineering toolbox. To this end, we first trained artificial neural networks (ANNs) to predict eighteen of the most abundant PTMs, including protein glycosylation, phosphorylation, methylation, and deamidation. In a second step, these models were implemented inside the computational protein modeling suite Rosetta, which allows flexible combination with existing protocols to model the modified sites and understand their impact on protein stability as well as function. Lastly, we developed a new design protocol that either maximizes or minimizes the predicted probability of a particular site being modified. We find that this combination of ANN prediction and structure-based design can enable the modification of existing, as well as the introduction of novel, PTMs. The potential applications of our work include, but are not limited to, glycan masking of epitopes, strengthening protein-protein interactions through phosphorylation, as well as protecting proteins from deamidation liabilities. These applications are especially important for the design of new protein therapeutics where PTMs can drastically change the therapeutic properties of a protein. Our work adds novel tools to Rosetta's protein engineering toolbox that allow for the rational design of PTMs.

Perturbative diffraction methods resolve a conformational switch that facilitates a two-step enzymatic mechanism.

Enzymes catalyze biochemical reactions through precise positioning of substrates, cofactors, and amino acids to modulate the transition-state free energy. However, the role of conformational dynamics remains poorly understood due to poor experimental access. This shortcoming is evident with Escherichia coli dihydrofolate reductase (DHFR), a model system for the role of protein dynamics in catalysis, for which it is unknown how the enzyme regulates the different active site environments required to facilitate proton and hydride transfer. Here, we describe ligand-, temperature-, and electric-field-based perturbations during X-ray diffraction experiments to map the conformational dynamics of the Michaelis complex of DHFR. We resolve coupled global and local motions and find that these motions are engaged by the protonated substrate to promote efficient catalysis. This result suggests a fundamental design principle for multistep enzymes in which pre-existing dynamics enable intermediates to drive rapid electrostatic reorganization to facilitate subsequent chemical steps.

The impact of psychiatric comorbidity on Parkinson's disease outcomes: a systematic review and meta-analysis.

Background: The burden of psychiatric symptoms in Parkinson's disease includes depression, anxiety, apathy, psychosis, and impulse control disorders. However, the relationship between psychiatric comorbidities and subsequent prognosis and neurological outcomes is not yet well understood. In this systematic review and meta-analysis, in individuals with Parkinson's disease, we aimed to characterise the association between specific psychiatric comorbidities and subsequent prognosis and neurological outcomes: cognitive impairment, death, disability, disease progression, falls or fractures and care home admission. Methods: We searched MEDLINE, Embase, PsycINFO and AMED up to 13th November 2023 for longitudinal observational studies which measured disease outcomes in people with Parkinson's disease, with and without specific psychiatric comorbidities, and a minimum of two authors extracted summary data. Studies of individuals with other parkinsonian conditions and those with outcome measures that had high overlap with psychiatric symptoms were excluded to ensure face validity. For each exposure-outcome pair, a random-effects meta-analysis was conducted based on standardised mean difference, using adjusted effect sizes-where available-in preference to unadjusted effect sizes. Study quality was assessed using the Newcastle-Ottawa Scale. Between-study heterogeneity was assessed using the I2 statistic and publication bias was assessed using funnel plots. PROSPERO Study registration number: CRD42022373072. Findings: There were 55 eligible studies for inclusion in meta-analysis (n = 165,828). Data on participants' sex was available for 164,514, of whom 99,182 (60.3%) were male and 65,460 (39.7%) female. Study quality was mostly high (84%). Significant positive associations were found between psychosis and cognitive impairment (standardised mean difference [SMD] 0.44, [95% confidence interval [CI] 0.23-0.66], I2 30.9), psychosis and disease progression (SMD 0.46, [95% CI 0.12-0.80], I2 70.3%), depression and cognitive impairment (SMD 0.37 [95% CI 0.10-0.65], I2 27.1%), depression and disease progression (SMD 0.46 [95% CI 0.18-0.74], I2 52.2), depression and disability (SMD 0.42 [95% CI 0.25-0.60], I2 7.9%), and apathy and cognitive impairment (SMD 0.60 [95% CI 0.02-1.19], I2 27.9%). Between-study heterogeneity was moderately high. Interpretation: Psychosis, depression, and apathy in Parkinson's disease are all associated with at least one adverse outcome, including cognitive impairment, disease progression and disability. Whether this relationship is causal is not clear, but the mechanisms underlying these associations require exploration. Clinicians should consider these psychiatric comorbidities to be markers of a poorer prognosis in people with Parkinson's disease. Future studies should investigate the underlying mechanisms and which treatments for these comorbidities may affect Parkinson's disease outcomes. Funding: Wellcome Trust, UK National Institute for Health Research (NIHR), National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at University College London Hospitals NHS Foundation Trust, National Brain Appeal.

Inpatient Rehabilitation of Hematopoietic Stem Cell Transplant Patients: Managing Challenging Impairments and Medical Fragility.

ABSTRACT: Hematopoietic stem cell transplants play an important role in the treatment of cancer, particularly hematologic malignancies. These patients can encounter functional impairments unique to hematopoietic stem cell transplant, including deconditioning, cancer-related fatigue, steroid myopathy, graft versus host disease, and capillary leak syndrome. Medical fragility and increased risk of infection may make rehabilitation challenging on the acute care and postacute care settings. Patients admitted to acute inpatient rehabilitation experience a high rate of transfer to the primary acute service and high rate of mortality after transfer back. Physical medicine and rehabilitation physicians can use a number of strategies to mitigate these patients' risk of medical complications including evidence-based predictive models to assist with postacute rehabilitation triage, physiatry-led consult-based rehabilitation, and oncology hospitalist comanagement on inpatient rehabilitation.

Cognitive domains affected post-COVID-19; a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: This review aims to characterize the pattern of post-COVID-19 cognitive impairment, allowing better prediction of impact on daily function to inform clinical management and rehabilitation. METHODS: A systematic review and meta-analysis of neurocognitive sequelae following COVID-19 was conducted, following PRISMA-S guidelines. Studies were included if they reported domain-specific cognitive assessment in patients with COVID-19 at >4 weeks post-infection. Studies were deemed high-quality if they had >40 participants, utilized healthy controls, had low attrition rates and mitigated for confounders. RESULTS: Five of the seven primary Diagnostic and Statistical Manual of Mental Disorders (DSM-5) cognitive domains were assessed by enough high-quality studies to facilitate meta-analysis. Medium effect sizes indicating impairment in patients post-COVID-19 versus controls were seen across executive function (standardised mean difference (SMD) -0.45), learning and memory (SMD -0.55), complex attention (SMD -0.54) and language (SMD -0.54), with perceptual motor function appearing to be impacted to a greater degree (SMD -0.70). A narrative synthesis of the 56 low-quality studies also suggested no obvious pattern of impairment. CONCLUSIONS: This review found moderate impairments across multiple domains of cognition in patients post-COVID-19, with no specific pattern. The reported literature was significantly heterogeneous, with a wide variety of cognitive tasks, small sample sizes and disparate initial disease severities limiting interpretability. The finding of consistent impairment across a range of cognitive tasks suggests broad, as opposed to domain-specific, brain dysfunction. Future studies should utilize a harmonized test battery to facilitate inter-study comparisons, whilst also accounting for the interactions between COVID-19, neurological sequelae and mental health, the interplay between which might explain cognitive impairment.

Communicating computational workflows in a regulatory environment.

The volume of nucleic acid sequence data has exploded recently, amplifying the challenge of transforming data into meaningful information. Processing data can require an increasingly complex ecosystem of customized tools, which increases difficulty in communicating analyses in an understandable way yet is of sufficient detail to enable informed decisions or repeats. This can be of particular interest to institutions and companies communicating computations in a regulatory environment. BioCompute Objects (BCOs; an instance of pipeline documentation that conforms to the IEEE 2791-2020 standard) were developed as a standardized mechanism for analysis reporting. A suite of BCOs is presented, representing interconnected elements of a computation modeled after those that might be found in a regulatory submission but are shared publicly - in this case a pipeline designed to identify viral contaminants in biological manufacturing, such as for vaccines.