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NPJ Parkinson's Disease May 2024Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis...
Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis Initiative seeks to characterize molecular and clinical features of every PD patient at the University of Pennsylvania (UPenn). The objectives of this study are to determine the feasibility of genetic characterization in PD and assess clinical features by sex and GBA1/LRRK2 status on a clinic-wide scale. All PD patients with clinical visits at the UPenn PD Center between 9/2018 and 12/2022 were eligible. Blood or saliva were collected, and a clinical questionnaire administered. Genotyping at 14 GBA1 and 8 LRRK2 variants was performed. PD symptoms were compared by sex and gene groups. 2063 patients were approached and 1,689 (82%) were enrolled, with 374 (18%) declining to participate. 608 (36%) females were enrolled, 159 (9%) carried a GBA1 variant, and 44 (3%) carried a LRRK2 variant. Compared with males, females across gene groups more frequently reported dystonia (53% vs 46%, p = 0.01) and anxiety (64% vs 55%, p < 0.01), but less frequently reported cognitive impairment (10% vs 49%, p < 0.01) and vivid dreaming (53% vs 60%, p = 0.01). GBA1 variant carriers more frequently reported anxiety (67% vs 57%, p = 0.04) and depression (62% vs 46%, p < 0.01) than non-carriers; LRRK2 variant carriers did not differ from non-carriers. We report feasibility for near-clinic-wide enrollment and characterization of individuals with PD during clinical visits at a high-volume academic center. Clinical symptoms differ by sex and GBA1, but not LRRK2, status.
PubMed: 38702337
DOI: 10.1038/s41531-024-00690-6 -
Cell Chemical Biology Jun 2024The modulation of protein-protein interactions with small molecules is one of the most rapidly developing areas in drug discovery. In this review, we discuss advances... (Review)
Review
The modulation of protein-protein interactions with small molecules is one of the most rapidly developing areas in drug discovery. In this review, we discuss advances over the past decade (2014-2023) focusing on molecular glues (MGs)-monovalent small molecules that induce proximity, either by stabilizing native interactions or by inducing neomorphic interactions. We include both serendipitous and rational discoveries and describe the different approaches that were used to identify them. We classify the compounds in three main categories: degradative MGs, non-degradative MGs or PPI stabilizers, and MGs that induce self-association. Diverse, illustrative examples with structural data are described in detail, emphasizing the elements of molecular recognition and cooperative binding at the interface that are fundamental for a MG mechanism of action.
Topics: Protein Binding; Proteins; Humans; Small Molecule Libraries; Drug Discovery
PubMed: 38701786
DOI: 10.1016/j.chembiol.2024.04.002 -
BMC Neurology May 2024Sleep disorders are a prevalent non-motor symptom of Parkinson's disease (PD), although reliable biological markers are presently lacking.
BACKGROUND
Sleep disorders are a prevalent non-motor symptom of Parkinson's disease (PD), although reliable biological markers are presently lacking.
OBJECTIVES
To explore the associations between sleep disorders and serum neurofilament light chain (NfL) levels in individuals with prodromal and early PD.
METHODS
The study contained 1113 participants, including 585 early PD individuals, 353 prodromal PD individuals, and 175 healthy controls (HCs). The correlations between sleep disorders (including rapid eye movement sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS)) and serum NfL levels were researched using multiple linear regression models and linear mixed-effects models. We further investigated the correlations between the rates of changes in daytime sleepiness and serum NfL levels using multiple linear regression models.
RESULTS
In baseline analysis, early and prodromal PD individuals who manifested specific behaviors of RBD showed significantly higher levels of serum NfL. Specifically, early PD individuals who experienced nocturnal dream behaviors (β = 0.033; P = 0.042) and movements of arms or legs during sleep (β = 0.027; P = 0.049) showed significantly higher serum NfL levels. For prodromal PD individuals, serum NfL levels were significantly higher in individuals suffering from disturbed sleep (β = 0.038; P = 0.026). Our longitudinal findings support these baseline associations. Serum NfL levels showed an upward trend in early PD individuals who had a higher total RBDSQ score (β = 0.002; P = 0.011) or who were considered as probable RBD (β = 0.012; P = 0.009) or who exhibited behaviors on several sub-items of the RBDSQ. In addition, early PD individuals who had a high total ESS score (β = 0.001; P = 0.012) or who were regarded to have EDS (β = 0.013; P = 0.007) or who exhibited daytime sleepiness in several conditions had a trend toward higher serum NfL levels.
CONCLUSION
Sleep disorders correlate with higher serum NfL, suggesting a link to PD neuronal damage. Early identification of sleep disorders and NfL monitoring are pivotal in detecting at-risk PD patients promptly, allowing for timely intervention. Regular monitoring of NfL levels holds promise for tracking both sleep disorders and disease progression, potentially emerging as a biomarker for evaluating treatment outcomes.
Topics: Humans; Parkinson Disease; Male; Female; Neurofilament Proteins; Middle Aged; Aged; Sleep Wake Disorders; Biomarkers; REM Sleep Behavior Disorder; Prodromal Symptoms
PubMed: 38693483
DOI: 10.1186/s12883-024-03642-y -
Scientific Reports May 2024Parkinson's disease is a progressive neurodegenerative disorder in which loss of dopaminergic neurons in the substantia nigra results in a clinically heterogeneous group...
Parkinson's disease is a progressive neurodegenerative disorder in which loss of dopaminergic neurons in the substantia nigra results in a clinically heterogeneous group with variable motor and non-motor symptoms with a degree of misdiagnosis. Only 3-25% of sporadic Parkinson's patients present with genetic abnormalities that could represent a risk factor, thus environmental, metabolic, and other unknown causes contribute to the pathogenesis of Parkinson's disease, which highlights the critical need for biomarkers. In the present study, we prospectively collected and analyzed plasma samples from 194 Parkinson's disease patients and 197 age-matched non-diseased controls. N-acetyl putrescine (NAP) in combination with sense of smell (B-SIT), depression/anxiety (HADS), and acting out dreams (RBD1Q) clinical measurements demonstrated combined diagnostic utility. NAP was increased by 28% in Parkinsons disease patients and exhibited an AUC of 0.72 as well as an OR of 4.79. The clinical and NAP panel demonstrated an area under the curve, AUC = 0.9 and an OR of 20.4. The assessed diagnostic panel demonstrates combinatorial utility in diagnosing Parkinson's disease, allowing for an integrated interpretation of disease pathophysiology and highlighting the use of multi-tiered panels in neurological disease diagnosis.
Topics: Humans; Parkinson Disease; Male; Biomarkers; Female; Aged; Middle Aged; Putrescine; Prospective Studies; Case-Control Studies
PubMed: 38693432
DOI: 10.1038/s41598-024-60872-3 -
The Journal of Allergy and Clinical... Apr 2024Benralizumab and mepolizumab are interleukin (IL)-5Rα/interleukin-5-targeted monoclonal antibodies indicated as add-on treatments for patients with uncontrolled severe...
BACKGROUND
Benralizumab and mepolizumab are interleukin (IL)-5Rα/interleukin-5-targeted monoclonal antibodies indicated as add-on treatments for patients with uncontrolled severe eosinophilic asthma (SEA).
OBJECTIVE
To evaluate and compare the safety of benralizumab and mepolizumab among patients with SEA treated in MELTEMI and COLUMBA open-label, long-term extension studies, respectively.
METHODS
MELTEMI was an extension study of benralizumab every 4 weeks (q4w) or every 8 weeks (q8w) for adults (aged 18-75 y) with SEA. MELTEMI participants transitioned from the BORA extension, preceded by participation in 1 of 3 placebo-controlled studies (SIROCCO, CALIMA, or ZONDA). COLUMBA was an extension study of mepolizumab for patients (aged ≥ 12 y) with SEA who transitioned from the dose-ranging DREAM study. Safety endpoints were presented as drug exposure patient-years (MELTEMI, q4w 784.28, q8w 797.03; COLUMBA 1,201) for nonserious adverse events, serious adverse events, and infections; malignancies were counted numerically.
RESULTS
This analysis included 446 MELTEMI patients (benralizumab q4w 220; benralizumab q8w 226) and 347 COLUMBA patients (mepolizumab q4w). Viral upper respiratory tract infection was the most common nonserious adverse event in both studies (MELTEMI q8w 46.5%; q4w 47.3%; COLUMBA, 48.7%). Asthma-related events were the most common serious adverse events in both studies: MELTEMI 8.0% (q8w) and 8.6% (q4w) and COLUMBA 9.5%. Serious infections included pneumonia (MELTEMI q8w, 2 [0.9%]; COLUMBA, 6 [1.7%]); cellulitis (MELTEMI q8w, 1 [0.4%]; COLUMBA, 2 [0.6%]); and respiratory tract infections (COLUMBA, 2 [0.6%]). COLUMBA reported 6 malignancies and MELTEMI reported 4 malignancies in each group.
CONCLUSIONS
This analysis demonstrated generally similar safety events between mepolizumab and benralizumab in patients with SEA.
PubMed: 38677588
DOI: 10.1016/j.jaip.2024.04.033 -
Scientific Reports Apr 2024Suicide is prevalent among young adults, and epidemiological studies indicate that insomnia, nightmares, and depression are significantly associated with a high...
Suicide is prevalent among young adults, and epidemiological studies indicate that insomnia, nightmares, and depression are significantly associated with a high incidence of suicidal ideation (SI). However, the causal relationship between these factors and SI remains unclear. Therefore, the purpose of this study was to examine the association between nightmares and depression and insomnia and SI in young adults, as well as to develop a mediation model to investigate the causal relationship between insomnia, nightmare, depression, and SI. We assessed insomnia, nightmares, depression, and SI in 546 young adults using the Insomnia Severity Scale (ISI), Disturbing Dream and Nightmare Severity Scale (DDNSI), Depression Study Scale (CESD-20), and Columbia-Suicide Severity Rating Scale (C-SSRS). Using the Bootstrap method, the mediation effects of nightmares and depression between insomnia and SI were calculated. The results demonstrated that nightmares and depression fully mediated the relationship between insomnia and SI, including the chain-mediation of insomnia and SI between nightmare and depression with an effect value of 0.02, 95% CI 0.01-0.04, and depression as a mediator between insomnia and SI with an effect value of 0.22, 95% CI 0.15-0.29. This study found that depression and nightmares may be risk and predictive factors between insomnia and SI, which implies that the assessment and treatment of depression and the simple or linked effect of nightmares play crucial roles in preventing SI in young adults.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Suicidal Ideation; Dreams; Male; Female; Depression; Young Adult; Adult; Adolescent; Risk Factors
PubMed: 38670978
DOI: 10.1038/s41598-024-58774-5 -
Radiotherapy and Oncology : Journal of... Jul 2024Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical... (Review)
Review
Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical knowledge and enabled effective cancer treatment to date. Remarkable advances in technology, computing, and experimental biology now create opportunities to incorporate this knowledge into enhanced computational models. The ESTRO DREAM (Dose Response, Experiment, Analysis, Modelling) workshop brought together experts across disciplines to pursue the vision of personalized radiotherapy for optimal outcomes through advanced modelling. The ultimate vision is leveraging quantitative models dynamically during therapy to ultimately achieve truly adaptive and biologically guided radiotherapy at the population as well as individual patient-based levels. This requires the generation of models that inform response-based adaptations, individually optimized delivery and enable biological monitoring to provide decision support to clinicians. The goal is expanding to models that can drive the realization of personalized therapy for optimal outcomes. This position paper provides their propositions that describe how innovations in biology, physics, mathematics, and data science including AI could inform models and improve predictions. It consolidates the DREAM team's consensus on scientific priorities and organizational requirements. Scientifically, it stresses the need for rigorous, multifaceted model development, comprehensive validation and clinical applicability and significance. Organizationally, it reinforces the prerequisites of interdisciplinary research and collaboration between physicians, medical physicists, radiobiologists, and computational scientists throughout model development. Solely by a shared understanding of clinical needs, biological mechanisms, and computational methods, more informed models can be created. Future research environment and support must facilitate this integrative method of operation across multiple disciplines.
Topics: Humans; Radiobiology; Neoplasms; Precision Medicine
PubMed: 38670264
DOI: 10.1016/j.radonc.2024.110277 -
Behavioral Sciences (Basel, Switzerland) Apr 2024Spontaneous, unwilled subjective imagery and symbols (including dreams) often emerge in psychotherapy that can appear baffling and confound interpretation. Early...
Spontaneous, unwilled subjective imagery and symbols (including dreams) often emerge in psychotherapy that can appear baffling and confound interpretation. Early psychoanalytic theories seemed to diverge as often as they agreed on the meaning of such content. Nevertheless, after reviewing key findings in the empirical science of spontaneous thought as well as insights gleaned from neuroscience and especially embodied cognition, it is now possible to construct a more coherent theory of interpretation that is clinically useful. Given that thought is so thoroughly embodied, it is possible to demonstrate that universalities in human physiology yield universalities in thought. Such universalities can then be demonstrated to form a kind of biologically directed universal "code" for understanding spontaneous symbolic expressions that emerge in psychotherapy. An example is given that illustrates how this can be applied to clinical encounters.
PubMed: 38667115
DOI: 10.3390/bs14040319 -
Midwifery Jul 2024There has been an increase in the number of single women deciding to have children through the use of medically assisted reproduction (MAR). These women are referred to...
PROBLEM
There has been an increase in the number of single women deciding to have children through the use of medically assisted reproduction (MAR). These women are referred to as 'single mothers by choice' (SMC).
BACKGROUND
Previous studies have shown how SMC can feel stigmatised.
AIM
Explore if single women seeking fertility treatment in Denmark feel stigmatised.
METHODS
Six single women undergoing MAR at a public fertility clinic in Denmark were interviewed. The interviews were audiotaped, anonymised, and transcribed in full, after provided written consent by the participants to take part in the study. Data were analysed using qualitative content analysis.
FINDINGS
The women would have preferred to have a child in a relationship with a partner. Despite their dream of the nuclear family meaning a family group consisting of two parents and their children (one or more), the women choose to become SMC because motherhood was of such importance, and they feared they would otherwise become too old to have children. The participants did not experience stigma or negative responses to their decision, but they all had an awareness of the prejudices other people might have towards SMC.
CONCLUSION
This study contributes to the understanding of the experiences of single women seeking fertility treatment in a welfare state where there are no differences in the possibilities for different social classes to seek MAR.
Topics: Humans; Female; Denmark; Adult; Pilot Projects; Mothers; Qualitative Research; Choice Behavior; Fertility Clinics; Single Person; Single Parent; Reproductive Techniques, Assisted
PubMed: 38663056
DOI: 10.1016/j.midw.2024.104013 -
Critical Care (London, England) Apr 2024Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring mechanical ventilation suffer from a high incidence of ventilator...
Ventilator-associated pneumonia related to extended-spectrum beta-lactamase producing Enterobacterales during severe acute respiratory syndrome coronavirus 2 infection: risk factors and prognosis.
BACKGROUND
Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring mechanical ventilation suffer from a high incidence of ventilator associated pneumonia (VAP), mainly related to Enterobacterales. Data regarding extended-spectrum beta-lactamase producing Enterobacterales (ESBL-E) VAP are scarce. We aimed to investigate risk factors and outcomes of ESBL-E related VAP among critically ill coronavirus infectious disease-19 (COVID-19) patients who developed Enterobacterales related VAP.
PATIENTS AND METHODS
We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU) that included 4929 COVID-19 critically ill patients. For the present analysis, only patients with complete data regarding resistance status of the first episode of Enterobacterales related VAP (ESBL-E and/or carbapenem-resistant Enterobacterales, CRE) and outcome were included.
RESULTS
We included 591 patients with Enterobacterales related VAP. The main causative species were Enterobacter sp (n = 224), E. coli (n = 111) and K. pneumoniae (n = 104). One hundred and fifteen patients (19%), developed a first ESBL-E related VAP, mostly related to Enterobacter sp (n = 40), K. pneumoniae (n = 36), and E. coli (n = 31). Eight patients (1%) developed CRE related VAP. In a multivariable analysis, African origin (North Africa or Sub-Saharan Africa) (OR 1.7 [1.07-2.71], p = 0.02), time between intubation and VAP (OR 1.06 [1.02-1.09], p = 0.002), PaO/FiO ratio on the day of VAP (OR 0.997 [0.994-0.999], p = 0.04) and trimethoprim-sulfamethoxazole exposure (OR 3.77 [1.15-12.4], p = 0.03) were associated with ESBL-E related VAP. Weaning from mechanical ventilation and mortality did not significantly differ between ESBL-E and non ESBL-E VAP.
CONCLUSION
ESBL-related VAP in COVID-19 critically-ill patients was not infrequent. Several risk factors were identified, among which some are modifiable and deserve further investigation. There was no impact of resistance of the first Enterobacterales related episode of VAP on outcome.
Topics: Humans; Pneumonia, Ventilator-Associated; Escherichia coli; Cohort Studies; Prospective Studies; Critical Illness; beta-Lactamases; COVID-19; Intensive Care Units; Risk Factors; Klebsiella pneumoniae; Prognosis
PubMed: 38641851
DOI: 10.1186/s13054-024-04906-2