Baseline predictors of progression of Parkinson’s disease in a sample of Egyptian patients: clinical and biochemical

Background Clinical progression of Parkinson’s disease (PD) is highly heterogeneous, and its predictors are generally lacking. Identifying predictors of early disease progression is important for patients’ management and follow-up. The current study aims to identify clinical, neuroimaging and biochemical baseline predictors of motor progression in patients with PD. Forty-five PD patients were assessed at baseline, 6 months and 1 year using MDS-UPDRS total and subscores, Hoehn and Yahr (H&Y), Schwab and England (S&E), International Physical Activity Questionnaire (IPAQ). Baseline New Freezing of Gait Questionnaire (NFOG-Q), Berg Balance Scale (BBS), Ten-Meter Walking Test (10-MWT), and Time Up and Go Test (TUG), Non-Motor Symptoms Scale (NMSS), Beck Depression Inventory (BDI), PD questionnaire 39 (PDQ-39), MRI brain, uric acid, lipid profile and glycated hemoglobin were performed. Results Significant worsening of MDS-UPDRS total, part III scores, H&Y, S&E and IPAQ (p < 0.001) was detected. One-year progression of H&Y and S&E were significantly correlated to disease duration (p = 0.014, p = 0.025, respectively). Progression of H&Y was correlated to baseline TUG (p = 0.035). S&E progression was correlated to baseline MDS-UPDRS total score (rho = 0.478, p = 0.001) and part III (rho = 0.350, p = 0.020), H&Y (rho = 0.401, p = 0.007), PIGD (rho = 0.591, p < 0.001), NFOG-Q (rho = 0.498, p = 0.001), and TUG (rho = 0.565, p = 0.001). Using linear regression, there was no predictors of clinical progression among the used baseline variables. Conclusion Despite the significant motor and physical activity progression over 1 year that was correlated to baseline motor and gait severity, but without predictive value, further similar and longitudinal studies are warranted to detect predictors of early progression and confirm findings.

Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers

KRAS G12C inhibitors, such as sotorasib, have rapidly moved through clinical development and are poised to transform care of patients with KRAS G12C mutant cancers, in particular non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Clinical efficacy is achieved in NSCLC as a single agent and in CRC in combination with anti-EGFR monoclonal antibodies, however, secondary resistance impairs the effects of KRAS G12C blockade. In this work, we sought to determine the mechanisms of acquired resistance to concomitant KRAS-EGFR inhibition. In cell lines, patient-derived xenograft, and patient samples, a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signalling by drug can be detected at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency that does not increase substantially and sometimes disappears over time, with the exception of KRAS G12C amplification which rises in step with tumour marker levels and clinical progression. Here we show that a CRC cell line that acquired resistance to sotorasib-cetuximab combination through KRAS G12C amplification became addicted to these agents and undergoes oncogene-induced senescence upon drug withdrawal. Accordingly, the KRAS G12C signal in circulating DNA from relapsed patients harbouring G12C amplification rapidly recedes upon treatment holiday. These data indicate that KRAS G12C amplification is a recurrent resistance mechanism to KRAS-EGFR co-inhibition and suggest a potential therapeutic vulnerability, whereby therapies that target this senescence response at drug withdrawal may overcome resistance to KRAS G12C-EGFR inhibition.

Confirming a Historical Diagnosis of Multiple Sclerosis: Challenges and Recommendations

Patients with a historical diagnosis of multiple sclerosis (MS) — a patient presenting with a diagnosis of MS made previously and by a different clinician — present specific diagnostic and therapeutic challenges in clinical practice. Application of the McDonald criteria is most straightforward when applied contemporaneously with a syndrome typical of an MS attack or relapse; however, retrospective application of the criteria in some patients with a historical diagnosis of MS can be problematic. Limited patient recollection of symptoms and evolution of neurological examination and MRI findings complicate confirmation of an earlier MS diagnosis and assessment of subsequent disease activity or clinical progression. Adequate records for review of prior clinical examinations, laboratory results, and/or MRI scans obtained at the time of diagnosis or during ensuing care may be inadequate or unavailable. This paper provides recommendations for a clinical approach to the evaluation of patients with a historical diagnosis of MS to aid diagnostic confirmation, avoid misdiagnosis, and inform therapeutic decision-making.

Full title: COVID-19 disease progression according to initial symptoms. A telemedicine cohort study.

Objective COVID-19 progression to severe or critical illness may be related to initial clinical presentation. Main objective was to identify initial symptoms related to highest risk of disease progression, in mild or moderate suspected or confirmed COVID-19 patients or in asymptomatic subjects in contact with a recently diagnosed patient. Design and methods Historic cohort study of Mexican patients with suspected or confirmed mild or moderate COVID-19 or asymptomatic subjects in recent contact with positive patients. They sought medical attention in Centro Medico ABC or claimed for remote attention, and daily telemedicine follow up until recovery or illness progression, from April 17th to October 08th 2020. Data excerpted for analysis were sex, age, body mass index, comorbidities, and signs, and symptoms presented in first day of disease manifestations and during follow up. We used logistic regression to identify initial symptoms associated with progression disease and through a conjunctive consolidation analysis a symptom index was created. Results 120 of 1635 patients (7.2%) had clinical progression disease. By logistic regression we found as initial symptoms related to progression: fever OR 3 (1.89-4.77, p<0.001), cough OR 2.34 (1.56-3.52, p<0.001), myalgias or arthralgias OR 1.69 (1.09-2.63, p=0.018), and fatigue OR 1.65 (1.08-2.53, p=0.019). Conjunctive consolidation was processed with the previous symptoms, and a 3 groups score resulted C-19PAIS Index: 1) Fever with cough or fever with fatigue, with a probability of progression disease of 29% (31/106 patients), 2) Fever or cough or fatigue or cough with fatigue, 10.7% (66/615 patients) and 3) No fever, no cough, no fatigue, 2% (23/914). Conclusions Initial symptoms predict clinical progression in COVID-19 patients.

Clinical progression of COVID-19 coinfection in people living with the human immunodeficiency virus: scoping review

ABSTRACT Objectives: to map the production of scientific knowledge on the clinical progression of COVID-19 coinfection in people living with the human immunodeficiency virus (HIV). Methods: scoping review, with search strategies in MEDLINE, Scopus, Embase, Web of Science, and LILACS. Dual independent data extraction and analysis of the material with similarity compilation and narrative synthesis. Results: sample consisted of 35 articles. Fever, cough, and dyspnea were the most prevalent signs/symptoms. Recurrent complications involved desaturation/worsening of oxygen desaturation and pneumonia. No standard pharmacological treatment was identified, and the main interventions involved the provision of supplemental oxygen and mechanical ventilation. The studies recommended preventive, care, and pharmacological practices. Conclusions: the clinical manifestations, complications, and treatments/assistance care for people coinfected with SARS CoV-2/HIV are similar to those of the general population. Coinfection, overall, does not infer a worse prognosis.

Parkinson’s Disease Progression and Statins: Hydrophobicity Matters

Background: Recent randomized clinical trials using hydrophobic statins reported no influence on Parkinson’s disease (PD) clinical progression. Hydrophobicity is a key determinant for blood-brain barrier penetrance. Objective: Investigate a potential effect of statins on PD progression. Methods: Statin use was determined at baseline and subtyped according to hydrophobicity in 125 PD patients participated PD Biomarker Program (PDBP, 2012–2015) at our site. Clinical (N = 125) and susceptibility MRI (N = 86) data were obtained at baseline and 18-months. Movement Disorders Society-Unified PD Rating Scales were used to track progression of non-motor (MDS-UPDRS-I) and motor (MDS-UPDRS-II) symptoms, and rater-based scores (MDS-UPDRS-III) of patients in the “on” drug state. R2 * values were used to capture pathological progression in the substantia nigra. Associations between statin use, its subtypes, and PD progression were evaluated with linear mixed effect regressions. Results: Compared to statin non-users, overall statin or lipophilic statin use did not significantly influence PD clinical or imaging progression. Hydrophilic statin users, however, demonstrated faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 4.8, p = 0.010)] and nigral R2 * (β= 3.7, p = 0.043). A similar trend was found for MDS-UPDRS-II (β= 3.9, p = 0.10), but an opposite trend was observed for rater-based MDS-UPDRS-III (β= –7.3, p = 0.10). Compared to lipophilic statin users, hydrophilic statin users also showed significantly faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 5.0, p = 0.020)], but R2 * did not reach statistical significance (β= 2.5, p = 0.24). Conclusion: This study suggests that hydrophilic, but not lipophilic, statins may be associated with faster PD progression. Future studies may have clinical and scientific implications.

Assessment of Structural Disconnections In Gliomas: Comparison of Indirect And Direct Approaches

Gliomas are amongst the most common primary brain tumours in adults and are often associated with poor prognosis. Understanding the extent of white matter (WM) which is affected outside the tumoral lesion may be of paramount importance to explain cognitive deficits and the clinical progression of the disease. To this end, we explored both direct (i.e., tractography based) and indirect (i.e., atlas based) approaches to quantifying WM structural disconnections in a cohort of 50 high- and low-grade glioma patients. While these methodologies have recently gained popularity in the context of stroke, to our knowledge this is the first time they are applied in patients with brain tumours. More specifically, in this work we present a quantitative comparison of the disconnection maps provided by the two methodologies by applying well known metrics of spatial similarity, extension and correlation. Given the important role the oedematous tissue plays in the physiopathology of tumours, we performed these analyses both by including and excluding it in the definition of the tumoral lesion. This was done to investigate possible differences determined by this choice.We found that direct and indirect approaches offer two distinct pictures of structural disconnections in patients affected by brain gliomas, presenting key differences in several regions of the brain. Following the outcomes of our analysis, we eventually discuss the strengths and pitfalls of these two approaches when applied in this critical field.