Search

BACKGROUND: Varoglutamstat is a first-in-class, small molecule being investigated as a treatment for early Alzheimers disease (AD). It is an inhibitor of glutaminyl cyclase (QC), the enzyme that post-translationally modifies amyloid-β (Aβ) peptides into a toxic form of pyroglutamate Aβ (pGlu-Aβ) and iso-QC which post-translationally modifies cytokine monocyte chemoattractant protein-1 (CCL2) into neuroinflammatory pGlu-CCL2. Early phase clinical trials identified dose margins for safety and tolerability of varoglutamstat and biomarker data supporting its potential for clinical efficacy in early AD. OBJECTIVE: Present the scientific rationale of varoglutamstat in the treatment of early AD and the methodology of the VIVA-MIND (NCT03919162) trial, which uses a seamless phase 2A-2B design. Our review also includes other pharmacologic approaches to pGlu-Aβ. METHODS: Phase 2A of the VIVA-MIND trial will determine the highest dose of varoglutamstat that is safe and well tolerated with sufficient plasma exposure and a calculated target occupancy. Continuous safety evaluation using a pre-defined safety stopping boundary will help determine the highest tolerated dose that will carry forward into phase 2B. An interim futility analysis of cognitive function and electroencephalogram changes will be conducted to inform the decision of whether to proceed with phase 2B. Phase 2B will assess the efficacy and longer-term safety of the optimal selected phase 2A dose through 72 weeks of treatment. CONCLUSIONS: Varoglutamstat provides a unique dual mechanism of action addressing multiple pathogenic contributors to the disease cascade. VIVA-MIND provides a novel and efficient trial design to establish its optimal dosing, safety, tolerability, and efficacy in early AD.

There exists a variety of interval estimators for the overall treatment effect in a random-effects meta-analysis. A recent literature review summarizing existing methods suggested that in most situations, the Hartung-Knapp/Sidik-Jonkman (HKSJ) method was preferable. However, a quantitative comparison of those methods in a common simulation study is still lacking. Thus, we conduct such a simulation study for continuous and binary outcomes, focusing on the medical field for application. Based on the literature review and some new theoretical considerations, a practicable number of interval estimators is selected for this comparison: the classical normal-approximation interval using the DerSimonian-Laird heterogeneity estimator, the HKSJ interval using either the Paule-Mandel or the Sidik-Jonkman heterogeneity estimator, the Skovgaard higher-order profile likelihood interval, a parametric bootstrap interval, and a Bayesian interval using different priors. We evaluate the performance measures (coverage and interval length) at specific points in the parameter space, that is, not averaging over a prior distribution. In this sense, our study is conducted from a frequentist point of view. We confirm the main finding of the literature review, the general recommendation of the HKSJ method (here with the Sidik-Jonkman heterogeneity estimator). For meta-analyses including only two studies, the high length of the HKSJ interval limits its practical usage. In this case, the Bayesian interval using a weakly informative prior for the heterogeneity may help. Our recommendations are illustrated using a real-world meta-analysis dealing with the efficacy of an intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting.

ABSTRACT Background Aim Methods Results Conclusions The heart rate variability–based Newborn Infant Parasympathetic Evaluation (NIPE) Index is a continuous noninvasive tool for the assessment of pain and discomfort in infants. Little is known about its performance in the pediatric intensive care unit (PICU) setting, where assessment of pain/discomfort is usually based on discontinuous observational scoring systems or personal experience of medical staff.Evaluation of the performance of NIPE as an indicator of procedural pain and/or discomfort in conscious mechanically ventilated PICU patients.Procedural pain/discomfort was simultaneously assessed during pain‐ or stressful procedures by two validated discontinuous clinical scoring systems (FLACC and COMFORT‐B scale) and the NIPE.NIPE values, FLACC‐ and COMFORT‐B scores were recorded in 17 infants with a mean age of 1.2 (range 0.8–5.9) months. NIPE values associated with positive FLACC‐ (≥ 4; indicative of pain) and/or COMFORT‐B (≥ 17, indicative of discomfort) scores were lower (p < 0.001) than when associated with negative FLACC (< 4) and/or COMFORT‐B (< 17) scores with 95% CI's of a difference of −14 to −11 (FLACC), −13 to −11 (COMFORT‐B) and −14 to −11 (FLACC and COMFORT‐B), with significant interindividual variability in NIPE values. Logistic regression analyses revealed odds ratios between 0.84 and 0.85; the adjacent receiver operating curve analyses showed areas under the curve between 0.83 and 0.88. NIPE data recording failure occurred during 49.3% of the periods with a FLACC ≥ 4% and 40.7% with a COMFORT‐B ≥ 17.The NIPE detects procedural pain and discomfort in conscious mechanically ventilated infants with an accuracy comparable to established clinical scoring systems. However, because of significant interindividual variability of NIPE values and frequent data recording failure associated with patient movement, we believe it is premature to recommend its use in conscious infants. [ABSTRACT FROM AUTHOR]

The standard estimator for the log odds ratio (the unconditional maximum likelihood estimator) and the delta-method estimator for its standard error are not defined if the corresponding 2 x 2 table contains at least one "zero cell". This is also an issue when estimating the overall log odds ratio in a meta-analysis. It is well known that correcting for zero cells by adding a small increment should be avoided. Nevertheless, these zero-cell corrections continue to be used. With this Brief Method Note, we want to warn of a particularly bad zero-cell correction. For this, we conduct a simulation study comparing the following two zero-cell corrections under the ordinary random-effects model: (a) adding 1/2 to all cells of all the individual studies' 2 x 2 tables independently of any zero-cell occurrences and (b) adding 1/2 to all cells of only those 2 x 2 tables containing at least one zero cell. The main finding is that correction (a) performs worse than correction (b). Thus, we strongly discourage the use of correction (a).

Background: The aim of this study is to describe the management and associated follow-up strategies adopted by thyroid surgeons with different surgical volumes when loss of signal (LOS) occurred on the first side of planned bilateral thyroid surgery, and to further define the consensus on intraoperative neuromonitoring (IONM) applications. Methods: The International Neural Monitoring Study Group (INMSG) web-based survey was sent to 950 thyroid surgeons worldwide. The survey included information on the participants, IONM team/equipment/procedure, intraoperative/postoperative management of LOS, and management of LOS on the first side of thyroidectomy for benign and malignant disease. Results: Out of 950, 318 (33.5%) respondents completed the survey. Subgroup analyses were performed based on thyroid surgery volume: <50 cases/year (n = 108, 34%); 50 to 100 cases/year (n = 69, 22%); and >100 cases/year (n = 141, 44.3%). High-volume surgeons were significantly (P <.05) more likely to perform the standard procedures (L1-V1-R1-S1-S2-R2-V2-L2), to differentiate true/false LOS, and to verify the LOS lesion/injury type. When LOS occurs, most surgeons arrange otolaryngologists or speech consultation. When first-side LOS occurs, not all respondents decided to perform stage contralateral surgery, especially for malignant patients with severe disease (eg, extrathyroid invasion and poorly differentiated thyroid cancer). Conclusions: Respondents felt that IONM was optimized when conducted under a collaborative team-based approach, and completed IONM standard procedures and management algorithm for LOS, especially those with high volume. In cases of first-site LOS, surgeons can determine the optimal management of disease-related, patient-related, and surgical factors. Surgeons need additional education on LOS management standards and guidelines to master their decision-making process involving the application of IONM. [ABSTRACT FROM AUTHOR]

Background: Skip metastases, node metastases in the lateral neck sparing the ipsilateral central neck, challenge the current concept of central-to-lateral lymphatic spread. This study sought to delineate patterns of central and lateral neck involvement in unilateral papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC). Methods: This was a retrospective correlative analysis of nodal patterns in surgical specimens from patients with unilateral PTC or MTC who had undergone thyroidectomy with at least ipsilateral central neck dissection between November 1994 and January 2024 at a tertiary referral center. Results: Included were 833 patients with unilateral PTC and 640 patients with unilateral MTC. Simultaneous presence or absence of node metastases was noted in ipsilateral central and lateral neck compartments in 76.6–78.1% of patients with PTC (both node positive in 27.0–54.7% and both node negative in 23.4–49.6%) and 77.3–80.0% of patients with MTC (both node positive in 26.6–33.2% and both node negative in 44.1–53.4%). Only one ipsilateral neck compartment was node positive in 21.9–23.4% of patients with PTC and 20.0–22.7% of patients with MTC. The ipsilateral central, but not the ipsilateral lateral compartment, was node positive in 8.8–16.9% with PTC and 8.6–8.8% of patients with MTC, whereas the ipsilateral lateral, but not the ipsilateral central compartment, was node positive in 6.5–13.1% with PTC and 11.3–14.1% with MTC. Ipsilateral lateral neck involvement sparing the ipsilateral central neck was 1.5–2 times more frequent in patients with node positive MTC than patients with node positive PTC (24.2–25.2% vs. 12.9–17.1%). Greater numbers of node metastases in the ipsilateral central neck compartment were associated with more frequent involvement of the ipsilateral lateral, contralateral central, and contralateral lateral neck compartments. Thyroid tumor diameter intensified nodal spread without changing nodal spread patterns. Conclusions: These histopathological findings, which need to be interpreted in light of the respective tumor biology, offer an unprecedented glimpse at the metastatic patterns of unilateral PTC and MTC. Customizing neck dissection to the patterns of nodal spread, considering operative status (initial vs. reoperative surgery) and experience with neck dissection, may require more frequent concomitant dissections of ipsilateral central and ipsilateral lateral neck compartments. [ABSTRACT FROM AUTHOR]

The age-specific development of the three constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620, or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804, or 891). There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node negative medullary thyroid cancer (MTC), from node negative to node positive MTC, from node positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range: 0.5-50 years), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 years and 35 years, respectively. The age-specific development of MTC differed significantly between the four RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the two strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the three constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward. [ABSTRACT FROM AUTHOR]

Little is known about axillary node metastasis of medullary thyroid cancer (MTC). To address this, a comparative study of patients with and without axillary node metastases of MTC was conducted. Among 1215 consecutive patients with MTC, 482 patients had node-negative MTC and 733 patients node-positive MTC. Among the 733 patients with node-positive MTC, 4 patients (0.5%) had axillary node metastases, all of which were ipsilateral. Patients with axillary node metastases had 5.7–6.9-fold more node metastases removed, both at the authors' institution (medians of 34.5 vs. 5 metastases; p=0.011) and in total (medians of 57 vs. 10 metastases; p=0.013), developed more frequently distant metastases (3 of 4 vs. 178 of 729 patients, or 75 vs. 24%; p=0.049), specifically to bone (2 of 4 vs. 67 of 729 patients, or 50 vs. 9%; p=0.046) and brain (1 of 4 vs. 4 of 729 patients, or 25 vs. 0.5%; p=0.027), and more often succumbed to cancer-specific death (3 of 4 vs. 52 of 729 patients, or 75 vs. 14%; p=0.005). Altogether, patients with axillary node metastases revealed 4–8-fold more node metastases in the ipsilateral lateral neck (medians of 11 vs. 3 metastases; p=0.021) and in the ipsilateral central neck (medians of 8 vs. 1 metastases; p=0.079) patients without axillary node metastases. Cancer-specific survival of patients with vs. patients without axillary node metastases of MTC was significantly shorter (means of 41 vs. 224 months; p log-rank <0.001). These findings show that patients with axillary node metastases of MTC have massive metastatic dissemination with poor survival. [ABSTRACT FROM AUTHOR]

Ageing, immobilization, sepsis or cachexia reduce muscle mass and function. The age-related loss, i.e. sarcopenia, contributes to frailty and results in a loss of mobility and autonomy in aging and disease. Affected individuals are often socially isolated, have a greater risk of metabolic disorders and psychosomatic problems. As a result, quality of life and life expectancy are affected. Immobilization and lack of adequate stimuli to the skeletal muscle seem to play a central part in these problems. To overcome them, resistance training (i.e., weightlifting) is an effective intervention. Despite the efficacy of resistance training for increasing muscle mass and function, this treatment is underused in clinical practice. We argue that this is due to a lack of a generally applicable methodology. To address this and related problems, we have formed the Network of Expertise for Immobilization-induced Muscle Disorders (KNIMS) to develop a potential algorithm for treating sarcopenia and other immobilization-related muscle disorders. An important aspect of the proposed method is that it is defined as a formal algorithm that consists of two stages. Stage A aims to recover bed-ridden patients' ability to stand by applying vibration-tilt table technology. Stage B aims at rehabilitating compromised gait, using a combination of squats, lunges and single leg raises. It is anticipated that this algorithm-based approach will enhance the ability for standardization and documentation, whilst reducing resource efforts at the same time, which will be equally useful to clinical practice and to clinical research. [ABSTRACT FROM AUTHOR]