Nevin Manimala

Pharm Stat. 2021 Mar 24. doi: 10.1002/pst.2119. Online ahead of print.

ABSTRACT

Umbrella trials are an innovative trial design where different treatments are matched with subtypes of a disease, with the matching typically based on a set of biomarkers. Consequently, when patients can be positive for more than one biomarker, they may be eligible for multiple treatment arms. In practice, different approaches could be applied to allocate patients who are positive for multiple biomarkers to treatments. However, to date there has been little exploration of how these approaches compare statistically. We conduct a simulation study to compare five approaches to handling treatment allocation in the presence of multiple biomarkers – equal randomisation; randomisation with fixed probability of allocation to control; Bayesian adaptive randomisation (BAR); constrained randomisation; and hierarchy of biomarkers. We evaluate these approaches under different scenarios in the context of a hypothetical phase II biomarker-guided umbrella trial. We define the pairings representing the pre-trial expectations on efficacy as linked pairs, and the other biomarker-treatment pairings as unlinked. The hierarchy and BAR approaches have the highest power to detect a treatment-biomarker linked interaction. However, the hierarchy procedure performs poorly if the pre-specified treatment-biomarker pairings are incorrect. The BAR method allocates a higher proportion of patients who are positive for multiple biomarkers to promising treatments when an unlinked interaction is present. In most scenarios, the constrained randomisation approach best balances allocation to all treatment arms. Pre-specification of an approach to deal with treatment allocation in the presence of multiple biomarkers is important, especially when overlapping subgroups are likely.

PMID:33759353 | DOI:10.1002/pst.2119

Int J Clin Pract. 2021 Mar 24:e14161. doi: 10.1111/ijcp.14161. Online ahead of print.

ABSTRACT

OBJECTIVE: Our study was carried out on patients admitted to the emergency ward with acute stroke symptoms that were subsequently diagnosed with cerebrovascular disease. We aimed to examine the relationship between these patients’ admission lactate levels and their 1, 3, and 12-month mortality rates in order to evaluate the prognostic value of lactate levels.

METHODS: Our data was obtained retrospectively from 568 patients diagnosed with acute ischemic stroke at our emergency department between 01/01/2017 and 01/01/2018. Patient data was accessed via the hospital patient database. Included patients’ files were assessed for examination and history taken at admission, comorbid diseases, demographic characteristics, treatments utilized, and laboratory results. Hyperlactatemia was defined as a lactate level of over 2mmol/L. The relationship between lactate levels and survival was investigated. Patients’ complication rates after discharge were assessed alongside their 1, 3, and 12-month mortality.

RESULTS: Our study assessed 568 patients. Out of these patients, 400 patients met our inclusion criteria and constituted the study population. These patients were separated into two groups according to their lactate levels. The hyperlactatemic group had a statistically significant increase in 1, 3, and 12-month mortality rates in comparison to the other group.

CONCLUSIONS: Our study found that hyperlactatemia was associated with a higher risk of 1, 3, and 12 month mortality, suggesting that it has predictive prognostic value. In the future, we believe that prospective observational studies and/or large-scale retrospective studies will be of great value in providing more insight into this topic.

PMID:33759312 | DOI:10.1111/ijcp.14161

Int J Clin Pract. 2021 Mar 23:e14170. doi: 10.1111/ijcp.14170. Online ahead of print.

ABSTRACT

AIMS: The aim of the study was to evaluate the possible changes in sleep behavior and nutrition in children during the pandemic period.

METHODS: 114 parents who accepted to participate in the study aged 18 and over and who had children between the ages of 6 and 16 were included in the study. A questionnaire was carried out after written consents were obtained. In the first part of the questionnaire, there were a total of 9 questions including socio-demographic information and nutritional characteristics, and the second part included the “Sleep Disturbance Scale for Children” (SDSC). The data were analyzed with the SPSS 20 statistical program.

RESULTS: The total number of participants was 114 parents; 64 (56%) of the children were girls and 50 (43.9%) were boys. Among the participants, the number of children who had COVID-19 was 38 (33.3%). There was no statistically significant relationship between going through COVID-19 status and the variables examined in general. The proportion of participants who stated that if the pandemic period was prolonged, COVID-19 would not change their diet was found to be statistically significant (p=0.038). The SDSC score was found to be significantly high in girls (p<0.05).

CONCLUSION: Sleep and nutritional disorders affect the quality of life for all ages for both genders, and their importance increases even more in extraordinary periods such as pandemic. Sleep problems increasing especially with an accompanying anxiety state may lead to developmental problems as well as deepening psychological disorders.

PMID:33759311 | DOI:10.1111/ijcp.14170

J Appl Res Intellect Disabil. 2021 Mar 23. doi: 10.1111/jar.12866. Online ahead of print.

ABSTRACT

PURPOSE: People with Down syndrome (DS) have a unique medical profile which may impact views of health. We aimed to explore the use of global health measures in DS.

METHODS: Prospective survey in the Mass General Hospital Down Syndrome Program (MGH DSP) from December 2018 to July 2019 with Patient Reported Outcomes Measurement Information System (PROMIS)® instruments of global health. Analyses included use of scoring manuals, descriptive statistics and dependent samples t test.

RESULTS: Seventeen adolescents, 48 adults with DS and 88 caregivers returned surveys; 137 were complete. Incomplete responses and notes showed limitations of the instruments in this population. Global health T-scores did not differ from the available comparative standardized scores to these measures from PROMIS® reference population (p > 0.05).

CONCLUSIONS: In the MGH DSP, pilot global health instruments were completed by some adults with DS and caregivers, with some limitations and scores similar to the PROMIS® reference population.

PMID:33759305 | DOI:10.1111/jar.12866

Eur J Neurol. 2021 Mar 23. doi: 10.1111/ene.14834. Online ahead of print.

ABSTRACT

BACKGROUND: Alzheimer’s disease (AD) is considered a clinical and biological continuum identified via cerebrospinal fluid (CSF) or imaging biomarkers. Chronic hypoperfusion is held as one of the main features of Alzheimer’s disease, as part of the processes causing neuronal degeneration. The mechanism responsible for such condition is still debated, though recently a direct connection with amyloid peptides has been shown. Here we aimed at investigating whether measures of hypoperfusion change along the AD continuum.

METHODS: 70 patients with mild AD were recruited and stratified according to their CSF biomarkers profile – as indicated by the NIA-AA research framework – into patients with either isolated amyloid pathology (A+T-) or full-blown AD (A+T+), and further layered according to ApoE genotype. After evaluation of vascular risk factors, we performed a Trans Cranial Doppler (TCD) on each patient, to evaluate mean flow velocity and pulsatility index in the middle cerebral artery, and to calculate the breath holding index (BHI). Patients were compared to a cohort of 17 healthy controls.

RESULTS: The BHI was reduced in the AD continuum and resulted inversely correlated to CSF Aβ42 levels. Such correlation was stronger in the A+T+ than in A+T- group, and unexpectedly reached statistical significance only in the E3 and not in the E4 genotype carriers.

CONCLUSIONS: These results suggest a tight and effective relationship between Aβ42, vascular hypoperfusion, cerebrovascular reactivity and epsilon genotype.

PMID:33759296 | DOI:10.1111/ene.14834

J Viral Hepat. 2021 Mar 24. doi: 10.1111/jvh.13508. Online ahead of print.

ABSTRACT

Antiviral therapy improves survival in patients with hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC). However, the effect of antiviral therapy in patients with low-level viremia HBV-HCC receiving non-curative therapy remains unclear. We aimed to evaluate the role of antiviral therapy in patients with low-level viremia and treated with transarterial chemoembolization (TACE). This retrospective study evaluated 206 patients with HBV-HCC who underwent TACE as an initial treatment. Of those, 135 patients received antiviral therapy (antiviral group), and 71 did not (non-antiviral group). The definition of low-level viremia was an HBV DNA level <2,000 IU/mL. Kaplan-Meier curves, log-rank tests, and Cox regression analysis were used for statistical analyses. The median follow-up duration was 39 months (1-174 months). Overall survival (OS) did not differ between groups (P = 0.227). Barcelona Clinic Liver Cancer stage (BCLC), Child-Pugh (CP) class, and α-fetoprotein level were independent prognostic factors for OS. Antiviral therapy (hazard ratio [HR], 0.503, P = 0.022) was a prognostic factor for 2-year survival. On subgroup analysis, antiviral therapy improved short-term survival in patients with BCLC stage 0 and A (P = 0.037) and CP class A (P = 0.04). In patients with low-level viremia, antiviral therapy yielded short-term survival benefits, particularly in patients with early-stage HCC.

PMID:33759295 | DOI:10.1111/jvh.13508

Eur J Neurosci. 2021 Mar 23. doi: 10.1111/ejn.15199. Online ahead of print.

ABSTRACT

Emotion regulation is related to recovery after mild traumatic brain injury (mTBI). This longitudinal tractography study examined white matter tracts subserving emotion regulation across the spectrum of mTBI, with a focus on persistent symptoms. Four groups were examined: (1) symptomatic (n=33) and (2) asymptomatic (n=20) patients with uncomplicated mTBI (i.e., no lesions on computed tomography (CT)), (3) patients with CT-lesions in the frontal areas (n=14), and (4) healthy controls (n=20). Diffusion and conventional MRI were performed approximately one and three months post-injury. Whole brain deterministic tractography followed by region of interest analyses were used to identify forceps minor, uncinate fasciculus, and cingulum bundle as tracts of interest. An adjusted version of the ExploreDTI Atlas Based Tractography method was used to obtain reliable tracts for every subject. Mean fractional anisotropy (FA), radial and axial diffusivity (MD, RD, AD), and number of streamlines were studied per tract. Linear mixed models showed lower FA, and higher MD, and RD of the right uncinate fasciculus in asymptomatic patients with uncomplicated mTBI relative to symptomatic patients and healthy controls. Diffusion alterations were most pronounced in the group with frontal lesions on CT, particularly in the forceps minor and uncinate fasciculus; these effects increased over time. Within the group of patients with uncomplicated mTBI, there were no associations of diffusion measures with number of symptoms nor with lesions on conventional MRI. In conclusion, mTBI can cause microstructural changes in emotion regulation tracts, however, no explanation was found for the presence of symptoms.

PMID:33759227 | DOI:10.1111/ejn.15199

Muscle Nerve. 2021 Mar 23. doi: 10.1002/mus.27241. Online ahead of print.

ABSTRACT

Pain as a significant symptom in patients with Periodic Paralysis- A cross-sectional survey INTRODUCTION/AIMS: Periodic paralysis (PP) is thought to be limited to episodes of muscle weakness, however, there are reports of fibromyalgia-like pain in PP. We aimed to evaluate pain and comorbid sleep, fatigue, and mood disorders in PP patients.

METHODS: We administered a cross-sectional survey to PP patients at the 2019 Periodic Paralysis Conference. The survey consisted of the Brief Pain Inventory (BPI), Widespread pain index (WPI), Pittsburgh Sleep Quality Index (PSQI), Modified Fatigue Impact Scale (MFIS) and ten question Center for Epidemiologic Studies Depression Scale (CESD-10). Descriptive statistics for PP patients were calculated and compared to prior studies.

RESULTS: 44 persons with PP took the survey. 52.3% reported a moderate to severe interference of pain on their lives. 45.5% of patients met the study criteria for fibromyalgia. Patients with SCN4A mutations had higher rates of fibromyalgia than the next most prevalent gene mutation, CACNA1S. In patients with pain, there were increased rates of comorbid fatigue, depression, and poor sleep quality.

DISCUSSION: Pain, akin to fibromyalgia, is a significant symptom of PP and can affect quality of life. Pain in PP was more prevalent than in the general population, at a rate comparable to other chronic neuromuscular disease groups. PP patients could benefit from a multidisciplinary approach to assess their pain, sleep, fatigue and mood.

PMID:33759219 | DOI:10.1002/mus.27241

J Anim Ecol. 2021 Mar 23. doi: 10.1111/1365-2656.13486. Online ahead of print.

ABSTRACT

Theoretical and empirical research has shown that increased variability in demographic rates often results in a decline in the population growth rate. In order to reduce the adverse effects of increased variability, life-history theory predicts that demographic rates that contribute disproportionately to population growth should be buffered against environmental variation. To date, evidence of demographic buffering is still equivocal and limited to analyses on a reduced number of age-classes (e.g. juveniles and adults), and on single sex models. Here we used Bayesian inference models for age-specific survival and fecundity on a long-term dataset of wild mountain gorillas. We used these estimates to parameterize two-sex, age-specific stochastic population projection models that accounted for the yearly covariation between demographic rates. We estimated the sensitivity of the long-run stochastic population growth rate to reductions in survival and fecundity on ages belonging to nine sex-age-classes for survival and three age-classes for female fecundity. We found a statistically significant negative linear relationship between the sensitivities and variances of demographic rates, with strong demographic buffering on young adult female survival and low buffering on older female and silverback survival and female fecundity. We found moderate buffering on all immature stages and on prime-age females. Previous research on long-lived slow species has found high buffering of prime-age female survival and low buffering on immature survival and fecundity. Our results suggest that the moderate buffering of the immature stages can be partially due to the mountain gorilla social system and the relative stability of their environment. Our results provide clear support for the demographic buffering hypothesis and its predicted effects on species at the slow end of the slow-fast life history continuum, but with the surprising outcome of moderate social buffering on the survival of immature stages. We also demonstrate how increasing the number of sex-age-classes can greatly improve the detection of demographic buffering in wild populations.

PMID:33759185 | DOI:10.1111/1365-2656.13486

Turk Neurosurg. 2021 Mar 8. doi: 10.5137/1019-5149.JTN.33332-20.3. Online ahead of print.

ABSTRACT

AIM: An increasing number of biomarkers of primary glioblastoma (GBM) have recently been described. We aimed to investigate the biological and clinical factors that affect survival in Turkish patients with primary GBM.

MATERIAL AND METHODS: The clinical and demographic data of all patients with primary GBM diagnosed between 2007 and 2016 were evaluated. In all the patients’ pathological specimens, O6 methylguanine-DNA methyltransferase (MGMT) methylation and isocitrate dehydrogenase (IDH) 1 mutation were detected retrospectively by immunohistochemistry. Kaplan-Meier survival analysis, log-rank test, and multivariate analyses of the Cox hazard proportional model for all the variables were performed using the SPSS statistical package. The treatment details and other patient-related factors were identified, and their correlations were analyzed.

RESULTS: We enrolled 137 primary GBM patients to the study. Median progression free survival (PFS) was 8.57 months (95% CI: 6.8-9.5) and median overall survival (OS) was 12 months (95 % CI: 10.8-13.3). IDH-1 mutations were detected in 21 primary GBMs (15.3%). PFS was 15.43 ± 1.95 months. Survival rates were higher, but no statistically significant difference (p: 0.074). MGMT methylation was detected in 40 primary GBMs (29.2%). OS and PFS of MGMT (+) cases were higher than MGMT(-)cases (p: 0.001; p: 0.001 respectively). Ki67 (%) measurement (10%-90%) average is 32.64 ± 16.56.No statistically significant between higher and lower ki67 levels (p : 0.510, p: 0.505 respectively). KPS(%) more than 70 at the time of diagnosis statistically significant longer median OS and PFS (p: 0.001) .PFS and OS were higher in all treatment modalities.

CONCLUSION: The most important factors that affected survival were performance score, MGMT methylation status, systemic oncologic therapy, and IDH mutation in the Turkish population with primary GBM. We demonstrated that MGMT methylation and higher KPS levels were associated with significiantly longer OS and PFS.

PMID:33759174 | DOI:10.5137/1019-5149.JTN.33332-20.3