Nevin Manimala

An integrated metagenomics and metabolomics approach implicates the microbiota-gut-brain axis in the pathogenesis of Huntington’s disease.

Neurobiol Dis. 2020 Nov 26;:105199

Authors: Kong G, Ellul S, Narayana VK, Kanojia K, Ha HTT, Li S, Renoir T, Cao KL, Hannan AJ

Abstract
BACKGROUND: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder with onset and severity of symptoms influenced by various environmental factors. Recent discoveries have highlighted the importance of the gastrointestinal microbiome in mediating the gut-brain-axis bidirectional communication via circulating factors. Using shotgun sequencing, we investigated the gut microbiome composition in the R6/1 transgenic mouse model of HD from 4 to 12 weeks of age (early adolescent through to adult stages). Targeted metabolomics was also performed on the blood plasma of these mice (n = 9 per group) at 12 weeks of age to investigate potential effects of gut dysbiosis on the plasma metabolome profile.
RESULTS: Modelled time profiles of each species, KEGG Orthologs and bacterial genes, revealed heightened volatility in the R6/1 mice, indicating potential early effects of HD mutation in the gut. In addition to gut dysbiosis in R6/1 mice at 12 weeks of age, gut microbiome function was perturbed. In particular, the butanoate metabolism pathway was elevated, suggesting increased production of the protective SCFA, butyrate, in the gut. No significant alterations were found in the plasma butyrate and propionate levels in the R6/1 mice at 12 weeks of age. The statistical integration of the metagenomics and metabolomics unraveled several Bacteroides species that were negatively correlated with ATP and pipecolic acid in the plasma.
CONCLUSIONS: The present study revealed the instability of the HD gut microbiome during the pre-motor symptomatic stage of the disease which may have dire consequences on the host’s health. Perturbation of the HD gut microbiome function prior to significant cognitive and motor dysfunction suggest the potential role of the gut in modulating the pathogenesis of HD, potentially via specific altered plasma metabolites which mediate gut-brain signaling.

PMID: 33249136 [PubMed – as supplied by publisher]

Randomized Trial of Scrambler Therapy for Chemotherapy-Induced Peripheral Neuropathy: Crossover Analysis.

J Pain Symptom Manage. 2020 Nov 26;:

Authors: Childs DS, Le-Rademacher JG, McMurray R, Bendel M, O’Neill C, Smith TJ, Loprinzi CL

Abstract
BACKGROUND: Preliminary trials report that Scrambler Therapy, a form of electroanalgesia, may improve discomfort from chemotherapy-induced peripheral neuropathy (CIPN). The objective of this phase II, randomized controlled trial was to evaluate the efficacy of Scrambler Therapy versus Transcutaneous Electrical Nerve Stimulation (TENS) in treating CIPN.
METHODS: Fifty patients were accrued for the first half of this two-part, crossover trial consisting of a 2-week treatment period with either Scrambler or TENS, followed by an 8-week observation period, and then crossover treatment. Twenty-two patients proceeded to the crossover phase. The primary means of assessment was patient reported outcomes, including symptom severity scales and Global Impression of Change questionnaires. Symptoms were assessed daily during the treatment period and weekly during an 8-week observation period.
RESULTS: A 50% or greater reduction in primary symptom (pain or tingling) score on the last day of treatment was achieved by 6 of 10 Scrambler-treated patients (60%) and 3 of 12 TENS-treated patients (25%) following crossover (p=0.11). By day 4 of treatment, the two arms diverged with respect to mean change in primary symptom score; this effect was largely carried through to the end of the two-week treatment period. Similarly, Scrambler Therapy appeared better than TENS when assessed by Global Impression of Change for neuropathy, pain, and overall quality of life.
CONCLUSIONS: Similar findings from the initial randomization and crossover phases of this study support further evaluation of the efficacy of Scrambler Therapy in alleviating CIPN symptoms. Evaluation in a larger, randomized controlled trial with standardized treatment is warranted.

PMID: 33249081 [PubMed – as supplied by publisher]

Predictors of treatment decisions made by adult orthodontic patients presenting with unerupted permanent teeth.

Int Orthod. 2020 Nov 25;:

Authors: Liu C, Wong L, Hameed O, Pandis N, Seehra J

Abstract
OBJECTIVE: Unerupted permanent teeth are amongst the most commonly occurring dental anomalies in adults and present unique treatment challenges. The aim of this retrospective study was to (1) identify the prevalence of adult patients with unerupted teeth attending a multidisciplinary clinic and (2) to identify predictors (age, gender, incisor and skeletal classification) which influence the patients treatment decision.
MATERIAL AND METHODS: Consecutive adult patients with unerupted permanent teeth attending the Joint Orthodontic-Restorative clinic were identified. Study variables were collected using a prespecified data collection form. Descriptive statistics were employed; Fisher’s exact test was used to detect associations between variables and treatment decision outcome. Ordinal logistic regression derived multinomial regression relative risk ratios (RRR) and 95% confidence intervals (CI) were calculated for the effect of age, gender, incisor and skeletal classification on treatment decision/outcome.
RESULTS: Sixty-six patients with impacted teeth were identified from a sample of 483. The prevalence of adults with unerupted teeth was 13.7%. The mean age was 30.7 years (SD 11.2). The majority of the sample had a Class I incisor relationship (54.6%) or Class I skeletal base relationship (54.6%), and the most common distribution of impacted teeth was a single unerupted upper right canine (34.9%). Orthodontic treatment (non-extraction or extraction basis incorporating the alignment or removal of impacted teeth) and restorative treatment only were equally favoured. Factors including age, gender, incisor and skeletal classification did not appear to influence or predict the final treatment decision.
CONCLUSIONS: In this sample, adults presenting with impacted teeth favoured certain treatment modalities: orthodontic treatment only and restorative treatment only. Factors such as age, gender, incisor and skeletal classification did not influence the outcome.

PMID: 33248909 [PubMed – as supplied by publisher]

Feasibility of a hearing screening programme using DPOAEs in 3-year-old children in South Auckland.

Int J Pediatr Otorhinolaryngol. 2020 Nov 18;:110510

Authors: Su E, Leung JH, Morton RP, Dickinson LJ, Vandal AC, Balisa NB, Purdy SC

Abstract
OBJECTIVES: In New Zealand (NZ), permanent hearing loss is associated with higher levels of socioeconomic deprivation, and is more prevalent amongst Māori and Pacific than NZ European children. Many of these hearing losses are detected through newborn hearing screening, however there is a need to screen children again later, to look for childhood hearing losses that are either late-onset, progressive, or acquired. This study evaluated the feasibility of implementing an objective screening protocol that includes otoscopy, distortion product otoacoustic emission screening (DPOAEs), and tympanometry. It also evaluated the feasibility of using Early Learning Centres (ELCs) to contact families, recruit, and test 3-year-old children from an area of high socioeconomic deprivation in Auckland, New Zealand.
METHODS: Sixty-one 3-year-old children were recruited from ELCs within the Counties Manukau District Health Board (CMDHB) region which services the geographical area of South Auckland. The first part of the screening protocol consisted of otoscopy, DPOAEs, and tympanometry. Children identified with hearing loss and/or middle ear problems were either referred directly to Otolaryngology/Audiology at the local hospital or invited back for a re-screen 4-8 weeks later. Children who were referred from the screening were followed up to track and document their subsequent clinical pathway through the public health system.
RESULTS: Mean overall time for the screening protocol was 4.1 minutes. The combination of otoscopy, DPOAEs, and tympanometry was well accepted by the 3-year-old children. DPOAE amplitude and signal-to-noise ratio results significantly differentiated between different tympanometry results, providing support for this combination of measures to accurately screen for hearing loss and/or middle ear disease. Thirty-eight of the 61 children (62%) passed the screening protocol. Of the remaining 23 children, five were referred to the hospital after not passing the screening, but following more in-depth audiological testing, were discharged with normal hearing. Six children referred to the hospital were diagnosed with varying degrees of conductive hearing loss, and two of the six received grommet insertion surgery. The remaining 12 children who were referred to the hospital were lost to follow-up, highlighting challenges for the families to successfully navigate the current public health system.
CONCLUSION: This study demonstrates that identifying hearing loss and ear disease in 3-year-old children in the pre-school setting is feasible. A number of barriers were identified in the current health system that contribute to a large proportion of children referred with suspected hearing loss and ear disease being unsuccessful in accessing Otolaryngology/Audiology clinical care through the local hospital.

PMID: 33248714 [PubMed – as supplied by publisher]

Prospectively Assigned AAST Grade versus Modified Hinchey Class and Acute Diverticulitis Outcomes.

J Surg Res. 2020 Nov 25;:

Authors: Choi J, Bessoff K, Bromley-Dulfano R, Li Z, Gupta A, Taylor K, Wadhwa H, Seltzer R, Spain DA, Knowlton LM

Abstract
BACKGROUND: The American Association for the Surgery of Trauma (AAST) recently developed a classification system to standardize outcomes analyses for several emergency general surgery conditions. To highlight this system’s full potential, we conducted a study integrating prospective AAST grade assignment within the electronic medical record.
METHODS: Our institution integrated AAST grade assignment into our clinical workflow in July 2018. Patients with acute diverticulitis were prospectively assigned AAST grades and modified Hinchey classes at the time of surgical consultation. Support vector machine-a machine learning algorithm attuned for small sample sizes-was used to compare the associations between the two classification systems and decision to operate and incidence of complications.
RESULTS: 67 patients were included (median age of 62 y, 40% male) for analysis. The decision for operative management, hospital length of stay, intensive care unit admission, and intensive care unit length of stay were associated with both increasing AAST grade and increasing modified Hinchey class (all P < 0.001). AAST grade additionally showed a correlation with complication severity (P = 0.02). Compared with modified Hinchey class, AAST grade better predicted decision to operate (88.2% versus 82.4%).
CONCLUSIONS: This study showed the feasibility of electronic medical record integration to support the full potential of AAST classification system’s utility as a clinical decision-making tool. Prospectively assigned AAST grade may be an accurate and pragmatic method to find associations with outcomes, yet validation requires further study.

PMID: 33248670 [PubMed – as supplied by publisher]

A non-invasive tool for early detection of acute leukemia in children using a paper-based optoelectronic nose based on an array of metallic nanoparticles.

Anal Chim Acta. 2021 Jan 02;1141:28-35

Authors: Bordbar MM, Barzegar H, Tashkhourian J, Bordbar M, Hemmateenejad B

Abstract
Volatile organic compounds (VOCs) in blood samples can be used as useful biomarkers to diagnose various human diseases. This study describes the potential of a paper-based sensor array for detecting leukemia using blood VOCs. Blood samples were collected from 59 new leukemia cases and 47 healthy cases as a control group. Each blood sample was divided into two parts; one for a laboratory test and the other was used in our study. Samples were mixed with heparin and then transferred to a sterile container, and a sensor was stacked on its cap. This sensor array contains 16 nanoparticles deposited on a sheet of hydrophobic paper in a 4 × 4 array format. Containers were stored in an oven at 60 °C for 4.5 h. Then, the image of sensors was recorded by a scanner and compared to the image before exposing the blood vapor. The sensor responses were subjected to different multivariate statistical methods to develop models that discriminate between control and leukemia samples. The interaction of nanoparticles with the volatile metabolome of blood caused aggregation and consequently changing in the color of nanoparticles. The color changes resulted in a specific pattern for blood samples with leukemia, which is different from those obtained from healthy specimens. The discrimination analysis was approved by pattern recognition methods such as principal component analysis with 97% accuracy. Among 59 patients, the mean age was 6.02 ± 4.55 years (range 1-16 y). The mean total response was 652.83 ± 117.02. The rock curve showed an accuracy of 96% for classifying patients from the control group. The logistic regression model showed that 93.6% of healthy and 93.2% of patients were classified correctly by using this method. These statistics agree with the classification results obtained by principal component analysis. For every 5000-unit increase in platelet count, the chance of leukemia decreased by 9%. Additionally, the chance of being categorized as a patient decreased by 10% for every 20-unit increase in total response. The electronic nose using VOC’s of blood is a non-invasive and inexpensive tool for detecting new cases of leukemia with high sensitivity and specificity. Platelet count is an essential para-clinical parameter determining the total response of the sensors. Follow up studies with a larger sample size are warranted to elucidate its clinical applicability.

PMID: 33248659 [PubMed – as supplied by publisher]

Economic Evaluations in National Cancer Institute-Sponsored Network Cancer Clinical Trials.

Value Health. 2020 Dec;23(12):1653-1661

Authors: Nghiem VT, Vaidya R, Lyman GH, Hershman DL, Ramsey SD, Unger JM

Abstract
OBJECTIVES: Amid a rapid increase in cancer care costs, we examined the extent to which economic evaluations (EEs) were conducted for new treatments evaluated in clinical trials at SWOG, a large National Cancer Institute-sponsored cancer research network.
METHODS: We investigated phase III cancer treatment clinical trials activated from 1980 onward with primary articles reporting the protocol-designated endpoints published in scientific journals by 2017. Using PubMed, Web of Science, and EconLit, we searched for EEs using trial name, cancer type, information on the comparison arms, and refined keywords for EE designs. We reported the overall proportion of trials with associated EEs and trends of this proportion over time. We synthesized and analyzed information on funding sources, health outcomes, and sources of quality-of-life and cost data from the EEs.
RESULTS: Among 182 examined trials, 15 EEs were associated with 13 (7.1%) trials. Among the EEs, almost half (7 of 15) were either unfunded or did not report funding information, whereas nearly half (7 of 15) were funded by pharmaceutical companies and 2 (2 of 15, 13.3%) were supported by federal funding. All EEs reported a healthcare payer perspective. The proportion of trials with an associated EE increased from 1980 to 1989 and 2000 to 2009, but never exceeded 11%. Sources for cost and quality-of-life data for the EEs primarily came from outside the clinical trials.
CONCLUSIONS: Few economic studies of treatments evaluated in National Cancer Institute-sponsored clinical trials have been conducted. Policymakers, payers, and patients lack economic evidence to consider newly evaluated cancer treatments, despite an urgent need to control healthcare costs.

PMID: 33248521 [PubMed – as supplied by publisher]

Comprehensive Benefit-Risk Assessment of Noninferior Treatments Using Multicriteria Decision Analysis.

Value Health. 2020 Dec;23(12):1622-1629

Authors: Sidi Y, Harel O

Abstract
OBJECTIVES: To develop a simple approach for evaluating the overall benefit-risk of a new noninferiority treatment compared with a standard of care.
METHODS: We propose using multicriteria decision analysis that accounts for uncertainty associated with both clinical outcomes and patient preference data. Because patients’ preferences are likely to be influenced by their baseline characteristics, we suggest carrying out a preference study at the beginning of a trial. To reduce the burden of an additional study questionnaire, preference elicitation could be done on a small sample of trial participants. To restore preferences for all trial participants, we propose using multiple imputation (MI). Using simulations, we examine whether 3 different MI procedures lead to the same benefit-risk assessment conclusion, as if all trial participant preferences were obtained. We also compare MI results to complete case analysis, where only preferences of the small sample of trial participants are considered.
RESULTS: We show that the MI procedure successfully restores patients’ preferences for the trial participants using different outcome criteria and preferences. For example, using 3 outcome criteria with only 10% of the trial participants providing their preferences, complete case analysis demonstrated a new noninferior treatment as favorable only 5.1% of the time, whereas MI procedures did so between 16.2% and 17.9% of the time. Given that 17.6% correspond to the fully observed weights, the MI methods demonstrate favorable results.
CONCLUSIONS: The MI procedure can help facilitate a simple comprehensive benefit-risk assessment for new noninferior treatments.

PMID: 33248518 [PubMed – as supplied by publisher]

Maternal and fetal outcomes in phaeochromocytoma and pregnancy: a multicentre retrospective cohort study and systematic review of literature.

Lancet Diabetes Endocrinol. 2020 Nov 26;:

Authors: Bancos I, Atkinson E, Eng C, Young WF, Neumann HPH, International Pheochromocytoma and Pregnancy Study Group

Abstract
BACKGROUND: Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy.
METHODS: We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases. The inclusion criteria were pregnancy after 1980 and PPGL before or during pregnancy or within 12 months post partum. Eligible patients from the retrospective study and systematic review were included in the analysis. Outcomes of interest were maternal or fetal death and maternal severe cardiovascular complications of catecholamine excess. Potential variables associated with these outcomes were evaluated by logistic regression.
FINDINGS: The systematic review identified seven studies (reporting on 63 pregnancies in 55 patients) that met the eligibility criteria and were of adequate quality. A further 197 pregnancies in 186 patients were identified in the International Pheochromocytoma and Pregnancy Registry. After excluding 11 pregnancies due to potential overlap, the final cohort included 249 pregnancies in 232 patients with PPGL. The diagnosis of PPGL was made before pregnancy in 37 (15%) pregnancies, during pregnancy in 134 (54%), and after delivery in 78 (31%). Of 144 patients evaluated for genetic predisposition for phaeochromocytoma, 95 (66%) were positive. Unrecognised PPGL during pregnancy (odds ratio 27·0; 95% CI 3·5-3473·1), abdominal or pelvic tumour location (11·3; 1·5-1440·5), and catecholamine excess at least ten-times the upper limit of the normal range (4·7; 1·8-13·8) were associated with adverse outcomes. For patients diagnosed during pregnancy, α-adrenergic blockade therapy was associated with fewer adverse outcomes (3·6; 1·1-13·2 for no α-adrenergic blockade vs α-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0·9; 0·3-3·9 for no surgery vs surgery).
INTERPRETATION: Unrecognised and untreated PPGL was associated with a substantially higher risk of either maternal or fetal complications. Appropriate case detection and counselling for premenopausal women at risk for PPGL could prevent adverse pregnancy-related outcomes.
FUNDING: US National Institutes of Health.

PMID: 33248478 [PubMed – as supplied by publisher]

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