Nevin Manimala

Diabetes Obes Metab. 2023 Aug 30. doi: 10.1111/dom.15248. Online ahead of print.

ABSTRACT

BACKGROUND: Donor hyperglycaemia following brain death has been attributed to reversible insulin resistance. However, our islet and pancreas transplant data suggest that other mechanisms may be predominant. We aimed to determine the relationships between donor insulin use and markers of beta-cell death and beta-cell function in pancreas donors after brain death.

METHODS: In pancreas donors after brain death, we compared clinical and biochemical data in ‘insulin-treated’ and ‘not insulin-treated donors’ (IT vs. not-IT). We measured plasma glucose, C-peptide and levels of circulating unmethylated insulin gene promoter cell-free DNA (INS-cfDNA) and microRNA-375 (miR-375), as measures of beta-cell death. Relationships between markers of beta-cell death and islet isolation outcomes and post-transplant function were also evaluated.

RESULTS: Of 92 pancreas donors, 40 (43%) required insulin. Glycaemic control and beta-cell function were significantly poorer in IT donors versus not-IT donors [median (IQR) peak glucose: 8 (7-11) vs. 6 (6-8) mmol/L, p = .016; C-peptide: 3280 (3159-3386) vs. 3195 (2868-3386) pmol/L, p = .046]. IT donors had significantly higher levels of INS-cfDNA [35 (18-52) vs. 30 (8-51) copies/ml, p = .035] and miR-375 [1.050 (0.19-1.95) vs. 0.73 (0.32-1.10) copies/nl, p = .05]. Circulating donor miR-375 was highly predictive of recipient islet graft failure at 3 months [adjusted receiver operator curve (SE) = 0.813 (0.149)].

CONCLUSIONS: In pancreas donors, hyperglycaemia requiring IT is strongly associated with beta-cell death. This provides an explanation for the relationship of donor IT with post-transplant beta-cell dysfunction in transplant recipients.

PMID:37646197 | DOI:10.1111/dom.15248

Psychiatry Clin Neurosci. 2023 Aug 30. doi: 10.1111/pcn.13593. Online ahead of print.

ABSTRACT

AIM: The present study examined the microbiome abundance and composition of drug-naïve or drug-free patients with obsessive-compulsive disorder (OCD) compared to healthy controls. In addition, in the OCD group, the microbiome composition was compared between early-onset and late-onset OCD.

METHODS: Serum samples were collected from 89 patients with OCD and 107 age- and sex-matched healthy controls. Bacterial DNA was isolated from bacteria-derived extracellular vesicles in serum and then amplified and quantified using primers specific to the V3-V4 hypervariable region of the 16S rDNA gene. The 16S rRNA gene amplicon sequencing was performed.

RESULTS: The pooled estimate showed that alpha diversity was significantly reduced in patients with OCD compared to that in healthy controls (p_Shannon = 0.00015). In addition, a statistically significant difference was observed in beta diversity between patients with OCD and healthy controls at the order (p = 0.012), family (p = 0.003), genus (p < 0.001), and species (p = 0.005) levels. In the microbiome composition, Pseudomonas, Caulobacteraceae(f), Streptococcus, Novosphingobium, and Enhydrobacter at the genus level were significantly less prevalent in patients with OCD than in controls. In addition, among patients with OCD, the microbial composition in the early-onset versus late-onset types was significantly different with respect to the genera Corynebacterium and Pelomonas.

CONCLUSION: The present study showed an aberrant microbiome in patients with OCD, suggesting a role of the microbiota-brain interaction in the pathophysiology of OCD. Further longitudinal studies with larger sample sizes adjusting for various confounders are warranted. This article is protected by copyright. All rights reserved.

PMID:37646189 | DOI:10.1111/pcn.13593

Med Care Res Rev. 2023 Aug 30:10775587231194658. doi: 10.1177/10775587231194658. Online ahead of print.

ABSTRACT

We conducted a secondary analysis of the evaluations of 22 sites participating in four primary care redesign initiatives funded by the Centers for Medicare and Medicaid Services or the Center for Medicare and Medicaid Innovation. Our objectives were to determine the overall impact of the initiatives on Medicare expenditures and whether specific site-level program features influenced expenditure findings. Averaged over sites, the mean intervention effect was a statistically insignificant US$26 per beneficiary per year. Policy implications from meta-regression results suggest that funders should consider supporting technical assistance efforts and pay for performance incentives to increase savings. There was no evidence that paying for medical home transformation produced savings in total cost of care. We estimate that in future evaluations, data from 35 sites would be needed to detect feature effects of US$300 per beneficiary per year.

PMID:37646166 | DOI:10.1177/10775587231194658

Acta Oncol. 2023 Aug 30:1-10. doi: 10.1080/0284186X.2023.2249225. Online ahead of print.

ABSTRACT

PURPOSE: Triplet chemotherapy might be more effective than doublet chemotherapy in metastatic colorectal cancer (mCRC), but it may also be marked by increased toxicity. To investigate whether δ-tocotrienol, a vitamin E analogue, with possible neuroprotective and anti-inflammatory effects, reduces the toxicity of triplet chemotherapy, we conducted a randomized, double-blind, placebo-controlled trial in mCRC patients receiving first-line 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI).

MATERIAL AND METHODS: Seventy patients with mCRC were randomly assigned (1:1) to receive FOLFOXIRI plus either δ-tocotrienol or placebo at the Department of Oncology, Vejle Hospital, Denmark. Eligibility criteria were adenocarcinoma in the colon or rectum, age 18-75 years and ECOG performance status 0-1. FOLFOXIRI was given in eight cycles followed by four cycles of 5-fluorouracil. δ-tocotrienol 300 mg or placebo × 3 daily was added during chemotherapy and for a maximum of two years. The primary endpoint was time to hospitalization or death during treatment with chemotherapy.

RESULTS: Median time to first hospitalization or death was 3.7 months in the placebo group (95% CI 1.93-not reached (NR)), and was NR in the δ-tocotrienol group (95% CI 1.87-NR) with a hazard ratio of 0.70 (95% CI 0.36-1.36). Grade 3-4 toxicities were uncommon in both groups, except for neutropenia, which occurred in 19 patients (58%) in the placebo group and 17 patients (50%) in the δ-tocotrienol group. There were no grade 3 or 4 peripheral sensory neuropathy. In the placebo group, 24 patients (71%) had oxaliplatin dose reductions compared to 17 patients (47%) in the δ-tocotrienol group (p = 0.047).

CONCLUSION: The addition of δ-tocotrienol to FOLFOXIRI did not statistically significant prolong the time to first hospitalization or death compared to FOLFOXIRI plus placebo. Toxicity was manageable and not statistically different. There was a statistically significant difference in dose reductions of oxaliplatin pointing to a possible neuroprotective effect of δ-tocotrienol.

PMID:37646150 | DOI:10.1080/0284186X.2023.2249225

Schweiz Arch Tierheilkd. 2023 Sep;165(9):573-584. doi: 10.17236/sat00402.

ABSTRACT

This study aimed to describe equine transportation practices and transport-related behavioural and health problems in Switzerland and to identify possible associations between them. An online survey was disseminated to Swiss equine industry members and questioned respondents’ details, transport practices (before, during, and after journeys), horse transport-related behavioural (TRPBs) and health problems (TRHPs) experienced in the previous 2 years. The survey generated 441 valid responses, analysed using descriptive statistics and logistic regression models (outcomes: TRPBs, TRHPs, injuries, diarrhea). Respondents were mainly women (79,5 %), younger than 50 years (75 %), and amateurs (80 %). Most of the respondents transported one or two horses (88,7 %), for a short (< 2 hours) journey (75,5 %). Pre-transport practices were performed by 72,1 % of respondents and horses’ fitness for travel was assessed in the majority of cases (66,5 %). During the journey, horses were tethered (92,6 %) and monitored (52,7 %). The majority of respondents (74,9 %) assessed also the horses’ fitness after travel. TRPBs were reported by 13,4 % of respondents. TRPBs’ likelihood increased when the respondents were women, performed pre-transport practices and training for transport, did not assess drinking behaviour and general health before journey, and the horses experienced also TRHPs. TRHPs were reported by 34 % of the respondents and were associated with younger respondents, use of trucks, doing pre-transport practices, wearing protections, not monitoring horses during transport and preexisting TRPBs. Among TRHPs the most frequent were injuries (72,1 %) and diarrhea (41 %). The likelihood of injuries increased with younger respondents, use of trucks, wearing protections, lack of monitoring during transport and TRPBs. While younger respondents, longer journeys, wearing protections, lack of monitoring during transport, measuring rectal temperature after journeys and TRPBs increased the odds of reporting diarrhea. Even though our findings must be interpreted with caution due to survey limitations, considering that the found associations do not always mean causation, they highlight the strengths and weaknesses of transport practices in Switzerland and report evidence to implement current regulations on the protection of horse welfare during transport.

PMID:37646097 | DOI:10.17236/sat00402

Hum Reprod. 2023 Aug 29:dead173. doi: 10.1093/humrep/dead173. Online ahead of print.

ABSTRACT

STUDY QUESTION: Does assisted hatching increase the cumulative live birth rate in subfertile couples with repeated implantation failure?

SUMMARY ANSWER: This study showed no evidence of effect for assisted hatching as an add-on in subfertile couples with repeated implantation failure.

WHAT IS KNOWN ALREADY: The efficacy of assisted hatching, with regard to the live birth rate has not been convincingly demonstrated in randomized trials nor meta-analyses. It is suggested though that especially poor prognosis women, e.g. women with repeated implantation failure, might benefit most from assisted hatching.

STUDY DESIGN, SIZE, DURATION: The study was designed as a double-blinded, multicentre randomized controlled superiority trial. In order to demonstrate a statistically significant absolute increase in live birth rate of 10% after assisted hatching, 294 participants needed to be included per treatment arm, being a total of 588 subfertile couples. Participants were included and randomized from November 2012 until November 2017, 297 were allocated to the assisted hatching arm of the study and 295 to the control arm. Block randomization in blocks of 20 participants was applied and randomization was concealed from participants, treating physicians, and laboratory staff involved in the embryo transfer procedure. Ovarian hyperstimulation, oocyte retrieval, laboratory procedures, embryo selection for transfer and cryopreservation, the transfer itself, and luteal support were performed according to local protocols and were identical in both the intervention and control arm of the study with the exception of the assisted hatching procedure which was only performed in the intervention group. The laboratory staff performing the assisted hatching procedure was not involved in the embryo transfer itself.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were eligible for inclusion in the study after having had either at least two consecutive fresh IVF or ICSI embryo transfers, including the transfer of frozen and thawed embryos originating from those fresh cycles, and which did not result in a pregnancy or as having had at least one fresh IVF or ICSI transfer and at least two frozen embryo transfers with embryos originating from that fresh cycle which did not result in a pregnancy. The study was performed at the laboratory sites of three tertiary referral hospitals and two university medical centres in the Netherlands.

MAIN RESULTS AND THE ROLE OF CHANCE: The cumulative live birth rate per started cycle, including the transfer of fresh and subsequent frozen/thawed embryos if applicable, resulted in 77 live births in the assisted hatching group (n = 297, 25.9%) and 68 live births in the control group (n = 295, 23.1%). This proved to be statistically not significantly different (relative risk: 1.125, 95% CI: 0.847 to 1.494, P = 0.416).

LIMITATIONS, REASONS FOR CAUTION: There was a small cohort of subfertile couples that after not achieving an ongoing pregnancy, still had cryopreserved embryos in storage at the endpoint of the trial, i.e. 1 year after the last randomization. It cannot be excluded that the future transfer of these frozen/thawed embryos increases the cumulative live birth rate in either or both study arms. Next, at the start of this study, there was no international consensus on the definition of repeated implantation failure. Therefore, it cannot be excluded that assisted hatching might be effective in higher order repeated implantation failures.

WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated no evidence of a statistically significant effect for assisted hatching by increasing live birth rates in subfertile couples with repeated implantation failure, i.e. the couples which, based on meta-analyses, are suggested to benefit most from assisted hatching. It is therefore suggested that assisted hatching should only be offered if information on the absence of evidence of effect is provided, at no extra costs and preferably only in the setting of a clinical trial taking cost-effectiveness into account.

STUDY FUNDING/COMPETING INTEREST(S): None.

TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR 3387, NL 3235, https://www.clinicaltrialregister.nl/nl/trial/26138).

TRIAL REGISTRATION DATE: 6 April 2012.

DATE OF FIRST PATIENT’S ENROLMENT: 28 November 2012.

PMID:37646072 | DOI:10.1093/humrep/dead173

Neurol Clin Pract. 2023 Oct;13(5):e200180. doi: 10.1212/CPJ.0000000000200180. Epub 2023 Aug 28.

ABSTRACT

BACKGROUND AND OBJECTIVES: To develop a valid, disease-specific, patient-reported outcome (PRO) measure for adolescents and adults with Friedreich ataxia (FA) for use in therapeutic trials.

METHODS: We conducted semistructured qualitative interviews and a national cross-sectional study of individuals with FA to determine the most prevalent and burdensome symptoms and symptomatic themes to this population. These symptoms and symptomatic themes were included as questions in the first version of the Friedreich’s Ataxia-Health Index (FA-HI). We subsequently used factor analysis, beta interviews with 17 individuals with FA, and test-retest reliability assessments with 20 individuals with FA to evaluate, refine, and optimize the FA-HI. Finally, we determined the capability of the FA-HI to differentiate between subgroups of FA participants with varying levels of disease severity.

RESULTS: Participants with FA identified 18 symptomatic themes of importance to be included as subscales in the FA-HI. The FA-HI demonstrates high internal consistency and test-retest reliability, and it was identified by participants as highly relevant, comprehensive, and easy to complete. FA-HI total and subscale scores statistically differentiated between subgroups of participants with varying levels of disease burden.

DISCUSSION: Initial evaluation of the FA-HI supports its validity and reliability as a PRO for assessing how individuals with FA feel and function.

PMID:37646046 | PMC:PMC10462051 | DOI:10.1212/CPJ.0000000000200180

Front Immunol. 2023 Aug 14;14:1171176. doi: 10.3389/fimmu.2023.1171176. eCollection 2023.

ABSTRACT

Decades of research have probed the molecular and cellular mechanisms that control the immune response to malaria. Yet many studies offer conflicting results on the functional impact of innate immunity for controlling parasite replication early in infection. We conduct a meta-analysis to seek consensus on the effect of innate immunity on parasite replication, examining three different species of rodent malaria parasite. Screening published studies that span four decades of research we collate, curate, and statistically analyze infection dynamics in immune-deficient or -augmented mice to identify and quantify general trends and reveal sources of disagreement among studies. Additionally, we estimate whether host factors or experimental methodology shape the impact of immune perturbations on parasite burden. First, we detected meta-analytic mean effect sizes (absolute Cohen’s h) for the difference in parasite burden between treatment and control groups ranging from 0.1475 to 0.2321 across parasite species. This range is considered a small effect size and translates to a modest change in parasitaemia of roughly 7-12% on average at the peak of infection. Second, we reveal that variation across studies using P. chabaudi or P. yoelii is best explained by stochasticity (due to small sample sizes) rather than by host factors or experimental design. Third, we find that for P. berghei the impact of immune perturbation is increased when young or female mice are used and is greatest when effector molecules (as opposed to upstream signalling molecules) are disrupted (up to an 18% difference in peak parasitaemia). Finally, we find little evidence of publication bias suggesting that our results are robust. The small effect sizes we observe, across three parasite species, following experimental perturbations of the innate immune system may be explained by redundancy in a complex biological system or by incomplete (or inappropriate) data reporting for meta-analysis. Alternatively, our findings might indicate a need to re-evaluate the efficiency with which innate immunity controls parasite replication early in infection. Testing these hypotheses is necessary to translate understanding from model systems to human malaria.

PMID:37646037 | PMC:PMC10461630 | DOI:10.3389/fimmu.2023.1171176

Front Immunol. 2023 Aug 14;14:1211980. doi: 10.3389/fimmu.2023.1211980. eCollection 2023.

ABSTRACT

BACKGROUND: Clinically, some patients whose HBsAg becomes negative owing to antiviral therapy or spontaneously still show a low level of HBV DNA persistence in serum. T-lymphocyte subsets, cytokine levels and HBV S gene sequences were analyzed in this study.

METHODS: A total of 52 HBsAg-negative and HBV DNA-positive patients(HBsAg-/HBV DNA+ patients), 52 persistently HBsAg-positive patients(HBsAg+/HBV DNA+ patients) and 16 healthy people were evaluated. T-lymphocyte subsets of these patients were detected by flow cytometry, serum cytokines and chemokines were detected by the Luminex technique, and the HBV S region was evaluated by Sanger sequencing. T%, T-lymphocyte, CD8+ and CD4+T lymphocyte were lower in the HBsAg-negative group than in the HC group. Compared with the HBsAg-positive group, the HBsAg-negative group had lower levels in T lymphocyte %, CD8+T lymphocyte %, CD8+T lymphocyte and CD4/CD8. These difference were statistically significant (P<0.05). Serum IFN-γ, IFN-α and FLT-3L levels were significantly higher in the HBsAg-negative group than in the HBsAg-positive group (P<0.05). However, levels of many cytokines related to inflammation (i.e., IL-6, IL-8, IL10, IL-12, IL-17A) were lower in the HBsAg-negative group. Fifty-two HBsAg-negative samples were sequenced, revealing high-frequency amino acid substitution sites in the HBV S protein, including immune escape mutations (i.e., Y100C, S114T, C124Y, P127L, G130R, T131N, M133T, C137S, G145A) and TMD region substitutions (i.e., E2K/R/D, G7D/R, G10D, A17R, F20L/S, L21V, L22V).

CONCLUSIONS: According to the results of T-lymphocyte subsets and serum cytokines, it can be deduced that the cellular immune function of HBsAg-negative patients is superior to that of HBsAg-positive patients, with attenuation of liver inflammation. HBsAg-negative patients may show a variety of mutations and amino acid replacement sites at high frequency in the HBV S region, and these mutations may lead to undetectable HBsAg, HBsAg antigenic changes or secretion inhibition.

PMID:37646026 | PMC:PMC10461097 | DOI:10.3389/fimmu.2023.1211980

Front Immunol. 2023 Aug 14;14:1235914. doi: 10.3389/fimmu.2023.1235914. eCollection 2023.

ABSTRACT

INTRODUCTION: SARS-CoV-2 elicits a hyper-inflammatory response that contributes to increased morbidity and mortality in patients with COVID-19. In the case of HIV infection, despite effective anti-retroviral therapy, people living with HIV (PLWH) experience chronic systemic immune activation, which renders them particularly vulnerable to the life-threatening pulmonary, cardiovascular and other complications of SARS-CoV-2 co-infection. The focus of the study was a comparison of the concentrations of systemic indicators of innate immune dysfunction in SARS-CoV-2-PCR-positive patients (n=174) admitted with COVID-19, 37 of whom were co-infected with HIV.

METHODS: Participants were recruited from May 2020 to November 2021. Biomarkers included platelet-associated cytokines, chemokines, and growth factors (IL-1β, IL-6, IL-8, MIP-1α, RANTES, PDGF-BB, TGF-β1 and TNF-α) and endothelial associated markers (IL-1β, IL-1Ra, ICAM-1 and VEGF).

RESULTS: PLWH were significantly younger (p=0.002) and more likely to be female (p=0.001); median CD4+ T-cell count was 256 (IQR 115 -388) cells/μL and the median HIV viral load (VL) was 20 (IQR 20 -12,980) copies/mL. Fractional inspired oxygen (FiO2) was high in both groups, but higher in patients without HIV infection (p=0.0165), reflecting a greater need for oxygen supplementation. With the exception of PDGF-BB, the levels of all the biomarkers of innate immune activation were increased in SARS-CoV-2/HIV-co-infected and SARS-CoV-2/HIV-uninfected sub-groups relative to those of a control group of healthy participants. The magnitudes of the increases in the levels of these biomarkers were comparable between the SARS-CoV-2 -infected sub-groups, the one exception being RANTES, which was significantly higher in the sub-group without HIV. After adjusting for age, sex, and diabetes in the multivariable model, only the association between HIV status and VEGF was statistically significant (p=0.034). VEGF was significantly higher in PLWH with a CD4+ T-cell count >200 cells/μL (p=0.040) and those with a suppressed VL (p=0.0077).

DISCUSSION: These findings suggest that HIV co-infection is not associated with increased intensity of the systemic innate inflammatory response during SARS-CoV-2 co-infection, which may underpin the equivalent durations of hospital stay, outcome and mortality rates in the SARS-CoV-2/HIV-infected and -uninfected sub-groups investigated in the current study. The apparent association of increased levels of plasma VEGF with SARS-CoV-2/HIV co-infection does, however, merit further investigation.

PMID:37646024 | PMC:PMC10461055 | DOI:10.3389/fimmu.2023.1235914