Nevin Manimala

Cost Eff Resour Alloc. 2023 Jan 26;21(1):10. doi: 10.1186/s12962-023-00420-4.

ABSTRACT

OBJECTIVE: Renal cell carcinoma (RCC) is the most common type of kidney cancer. VEGF inhibitors and mTORs are the most common therapeutic options among the different classes of available treatments. In this study, the effectiveness of Everolimus was compared to Temsirolimus, and Everolimus plusLenvatinib in renal cell carcinoma patients by review of the international clinical evidence.

MATERIALS AND METHODS: A systematic review was conducted and all relevant published clinical studies on the efficacy and cost-effectiveness of Everolimus, Temsirolimus, and Lenvatinib plus Everolimus were searched comprehensively in electronic databases including Pubmed, Scopus, Medline, Cochrane Library, and ISI web of science. The Q score and I2 test checked the Heterogeneity and publication bias test, respectively. Egger’s test and Begg’s test were used to checking publication bias. The hazard ratio (HR) of included studies and subclass analysis were estimated by fixed and random effect models.

RESULTS: Out of 1816 found studies, ultimately, were included considering inclusion and exclusion criteria. None of these studies evaluated all three treatment strategies together and each study was about one strategy. Only one study was found for Everolimus plus Lenvatinib, so it was excluded from meta-analysis. Overall, data from 526 patients on Temsirolimus and 648 patients on Everolimus were included in Meta-Analysis. Accordingly, the efficacy of Everolimus and Temsirolimus was not statistically significant in assessed outcomes (PFS, TTSF, and death). However, Everlimus is superior to Temsirolimus in OS (Q = 3.61, p-value: 0.462, I2 = 0%). No heterogeneity or bias was detected.

CONCLUSION: According to the results of this study, Everolimus could be related to an increase of OS versus Temsirolimus as a second line treatment of ORCC patients.

PMID:36703202 | DOI:10.1186/s12962-023-00420-4

Fluids Barriers CNS. 2023 Jan 26;20(1):7. doi: 10.1186/s12987-023-00407-6.

ABSTRACT

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a progressive and partially reversible form of dementia, characterized by impaired interactions between multiple brain regions. Because of the presence of comorbidities and a lack of accurate diagnostic and prognostic biomarkers, only a minority of patients receives disease-specific treatment. Recently, resting-state functional-magnetic resonance imaging (rs-fMRI) has demonstrated functional connectivity alterations in inter-hemispheric, frontal, occipital, default-mode (DMN) and motor network (MN) circuits. Herein, we report our experience in a cohort of iNPH patients that underwent cerebrospinal fluid (CSF) dynamics evaluation and rs-fMRI. The study aimed to identify functional circuits related to iNPH and explore the relationship between DMN and MN recordings and clinical modifications before and after infusion and tap test, trying to understand iNPH pathophysiology and to predict the best responders to ventriculoperitoneal shunt (VPS) implant.

METHODS: We prospectively collected data regarding clinical assessment, neuroradiological findings, lumbar infusion and tap test of thirty-two iNPH patients who underwent VPS implant. Rs-fMRI was performed using MELODIC-ICA both before and after the tap test. Rs-fMRI data of thirty healthy subjects were also recorded.

RESULTS: At the baseline, reduced z-DMN and z-MN scores were recorded in the iNPH cohort compared with controls. Higher z-scores were recorded in more impaired patients. Both z-scores significantly improved after the tap test except in subjects with a low resistance to outflow value and without a significant clinical improvement after the test. A statistically significant difference in mean MN connectivity scores for tap test responders and non-responders was demonstrated both before (p = 0.0236) and after the test (p = 0.00137). A statistically significant main effect of the tap test on DMN connectivity after CSF subtraction was recorded (p = 0.038).

CONCLUSIONS: Our results suggest the presence of a partially reversible plasticity functional mechanism in DMN and MN. Low values compensate for the initial stages of the disease, while higher values of z-DMN were recorded in older patients with a longer duration of symptoms, suggesting an exhausted plasticity compensation. The standardization of this technique could play a role as a non-invasive biomarker in iNPH disease, suggesting the right time for surgery. Trial Registration Prot. IRB 090/2021.

PMID:36703181 | DOI:10.1186/s12987-023-00407-6

J Foot Ankle Res. 2023 Jan 26;16(1):2. doi: 10.1186/s13047-023-00601-7.

ABSTRACT

AIM: This study aims to explore the feasibility of using serial MRI without contrast in the monitoring of Charcot neuroarthropathy to reduce duration of immobilisation of the foot, in order to decide whether a large-scale trial is warranted.

METHODS: A multicentre, randomised, prospective, two arm, open, feasibility study (CADOM) of people with diabetes with a suspected or confirmed diagnosis of Charcot neuroarthropathy. Participants were randomised (1:1) to ‘standard care plus’, including repeated foot temperature measurements and X-rays, or the intervention arm, with additional three-monthly MRI, until remission of Charcot neuroarthropathy or a maximum 12 months (active phase). Participants were then followed-up for a further 6 months, post remission to monitor for relapse of the Charcot neuroarthropathy (follow-up phase). Feasibility outcomes were recruitment, retention, data completeness, adherence to study procedures and safety of the intervention MRI. We also collected clinical efficacy outcomes, this included time in cast/off-loading device which will be the primary outcome of a future definitive trial. Finally, we collected patient reported outcomes, and data on health and social care usage.

RESULTS: One-hundred and five people were assessed for eligibility at five sites. 64/105 potential participants meet the eligibility criteria to participate in the study. Forty-three participants were randomised: 20 to standard care plus and 23 to MRI intervention. The main reason for ineligibility was a previous episode of Charcot neuroarthropathy. Thirteen participants were withdrawn post-randomisation due to an alternative diagnosis being made. Of the remaining 30 participants, 19 achieved remission, 6 had not gone into remission at the end of the 12 month active phase so exited the study. Five participants were lost to follow-up. Of the MRIs that were not disrupted by COVID-19 pandemic 26/31 (84%) were completed. For the visits that were conducted face-to-face, completion rates of patient-reported outcome measures were between 71 and 100%. There were no safety incidents associated with the intervention MRI. As this was a feasibility study it was not designed to test the effectiveness of serial MRI in diagnosing remission. The time in cast/off-loading device was 235 (±108.3) days for the standard care plus arm compared to 292 (±177.4) days for the intervention arm. There was no statistical difference in the time in cast/off-loading device between the two arms of the study: Hazard Ratio (HR) 0.405 (95% CI 0.140-1.172), p = 0.096.

DISCUSSION: The findings support a definitive randomised controlled trial to evaluate the effectiveness of MRI in diagnosing remission in Charcot neuroarthropathy. The rates of recruitment, retention, data, and MRI completeness show that a definitive study is feasible.

STUDY REGISTRATION: ISRCTN, 74101606 . Registered on 6 November 2017.

PMID:36703174 | DOI:10.1186/s13047-023-00601-7

Reprod Biol Endocrinol. 2023 Jan 26;21(1):8. doi: 10.1186/s12958-023-01065-x.

ABSTRACT

STUDY QUESTION: To construct prediction models based on the Bayesian network (BN) learning method for the probability of fertilization failure (including low fertilization rate [LRF] and total fertilization failure [TFF]) in assisted reproductive technology (ART) treatment. A BN model was developed to predict TFF/LFR. The model showed relatively high calibration in external validation, which could facilitate the identification of risk factors for fertilization disorders and improve the efficiency of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment.

WHAT IS KNOWN ALREADY: The prediction of TFF/LFR is very complex. Although some studies attempted to construct prediction models for TFF/LRF, most of the reported models were based on limited variables and traditional regression-based models, which are unsuitable for analyzing real-world clinical data. Therefore, none of the reported models have been widely used in routine clinical practice. To date, BN modeling analysis is a prominent and increasingly popular machine learning method that is powerful in dealing with dynamic and complex real-world data.

STUDY DESIGN, SIZE, DURATION: A retrospective study was performed with 106,640 fresh embryo IVF/ICSI cycles from 2009 to 2019 in one of China’s largest reproductive health centers.

PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 106, 640 cycles were included in this study, including 97,102 controls, 4,339 LFR cases, and 5,199 TFF cases. Twenty-four predictors were initially included, including 13 female-related variables, five male-related variables, and six variables related to IVF/ICSI treatment. BN modeling analysis with tenfold cross-validation was performed to construct the predictive model for TFF/LFR. The receiver operating characteristic (ROC) curves and the corresponding area under the curves (AUCs) were used to evaluate the performance of the BN model.

MAIN RESULTS AND THE ROLE OF CHANCE: All twenty-four predictors were first organized into seven hierarchical layers in a theoretical BN model, according to prior knowledge from previous literature and clinical practice. A machine-learning BN model was generated based on real-world clinical data, containing a total of eighteen predictors, of which the infertility type, ART method, and number of retrieved oocytes directly influence the probabilities of LFR/TFF. The prediction accuracy of the BN model was 91.7%. The AUC of the TFF versus control groups was 0.779 (95% CI: 0.766-0.791), with a sensitivity of 71.2% and specificity of 70.1%; the AUC of of TFF versus LFR groups was 0.807 (95% CI: 0.790-0.824), with a sensitivity of 49.0% and specificity of 99.0%.

LIMITATIONS, REASON FOR CAUTION: First, our study was based on clinical data from a single center, and the results of this study should be further verified by external data. In addition, some critical data (e.g., the detailed IVF laboratory parameters of the sperm and oocytes used for insemination) were not available in this study, which should be given full consideration when further improving the performance of the BN model.

WIDER IMPLICATIONS OF THE FINDINGS: Based on extensive clinical real-world data, we developed a BN model to predict the probabilities of fertilization failures in ART, which provides new clues for clinical decision-making support for clinicians in formulating personalized treatment plans and further improving ART treatment outcomes.

STUDY FUNDING/COMPETING INTEREST(S): Dr. Y. Wang was supported by grants from the Beijing Municipal Science & Technology Commission (Z191100006619086). We declare that there are no conflicts of interest.

TRIAL REGISTRATION NUMBER: N/A.

PMID:36703171 | DOI:10.1186/s12958-023-01065-x

BMC Public Health. 2023 Jan 26;23(1):177. doi: 10.1186/s12889-022-14909-9.

ABSTRACT

BACKGROUND: Given the nature of the spread of SARS-CoV-2, strong regional patterns in the fatal consequences of the COVID-19 pandemic related to local characteristics such as population and health care infrastructures were to be expected. In this paper we conduct a detailed examination of the spatial correlation of deaths in the first year of the pandemic in two neighbouring countries – Germany and Poland, which, among high income countries, seem particularly different in terms of the death toll associated with the COVID-19 pandemic. The analysis aims to yield evidence that spatial patterns of mortality can provide important clues as to the reasons behind significant differences in the consequences of the COVID-19 pandemic in these two countries.

METHODS: Based on official health and population statistics on the level of counties, we explore the spatial nature of mortality in 2020 in the two countries – which, as we show, reflects important contextual differences. We investigate three different measures of deaths: the officially recorded COVID-19 deaths, the total values of excessive deaths and the difference between the two. We link them to important pre-pandemic regional characteristics such as population, health care and economic conditions in multivariate spatial autoregressive models. From the point of view of pandemic related fatalities we stress the distinction between direct and indirect consequences of COVID-19, separating the latter further into two types, the spatial nature of which is likely to differ.

RESULTS: The COVID-19 pandemic led to much more excess deaths in Poland than in Germany. Detailed spatial analysis of deaths at the regional level shows a consistent pattern of deaths officially registered as related to COVID-19. For excess deaths, however, we find strong spatial correlation in Germany but little such evidence in Poland.

CONCLUSIONS: In contrast to Germany, for Poland we do not observe the expected spatial pattern of total excess deaths and the excess deaths over and above the official COVID-19 deaths. This difference cannot be explained by pre-pandemic regional factors such as economic and population structures or by healthcare infrastructure. The findings point to the need for alternative explanations related to the Polish policy reaction to the pandemic and failures in the areas of healthcare and public health, which resulted in a massive loss of life.

PMID:36703167 | DOI:10.1186/s12889-022-14909-9

Genome Med. 2023 Jan 26;15(1):7. doi: 10.1186/s13073-022-01152-5.

ABSTRACT

BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.

METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.

RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10^-6) and AC058822.1 (P = 1.47 × 10^-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.

CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10^-5), demonstrating the importance of diversifying study cohorts.

PMID:36703164 | DOI:10.1186/s13073-022-01152-5

BMC Med Educ. 2023 Jan 26;23(1):65. doi: 10.1186/s12909-023-04027-4.

ABSTRACT

BACKGROUND: The Recorded Consultation Assessment (RCA) was developed rapidly during the COVID-19 pandemic to replace the Clinical Skills Assessment (CSA) for UK general practice licensing. Our aim was to evaluate examiner perceptions of the RCA.

METHODS: We employed a cross-sectional design using a questionnaire survey of RCA examiners with attitudinal (relating to examiners thoughts and perceptions of the RCA) and free text response options. We conducted statistical descriptive and factor analysis of quantitative data with qualitative thematic analysis of free text responses.

RESULTS: Overall, 182 of 260 (70%) examiners completed the questionnaire. Responders felt that consultations submitted were representative of the work of a typical GP during the pandemic and provided a good sample across the curriculum. They were also generally positive about the logistic, advisory and other support provided as well as the digital platform. Despite responders generally agreeing there was sufficient information available in video or audio consultations to judge candidates’ data gathering, clinical management, and interpersonal skills, they were less confident about their ability to make judgments of candidates’ performance compared with the CSA. The qualitative analysis of free text responses detailed the problems of case selection and content, explained examiners’ difficulties when making judgments, and detailed the generally positive views about support, training and information technology. Responders also provided helpful recommendations for improving the assessment.

CONCLUSION: The RCA was considered by examiners to be feasible and broadly acceptable, although they experienced challenges from candidate case selection, case content and judgments leading to suggested areas for improvement.

PMID:36703159 | DOI:10.1186/s12909-023-04027-4

Parasit Vectors. 2023 Jan 26;16(1):36. doi: 10.1186/s13071-023-05658-8.

ABSTRACT

BACKGROUND: The invasive tick species, Haemaphysalis longicornis, is becoming established in the USA, presenting a growing threat to dogs and cats. Two 90-day studies were initiated, the same protocol in each, to confirm the efficacy of a single application of two fluralaner formulations against H. longicornis infestations of cats.

METHODS: Cats were randomized among three groups in a 1:1:1 ratio (10 cats/group). Group 1 cats were untreated controls; Group 2 cats were treated with a topical fluralaner formulation (Bravecto®); Group 3 cats received a topical formulation containing fluralaner and moxidectin (Bravecto® Plus). Treatments were administered once (Day 0) at the label dose rates. Each cat was infested with 50 H. longicornis ticks on Day 7 for study qualification and also infested with 50 ticks on Days 2, 28, 58 and 88. Tick counts were completed on Days 5, 2, 30, 60 and 90. The primary objective was based on percentage reductions in arithmetic mean tick counts.

RESULTS: Pre-study infestations showed all study cats were susceptible to tick challenge. Except for Day 2 in one study, at least six control cats retained ≥ 25% of each challenge, demonstrating an adequate infestation for efficacy assessments. Across studies on Days 2, 30, 60 and 90, the mean live tick infestation rate (number of ticks recovered from each cat/infesting challenge to each cat) of Group 1 cats ranged from 25.0 to 69.6%. Efficacy of each formulation, based on live tick counts, was 100% on Day 2 and > 95 to 100% at each subsequent assessment. Between-group differences were statistically significant (P < 0.0001) for each treatment versus control comparison.

CONCLUSION: At the label dose rate, both topical fluralaner formulations were 100% effective in eliminating H. longicornis ticks from cats infested at the time of treatment. Efficacy of > 95 to 100% was then maintained through 90 days following a single application. Fluralaner is therefore a treatment of choice for protecting cats against this invasive tick species.

PMID:36703156 | DOI:10.1186/s13071-023-05658-8

BMC Surg. 2023 Jan 27;23(1):21. doi: 10.1186/s12893-022-01897-1.

ABSTRACT

BACKGROUND: The number of older patients with multiple comorbidities in the emergency service is increasingly frequent, which implies the risk of incurring in futile surgical interventions. Some interventions generate false expectations of survival or quality of life in patients and families and represent a negligible therapeutic benefit in patients whose chances of survival are minimal. In order to address this dilemma, we describe mortality in a cohort of patients undergoing emergency laparotomy with a risk ≥ 75% per the ACS NSQIP Surgical Risk Calculator.

METHODS: A retrospective observational study was designed to analyze postoperative mortality and factors associated with postoperative mortality in a cohort of patients undergoing emergency laparotomy between January 2018 and December 2021 in a high-complexity hospital who had a mortality risk ≥ 75% per the ACS NSQIP Surgical Risk Calculator.

RESULTS: A total of 890 emergency laparotomies were performed during the study period, and 50 patients were included for the analysis. Patient median age was 82.5 (IQR: 18.25) years old and 33 (66.00%) were male. The most frequent diagnoses were mesenteric ischemia 21 (42%) and secondary peritonitis 18 (36%). Mortality in the series was 92%. Twenty-four (54.34%) died within the first 24 h of the postoperative period; 11 (23.91%) within 72 h and 10 (21.73%) within 30 days. APACHE II and SOFA scores were statistically significantly higher in patients who died.

CONCLUSIONS: All available tools should be used to make decisions, with the most reliable and objective information possible, and be particularly vigilant in patients at extreme risk (mortality risk greater than 75% according to ACS NSQIP Surgical Risk Calculator) to avoid futility and its consequences. The available information should be shared with the patient, the family, or their guardians through an assertive and empathetic communication strategy. It is necessary to insist on a culture of surgical ethics based on reflection and continuous improvement in patient care and to know how to accompany them in order to have a proper death.

PMID:36703155 | DOI:10.1186/s12893-022-01897-1

BMC Med Inform Decis Mak. 2023 Jan 26;23(1):19. doi: 10.1186/s12911-023-02098-3.

ABSTRACT

The coronavirus disease 2019 (COVID-19) has developed into a pandemic. Data-driven techniques can be used to inform and guide public health decision- and policy-makers. In generalizing the spread of a virus over a large area, such as a province, it must be assumed that the transmission occurs as a stochastic process. It is therefore very difficult for policy and decision makers to understand and visualize the location specific dynamics of the virus on a more granular level. A primary concern is exposing local virus hot-spots, in order to inform and implement non-pharmaceutical interventions. A hot-spot is defined as an area experiencing exponential growth relative to the generalised growth of the pandemic. This paper uses the first and second waves of the COVID-19 epidemic in Gauteng Province, South Africa, as a case study. The study aims provide a data-driven methodology and comprehensive case study to expose location specific virus dynamics within a given area. The methodology uses an unsupervised Gaussian Mixture model to cluster cases at a desired granularity. This is combined with an epidemiological analysis to quantify each cluster’s severity, progression and whether it can be defined as a hot-spot.

PMID:36703133 | DOI:10.1186/s12911-023-02098-3