Nevin Manimala

World J Nucl Med. 2022 Sep 9;21(4):302-313. doi: 10.1055/s-0042-1750400. eCollection 2022 Dec.

ABSTRACT

Background Conventional imaging is useful to assess interbody fusion by showing complete trabecular bony bridging, but has a low positive predictive value for pseudarthrosis. Because alterations of bone metabolism may precede structural anatomical changes on computed tomography (CT), we aimed to investigate the ability of fluorine 18 sodium fluoride positron emission tomography/computed tomography ( ¹⁸ F-NaF PET/CT) to identify pseudarthrosis after spinal fusion using surgical revision as the reference standard. Methods We retrospectively reviewed ¹⁸ F-NaF PET/CT scans performed between February 2019 and September 2020 in patients experiencing pain after spinal fusion. We included the 18 patients who underwent revision surgery for suspicion of pseudarthrosis. Five consecutive patients who were clearly fused on CT served as the control group. Results In the revision surgery group ( n =18), visual assessment by ¹⁸ F-NaF PET/CT revealed that all 22 cages with an increased ¹⁸ F-NaF uptake around intercorporal fusion material had mobility at revision surgery, whereas none of the fused patients ( n =5) showed uptake around cage/intervertebral disk space. Among the 18 patients with presumed aseptic pseudarthrosis, intraoperative cultures revealed surgical site infection (SSI) caused by Cutibacterium acnes ( C. acnes ) in seven patients (38.9%). There was a statistically significant difference in standardized uptake values and uptake ratios between the revision surgery and control groups ( p =5.3× 10 ^-6 and p =0.0002, respectively). Conclusions ¹⁸ F-NaF PET/CT imaging appeared as a useful tool to identify pseudarthrosis following spinal fusion. The unexpectedly high prevalence (38.9%) of SSI caused by C. acnes found in presumed aseptic patients supports the utility of intraoperative cultures in revision cases for pseudarthrosis, even without preoperative clinical suspicion of SSI.

PMID:36398308 | PMC:PMC9666003 | DOI:10.1055/s-0042-1750400

World J Nucl Med. 2022 Sep 2;21(4):283-289. doi: 10.1055/s-0042-1750015. eCollection 2022 Dec.

ABSTRACT

Aim Radium-223 has been the first-approved targeted Alpha therapy agent. We retrospectively assessed different factors influencing the overall survival (OS) and patient management. Setting and Design Thirty-two metastatic castration-resistant prostate cancer (mCRPC) patients’ hematological parameters, number of cycles, performance status, and toxicities were evaluated for OS. Radium 223 dichloride (Radium-223) was administered every 4 weeks for a maximum of six cycles. Primary and secondary end points were OS, progression free survival (PFS), therapy toxicities, change in performance status, biochemical response, and skeletal-related events (SREs). Materials and Methods Patients’ median age was 77 years (range: 57-90 years) and median follow-up was 399 days (range: 5-1,761 days). A total of 163 cycles were administered in 32 patients, with 4 or less cycles in 8 patients (25%) and 5 or more cycles in 24 patients (75%). Among eight patients with 4 or less cycles, three patients died, of which two patients died due to neutropenic sepsis. Statistical Analysis Mann-Whitney test was used to compare the cycle groups; Spearman’s correlation coefficient was used to see the relation of different variables with OS. Log rank test was used for group comparison while Kaplan-Meier survivorship was used for OS. Results Statistical correlation was seen between the number of cycles ( p =0.037) and hemoglobin ( p =0.028). Kaplan-Meier OS ( p =0.038) was correlated with the number of cycles (≤ 4 cycles and ≥ 5 cycles). OS was 173 days in patients with one to four cycles, 226 days in five cycles, and 493 days in six cycles. Myelosuppression leading to stopping of full six cycles was seen in 7 of 32 patients (22%) and significantly correlated to inferior OS ( p =0.048). Conclusion Higher number of Radium-223 cycles was seen to be associated with better OS. Prior myelosuppression was associated with poor OS. Patients with better hematological profile were more likely to complete the maximum number of the cycles with a better OS.

PMID:36398304 | PMC:PMC9665971 | DOI:10.1055/s-0042-1750015

Drug Saf. 2022 Nov 17. doi: 10.1007/s40264-022-01254-4. Online ahead of print.

ABSTRACT

INTRODUCTION: Electronic health record (EHR) or medical claims-based algorithms (i.e., operational definitions) can be used to define safety outcomes using real-world data. However, existing tools do not allow researchers and decision-makers to adequately appraise whether a particular algorithm is fit for purpose (FFP) to support regulatory decisions on drug safety surveillance. Our objective was to develop a tool to enable regulatory decision-makers and other stakeholders to appraise whether a given algorithm is FFP for a specific decision context.

METHODS: We drafted a set of 77 generic items informed by regulatory guidance documents, existing instruments, and publications. The outcome of ischemic stroke served as an exemplar to inform the development of draft items. The items were designed to be outcome independent. We conducted a three-round online Delphi panel to develop and refine the tool and achieve consensus on items (> 70% agreement) among panel participants composed of regulators, researchers from pharmaceutical organizations, academic clinicians, methodologists, pharmacoepidemiologists, and cardiologists. We conducted a qualitative analysis of panel responses. Five pairs of reviewers independently evaluated two ischemic stroke algorithm validation studies to test its application. We developed a user guide, with explanation and elaboration for each item, guidance on essential and additional elements for user responses, and an illustrative example of a complete assessment. Furthermore, we conducted a 2-h online stakeholder panel of 16 participants from regulatory agencies, academic institutions, and industry. We solicited input on key factors for an FFP assessment, their general reaction to the Algorithm CErtaInty Tool (ACE-IT), limitations of the tool, and its potential use.

RESULTS: The expert panel reviewed and made changes to the initial list of 77 items. The panel achieved consensus on 38 items, and the final version of the ACE-IT includes 34 items after removal of duplicate items. Applying the tool to two ischemic stroke algorithms demonstrated challenges in its application and identified shared concepts addressed by more than one item. The ACE-IT was viewed positively by the majority of stakeholders. They identified that the tool could serve as an educational resource as well as an information-sharing platform. The time required to complete the assessment was identified as an important limitation. We consolidated items with shared concepts and added a preliminary screen section and a summary assessment box based on their input. The final version of the ACE-IT is a 34-item tool for assessing whether algorithm validation studies on safety outcomes are FFP. It comprises the domains of internal validity (24 items), external validity (seven items), and ethical conduct and reporting of the validation study (three items). The internal validity domain includes sections on objectives, data sources, population, outcomes, design and setting, statistical methods, reference standard, accuracy, and strengths and limitations. The external validity domain includes items that assess the generalizability to a proposed target study. The domain on ethics and transparency includes items on ethical conduct and reporting of the validation study.

CONCLUSION: The ACE-IT supports a structured, transparent, and flexible approach for decision-makers to appraise whether electronic health record or medical claims-based algorithms for safety outcomes are FFP for a specific decision context. Reliability and validity testing using a larger sample of participants in other therapeutic areas and further modifications to reduce the time needed to complete the assessment are needed to fully evaluate its utility for regulatory decision-making.

PMID:36396894 | DOI:10.1007/s40264-022-01254-4

Brain Imaging Behav. 2022 Nov 17. doi: 10.1007/s11682-022-00737-3. Online ahead of print.

ABSTRACT

Motor disability is a dominant and restricting symptom in multiple sclerosis, yet its neuroimaging correlates are not fully understood. We apply statistical and machine learning techniques on multimodal neuroimaging data to discriminate between multiple sclerosis patients and healthy controls and to predict motor disability scores in the patients. We examine the data of sixty-four multiple sclerosis patients and sixty-five controls, who underwent the MRI examination and the evaluation of motor disability scales. The modalities used comprised regional fractional anisotropy, regional grey matter volumes, and functional connectivity. For analysis, we employ two approaches: high-dimensional support vector machines run on features selected by Fisher Score (aiming for maximal classification accuracy), and low-dimensional logistic regression on the principal components of data (aiming for increased interpretability). We apply analogous regression methods to predict symptom severity. While fractional anisotropy provides the classification accuracy of 96.1% and 89.9% with both approaches respectively, including other modalities did not bring further improvement. Concerning the prediction of motor impairment, the low-dimensional approach performed more reliably. The first grey matter volume component was significantly correlated (R = 0.28-0.46, p < 0.05) with most clinical scales. In summary, we identified the relationship between both white and grey matter changes and motor impairment in multiple sclerosis. Furthermore, we were able to achieve the highest classification accuracy based on quantitative MRI measures of tissue integrity between patients and controls yet reported, while also providing a low-dimensional classification approach with comparable results, paving the way to interpretable machine learning models of brain changes in multiple sclerosis.

PMID:36396890 | DOI:10.1007/s11682-022-00737-3

Int J Obes (Lond). 2022 Nov 17. doi: 10.1038/s41366-022-01239-4. Online ahead of print.

ABSTRACT

OBJECTIVES: The aim of this study was to investigate the relationship between body composition and leukocyte telomere length (LTL) in healthy Chinese children aged 6-11 years.

METHODS: This cross-sectional study enrolled 406 healthy children (175 girls and 231 boys). The relative telomere length in their peripheral blood leukocytes was determined via quantitative polymerase chain reaction. Dual-energy X-ray absorptiometry was used to determine body fat content and regional fat distribution, appendicular skeletal muscle mass (ASM), bone mineral density (BMD) and bone mineral content (BMC) at the total body (TB) and total body less head (TBLH) levels, and total body lean mass (TBLM) was then determined. ASM/height² (ASMI) was also calculated.

RESULTS: After adjusting for potential covariates, multiple linear regression analyses revealed that neither body fat content nor regional body fat distribution were significantly associated with LTL (β = -8.48 × 10^-6-1.44 × 10^-1, p = 0.227-0.959). However, ASM, ASMI, TB BMC/TB BMD, TBLH BMC/TBLH BMD and TBLM were positively associated with LTL (β = 8.95 × 10^-6-4.95 × 10^-1, p = 0.005-0.035). Moreover, analysis of covariance revealed there was a statistically significant dose-dependent positive association between LTL and ASM, TB BMC/BMD, TBLH BMC/BMD, and TBLM (p-trend = 0.002-0.025).

CONCLUSIONS: Skeletal muscle mass and bone mass but not body fat content or distribution were significantly associated with LTL in this pediatric population.

PMID:36396857 | DOI:10.1038/s41366-022-01239-4

J Nephrol. 2022 Nov 18. doi: 10.1007/s40620-022-01478-8. Online ahead of print.

ABSTRACT

BACKGROUND: Tubulointerstitial nephritis and uveitis syndrome (TINU) is a rare condition characterised by bilateral uveitis and interstitial nephritis. There is no nationally, or internationally agreed upon treatment regimen. A systematic review was undertaken to report the renal outcomes in TINU, and treatments used.

METHODS: Medline (1969-2021) and EMBASE (1988-2021) databases were searched for primary studies, clinical practice guidelines and case reports of adult and paediatric TINU cases, as defined by Mandeville criteria. Two reviewers identified articles meeting inclusion criteria (registered with PROSPERO). Data were extracted into a synthesis table and meta-analysis performed. Quality of case series was also assessed.

RESULTS: One hundred twenty-two articles were identified, totalling 257 cases included in the meta-analysis. Females were more commonly affected than males (2:1), and median age was 19 years. GFR at follow-up correlated with nadir GFR, and the proportion with GFR <90 ml/min/1.73 m² was statistically different between adult and paediatric groups. Of the entire cohort, 40% had GFR <90 ml/min/1.73 m² at follow-up. Glucocorticoid monotherapy was the most common treatment (70%); other strategies included no treatment (9%) and immunosuppressant drugs (e.g. azathioprine), mostly in steroid-resistant cases, or as ‘steroid-sparing’ alternatives.

CONCLUSIONS: The majority of literature regarding TINU is limited to case reports and case series. There are no prospective trials assessing the effects of different treatments on renal outcomes, and currently employed treatment strategies are physician-specific without a reliable evidence-base. Prospective data collection as part of multicentre trials should be a research focus to improve the evidence-base.

PMID:36396848 | DOI:10.1007/s40620-022-01478-8

Sci Rep. 2022 Nov 17;12(1):19736. doi: 10.1038/s41598-022-21242-z.

ABSTRACT

Rapid industrialization and urbanization have resulted in environmental pollution and unsustainable development of cities. The concentration of 12 potentially toxic metal(loid)s in windowsill dust samples (n = 50) were investigated from different functional areas of Qom city with the highest level of urbanization in Iran. Spatial analyses (ArcGIS 10.3) and multivariate statistics including Principal Component Analysis and Spearman correlation (using STATISTICA-V.12) were adopted to scrutinize the possible sources of pollution. The windowsill dust was very highly enriched with Sb (50 mg/kg) and Pb (1686 mg/kg). Modified degree of contamination (mC_d) and the pollution load indices (PLI_zone) indicate that windowsill dust in all functional areas was polluted in the order of industrial > commercial > residential > green space. Arsenic, Cd, Mo, Pb, Sb, Cu, and Zn were sourced from a mixture of traffic and industrial activities, while Mn in the dust mainly stemmed from mining activities. Non-carcinogenic health risk (HI) showed chronic exposure of Pb for children in the industrial zone (HI = 1.73). The estimations suggest the possible carcinogenic risk of As, Pb, and Cr in the dust. The findings of this study reveal poor environmental management of the city. Emergency plans should be developed to minimize the health risks of dust to residents.

PMID:36396803 | DOI:10.1038/s41598-022-21242-z

Biol Cybern. 2022 Nov 18. doi: 10.1007/s00422-022-00951-8. Online ahead of print.

ABSTRACT

Motor systems show an overall robustness, but because they are highly nonlinear, understanding how they achieve robustness is difficult. In many rhythmic systems, robustness against perturbations involves response of both the shape and the timing of the trajectory. This makes the study of robustness even more challenging. To understand how a motor system produces robust behaviors in a variable environment, we consider a neuromechanical model of motor patterns in the feeding apparatus of the marine mollusk Aplysia californica (Shaw et al. in J Comput Neurosci 38(1):25-51, 2015; Lyttle et al. in Biol Cybern 111(1):25-47, 2017). We established in (Wang et al. in SIAM J Appl Dyn Syst 20(2):701-744, 2021. https://doi.org/10.1137/20M1344974 ) the tools for studying combined shape and timing responses of limit cycle systems under sustained perturbations and here apply them to study robustness of the neuromechanical model against increased mechanical load during swallowing. Interestingly, we discover that nonlinear biomechanical properties confer resilience by immediately increasing resistance to applied loads. In contrast, the effect of changed sensory feedback signal is significantly delayed by the firing rates’ hard boundary properties. Our analysis suggests that sensory feedback contributes to robustness in swallowing primarily by shifting the timing of neural activation involved in the power stroke of the motor cycle (retraction). This effect enables the system to generate stronger retractor muscle forces to compensate for the increased load, and hence achieve strong robustness. The approaches that we are applying to understanding a neuromechanical model in Aplysia, and the results that we have obtained, are likely to provide insights into the function of other motor systems that encounter changing mechanical loads and hard boundaries, both due to mechanical and neuronal firing properties.

PMID:36396795 | DOI:10.1007/s00422-022-00951-8

Eur Radiol. 2022 Nov 18. doi: 10.1007/s00330-022-09216-1. Online ahead of print.

ABSTRACT

OBJECTIVES: To develop a U-Net-based deep learning model for automated segmentation of craniopharyngioma.

METHODS: A total number of 264 patients diagnosed with craniopharyngiomas were included in this research. Pre-treatment MRIs were collected, annotated, and used as ground truth to learn and evaluate the deep learning model. Thirty-eight patients from another institution were used for independently external testing. The proposed segmentation model was constructed based on a U-Net architecture. Dice similarity coefficients (DSCs), Hausdorff distance of 95% percentile (95HD), Jaccard value, true positive rate (TPR), and false positive rate (FPR) of each case were calculated. One-way ANOVA analysis was used to investigate if the model performance was associated with the radiological characteristics of tumors.

RESULTS: The proposed model showed a good performance in segmentation with average DSCs of 0.840, Jaccard of 0.734, TPR of 0.820, FPR of 0.000, and 95HD of 3.669 mm. It performed feasibly in the independent external test set, with average DSCs of 0.816, Jaccard of 0.704, TPR of 0.765, FPR of 0.000, and 95HD of 4.201 mm. Also, one-way ANOVA suggested the performance was not statistically associated with radiological characteristics, including predominantly composition (p = 0.370), lobulated shape (p = 0.353), compressed or enclosed ICA (p = 0.809), and cavernous sinus invasion (p = 0.283).

CONCLUSIONS: The proposed deep learning model shows promising results for the automated segmentation of craniopharyngioma.

KEY POINTS: • The segmentation model based on U-Net showed good performance in segmentation of craniopharyngioma. • The proposed model showed good performance regardless of the radiological characteristics of craniopharyngioma. • The model achieved feasibility in the independent external dataset obtained from another center.

PMID:36396792 | DOI:10.1007/s00330-022-09216-1

Neuropsychopharmacology. 2022 Nov 18. doi: 10.1038/s41386-022-01497-w. Online ahead of print.

ABSTRACT

Post-traumatic stress disorder (PTSD) leads to enhanced alcohol drinking and development of alcohol use disorder (AUD). Identifying shared neural mechanisms might help discover new therapies for PTSD/AUD. Here, we employed a rat model of comorbid PTSD/AUD to evaluate compounds that inhibit FK506-binding protein 51 (FKBP5), a co-chaperone modulator of glucocorticoid receptors implicated in stress-related disorders. Male and female rats received a familiar avoidance-based shock stress followed by voluntary alcohol drinking. We then assessed trauma-related behaviors through sleep bout cycles, hyperarousal, fear overgeneralization, and irritability. To evaluate the role of stress and alcohol history on the sensitivity to FKBP5 inhibitors, in two separate studies, we administered two FKBP5 inhibitors, benztropine (Study 1) or SAFit2 (Study 2). FKBP5 inhibitors were administered on the last alcohol drinking session and prior to each trauma-related behavioral assessment. We also measured plasma corticosterone to assess the actions of FKBP5 inhibitors after familiar shock stress and alcohol drinking. Benztropine reduced alcohol preference in stressed males and females, while aggressive bouts were reduced in benztropine-treated stressed females. During hyperarousal, benztropine reduced several startle response outcomes across stressed males and females. Corticosterone was reduced in benztropine-treated stressed males. The selective FKBP5 inhibitor, SAFit2, reduced alcohol drinking in stressed males but not females, with no differences in irritability. Importantly, SAFit2 decreased fear overgeneralization in stressed males and females. SAFit2 also reduced corticosterone across stressed males and females. Neither FKBP5 inhibitor changed sleep bout structure. These findings indicate that FKBP5 inhibitors modulate stress-related alcohol drinking and partially modulate trauma-related behaviors. This work supports the hypothesis that targeting FKBP5 may alleviate PTSD/AUD comorbidity.

PMID:36396784 | DOI:10.1038/s41386-022-01497-w