The lymph node posterior to the right recurrent laryngeal nerve (LN-prRLN) is a crucial component of the central lymph nodes (LNs). We aimed to evaluate multimodal predictive factors of LN-prRLN metastasis in patients with papillary thyroid carcinomas (PTCs), including the clinical data, pathologic data, and preoperative sonographic characteristics of PTCs.A total of 403 diagnosed PTC patients who underwent unilateral, sub-total, or total thyroidectomy with central neck dissection were enrolled in this retrospective study. The clinical data, pathologic data, conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS) characteristics of PTCs were collected and evaluated for predicting LN-prRLN metastasis.In this study, 96 PTC patients with LN-prRLN metastasis and 307 PTC patients without LN-prRLN metastasis were included. Univariate analysis demonstrated that PTC patients with LN-prRLN metastasis more often had younger age, larger size, multifocal cancers, A/T < 1, well-margins, microcalcification, petal-like calcification, internal vascularity, centripetal perfusion pattern and surrounding ring enhancement. Multivariate logistic regression analysis revealed that the CEUS centripetal perfusion pattern, central LN detected by ultrasound and LN-arRLN metastasis were independent characteristics for predicting LN-prRLN metastasis in PTC patients.According to our research, it is essential for clinicians to thoroughly dissect central LNs, particularly LN-prRLNs. PTCs are one of the most prevalent thyroid cancer histological subtypes, with rising incidence and substantial lymph node metastatic rates , 2. AccoDue to the difficult surgical technique and the high rate of complications as a result of the deep position with confined exposure, some researchers contend that routine LN-prRLN removal is not necessary. Furthermore, it can be difficult to assess metastases before surgery, and even experienced surgeons are likely to ignore this location. However, the LN-prRLN metastasis rate in PTC patients has been reported to be as high as 2.7–30.4% , 7. The Some studies have reported the clinicopathologic risk factors for LN-prRLN metastasis for PTCs. Zhang et al. reported that tumor size larger than 1 cm, multifocality, and extrathyroidal extension were independent predictors of LN-prRLN metastasis in right-sided PTC . Zhou etCEUS, which provides more information about vascularity than conventional US, could reveal the thyroid nodule’s microvasculature and increase the diagnostic accuracy of thyroid nodules , 13. OurBy analyzing the preoperative US characteristics of PTCs and the postoperative pathological data in 403 PTC patients, this study seeks to identify potential predictors for the preoperative clinical evaluation of LN-prRLN metastases.The study was approved by the Ethical Committee of the Second Xiangya Hospital of Central South University in China and performed in accordance with the Declaration of Helsinki for human study. The requirement of informed consent from human subjects was waived by IRBs due to the retrospective nature of the review of images acquired for clinical diagnostic purposes. From May 2021 to August 2022, 1253 consecutive patients with thyroid nodules who received conventional US and CEUS examinations were prospectively enrolled in this single-center study. The inclusion criteria were as follows: (i) patients with thyroid nodules who underwent conventional US and CEUS examinations and (ii) pathological examination confirming PTCs after surgery. Patients with the following criteria were excluded: (i) a history of neck surgery or neck radiotherapy; (ii) central cervical lymph node dissection not performed; and (iii) LN-prRLN without clear pathological diagnosis. The final diagnosis of malignant thyroid nodules and metastatic lymph nodes was confirmed by histopathology after surgery. For patients with multifocal PTCs, the largest one was selected for CEUS examination. Finally, 403 PTC patients  were included in this study. In addition, TSH, thyroid peroxidase antibody (A-TPO), and thyroglobulin antibody (A-TG) levels were evaluated in all patients within one week before surgery.A GE E11 US scanner with a 3-12L (3-12 MHz) linear array transducer or Siemens Acuson S3000 US scanner with a 9L4 (4–9 MHz) linear array transducer was used for conventional US and CEUS examination. All examinations were performed by operators with more than ten years of experience in thyroid ultrasound diagnosis and five years of experience in performing CEUS examinations. Two other investigators with 5 years of experience in thyroid ultrasound diagnosis analyzed the US images independently. Disagreements were solved by consensus. Two-milliliters of SonoVue  or 0.4 mL of Sonozoid  was injected intravenously, followed by a saline flush of 5 mL. Thyroid nodule imaging lasted at least 30 seconds.Conventional US features of the thyroid nodules were classified as follows : shape  and inteThe following categories describe the thyroid nodules’ CEUS characteristics : enhanceThree surgical options  are available, according to the Chinese Thyroid Association’s guidelines. The procedure was chosen based on the surgeon’s desire and a comprehensive analysis of the patient’s condition. Prelaryngeal LN, pretracheal LN, left paratracheal LN, LN-arRLN, and LN-prRLN were the five subgroups of the central LNs and sent for individual pathological evaluation. If the lateral cervical LNs were diagnosed as metastatic LNs from PTCs, lateral cervical lymph node dissection was performed.The histopathological results after surgery were used as the only reference standard for the final diagnosis of malignant thyroid nodules and metastatic lymph nodes.The statistical analysis was carried out using SPSS version 21.0. . The mean and standard deviation (SD) of continuous data were displayed, and they were compared using an independent t test. Categorical data were evaluated using the chi-square test and are shown as percentages. To evaluate multimodal factors and their independent associations with LN-prRLN metastasis, binary logistic regression was performed. P < 0.05 was used to evaluate whether differences were statistically significant.This study comprised a total of 403 PTC patients, including 307 individuals without LN-prRLN metastasis and 96 patients with LN-prRLN metastasis. The univariate analysis of predictors for LN-prRLN is reported in Compared with PTCs without LN-prRLN metastasis, PTCs with LN-prRLN metastasis had more A/T < 1 and well-defined margins, microcalcification, petal-like calcification and internal vascularity on conventional US images. For CEUS images, the PTCs with LN-prRLN metastasis showed a more centrifugal perfusion pattern and the presence of surrounding ring enhancement than the PTCs without LN-prRLN metastasis 2.Level VI lymph nodes were detected in 74 (77.1%) patients in the PTC with LN-prRLN metastasis group compared with 102 (33.2%) patients in the PTC without LN-prRLN metastasis group on preoperative conventional US examination. In addition, all metastatic rates of left paratracheal LNs, prelaryngeal LNs, pretracheal LNs, LN-arRLNs, LN-prRLNs and lateral LNs were higher than those of the PTCs without LN-prRLN metastasis group on histopathological examination.All of the statistically significant factors (p < 0.05) underwent multivariate logistic regression analysis. The outcomes showed that the CEUS centrifugal perfusion pattern , central LN detected by ultrasound , and LN-arRLN metastasis  were independent characteristics for predicting LN-prRLN metastasis Table 3.Currently, there is still controversy about whether to dissect the LN-prRLN in the absence of certain LNs that are positive. Dissection of the LN-prRLN requires patience and experience and could lead to nerve damage and parathyroid injury, affecting the patient’s quality of life . AccordiAlthough PTCs have a favorable prognosis, other scholars contend that the central LNs are the most frequent sites for lymph node metastasis with a high incidence of 13.7%-72.2% , 16, 21.Univariate analysis in this study demonstrated that age < 45 years was a clinical risk factor related to LN-prRLN metastasis in PTC patients, demonstrating that patients with LN-prRLN metastasis were more likely to be young people, which was consistent with other previous studies , 26. In Recent studies have shown that US characteristics could help predict cervical central LN metastasis in PTC patients , 10, 27.Compared to color Doppler technology, the accuracy of thyroid nodule diagnosis may improve with the use of CEUS, which can detect more tumor microvessels. However, to the best of our knowledge, these CEUS parameters for predicting LN-prRLN metastasis in PTC patients have not been explored to date. In our study, we found that the centrifugal perfusion pattern and presence of surrounding ring enhancement were significantly associated with LN-prRLN metastasis in PTC patients. Multivariate analysis demonstrated that the centrifugal perfusion pattern was one of the independent characteristics for the presence of LN-prRLN metastasis.Although central LNs have a low display rate on preoperative conventional US examination, the present study found central LNs in 176 (43.7%) patients. Moreover, the display rate of central LNs in the PTC with LN-prRLN metastasis group was as high as 77.1%, which was significantly higher than that of 33.2% in PTC without LN-prRLN metastasis group. Multivariate analysis demonstrated that central LN detected by US was another independent characteristic for the prediction of LN-prRLN metastasis, indicating that the centrifugal perfusion pattern on CEUS and central LN detected by US could serve as preoperative factors for predicting LN-prRLN metastasis. In addition, all histopathological metastatic rates of left paratracheal LNs, prelaryngeal LNs, pretracheal LNs, LN-arRLNs, LN-prRLNs and lateral LNs were significantly higher than those of PTCs without LN-prRLN metastasis. In this study, individuals who had LN-arRLN metastases had a nearly fourfold increased probability of LN-prRLN metastasis than patients who did not. According to the multivariate analysis, LN-arRLN metastasis in PTC patients was a significant risk factor for LN-prRLN metastasis, suggesting that the LN-arRLN compartment may be used intraoperatively to predict LN-prRLN metastasis.According to the findings of univariate and multivariate analyses, the centrifugal perfusion pattern on CEUS, central LN detected by US, and LN-arRLN metastasis were independent predictors of LN-prRLN metastasis in these patients. In that case, suggesting that the LN-prRLN should be removed with thorough neck dissection to prevent metastasis.There are several limitations to our study. First, it was a single institutional retrospective analysis, hence the findings may not have been applicable to other PTC patient populations. Second, selection bias was also present. To further explain these findings, a large-scale prospective multicenter investigation is needed.In summary, complete central LN dissection should be taken into consideration given the rate of LN-prRLN metastasis and the challenges and complications of reoperation. Centrifugal perfusion patterns on CEUS, central LN detected by US and LN-arRLN metastasis are helpful in predicting metastasis to LN-prRLNs. Thus, preoperative conventional US and CEUS may serve as useful tools in predicting LN-prRLN metastasis in PTC patients.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Ethics Committee of Second Xiangya Hospital, Central South University, China. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.CN contributed to the conception and design of the work. YG participated to data analysis and manuscript writing. ZZ, KT, YX, RZ and QP participated to data collection and patients’ follow-up. All authors contributed to the article and approved the submitted version.


Refugees and asylum seekers are at high risk of mental disorders due to various stressors before, during and after forceful displacement. The WHO Self-Help Plus (SH+) intervention was developed to manage psychological distress and a broad range of mental health symptoms in vulnerable populations. This study aimed to examine the effects and moderators of SH+ compared with Enhanced Care as Usual (ECAU) in reducing depressive symptoms among refugees and asylum seekers.Three randomised trials were identified with 1795 individual participant data (IPD). We performed an IPD meta-analysis to estimate the effects of SH+, primarily on depressive symptoms and second on post-traumatic stress, well-being, self-identified problems and functioning. Effects were also estimated at 5–6 months postrandomisation (midterm).There was no evidence of a difference between SH+ and ECAU+ in reducing depressive symptoms at postintervention. However, SH+ had significantly larger effects among participants who were not employed  and had lower mental well-being levels . At midterm, SH+ was significantly more effective than ECAU in improving depressive symptoms , self-identified problems  and well-being .Although SH+ did not differ significantly from ECAU in reducing symptoms of depression at postintervention, it did present benefits for particularly vulnerable participants , and benefits were also evident at midterm follow-up. These results are promising for the use of SH+ in the management of depressive symptoms and improvement of well-being and self-identified problems among refugees and asylum seekers. Refugees and asylum seekers are at high risk of mental disorders like depression.Effective, low-intensity and scalable interventions are needed to meet the mental health needs of this disadvantaged population.Very little is known regarding individual participant differences in response to the WHO Self-Help Plus (SH+) intervention among refugees and asylum seekers.SH+ has promising effects in reducing depressive symptoms over the midterm and in improving self-identified problems and well-being.Employment and levels of well-being significantly moderated SH+ effects.The present work offers encouraging evidence supporting scaling up SH+ to address the mental health needs of refugees and asylum seekers.The identified moderators could inform SH+ tailoring, thereby enhancing its effectiveness in reducing symptoms of depression in refugees and asylum seekers.In 2022, more than 101 million people were forcibly displaced worldwide because of war, armed conflict, persecution, violence and human rights violations.The WHO has developed a guided self-help intervention, named Self-Help Plus (SH+), to fill the gap between the limited treatment supply and enormous demand in humanitarian settings.We conducted an IPD meta-analysis to examine the effects of SH+ compared with Enhanced Care as Usual (ECAU) in reducing depressive symptoms among refugees and asylum seekers. Secondary outcomes were post-traumatic stress symptoms, well-being, self-identified problems and functioning. We also aimed to evaluate the moderating effects of participants’ sociodemographic, migratory and mental health characteristics on the differential effectiveness of SH+ relative to ECAU in reducing depressive symptoms among refugees and asylum seekers.https://osf.io/jg4hs).The methods are described in detail in our published protocolFor the present IPD meta-analysis, a systematic literature search was not needed. We focused on the SH+ intervention, which was not publicly available when this study was conducted, and all trials on SH+ required to be approved by the WHO. Thus, through the WHO, we identified three RCTsAlthough a systematic literature search was not needed, to increase replicability and rule out any possibility of missing existent trials conducted after the intervention release, we ran a search strategy on 28 March 2023. We obtained 1461 records, with 15 full texts potentially eligible. No additional studies tested SH+ as a stand-alone intervention for asylum seekers and refugees see .10.1136/bmjment-2023-300672.supp1Supplementary datahttps://www.who.int/publications/i/item/9789240003927). This format enables delivery by briefly trained non-specialist peer facilitators, who play audio, encourage participants to practise the guided stress management exercises, read out discussion questions to make the groups interactive, and address any questions or safety issues that may arise. In the studies used for the present IPD meta-analysis, facilitators were non-specialists and some experienced as volunteers, community workers or similar profiles, and some had worked in healthcare or related settings.Details about the intervention are summarised in our protocol.In this control group, participants received routine social support or healthcare support and treatment according to the local regulations and practices of the host country. The word ‘enhanced’ was used to emphasise that participants were provided with specific information and practical support on social, care, and legal services for asylum seekers and refugees available locally at each site.Study-level variables were extracted from the published reports of the trials, including the time of postintervention assessment, the country where the study was conducted, the target group and data related to the risk-of-bias assessment as described below. Regarding individual participant-level variables, the primary authors of the trials provided data for each participant at baseline, post-treatment, and 5 to 6 month post-randomisation scores of depressive and post-traumatic stress symptoms, functioning, self-identified problems, and well-being. Next, all information related to sociodemographic and migration information was gathered and synthesised per participant: that is, the author provided sociodemographic information related to gender, age, country, relationship status, educational level, years of education, employment and length of stay in the host country. Finally, the authors provided data about exposure to traumatic events. Details about the procedures of data collection can be found in our published protocol.The Cochrane risk of bias tool 2.0The primary outcomes of this IPD meta-analysis were postintervention symptoms of depression on the Participant Health Questionnaire 9-items (PHQ-9).We performed the analyses under the intention-to-treat principle. Missing values were handled by multiple imputation under the missing-at-random assumption (20 imputations). To test the robustness of our findings, we performed sensitivity analyses using complete cases only.In a one-stage IPD meta-analysis, we synthesised all data from all trials with participants clustered within trials. The clustering of participants is accounted for using a random intercept for each study. The one-stage IPD meta-analysis approach offers more sophisticated modelling of the moderators, and thus, it is preferred over the two-stage IPD approach.First, to examine the effects of SH+ on reduction in postintervention depressive symptoms (secondary outcomes and outcomes at 5–6 months postrandomisation were examined in the same way), we performed a mixed-effects linear regression with random intercepts model with each trial having a random effect and a fixed effect for the intervention and the severity of depressive symptoms. The postintervention depressive symptoms were used as the dependent variable, while the condition (SH+ vs ECAU) was the independent variable while adjusting for baseline depression symptom severity. Second, we tested whether sociodemographic characteristics, mental health characteristics and migration variables moderated the effects of SH+ at postintervention. To do so, we added the interaction between each moderator and SH+ effect on depressive symptoms into the mixed-effects linear regression model. Each potential moderator was added into separate bivariate models.2, with values of 0% indicating no heterogeneity, 25% low heterogeneity, 50% moderate heterogeneity and 75% high heterogeneity.2 were calculated using the non-central χ2-based approach.To test the robustness of our findings, the analysis of the main outcomes was repeated using complete cases and in a two-stage IPD meta-analysis in which the data are analysed separately in each study and then the estimates are combined to calculate the pooled effect sizes for all outcomes using the random-effects model. Further, statistical heterogeneity was assessed using ITo evaluate the certainty of the evidence of our primary outcome , we used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology.Three RCTs were included in the present IPD meta-analysis with a total of 1795 participants comparing SH+ (n=883) to ECAU (n=912). These studies were conducted in western Europe ,All included studies were at low risk of bias across most domains. All trials had adequate randomisation and allocation concealment, and did not deviate from the intended intervention since all interventions were administered per protocol using an illustrated self-help book and prerecorded audio guide. Further, the non-specialist peer facilitators had adequate training and regular supervision to ensure intervention fidelity. Missing data were handled by the present Individual Participant Data Meta-Analysis (IPDMA) using multiple imputation. The percentage of missing values was small across the included studies  missingness at postintervention). Further, the missing values were acceptably balanced across the SH+ (17.5%) and ECAU (13.1%) conditions. Although all studies used assessors masked to the outcome of randomisation, participants were not masked due to the nature of the SH+ intervention; thus, we cannot rule out bias in the measurement of the outcome across all the included studies.2=92%; 95% CI 80% to 97%). In contrast with postintervention, at 5–6 months postrandomisation, the results of the one-stage IPDMA indicated a significant effect in favour of SH+ compared with ECAU in reducing symptoms of depression . Similar results were observed in the complete case  and two-stage IPDMAs . Heterogeneity dropped to 49% (95% CI 0% to 85%).10.1136/bmjment-2023-300672.supp2Supplementary data10.1136/bmjment-2023-300672.supp3Supplementary dataThere was no evidence of a difference between SH+ and ECAU in reducing symptoms of post-traumatic stress and improving functioning at postintervention and 5–6 months postrandomisation. These results were confirmed by the complete case and two-stage IPDMAs. However, the SH+ outperformed ECAU in improving self-identified problems  and mental well-being  at post-test. Results were replicated in complete case  and two-stage IPDMAs . Heterogeneity was 37% (95% CI 0% to 80%) for self-identified problems and 72% (95% CI 7% to 92%) for mental well-being. Similarly, at 5–6 months postrandomisation, there was a significant small effect in favour of SH+ on self-identified problems , which was replicated in complete case analysis  and two-stage IPDMAs . Heterogeneity was 31% (95% CI 0% to 93%). Finally, SH+ outperformed ECAU in improving mental well-being  at 5–6 months postrandomisation. These results were replicated in complete case  and two-stage IPDMAs . Heterogeneity was 32% (95% CI 0% to 93%). All secondary outcomes are presented in The results of the moderator analyses showed that employment was associated with reduction of depressive symptoms at postintervention , suggesting that those who were not employed benefited more from SH+ compared with ECAU. The moderating effect of employment was replicated in complete case analysis . Further, the lower the mental well-being at the baseline the greater the effects of SH+ compared with ECAU in reducing depressive symptoms at postintervention . The moderating effect of mental well-being was confirmed in complete case analysis . None of the other examined variables was significantly associated with SH+ outcomes , SH+ was more effective than ECAU in reducing depressive symptoms. Finally, regarding secondary outcomes, SH+ was more effective than ECAU in improving self-identified problems and well-being at both postintervention and follow-up, whereas there was no evidence of a difference between SH+ and ECAU in reducing post-traumatic stress symptoms and improving functioning at both time points.2=83%–89%), suggesting great variability among the effects of psychological interventions.The finding that SH+ did not have immediate effects on depressive and post-traumatic stress symptoms is not in line with the results of recent meta-analyses on the efficacy of higher intensity psychological interventions in refugees and asylum seekers.In contrast with postintervention, we did observe a significant impact on symptoms of depression at midterm. A plausible explanation for the change in the effects on depressive symptoms between postintervention and midterm may be the ‘incubation’ period needed for fully realising the impact of ACT.To our knowledge, this is the first study examining moderators of psychological interventions for refugees and asylum seekers at an IPD meta-analysis level. We found that SH+ was more effective for unemployed participants and those who had lower levels of well-being at baseline. Unemployment/underemployment has long been listed among the most critical resettlement-related stress sources.The present findings, nonetheless, should be interpreted considering several limitations. First, in our primary analyses , we observed considerable and significant heterogeneity, suggesting that the effects of SH+ varied among the included studies. Although the actual reason for this heterogeneity remains unclear, a possible reason for this discrepancy in studies’ effects is that refugees might have faced different postmigration stressors in the countries where the studies were conducted. Another plausible explanation is the difference in the eligibility criteria among the included studies, that is, two studies focused on prevention which included only participants without a mental disorder at baseline. The study in Uganda did not have this exclusion criterion and included both people with moderate and severe psychological distress according to the K-6 and did not perform diagnostic interviews. It therefore possibly included participants who met a diagnosis of depression. Second, we should also be mindful of the clinical diversity of the present sample. Although we examined a wide range of possible individual-level moderators to understand the clinical heterogeneity, there are important variables that we could not investigate in the present analyses . Future studies should explore such factors to better understand the effectiveness of SH+. Third, only three RCTs were conducted on this topic, suggesting that our conclusions are limited because of the small number of existing trials. Nevertheless, the number of participants was large, justifying the use of the IPD meta-analysis methodology. Fourth, we should acknowledge that the effect of SH+ in this study on self-identified problems and well-being might not be generalisable to interventions on asylum seekers and refugees affected by mental disorders since the present sample predominately consists of individuals with elevated levels of distress. Finally, the present analysis could not examine longer-term data since only one trial reported such outcomes. Future research should examine the effects of SH+ in the longer term.https://www.who.int/publications/i/item/9789240035119), and the present work provides essential insights to facilitate SH+ targeted dissemination. Considering the beneficial midterm outcomes, SH+ appears to be an appropriate intervention for the management of depressive symptoms among refugees and asylum seekers. Based on the present outcomes, SH+ can also be seen as a strategy to help the most vulnerable refugees and asylum seekers who struggle with unemployment and impaired well-being. Given its large group format, it may further be a useful first-line intervention to support refugees and asylum seekers and combined with more intensive interventions should they be required. SH+ could serve to boost psychological resilience through successful behavioural adaptation. Future studies should investigate adherence rates of SH+ and provide insights into whether increased well-being leads to better integration of refugees and asylum seekers in the host countries.Informed by the finding of the positive midterm effects, WHO has made SH+ publicly available (see In conclusion, although SH+ did not significantly reduce depressive symptoms at postintervention, the present findings are important considering the improvements in depressive symptoms and substantial benefits in well-being and self-identified problems. Next to that, subgroups of refugees and asylum seekers appear to benefit more from this intervention. Considering these benefits, SH+ could be scaled up as a public health strategy to improve well-being, self-identified problems, and possibly address depressive symptoms among refugees and asylum seekers.


Cognitive impairment in patients with Parkinson’s disease (PD) worsens the prognosis of PD and increases caregivers’ burden and economic consequences. Recently, subjective cognitive decline (SCD), which refers to self-reported cognitive decline without detectable objective cognitive dysfunction, has been regarded as an at-risk state of mild cognitive impairment (MCI) and a prodromal stage for dementia in Alzheimer’s disease (AD). However, studies on PD-SCD have thus far been scarce, and at present there is no consensus regarding the definition of SCD nor a gold standard as an evaluation tool. The present review aimed to look for an association between PD-SCD and objective cognitive function and found that PD with SCD occurred with brain metabolic changes, which were consistent with early aberrant pathological changes in PD. Moreover, PD patients with SCD were likely to progress to future cognitive impairment. It is necessary to establish a guideline for the definition and evaluation of SCD in PD. A larger sample size and more longitudinal investigations are needed to verify the predictive effectiveness of PD-SCD and to detect earlier subtle cognitive decline before MCI. Cognitive dysfunction, one of the most common non-motor symptoms (NMSs) in Parkinson’s disease (PD), is up to six times more common in PD than in the healthy aging population, worsens the prognosis of PD, and increases caregivers’ burden and economic consequences . It was p = 0.026) rather than Montreal Cognitive Assessment (MoCA) scores (p = 0.141) in PD with normal cognition (PD-NC), which suggested clinician to alert affective disorder in PD-SCD (Subjective cognitive decline (SCD) refers to decreases in cognitive capacity without detectable impairment on neuropsychological tests, indicating intact cognitive functions, accompanied by pathological changes, and was believed to be an at-risk state of MCI and a prodromal stage for dementia in Alzheimer’s disease (AD) . A studyn PD-SCD . Study ln PD-SCD .Overall, cognitive impairment in PD is a huge financial burden to society as well as caregivers, and it is time to highlight the importance of identifying cognitive decline as early as possible . HoweverThe review aimed to outline how SCD has been used as a diagnostic criterion in studies on PD as well as to describe the possible correlation related to objective cognitive impairment, help recognize SCD as an at-risk state early indicator and allow clinicians to predict conversion to PD-D more accurately.Our aim was to summarize the empirical literature on SCD in patients with PD. We used the following key words: “Parkinson’s disease” (PD) and subjective complaints (“subjective cognitive decline” (SCD), “subjective cognitive impairment” (SCI), “subjective memory complaint(s)” (SMC), “subjective ‘memory impairment” (SMI), or “subjective cognitive complaint(s)” (SCC) to search related literature in the PubMed, Web of Science, and Embase databases. All study designs and articles written in English from 1 January 1970 to 30 April 2023 were included; additionally, related reference lists were carried expand the literature results. The current available definition of SCD mainly focused on memory in the context of AD . UnfortuAlthough patients with PD mainly exhibit severe deficits in executive function, attention and visuospatial function rather than memory , studiesGiven that patients with PD manifest major impairments in executive function, attention and visuospatial function, not just memory , it is wSince there are no guidelines for PD-SCD, researchers have classified PD-SCD differently, and some studies have classified PD-SCD as coexisting with objective impairment. For example, among PD patients in the Dujardin cross-sectional study, 32.22% matched a classification of PD-SCD, of these patients with SCD, 44.83% of PD-SCD met the dementia criteria, of these patients without SCD, just 25.41% met the dementia criteria, suggesting that PD-SCD has a higher probability of manifesting cognitive dysfunction than PD without SCD . Erro reSome researchers defined SCD as subjective cognitive impairment without objective cognitive decline. Purri described a 53% incidence of PD-SCD among PD patients with normal cognition and thought PD-SCD may be an indicator of subsequent cognitive impairment . Hong shAbove all, there were some variations in the prevalence of PD-SCD among those studies, and the following reasons may be responsible for this. First, different demographic characteristics may contribute to the discrepancy; for example, an older cohort is prone to SCD since cognition declines with age. Second, the tool chosen to assess SCD may also be a factor, and a complete questionnaire may be more accurate than a single item. Third, the definition of SCD used in studies also influenced the results greatly, since PD may have normal memory but impaired planning ability, leading to some people being missed if the focus is only on memory. Finally, a state of anxiety, depression, and apathy in the PD group also accounted for the higher existence of SCD.n = 18 as PD-SCD, n = 12 as PD control), results revealed reduced FDG metabolism in the middle frontal, middle temporal, occipital areas, and angular gyrus of the cortex. These regions may be neural correlates of PD-SCD, and could demonstrate an early pathological change in PD-SCD  for global cognition, the semantic fluency/trail making test (TMT) for executive function, the word list verbal learning test for memory, the digit span test (DST)/symbol digits modalities test (SDMT) for attention, the naming test for language, and the Rey-Osterrieth complex figure test (ROCFT) for visuospatial ability. n = 49 PD-SCD, n = 23 controls), results showed PD-SCD have poorer performance in visual memory and executive functions, which was consistent with cortical thinning in frontal and posterior cortical areas, since frontal and posterior regions responsible for executive function and visual function, respectively. In n = 30) differed PD-without SCD (n = 47) in global cognition measured by MMSE and suggested PD-SCD may be a predictive biomarker on predementia. Lehrner was interested in the relationship between cognitive complaints and cognitive impairment, he found significant correlations between PD-SCD and worse MMSE performance . Hong etAttention and executive functions, which have neural correlates with the parietal and frontal lobes, were the most reported to have a strong correlation with the existence of PD-SCD, and these findings were consistent with the pathological changes in the early stage of PD. Some studies also found that PD-SCD was related to memory, and we think the results were affected by the assessed tools used as well as the targeted population. On the one hand, studies defined SCD as self-reported memory complaints, and the association investigated may be memory rather than other domains. On the other hand, studies comparing PD-SCD and PD-MCI concurrently may increase the correlation with one another. Dupouy and Copeland found no association between SCD and objective cognitive performance, which may be due to the assessment used or the psychiatric symptoms among their cohort. Overall, the association between SCD and objective cognitive performance remains unclear now. SCD are subjective and may be influenced by countless factors and the conflicting results obtained can be associated with measurements of cognitive status, definition of SCD, sample size, study design and so on. Thus, it is difficult to show a clear relationship between the two, especially when the methods applied are not precise or extensive enough to evaluate SCD or objective cognitive functions.n = 483 PD patients), a single item was used to assess PD-SCD, and the results revealed no relation between PD-SCD at baseline and PD-MCI/PDD 5 years later. A longitudinal study (n = 139 non-demented PD patients) adopted 4 methods to elicit PD-SCD, it explored the link between PD-SCD and cognitive performance subsequently, results here showed there was no correlation between PD-SCD and cognitive decline and no predictive value of PD-SCD over time (1–2 years) , which suggested the possible linguistic dysfunction in PD-SCD (n = 25) and found self-reported cognitive decline may be a marker for predicting cognitive ability decline after 1 year (n = 189), PD-SCD (n = 59), PD-MCI (n = 135), the longitudinal study (1–7.5 years) found PD-SCD showed memory impairment and greater reductions in attention and executive function compared with PD-NC, which suggested PD-SCD may be high risk individuals progression to cognitive decline later , they defined PS-SCD as subjective cognitive complaints with objective cognitive normality and found that the PD-SCD group performed worse on global cognition, executive function and processing speed than the PD without SCD group. Additionally, PD-SCD more easily converted cognitive impairment longitudinally, indicating that PD-SCD may be a warning of subtle cognitive decline (n = 336 patients with PD) led by n = 76) were independent predictor, which can predict the progression to MCI with 2 years longitudinal study, In 2 years) . Convers2 years) , at the n PD-SCD . Rosenblr 1 year . Han andne later , and thene later . In Purr decline . A largeIn summary, the majority of the above studies considered PD-SCD to be risk factor for impaired objective cognition, and PD-SCD may be a potential way to identify early cognitive decline. However, some problems should be noted. Most studies evaluated PD-SCD with a single item partly concerned with memory, which could eventually influence the results, thus, assessing PD-SCD according to more comprehensive cognitive domains may contribute to the consistency of subjects selected. Secondly, emotional factors should be emphasized and adjusted when exploring the correlation between cognitive performance and PD-SCD, because emotional factors influenced cognitive function and may be linked with PD-SCD, which interfered the results. Thirdly, it may be potential way to associate longitudinal study with more neuroimaging researches in PD-SCD.Subjective cognitive decline has been gaining increasing interest in recent years. Most of the results reported that patients with PD-SCD had a correlation with objective cognitive decline, and longitudinal studies also revealed a predictive risk for future cognitive dysfunction. Neuroimaging supported the above studies in terms of neural correlates as well as brain metabolism.However, there are still some problems that need to be solved as soon as possible. First, it is necessary to establish a consensus on PD with SCD. According to the SCD consensus on patients with AD, we recommend that the definition of PD-SCD should be purely self/informant-reported cognitive decline, and this definition may contribute to proving a pre-MCI stage of subtle cognitive decline. Next, studies used different methods to evaluate SCD, and assessments of SCD ranged from a single item to several face-to-face questions and a complete questionnaire. Given the specific characteristics of cognitive impairment in PD, a questionnaire including all five domains should be adopted. Additionally, information derived from caregivers may be useful to detect PD-SCD. Finally, the sample size should be larger, and more longitudinal investigations are needed to verify the predictive effectiveness of PD-SCD.Overall, a clear definition of PD-SCD would help identify earlier stages of cognitive impairment before PD-MCI, explore more risk factors associated with the existence of PD-SCD and allow for early attention and intervention in subtle cognitive decline stages, which may ultimately reduce the burden of cognitive impairment on society and caregivers.JH had the idea for the manuscript. WH critically revised the work. All authors contributed to the study conception and design, performed the literature search, data analysis, and drafted the manuscript.


Central obesity as measured by waist-to-hip circumference ratio (WHR) has been reported to be associated with renal hemodynamics and function. However, the adipose component of WHR, which is a composite measure of fat mass and fat-free mass, is small, particularly in nonobese subjects. Trunk-to-peripheral fat ratio as measured using dual-energy absorptiometry (DXA) is a more precise method for evaluating central fat distribution than WHR. The present study investigated the cross-sectional association between DXA-measured trunk-to-peripheral fat ratio and estimated glomerular filtration rate (eGFR) in community-dwelling elderly Japanese men.Participants were 575 men aged ≥65 years at the time of the baseline survey of the second Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) cohort study. Trunk-to-appendicular fat ratio (TAR) was calculated as trunk fat divided by appendicular fat (sum of arm and leg fat), and trunk-to-leg fat ratio (TLR) as trunk fat divided by leg fat.2, relative to the lowest quintile. In addition, a significant decreasing trend was observed for eGFR values from the lowest to the highest quintile of TAR/TLR after adjusting for confounding factors including whole-body fat.eGFR values significantly decreased from the lowest to the highest quintile of TAR/TLR. After adjusting for potential confounding factors including whole-body fat, the highest quintile of both TAR and TLR showed statistically significant odds ratios for the risk of eGFR <60 ml/min/1.73 mElderly men with a large trunk-to-peripheral fat ratio tended to have a lower eGFR. This association occurred independently of that between whole-body fat and eGFR. Obesity is associated with the pathogenesis of type 2 diabetes, hypertension, dyslipidemia, cardiovascular diseases, cancer, and kidney diseases . CentralDual-energy absorptiometry (DXA) is used widely for clinical assessment of a patient’s risk of osteoporosis and increasingly to measure body composition in terms of fat and fat-free mass . DXA hasThe present cross-sectional study used baseline data from the second Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) cohort study . The FOR2) [Whole-body fat and central fat distribution were assessed using the same DXA scanner  mounted on a mobile examination car as described previously . Quality2) .2). Blood pressure was measured using an automated device  with an appropriate cuff size. Participants were relaxed and seated with legs uncrossed in a quiet room with comfortable temperature. Measurements were performed with the right mid-arm at the heart level after resting for 5 minutes. The mean value of two readings was used for analysis.Body weight and height were measured in light clothing with no shoes. Body mass index (BMI) was calculated as weight divided by height squared (kg/m2) was calculated using the Modification of Diet in Renal Disease Study modified for Japanese individuals by the Japanese Society of Nephrology, as follows: eGFR = 194 × serum creatinine−1.094 × age−0.287 [Blood samples were obtained by vein puncture after an overnight fast, allowed to clot, and centrifuged. Levels of serum creatinine (mg/dl) were determined by the enzymatic method . eGFR  and eGFR (outcome), we obtained information on medical history and lifestyle factors including smoking status, physical activity, and dietary intake . ParticiParticipants with hypertension were defined as those with systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg following repeated examination  and/or tData were analyzed using SPSS Statistics Desktop for Japan, Version 26 . A P-value less than 0.05, or 95% confidence interval not containing the value 1, was considered statistically significant. Linear and nonlinear regression models were used to analyze the association between TAR/TLR and eGFR. Pearson’s correlation coefficients or Spearman’s rank correlation coefficients were used to assess associations between quintiles of TAR/TLR (predictor) and other variables, and between categories of eGFR (outcome) and other variables. To obtain an adjusted odds ratio (aOR), multivariate logistic regression analysis was used after adjusting for potential confounders that may affect associations between TAR/TLR (predictors) and eGFR (outcome). The logistic regression analysis incorporated potential confounders including variables that could be theorized, such as hypertension and diabetes mellitus. In addition to the theorized variables, those associated with both eGFR (outcome) and TAR/TLR (predictors) at a P-value <0.2 were used in the logistic regression analysis. Duplicate variables such as weight, BMI, whole-body fat, fat mass index, and body fat percentage were excluded from the same multivariate analysis. To assess linear trends of eGFR values from the lowest to the highest quintile of TAR/TLR, multivariate regression analysis was performed after adjusting for potential confounders. The dependent variable was eGFR value, and independent variables were potential confounding factors and TAR/TLR quintile.2 of the nonlinear  regression model was similar to that of the linear regression model. Subgroup characteristics stratified by quintile values of TAR/TLR and cutoff levels of eGFR are shown in Tables 2 in each quintile of TAR/TLR relative to the lowest quintile in total participants (575 men). In every model , aORs in the highest quintile were statistically significant, and the ratio of aOR for TLR to aOR for TAR in Model 3 was 1.18 in the highest quintile. In addition, eGFR values showed a significant trend to decrease from the lowest to the highest quintile of TAR/TLR after adjusting for confounding factors including whole-body fat in every model. Table 2 in each quintile of TAR/TLR relative to the lowest quintile in participants with BMI <25 kg/m2 (433 men without over weight). In every model , aORs in the highest quintile were statistically significant. In addition, eGFR values showed a significant trend to decrease from the lowest to the highest quintile of TAR/TLR after adjusting for confounding factors including whole-body fat in every model.Table icipants 75 men. IThe present study is the first to report on the association between eGFR and central fat distribution as precisely measured by DXA. In the present community-based single-center cross-sectional study among Japanese elderly men, a significant inverse association between eGFR and trunk-to-peripheral fat ratio was observed. Elderly men with a large distribution of central fat tended to have a lower eGFR. Moreover, this association remained significant after adjusting for potential confounding factors including whole-body fat. These findings suggest that the association between central fat distribution and eGFR is independent of the association between whole-body fat and eGFR. Central fat distribution as measured by DXA is an important determinant of renal function in this population. Not only overweight and obese subjects, but also subjects with central fat distribution, are at risk for renal impairment. DXA-measured trunk-to-peripheral fat ratio may serve as a clinical parameter that may aid in the prevention of chronic renal failure.A previous cross-sectional study in the Netherlands reported that not only obese subjects but also lean subjects with a high WHR were at risk for renal function impairment . AnotherThe pathophysiological background underlying the association between trunk-to-peripheral fat ratio and eGFR, independent of whole-body fat, was not explored in the present study. However, individuals who are not obese on the basis of height and weight can, like people with overt obesity, be hyperinsulinemic, insulin-resistant, and predisposed to type 2 diabetes, hypertriglyceridemia, and premature coronary heart disease . Such meAlthough WHR is the most common parameter related to central fat distribution for all age groups, it is not a direct measure of the proportion of body fat, but rather a composite measure of fat mass and fat-free tissue mass; the adipose component of WHR is small, particularly in nonobese subjects . IncreasThe present study has some limitations worth noting. First, participants were not randomly selected; the study population was made up of people who met the entry criteria and were accessible to the investigators. Because some participants were more likely than others to volunteer, they are not fully representative of the Japanese elderly population. Older adults who volunteer or engage in more hours of volunteering have been reported to show higher levels of well-being . In addiDXA-measured trunk-to-peripheral fat ratio, a parameter of central fat distribution, was associated with eGFR in elderly Japanese men. Elderly men with a large distribution of central fat tended to have a lower eGFR. Moreover, the observed association was independent of the association between whole-body fat and eGFR. Fat ratio parameters may be useful for predicting renal function, particularly in underweight to normal-weight populations. Trunk-to-peripheral fat ratios may allow for characterization of MONW individuals who are common in the general population. DXA-measured central fat distribution may serve as a clinical parameter that may aid in the prevention of chronic kidney disease in elderly men.


One major challenge is in collecting the MRI raw data (required for image reconstruction) from clinical scanning, as only magnitude images are typically saved and used for clinical assessment and diagnosis. The image phase and multi-channel RF coil information are not retained when magnitude-only images are saved in clinical imaging archives. Additionally, preprocessing used for data in clinical imaging can lead to biased results. While several groups have begun concerted efforts to collect large amounts of MRI raw data, current databases are limited in the diversity of anatomy, pathology, annotations, and acquisition types they contain. To address this, we present a method for synthesizing realistic MR data from magnitude-only data, allowing for the use of diverse data from clinical imaging archives in advanced MRI reconstruction development. Our method uses a conditional GAN-based framework to generate synthetic phase images from input magnitude images. We then applied ESPIRiT to derive RF coil sensitivity maps from fully sampled real data to generate multi-coil data. The synthetic data generation method was evaluated by comparing image reconstruction results from training Variational Networks either with real data or synthetic data. We demonstrate that the Variational Network trained on synthetic MRI data from our method, consisting of GAN-derived synthetic phase and multi-coil information, outperformed Variational Networks trained on data with synthetic phase generated using current state-of-the-art methods. Additionally, we demonstrate that the Variational Networks trained with synthetic  Current deep learning MRI reconstruction techniques use datasets [k-space MRI data and have enabled major advances in MRI reconstruction methods. However, they are limited in several ways. Magnitude images contained in these datasets are sometimes preprocessed which can lead to biased results for MRI reconstruction [Deep learning-based MRI reconstruction methods show promise in faithfully reconstructing MR images from undersampled datasets ,11,12,13truction  and are truction ,16, limiThere could be significant advantages to leveraging the diversity of existing clinical MRI databases as they contain a range of patient populations, anatomy, pathology, image contrasts, acquisition parameters, and data from different vendors. This would be particularly useful for multi-task networks, e.g., , that peHowever, we cannot simply use clinical datasets for MRI reconstruction algorithm development because they typically only contain magnitude images while image phase information is discarded. Furthermore, MRI data are acquired from multi-channel RF coils, but clinical images show a coil-combined image and, thus, the multi-channel information is lost. MRI phase data are important because they contain information related to contrast from chemical shift, magnetic susceptibility differences, inhomogeneities in the main magnetic field, RF coils used, fat/water separation, tissue interfaces, blood flow, and temperature change ,21,22,23Thus, the ability to recover or generate image phase from already completed scans could increase the utility and applicability of deep learning MRI reconstruction methods. While a variety of techniques aim to synthesize different MRI contrasts ,29,30,31k-space data is required.To address this, we present a method for synthesizing realistic MRI data, including image phase and multi-channel information, from magnitude-only images that, for example, are found in clinical imaging archives. Our method leverages recent advances in deep generative modeling ,38 to gek-space, magnitude, and phase in mathematical terms. We then describe generating synthetic phase images from input magnitude-only images using a conditional generative adversarial network (GAN) framework. Finally, we describe the evaluation of the synthetic data quality.We first start by defining k-space, can be expressed as:The signal acquired from a 2D slice  pulse sequence with an echo train length (ETL) of 4. For training, we divided the dataset into two datasets with 16-coil and 20-coil acquisitions. Each dataset consisted of Multi-coil  fastMRI  dataset We trained two generative models: A 16-coil model and a 20-coil model, trained on 22,691 and 18,519 magnitude-only brain images, respectively. During training, the U-net generator generated a synthetic phase image and the discriminator compared the generated image to the corresponding ground truth phase image (obtained from fastMRI) in a convolutional patch-wise manner. At inference time, magnitude-only images from the fastMRI test set were run through a forward pass of the trained generative models. In our experiments, this enabled the generation of 6541 synthetic phase images for the 16-coil model and 5845 synthetic phase images for the 20-coil model.k-space data synthesized from the generative model, we compared the quality of reconstructed MR images from reconstruction networks trained on ground-truth and synthetic data. Multiple equispaced undersampling masks of acceleration factors k-space data to be used for training. Two Variational Networks [k-space with a 80/10/10 training/validation/test split for a total of four trained reconstruction networks per acceleration factor. Each trained reconstruction model  was then run on the same ground-truth test set. The quality of reconstructed magnitude images was evaluated using standard quantitative image reconstruction metrics: PSNR, NMSE, SSIM [k-space and coil sensitivity maps as inputs into the unrolled network. Please see the To evaluate the utility of complex-valued multi-coil Networks  were theSE, SSIM . We deciAll models (generative and reconstruction) were implemented in PyTorch and were trained on NVIDIA  Titan RTX and Quadro RTX 8000 GPUs.k-space data, correspondingly. For k-space at k-space data. This work proposes a framework to generate synthetic multi-coil MRI data from magnitude-only MR images, and evaluates its utility by training a deep learning-based image reconstruction network using the synthesized datasets. The demonstrated framework aims to allow for the use of these large imaging databases for developing data-driven methods that require MRI raw data. We chose to evaluate using a Variational Network image reconstruction model as a proof of concept to demonstrate the effectiveness of the method. We believe a more significant opportunity for such a synthetic data pipeline is to train multi-task networks, e.g., networks that perform both image reconstruction and a downstream task such as image segmentation or classification [There is a massive amount of magnitude-only images as this is what is typically stored in clinical imaging databases , which do not usually contain phase and multi-coil information or raw fication . In thesOther approaches that generate synthetic MRI training data typically build on natural image datasets. For example, in , the autThe authors of  observe In addition to generating synthetic phase maps, a major aim of this work was to generate multi-coil data to increase the clinical relevancy of the technique. We take advantage of the well-established coil sensitivity map algorithm ESPIRiT  to estimN coils from a single magnitude-only image input. While this approach produced reasonable phase maps and comparable reconstructions for generative models trained on data acquired with a small number of coils  images from the fastMRI database were used to train the generative model. The exclusion of gradient-recalled echo (GRE) acquisition data in the training dataset makes the trained generative models and downstream reconstruction models susceptible to distribution shift errors. To address this limitation, future work could include fine-tuning the generative models trained on FSE data with GRE data. Additionally, quantifying the uncertainty in distributions not seen at inference time as proposed in  could prFinally, the evaluation of generative models, especially for synthetic medical imaging data, is still an open research direction . While tk-space and synthetic k-space data. Our results suggest that the proposed method for generating synthetic data (i) outperforms the current state-of-the-art methods for creating synthetic image phase and (ii) is adequate for training deep learning MRI reconstruction models at typical acceleration factors (up to 10×), shown by the Variational Networks results. Taken together, our results suggest that image-to-image translation generative adversarial networks are able to generate MRI phase images that are both realistic-looking and can also provide a good performance when used for training an image reconstruction network. This allows for the possibility of using large, diverse clinical imaging databases that contain magnitude-only images when developing deep learning MRI reconstruction methods.This work presents a new method for synthesizing realistic, multi-coil MRI data from magnitude-only images that uses a GAN to generate image phase and ESPIRiT-generated coil sensitivity maps. The synthetic data were evaluated by comparing the reconstruction performance of Variational Networks trained on real


Emerging evidence shows that patients with myasthenia gravis (MG) were at a higher risk for the co-occurrence of other autoimmune diseases, which reflects phenotypic heterogeneity in MG. The coexistence of MG and cryptogenic organizing pneumonia (COP) has rarely been reported. The present case is to report the coexistence of triple-seronegative MG and pathology-proven COP in a patient.The clinical data of the patient were derived from medical records of Nanjing First Hospital, Nanjing Medical University, China. Written informed consent was obtained from the patient.We presented a 56-year-old man with acute respiratory syndrome, who was diagnosed with COP based on the intra-alveolar fibroinflammatory buds (Masson's bodies) in the pathology of bronchoscopy biopsy. Oral prednisone induced dramatic symptomatic improvement and complete resolution of previous lung lesions. After a stable course of no respiratory symptom for 2 months, he was referred to the neurology department with complaints of fluctuating generalized muscle weakness. He was diagnosed with triple-seronegative MG based on fluctuating weakness, neostigmine test-positivity and RNS-positivity. After three-month treatment with pyridostigmine in combination with tacrolimus, the symptoms gradually improved and he achieved minimal symptom expression.This case highlights the rare coexistence of triple-seronegative MG and pathology-proven COP. However, a causal association between COP and MG cannot be explicitly ascertained. In future, more data are needed to clarify the relationship, taking into account the limited number of cases reported with this coexistence of the diseases. Myasthenia gravis (MG) is a rare autoimmune disease, which is characterized by fatigable muscle weakness. The disease is an organ-specific disease mediated by autoantibodies, including antibodies against acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK) and lipoprotein receptor-related protein 4 (LRP4) . HoweverHere, we reported the rare coexistence of triple-seronegative MG and pathology-proven cryptogenic organizing pneumonia (COP) in a patient. COP has no recognizable cause, which is classified as a subtype of idiopathic interstitial pneumonia. To the best of our knowledge, the coexistence of MG and COP in a single patient has not been reported in the literature.A 56-year-old man presented to the department of respiratory medicine with cough, sputum and mild chest pain for 4 days. He also reported fever with the highest temperature of 38°C. He denied dyspnea, night sweat and weight loss. The patient's medical history include hypertension, which was well controlled. His family history was unremarkable. Lung auscultation revealed normal breath sounds. Routine blood tests and biochemical tests were within normal ranges. Tumor markers and autoantibodies of connective tissue diseases were normal. The elevated C-reactive protein level of 87.27 mg/L  was revealed. Subsequent arterial blood gas analysis was normal. The blood culture and sputum culture were negative. High-resolution computed tomography (HRCT) indicated irregular nodular opacitie in the upper lobe and lower lobe of the right lung and the middle lobe of left lung –C. InitiThis report presented the coexistence of triple-seronegative MG and pathology-proven COP in a patient. MG with no detectable AChR, MuSK, or LRP4 antibodies in serum represents a heterogeneous group, which is classified triple-seronegative MG. Different methods are available for the detection of anti-AChR, anti-MuSK or anti-LRP4 antibodies, but the current gold standard remains the radioimmunoprecipitation assay (RIPA) . Damato The diagnosis and treatment are more challenging in triple-seronegative MG. As no detectable specific antibodies, diagnosis of triple-seronegative MG should be supported by adequate clinical characteristics and electrophysiological support, especially when the effectiveness of standard treatment is dissatisfactory. From a clinical point of view, it is observed that the clinical characteristics of triple-seronegative MG patients varied among different age groups . The oveIndividuals with MG have an increased vulnerability to other autoimmune diseases, which may manifest before or after the onset of MG. Notably, the incidence of autoimmune thyroid disease appears to be higher in patients with MG . We repoAs an idiopathic form of interstitial pneumonia, COP is pathologically characterized by intra-alveolar fibroinflammatory buds (Masson's bodies). The pathogenesis of COP still remains elusive. However, the abnormal immune process might play a pivotal role in the pathogenesis. The diagnosis of COP is an exclusive one to rule out infective pneumonia, eosinophilic pneumonia, other forms of interstitial pneumonia, alveolar hemorrhage, and malignancy and so on . The diaIn addition, COP is associated with a high recovery rate if managed appropriately . COP patIn a retrospective cohort with 91 patients initially diagnosed with COP, 4 patients were eventually identified as OP that was secondary to connective tissue diseases . NotablyMore interestingly, OP can coexist with autoimmune neurological diseases. A Japanese retrospective cohort study suggested that 4 in 52 patients with neuromyelitis optica spectrum disease showed pulmonary involvement with a diagnosis of OP, which preceded or coincided with neuromyelitis optica spectrum disease , 20. AntFew reports focus on any association between these two distinct conditions. It could be argued that an immune response to pulmonary antigens might elicit an immune attack against neuromuscular junction. To explore this association is crucial for both diagnosis and management of patients presenting with these rare conditions. There is another possibility that the coexistence of triple-seronegative MG and COP in this case could just be a simple coincidence.This case highlights the rare coexistence of pathology-proven COP and triple-seronegative MG. However, this descriptive study cannot definitively ascertained the causal association between COP and MG. In future, more data are needed to clarify the relationship, taking into account the limited number of cases reported with this coexistence of the diseases.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving humans were approved by Nanjing First Hospital, Nanjing Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.SQH: Conceptualization, Data curation, Writing—original draft. BW: Conceptualization, Data curation, Writing—review & editing. LG: Conceptualization, Writing—review & editing. MW: Conceptualization, Data curation, Writing—review & editing. HDZ: Writing—review & editing. JQS: Writing—review & editing.


Our framework is easy-to-use, also for non-programming-experts, and includes an automatic hyperparameter search using state-of-the-art Bayesian optimization. Moreover, easyPheno provides various benefits for bioinformaticians developing new prediction models. easyPheno enables to quickly integrate novel models and functionalities in a reliable framework and to benchmark against various integrated prediction models in a comparable setup. In addition, the framework allows the assessment of newly developed prediction models under pre-defined settings using simulated data. We provide a detailed documentation with various hands-on tutorials and videos explaining the usage of easyPheno to novice users.Predicting complex traits from genotypic information is a major challenge in various biological domains. With easyPheno is publicly available at https://github.com/grimmlab/easyPheno and can be easily installed as Python package via https://pypi.org/project/easypheno/ or using Docker. A comprehensive documentation including various tutorials complemented with videos can be found at https://easypheno.readthedocs.io/.Bioinformatics Advances online. BWGS  methods to modern deep learning (DL) architectures. Users can start the pipeline both for multiple prediction models and phenotypes simultaneously. Hence, easyPheno is a powerful tool also for users without ML and programming expertise, enabling them to conduct state-of-the-art phenotype prediction. An exemplary workflow of easyPheno with real and synthetic data is shown in easyPheno is offered as a Python package, i.a., to simplify the implementation of new functionalities for developers. Our framework is designed to enable a quick integration of new prediction models, especially for methods based on the most widely applied ML frameworks scikit-learn, PyTorch and TensorFlow. This easy-to-extend design allows bioinformaticians to focus on the model design while relying on thoroughly tested data pre-processing and state-of-the-art hyperparameter optimization. This is particularly interesting for DL-based methods, which are currently not widely used in the domain of phenotype prediction and might require new approaches to show their full potential. Hence, easyPheno supports a faster development of new prediction models, lowers the risk of errors and decreases testing efforts. Beyond that, easyPheno enables users to quickly benchmark newly developed prediction models against multiple comparison partners in a comparable and fair setup. Finally, also end users can benefit from this easy-to-extend design, making further prediction approaches available.Besides a command line interface enabling a straightforward application of state-of-the-art phenotype prediction approaches, easyPheno allows the creation of synthetic phenotypes based on real genotypic data. Due to the pre-defined settings, this synthetic data is especially beneficial to evaluate the strengths and limitations of newly implemented prediction models. To enable the evaluation of prediction models under pre-defined genotype-phenotype relationships, easyPheno provides functions to analyze prediction results, such as generating figures that provide a comparison of multiple predictors and phenotypes in a heat map. The framework supports the application of previously optimized models on new data, for instance to get predictions employing new samples of the same genotype-phenotype combination. Beyond that, easyPheno enables the integration of packages from R, thus allowing the enhancement of existing R code with new functionalities provided by our framework.Furthermore, easyPheno’s easy-to-use and easy-to-extend design provides various benefits for end users and developers. Subsequently, we provide more details on easyPheno’s main features and their implementation.As outlined, easyPheno accepts various file formats for genotypic and phenotypic data, e.g. PLINK and CSV files. Details on the required format and accepted file types can be found in our Data Guide: http://bioweb.me/ep-dataguide. First, the data is transformed and saved in a unified format to enable consistent handling. In addition, common pre-processing techniques such as minor allele frequency filtering and three parameterizable types of data splits  are implemented. Further, different genotype encodings are available through the preprocess module. All indices for data splits and pre-processing filters are stored in a dedicated HDF5 file referring to the usually large genotype data. This saves disk space and ensures a reproducible data preparation, even across different machines, and thus leads to comparable optimization results._base_model) as well as those with fixed parameters (_param_free_base_model). For both cases, we created a base class that contains useful methods for all related prediction models. Further, abstract methods and attributes are defined that have to be implemented in every child class. We provide classes already realizing most of the mandatory methods, e.g. the training loops, for the commonly used ML frameworks scikit-learn (_sklearn_model), PyTorch (_torch_model) and TensorFlow (_tensorflow_model). To implement a phenotype prediction model based on one of these widely used ML libraries, a user only needs to define two attributes, namely the default and possible nucleotide encodings, as well as two methods: the prediction model itself and potential hyperparameters including ranges. Hence, our design enables a straightforward and quick integration of further prediction models. In our online documentation, we show detailed information on how to integrate a new prediction model, including a step-by-step example in a video tutorial. Besides common genomic selection approaches, i.e. ridge regression best linear unbiased prediction (RR-BLUP) (R packages by utilizing BGLR’s (_bayesfromR). Detailed descriptions of all integrated prediction models can be found in our online documentation: http://bioweb.me/ep-models.We distinguish between approaches that require a hyperparameter search (g BGLR’s  efficienPython package Optuna (_param_free_base_model) that only need to be fitted to the training data. This allows the user to employ both model types in the same pipeline.We employ an automatic hyperparameter search using state-of-the-art Bayesian optimization via the easyPheno provides several methods to analyze prediction results, for which we also provide step-by-step tutorials in our documentation. For instance, we offer code to summarize the results of multiple optimization runs in a single CSV file. We further enable the generation of heat maps that contain prediction performances for multiple models and phenotypes.easyPheno offers to simulate phenotypic data based on real genotypic data. This simulation contains various parameterization options, for instance to model different numbers of causative markers and phenotypic distributions. More details regarding the underlying model and simulation options can be found in our online documentation: http://bioweb.me/ep-simulation. Hence, this enables the evaluation of a prediction model under pre-defined settings. To analyze how well the most influential markers are captured, easyPheno offers to plot the known effect sizes of simulated data against feature importances of several prediction models.Using a linear mixed model, easyPheno at https://easypheno.readthedocs.io/. In addition to a complete API reference (http://bioweb.me/ep-api), we provide an Installation Guide for setting up easyPheno with Docker and as a Python package: http://bioweb.me/ep-install. Besides the tutorials mentioned above on how to integrate a new prediction model and analyze results, we included additional hands-on guides and videos at http://bioweb.me/ep-tutorials. For instance, we show how to use easyPheno in combination with Docker. Furthermore, with a code walkthrough video, we support users to comprehend easyPheno’s structure. All video tutorials guiding through the framework are embedded in our documentation but can also be found on YouTube: http://bioweb.me/ep-youtube.We provide a comprehensive documentation for easyPheno, we present a comprehensive Python framework enabling the rigorous training, comparison and analysis of phenotype predictions for various models, ranging from common genomic selection approaches and classical ML to modern DL techniques. The framework allows state-of-the-art phenotype prediction also for non-programming-experts and fully automates the data pre-processing, the model optimization and the analysis of results. Further, the easy-to-extend design provides several benefits for bioinformaticians and invites other scientists to collaborate on easyPheno’s future. An additional advantage of our universal framework is the transfer to other prediction tasks with modest effort, as this only requires a re-implementation of the data pre-processing.With vbad035_Supplementary_DataClick here for additional data file.


Model-informed precision dosing (MIPD) has been shown to improve target exposure attainment. However, the clinical effectiveness of MIPD rests on the predictive accuracy of the model used. Despite increased aminoglycoside (AG) use, PK models remain sparse, leading to an ongoing search for viable models. This study aimed to determine whether the use of MIPD incorporating a PK model designed for a single AG drug could improve predictive accuracy in treatment across other AG drugs.Patient data entered into the InsightRX Nova MIPD platform during routine clinical care was de-identified and analyzed retrospectively. Patients were included for analysis if they received at least one dose of amikacin (AK), gentamicin (GM) or tobramycin (TO) and at least one therapeutic drug monitoring sample was collected within 48 hours of an administered dose. For each patient and for each model, samples were grouped by dosing interval and iteratively used to predict future levels  using Bayesian forecasting, mimicking clinical implementation of MIPD. Prediction error was assessed using root mean square error (RMSE) and percent of samples within 20% of predicted values.RMSE and percent of samples within range are shown in Figure 2 and Figure 3, respectively. For adults treated with AK (N = 145), the adult models for GM and TO and the pediatric model for GM on average performed better than the drug- and age-matched models. For adults treated with GM (N = 811), the adult AK models performed equally well as the drug- and age-matched models. For children treated with GM (N = 67), the drug- and age-matched model performed the best. For adults treated with TO (N = 239), the AK pediatric model and the adult GM model out-performed the age- and drug-matched model. For children treated with TO (N = 100), all models out-performed the age- and drug-matched model.Pharmacokinetic similarity between AGs translates to models that apply well to other drugs within this class, particularly when matching the development population age. However, there is considerable variability between models for a particular drug and age, so individual models should be validated in the intended MIPD population. Further study is needed to test the generalizability of these findings, and explore subpopulations.Jonathan Faldasz, PharmD, InsightRX: Salaried employee Jasmine Hughes, PhD, InsightRX: Employee


Cerebral venous sinus thrombosis (CVST) is a rare condition that can result in severe neurological complications when left untreated. Disease pathology results from thrombus development within the superficial cortical veins or the dural sinuses. Thrombosis impedes cerebral drainage leading to venous congestion and consequent increase in cerebral pressure, parenchymal damage, and blood-brain barrier disruption. Headache is the most common presenting symptom; other symptoms include focal neurological signs, seizures, papilledema, and altered sensorium. Diagnosis is typically made with visualization of obstructed flow in the cerebral venous system using one of three imaging modalities: computed tomography-venography (CTV), magnetic resonance imaging with venography (MRV), and diagnostic cerebral angiography. First-line therapy for CVST is anticoagulation, and the prognosis is generally favorable with early detection and prompt treatment. In this case report, we discuss a singular case of a patient presenting with loss of consciousness who was found to have CVST and treated with anticoagulation therapy in the setting of an intraparenchymal hemorrhage. Cerebral venous sinus thrombosis (CVST) is a rare condition with an approximate incidence rate of 1-2 per 100,000 person-years . PatientWithin an overview of intracranial venous drainage, blood from cerebral capillary networks collects into superficial and deep cerebral veins. The superficial and deep venous systems converge into larger dural sinuses that eventually flow into the internal jugular vein ,5-7. In Complications of CVST can be attributed to two mechanisms: increased intracranial pressure (ICP) and ischemia ,4-6. DecAdvancements in non-invasive diagnostic imaging have improved early detection and prompt intervention for CVST. Due to its rarity, it is often under-recognized and requires a high index of suspicion for appropriate diagnostics . Once diIn this case report, we discuss a male patient presenting with loss of consciousness and found incidentally to have CVST with underlying intraparenchymal hemorrhage treated with anticoagulation.We present a case of a 44-year-old gentleman with a history of hypertension and dyslipidemia. He was an on-duty correctional officer escorting an inmate to the county hospital when he collapsed in the computed tomography (CT) scanner room. The event, witnessed by staff, was described as abrupt seizure-like activity, resulting in code stroke initiation. The patient spontaneously returned to consciousness within 1-2 minutes, followed by a 15-20-minute period of disorientation. Neurological examination in the emergency room (ER) noted a Glasgow Coma Score (GCS) of 15, no focal neurological signs, and the patient demonstrating postictal confusion. Otherwise, additional neurological testing, including sensory, motor, and cranial nerve examinations, were unremarkable.Admission blood work and electrocardiogram were unremarkable. As part of the stroke workup, a non-contrast CT scan of the head revealed two small left parietal foci of intraparenchymal hemorrhage without ventricular extension, midline shift, or abnormalities of the basal cisterns Figures -1B.Additional imaging with a CT angiogram of the head and neck with contrast revealed a flow defect in the SSS, indicating sinus thrombosis Figures -2B. CT pDue to concern for heavy iodinated contrast load from multiple studies, the multidisciplinary care team made a choice for magnetic resonance (MR) over CT venography. The venogram demonstrated thrombosis in the posterior two-thirds of the SSS; two small foci of left parietal hemorrhage were also noted Figure -3E.The patient was admitted to the neuro-intensive care unit (Neuro-ICU) with heparin infusion for anticoagulation and phenytoin for seizure prophylaxis. The initial coagulopathy screen was unremarkable. Additionally, a confirmatory diagnostic cerebral angiogram, ordered to assess the extent of the disease burden, reconfirmed posterior SSS thrombosis with good venous return via multiple collaterals Figure .A subsequent repeat non-contrast CT head was stable. After two days of treatment, the care team transitioned therapy from heparin infusion to oral anticoagulation, and the patient was discharged after a full week in the inpatient ICU with a planned follow-up in the Neurology clinic. At the time of discharge, the exact etiology of the CVST was unclear as the workup for hypercoagulable states was thus far unremarkable. A more comprehensive workup was planned for the outpatient setting outside of the acute period.Most patients with CVST present with headache as the primary and often sole presenting symptom -7. ThougDue to the nonspecific clinical presentation of CVST, a high index of suspicion is necessary for diagnosis and treatment. Diagnosis requires visualization of the obstructive lesion in the cerebral venous system using three non-invasive modalities: CT-V, MR-V, and diagnostic cerebral angiography -5. MR-V The first-line therapy for CVST is anticoagulation -10. Of nContraindications for the use of heparin include thrombocytopenia, a history of heparin-induced thrombocytopenia, and the presence of active, uncontrollable bleeding . It is iRapid detection and treatment over the past decades have improved morbidity and mortality of CVST, with mortality currently estimated between 5% and 10% ,5. When This case report presents a patient with prolonged unremitting headaches and seizures secondary to CVST. The patient's hospital course highlights the various imaging modalities employed to diagnose his venous sinus thrombosis and anticoagulation therapy. Although heparin can complicate hemorrhage, it is the established first-line treatment. Due to the rarity and nonspecific presentation of venous sinus thrombosis, a high index of suspicion is necessary to include it in differential diagnoses for patients with headaches in the right clinical setting to ensure prompt management and a favorable outcome.


Web of Science, Embase, PubMed and Cochrane Library databases were searched for publications up to August 2021.The study noted clear inclusion and exclusion criteria. Search terms were provided; only observational studies were considered.A total of 122 studies were identified through the search strategy. Following deduplication, two reviewers conducted the screening.A total of 21 observational studies were included, involving cohort, case–control, and cross-sectional study designs. A meta-analysis identified increased risk of peri-implantitis in patients with diabetes mellitus and in smokers when compared to non-diabetic subjects and non-smokers. No significant association was found between poor plaque control or periodontal history and peri-implantitis.Patients with diabetes mellitus appear to have a higher risk of peri-implantitis. Li Y, Lu Z, Sun H.Biotechnol Genet Eng Rev 2023; 10.1080/02648725.2023.2184922.Impact of diabetes mellitus on the poor prognosis in patients with osseointegrated dental implants: a meta-analysis of observational studies. GRADE Rating:1. If not effectively managed, it can cause persistent hyperglycaemia. This, in turn, can give rise to a multitude of complications, including microvascular disorders, compromised bone metabolism, increased vulnerability to infections, and delayed wound healing1. Therefore, it is important to assess and maintain optimal blood glucose control before undertaking invasive and potentially costly dental procedures, such as the placement of dental implants, to ensure their long-term success and durability.Diabetes Mellitus (DM) is a complex metabolic disorder characterised by abnormalities in insulin secretion, absorption, or both, leading to significant health challengesThe objective of this meta-analysis was to examine the association between DM and implant-related conditions with an impact on their long-term prognosis, including peri-implantitis and peri-implant mucositis. The authors conducted a search across four databases to identify relevant observational studies in English, involving patients with dental implants. The study population encompassed both individuals with DM and those with normal blood glucose levels (non-DM). Data collection and extraction was carried out by two independent reviewers, with the involvement of a third reviewer in case of any disagreements.A total of 122 studies were identified. Following deduplication, ninety-six records were retrieved, thirty-five titles and abstracts were screened for eligibility and twenty-one studies were included in the meta-analysis. Among these, none of the studies were incorporated in the quantitative analysis to calculate a pooled Odds Ratio, capturing the relationship between DM and implant diseases. The combined dataset involved a cohort of 24,953 patients, with 1,526 individuals having DM and 23,427 individuals without DM. To assess any potential publication bias, an evaluation was performed utilising Begg’s test, revealing no evidence of publication bias across the included studies.p = 0.01). When compared to the non-DM group, the DM implant group displayed a 0.55-fold increased risk of developing peri-implantitis. Interestingly, the analysis did not uncover a heightened risk of peri-implant mucositis associated with DM (p = 0.34).The meta-analysis involved several outcomes of interest. Nine studies were dedicated to examining the incidence of peri-implantitis between individuals with DM and non-DM, revealing a significant association between DM and peri-implantitis (p < 0.001), increasing the likelihood of peri-implantitis by 1.754-fold compared to non-smokers. On the other hand, the analysis indicated that a history of periodontal disease was not significantly associated with peri-implantitis (p = 0.10). Similarly, plaque control did not demonstrate a significant correlation with peri-implantitis (p = 0.52).Furthermore, when investigating potential confounding factors related to peri-implantitis, smoking emerged as a significant risk factor (While this meta-analysis was well-conducted, it is important to highlight several limitations. Firstly, the absence of a registered study protocol and the lack of adherence to PRISMA guidelines may raise concerns regarding the transparency and reproducibility of the study. Moreover, the search strategy did not incorporate grey literature or manual searching, potentially limiting the comprehensiveness of the review. Additionally, the inclusion criteria failed to provide a clear distinction between type 1 and type 2 DM. Consequently, the results did not differentiate between these two groups, which may have significant clinical implications. Furthermore, there was no explicit mention of the peri-implant disease classification employed in each study or whether it was determined through clinical or radiographic confirmation. Given the existence of various globally utilised classifications, this could introduce inconsistencies in the diagnosis of implant diseases, potentially impacting the comparability of results across studies. The study selection process also raises some concerns. Although 96 studies were identified after deduplication, the subsequent removal of studies was not adequately explained. Additionally, the number of studies that underwent full-text review and were ultimately excluded remains undisclosed. Furthermore, it is worth noting that out of the total participants included, only 1526 individuals had DM, compared to 23,427 non-DM patients. This significant difference in sample size may limit the generalisability of the findings, particularly for the DM group. Lastly, one of the reported results stated that peri-implantitis among non-smokers was associated with the risk of diabetes. However, this finding appears questionable, as it is well-established that multiple factors contribute to the development of diabetes, and it is unlikely that peri-implantitis alone would significantly influence diabetes risk. The abovementioned factors should be considered when interpreting the findings of this study.2. Projections indicate that this number is expected to rise by 25% by 2030 and surpass 50% by 20452. These alarming statistics highlight the need to increase our understanding of diabetes and take proactive measures to mitigate the potential negative impact. It is important to note that DM prevalence is particularly high in urban communities and affluent nations3. These demographic factors should be considered, as dental implant procedures are frequently performed in urban populations with higher socioeconomic status. Furthermore, a significant concern is that half of all individuals living with diabetes remain undiagnosed2.The global burden of DM is staggering, with just under half a billion people worldwide currently living with this condition5.As demonstrated by this meta-analysis and other related studies, DM influences the long-term prognosis of dental implants. Notably, research has shown that diabetic patients who maintain good blood sugar control exhibit implant failure rates similar to those without diabetesTherefore, the implementation of preoperative testing for glucose control could be suggested, ideally assessing and optimising the patient’s HbA1c levels, before proceeding with dental implant placement. This approach would not only facilitate the identification of patients with diabetes but also enable timely intervention to manage glucose levels effectively, consequently improving the overall survival and prognosis of dental procedures.Practice pointsSub-optimal glycaemic control in patients with diabetes may increases the risk of peri-implantitis.Smokers are also at a higher risk of peri-implant disease compared to non-smokers.Future studies should collect longitudinal data to quantify the risks of peri-implant disease in patients with diabetes mellitus.