Acidimicrobiales dominated in GK and NR, unidentified Intrasporangiaceae and Solirubobacterales in NR, and Corynebacterium, Propionibacterium, and Streptomyces species in VV. The fungal phyla, Ascomycota and Basidiomycota, dominated all three sites, and harbored unique fungal taxa belonging to a wide range of fungal guilds. Physicochemical properties of the peat collected from the three sites were analyzed in association with microbial community structures in order to determine which parameters acted as the main drivers for microbial diversity. BEST analysis  showed that nitrogen (N), aluminum (Al), phosphorus (P), and potassium (K) were the most significant physicochemical drivers of actinobacterial community structure, while iron (Fe) and humification were the environmental parameters that affected the fungal communities the most. In conclusion, this study has provided some insight into the fungal and actinobacterial communities associated with three South African peatlands and the main environmental drivers that influence these communities.Peatlands are complex wetland-like ecosystems that harbor diverse microbial communities. In this study, the microbial communities  associated with an unimpacted peatland , an impacted peatland , and a developing peatland  were determined through ITS and 16S rRNA metataxonomic analyses. Unidentified  It is gmisphere ,8. It wamisphere .Sphagnum species), but that microbial communities involved in the biogeochemical cycling also need to be restored, a process that takes time. A study by Nwaishi et al. [Peatlands provide valuable ecosystem services such as hydrological buffering and climate change mitigation through carbon storage . Worldwii et al.  summarizThe occurrence of peatlands in South Africa is often considered a mystery. South Africa has a low average rainfall and a high evaporation rate up to 200%) when compared to the areas in the Northern Hemisphere with a known abundance of sphagnum-associated peatlands 00% when . Eleven Samples were obtained from three different wetland systems in the Western Cape province of South Africa: VV near Sedgefield (34.01167 S 22.90333 E), GK near Riversdale (34.02361 S 21.30333 E), and NR located on the Agulhas plain (34.74111 S 19.91222 E). The sample collection from VV is described in Strobel et al. , which f2 was added to 10 g of peat. The peat–CaCl2 was stirred and allowed to settle for 1 h. The pH meter  was calibrated (according to the manufacturer’s instructions), and the pH of the peat samples measured and recorded (in triplicate). For the samples VV5 and VV10, litmus paper was used due to the small sample size.Peat samples were submitted to Bemlab  for C, hydrogen (H), and N analysis by elemental analyzer and to the Central Analytical Facility at the Stellenbosch University for analysis of major elements by X-ray fluorescence (XRF). In order to determine the pH of the samples, 10 mL of 0.01 M CaClFor the determination of organic matter content, 20 g of peat was weighed out and dried for 24 h at 100 °C. After 24 h, the crucibles were placed in a desiccator for 30 min, allowing the samples to cool. The mass of the peat samples was recorded. The peat samples were placed in a furnace at 550 °C for 4 h. After 4 h, the crucibles were placed in a desiccator, allowing the sample to cool down, and the recorded mass and percentage of organic matter were calculated using Equation 1 .OrganicThe method described by Blackford and Chambers  was usedMetagenomic DNA was extracted using the DNeasy® PowerSoil® kit (QIAGEN) with the following modification: 1 g (instead of 0.25 g) of the sample was used for the extraction. A control (no soil) was included during the processing to ensure that no contaminants were introduced during the isolation of metagenomic DNA. In order to determine actinobacterial diversity, the actinobacterial-specific 16S rRNA gene primer pair  ,20. IlluMetataxonomic analysis was performed using QIIME v1.9.1  in a min® software  according to the developer’s instructions [p ≤ 0.05) and S ; therefore, these were included as the proxy values for actinobacteria and fungi, respectively. Secondly, separate BEST analyses were run for actinobacteria and fungi using the parameters determined using XRF. The highest significant (p ≤ 0.05) global R values of 0.676 and 0.596 were obtained from combinations of aluminum (Al), calcium (Ca), phosphorus (P), and titanium (Ti) (actinobacteria), and Al, Ca, potassium (K), P, and Ti (fungi), respectively. The parameters that were included in the final BEST analyses were selected on the highest single R values obtained. The final physicochemical dataset for actinobacterial BEST analysis was N , Al, Ca, P, Ti, K, silica (Si), iron (Fe), magnesium (Mg), humification, and pH. The final physicochemical dataset for fungal BEST analysis was S , Al, Ca, K, P, Ti, Si, Mg, Fe, humification, and pH.Statistical analyses were performed using Primer 7ructions ,27. AnalTo determine the most important drivers (and the concentrations thereof) for the selection of the microbial community structures, constrained cluster analyses (LINKTREE) were performed using Bray–Curtis similarity matrices  and the physicochemical datasets determined using BEST.Acidimicrobiales, Actinomycetales, Gaiellales, and Solirubrobacterales were present in the highest relative abundances (RA) at all three sampling sites from 0 to 50 cm depth .The actinobacterial orders cm depth , furthercm depth . An incrThe observed species richness and the predicted species richness a,b indicAscomycota, Basidiomycota, Chytridiomycota, Glomeromycota, and Zygomycota) were detected in this study, representing 20 fungal classes, 53 orders, and 248 genera. Of the phyla detected, the Ascomycota and Basidiomycota dominated all three environments .In this study, there were highly significant differences in the overall actinobacterial and fungal community compositions from the three peatlands, evidenced by ANOSIM  and visuDue to inherent differences in the geography of the sites, the depths of the peat layers, and the availability of more sophisticated sampling equipment at VV, deeper samples were taken at VV than at the other sites. The maximum depth of samples from GK and NR was 50 cm, while samples were taken up to 2000 cm at VV. The actinobacterial communities at depths > 1180 cm at VV were significantly different from those at depths ≤ 1000 cm C. It is Acidimicrobiales (families: unidentified and AKIW874), Actinomycetales , 0319-7L14 (families: unidentified), Gaiellales (family: Gaiellaceae), and Solirubrobacterales (families: unidentified and Conexibacteraceae). Interestingly, there were far more fungal OTUs in common among the three sampling sites than there were shared actinobacterial OTUs. The Ascomycota represented the majority of the shared fungal OTUs (29/42), followed by the Basidiomycota (11/42), and two groups where assignment could not be made to the phylum level  compared to the low pH levels of GK and VV. With the exception of the deep samples (≥1180 cm), ostensibly from the peatland bed, the C concentrations  ttrations F.p > 0.05) were found for the factor ‘depth’ in samples from NR or GK. Overall, the differences in the individual physicochemical parameters , an impacted peatland (GK), and a developing peatland (NR). Actinobacteria were detected at all depths of the sites studied. In a study by Aksenov et al.  which foAcidimicrobiales (AKIW874), Actinomycetales (Intrasporangiaceae), Gaiellales (Gaiellaceae), and Solirurobacteriaceae), one order dominated the GK site , and one order dominated the VV site ). These results are further corroborated through indicator species analysis, with 0319-7L14 and Gaiellales dominating in frequency (p < 0.05) in the NR samples, Acidimicrobiales occurring in the highest frequency in the GK samples, and Corynebacterium and Propionibacterium dominating in the VV samples (p < 0.05). In a study by Jenkins et al. [Arthrobacter and Micrococcus, were more prevalent in organic-rich environments, while as seen in the study reported here, the genera Streptomyces and Acidimicrobium are more prevalent in acidic soils, with the dominance of Acidimicrobiales in the GK samples likely being a result of the low pH of the peatland (pH 2.93–3.31). The presence of Propionibacterium in peat was also reported in a study by Oloo et al. [Actinomycetales families detected are well known to produce hydrolytic enzymes involved in the degradation of both plant and animal polymers, as well as the production of oxidative enzymes that play a role in the decomposition of lignocellulose, releasing dissolved organic carbon in the peat environment [Acidimicrobiales AKIW874 family, which has been proposed as an indicator taxon for watering events in a semiarid grassland [Micrococcaceae, EB1017, Agromyces, Mycobacterium, Kribbella, Streptomyces, Micrococcales, Rubrobacter, Gaiellaceae, and Solirubrobacterales. In a similar study, Zhang et al. [Gaiella, Solirubrobacter, Nocardioides, Mycobacterium, and Pseudonocardia are core members of five different soil ecosystems collected from the Heihe River Basin, China. From their bacterial community studies, Shange et al. [Solirubrobacterales  seem to be highly adaptive and have the ability to colonize different soil environments.Five different actinobacterial orders dominated the NR site  [Ascomycota occurred in the highest frequency in all three sites, further corroborating the low levels of Zygomycota detected. The fact that Mortierella species (Zygomycota) can degrade chitin, an essential component of fungal hyphae, means that this phylum most probably also plays a key role in C cycling in peatlands, but is often overlooked [Sordariomycetes, Haematonectria; Tremellomycetes, Cryptococcus), symbiotic , and saprotrophic  fungal taxa. Pathogenic and parasitic fungi are generally poor competitors when it comes to accessing C from organic matter and utilize simple sugars and other compounds from their hosts, while saprotrophs have the ability to degrade various polymers  and recalcitrant compounds  [The occurrence of the five fungal phyla detected in this study corresponds to previous studies that focused on peat soil ,43,44,45erlooked . A wide c acids) . Endophyc acids) . From a c acids) , and ectc acids) .Based on the results obtained in this study, the NR site (if not impacted by human activity) could potentially develop into a rich fen fed by groundwater and some rainfall. Unlike the more mineral-poor GK and VV peatlands, the area surrounding NR contains high concentrations of mineral deposits ,50. In aWhen statistical analyses were performed, it was found that although the samples from NR and GK were only extracted to a depth of 50 cm, the general lack of significant differences in the actinobacterial and fungal community compositions with depth at all three sites was not expected. In a study on Malaysian forest peatlands, for example, both depth (0–20 cm versus 30–50 cm) and site were both found to be significant drivers of prokaryotic community composition . Similarp ≥ 0.5, ANOVA), substantiating the designation of this peatland as a developing rich fen. Furthermore, Pearson correlations between C and LOI (0.999), C and humification (0.841), and LOI and humification (0.847) were highly significant, indicating the abundance of humified organic matter at the undisturbed VV site in comparison to the low abundance at the minerotrophic NR and degraded GK. Lower concentrations of organic matter are expected in minerotrophic fens such as NR [Although many studies have focused on peatland vegetation, it has recently been suggested that abiotic factors and not vegetation types are the primary drivers of microbial community composition in peatlands . Variousch as NR ,56 and dch as NR . The resch as NR , who als3+–siderophore complex thereby alleviates Al toxicity. One of the most abundant actinobacterial taxa present in the VV deep samples (1180–1200 cm), Streptomyces, is known to produce siderophores allowing for varying degrees of metal tolerance [Analysis of the effect of physicochemical parameters on actinobacterial and fungal community distribution showed that pH is not the main driver for selection. However, the pH of the environment could play an indirect role; for example, in acidic soils, there is an increased amount of soluble ionic metal(loid)s . In contolerance . In the olerance . Similarolerance ,12. Microlerance .Candida, Epicoccum, Trichoderma) and basidiomycetes , which according to FUNGuild classification include saprotrophs . Saprotrophic fungi are well known for their ability to decompose complex polymers, and it is therefore not surprising that humification is a primary driver for this fungal community [3+ would be reduced to Fe2+, which is more bioavailable than the oxidized form and can be toxic in high concentrations [2+ toxicity. An evaluation of the most abundant fungal taxa of the two environments showed the presence of endophytic  and ectomycorrhizal  fungi in the GK samples, versus mostly saprotrophic fungi  in the NR samples, again reflecting the ‘young’ status of the latter wetland system. Endophytes and ectomycorrhizal fungi are known to produce siderophores and other compounds to the benefit of their plant host. Siderophores can scavenge, regulate, and transport Fe into the cell, depriving competing microorganisms, including plant pathogens, of the essential micronutrient [Humification and Fe concentration were found to be the main drivers for the fungal communities at the different sites. Humification is the continuous complex transformation of humic acids in soil and peat environments. These humic acids play key roles in peatlands, including the regulation of redox processes and controlling the mobility, bioavailability, and chemical speciation of micronutrients. In the case of fungi, humic acids can be used as an energy source and their decomposition can result in the release of micronutrients in the environment . The mosommunity . In the trations . In contnutrient ,61.Ascomycota, Basidiomycota, and Zygomycota) reported for bog and fen sites in the peatlands of northwestern Minnesota [Ascomycota and Basidiomycota) of the boreal peatlands in Finland was mostly affected by the dominant tree species as well as Ca, P, and Fe availability [Overall, the LINKTREE results clearly demonstrated that the abiotic parameters that drive community profiles of different microbial groups in peatlands can be completely different. This can also be seen from the different reports in the literature, as summarized by Zhang et al. . It was innesota . The samlability . In contlability . In the lability , which flability .The work reported here has provided some insight into the differences in microbial  community structures of a developing peatland (NR) and an unimpacted peatland (VV), and how human activities can change a peatland’s microbial community structure (GK). As indicated in


Patients with chronic kidney disease undergoing hemodialysis (HD) have a high incidence of falls. Impairment of balance function is a risk factor for falls in the general elderly, and no report examining the association between balance dysfunction and fall incidence in HD patients exists.This prospective cohort study was conducted at a single center. The timed-up-and-go test (TUG) as a dynamic balance function was performed and length of the center of pressure (CoP) as a static balance function was measured before and after the HD session at baseline. Data of the number and detailed information of accidental falls for 1 year were collected. Multiple regression analyses were performed to assess the relationships between the number of falls and balance function.p < 0.001, R2 0.413) and that in the post-HD session , but not with CoP.Forty-three patients undergoing HD were enrolled in the study. During 1 year of observation, 24 (55.8%) patients experienced accidental falls. TUG time was longer, and CoP was shorter in the post-HD session than in the pre-HD session. Adjusted multiple regression analyses showed that the number of accidental falls was independently associated with TUG time in the pre-HD session .This study was carried out with the approval of the Niigata Rinko Hospital Ethics Committee   and registered in The University Hospital Medical Information Network (registration number The online version contains supplementary material available at 10.1186/s12882-022-02877-6. Patients with chronic kidney disease (CKD), especially those undergoing hemodialysis (HD), present a high frequency of falls and fractures , 2. SeveBalance dysfunction is commonly cited as a risk factor for falls in the general population , 6. DynaThis prospective observational study was conducted in a single hospital. All HD patients at Niigata Rinko Hospital from December 2019 to May 2020 were recruited. The eligibility criteria were patients aged ≥20 years who had received HD for ≥3 months and consented to participate in this study. Patients in the hospital complaining of severe hypotension during or after HD and difficulty walking were excluded from the study. Patients who died or were transferred were excluded. Patient information was collected from medical records. Age, sex, height, dry weight (DW), change of DW in a year (%), body mass index, dialysis duration, primary cause of CKD, presence of comorbidities , Charlson Comorbidity Index (CCI), serum albumin level, blood pressure before and after dialysis, single pool Kt/v for urea, water removal amount, number of medications, blood hemoglobin level, and serum intact parathyroid hormone level, Japan Cardiovascular Health Study (J-CHS) and history of fall during a year were reported as basic characteristics. The balance functions before and after the HD session were measured by a physiotherapist.An accidental fall was defined as an unexpected event in which the participants rested on the ground, floor, or lower level . DetailsThe timed-up-and-go test (TUG) evaluates dynamic balance. Patients were seated in a chair with a backrest and placed the soles of their feet on the ground. Then, they stood up at the start signal, walked to the cone 3 m away at a maximum walking speed, turned around the cone, and were seated in the chair again. This event was performed twice. The time was measured, and the faster one was adopted .Body sway was measured using a force platform . The length of the center of pressure (CoP), in the open-eye standing position, was evaluated to assess static balance. The length of CoP was the distance traveled by the foot CoP. The posture was a closed leg standing position, with both arms alongside the body and the bare feet placed on the platform plate. Data were measured once at a sampling rate of 100 Hz. The patient had a black circle set 250 cm apart and maintained a constant posture for 60 s .Each indicator is shown as median (interquartile range) and percentage (%). The participants were divided into two groups by Pre-HD TUG consisting of the faster group and the slower group, and background data were compared using Mann-Whitney U test and chi-square test. The Spearman’s rank correlation coefficient test was performed to investigate the correlation between the number of falls and balance function before and after HD. In the multiple regression analyses, the number of falls and balance function were set as the independent and dependent variables, respectively. The covariates included age, sex and CCI , 13 for This study analyzed 43 patients with HD. Table p = 0.002]. The length of CoP, an index of static balance, at pre-HD was longer than that at post-HD  . However, no correlation was found between the length of CoP and the number of accidental falls . TUG time at the pre-HD session  and post-HD session , but not CoP, were independently associated with the number of accidental falls in HD patients in the multiple regression analysis adjusted with age, sex and CCI  vs. 8.9 (7.6–10.6) s, 1.8 vs. 8This study reported the relationship between accidental falls and balance functions in patients undergoing HD treatment. The main result of this study indicated that 55.8% of HD patients experienced falls within 1 year, and TUG was associated with the frequency of falls.It has been reported that approximately 30% of community-dwelling elderly, aged ≥70 years, experience a yearly fall . In thisFactors generally affecting balance function include the visual, vestibular, somatosensory, musculoskeletal, and central nervous systems . In thisIt is critical to intervene in balance disorders to reduce the incidence of falls in HD patients. Balance training included in endurance resistance programs has been shown to improve postural balance in HD patients . It has This study has several limitations. This study comprised a small sample size at a single center. Despite these limitations, to the best of our knowledge, this is the first prospective cohort study to determine the association between balance faction and fall incidence in HD patients. Further studies are needed to confirm our results with large-scale and multicenter studies.Frequent accidental falls were observed in patients undergoing HD. Dynamic balance, but not static balance, was associated with the frequency of accidental falls. Evaluation and intervention in balance function might reduce the risk of accidental falls in HD patients.Additional file 1.Additional file 2.Additional file 3.


Biomarkers are necessary to stratify the risk of diabetic foot ulcers (DFUs). This systematic review and meta-analysis aimed to evaluate the association between the lipid profile and apolipoproteins with the risk of DFU.  A systematic search was conducted in PubMed, Scopus, Cochrane Library, and Web of Science among adult patients. Cohort and case-control studies were included. Random-effects models were used for meta-analyses, and the effects were expressed as odds ratio (OR) and their 95% confidence intervals (CIs). We evaluated publication bias through Egger's test and funnel plot.  A total of 12 cohort studies and 26 case-control studies were included, with 17076 patients. We found that the higher values of total cholesterol (TC), low-density lipoprotein (LDL), triglycerides, and lipoprotein(a) (Lp(a)) were associated with a higher risk of developing DFU . Otherwise, the lower values of HDL were associated with a higher risk of developing DFU (OR: 0.49). Publication bias was not found for associations between TC, HDL, LDL, or TG and the risk of DFU.  The high values of LDL, TC, TG, and Lp(a) and low values of HDL are associated with a higher risk of developing DFU. Furthermore, we did not find a significant association for VLDL, ApoA1, ApoB, and ApoB/ApoA1 ratio. In 2019, the global prevalence of diabetes was estimated at 9.3%, which translates to 463 million people affected by this disease. It is expected that by 2030, the prevalence will increase to 10.2% and, by 2045, to 10.9% [Three factors are usually involved in DFU formation: diabetic neuropathy, trauma with secondary infection, and arterial occlusive disease . PatientThe most feared consequence of patients with DFU is amputation, which occurs in 6 to 43% of cases . CurrentThis systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CD42022308926). In addition, we followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement  see PRI and the A systematic search on articles evaluating the association between lipid biomarkers and apolipoproteins for the risk of developing DFU was carried out on December 20, 2021, in the following databases: PubMed, Scopus, Cochrane Library, and Web of Science. The search strategy was originally built in PubMed and adapted to the other databases (see Search Strategy in Supplementary We included studies that met the following criteria: (1) evaluation of the association between lipid profile and the risk of developing a DFU, (2) case-control and cohort studies, and (3) adult patients (≥18 years). We excluded studies that were (1) case reports, (2) studies carried out in animals, (3) cross-sectional studies, (4) scoping reviews, (5) narrative reviews, (6) systematic reviews, (7) conference abstracts, and (8) letters to editors.Regarding the selection process, after applying the search strategy to each database, the results were exported to the Rayyan QCRI program . After eThere was consensus among the authors in case of discrepancies about the inclusion/exclusion of an article at any stage of the selection process. We used a data extraction sheet built in Microsoft Excel for the data extraction. The following information was extracted from the selected articles independently by four authors : number of participants, year of publication, study design, population characteristics, and association or exposure measures.Quality assessment was evaluated with the Newcastle-Ottawa Scale (NOS)  independp value >0.1 was considered as indicative of no publication bias.The publication bias assessment was evaluated through funnel plots and the Egger test . A p valThe statistical analysis was performed using Review Manager 5.4 (RevMan 5.4)  and STATA Release 17.0 . Odds ratio (OR) and corresponding 95% conﬁdence intervals (CIs) were the only effective measures used. Values expressed as medians and their interquartile ranges (IQRs) were transformed into means and their corresponding standard deviations (SDs) using Hozo's method . Chinn's2 statistic and Cochran's Q statistic. For the I2 statistic, p values ≥60% were considered a sign of severe heterogeneity, and for the Cochran's Q test, p values <0.1 were considered a sign of heterogeneity. Subgroup analyses were carried out by study location. Sensitivity analyses were performed using only studies with a low risk of bias. A p value <0.05 was considered statistically significant.We performed a random-effects meta-analysis of the reported OR in all cases. The heterogeneity of the selected studies was analyzed using the IThe systematic search yielded 1325 records, and 820 duplicates were removed. According to the eligibility criteria, after excluding articles by title and abstract and assessing their full-text documents, 38 were identified as eligible for this systematic review –59. A PRCharacteristics from all included studies are summarized in Regarding the evaluation of the quality of the studies with the NOS, 13 studies were at a low risk of bias , and the remaining 25 studies were at a high risk of bias  (Supplementary n = 9951). We found that higher values of TC were associated with higher risk of developing DFU   and other countries subgroup  did not exhibit statistically significant associations. The Chinese studies subgroup  and Indian studies subgroup ; there was only a decrease in heterogeneity in the Chinese studies subgroup. Additionally, the sensitivity analysis showed a nonstatistically significant association but with reduced heterogeneity   . Due to 2 = 88%) . The Turn = 10982). We found that lower values of HDL were associated with a higher risk of developing DFU    . Due to 2 = 88%) . All subn = 15570). We found that higher values of LDL were associated with a higher risk of developing DFU  , Indian subgroup , and other countries subgroup . Turkish studies subgroup  was the only subgroup that kept the statistically significant association and showed a significant decrease in heterogeneity. The association was not statistically significant in sensitivity analysis but with low heterogeneity   . Due to 2 = 92%) . The stan = 11128). We found that higher values of TG were associated with a higher risk of developing DFU   and other countries subgroup  were the only ones that kept the association and showed a decrease in heterogeneity. In sensitivity analysis, the association remained, and the heterogeneity decreased significantly   . Due to 2 = 89%) . The Chin = 277). We found that higher values of Lp(a) were associated with a higher risk of developing DFU  . However, no statistically significant association was found between ApoB and risk of DFU  . However, no statistically significant association was found between ApoA1 and risk of DFU  . However, no statistically significant association was found between ApoB/ApoA1 ratio and risk of DFU  . However, no statistically significant association was found between high VLDL values and risk of DFU   were associated with the development of DFU. However, there were significant regional variations regarding these associations. Most of the studies showed a high risk of bias. Moreover, in the sensitivity analysis, only the association between HDL and TG with DFU remained statistically significant, with consistently less heterogeneity.Diabetic dyslipidemia (DD) is frequent, especially among patients with type 2 diabetes mellitus, where the prevalence is higher than 75% and is mainly mixed . DD is lDD is associated with a higher risk of cardiovascular events and peripheral vascular disease compared with subjects without diabetes, since it plays a central role in the genesis and progression of atherosclerosis –62. LikeThese data are relevant to our research because both neuropathy and peripheral vascular disease are involved in the development of DFU . In thisA previously published systematic review only included four studies . HoweverAlthough we have not evaluated the effect of nutritional status on our results, its influence on the lipid profile is well-known . In thisHowever, aspects such as the possible effect of gender of the patients included in the studies have not been considered. For example, a study in Chinese diabetic patients showed that the ApoB/ApoA1 ratio predicted cardiovascular disease risk in men. In contrast, TC, LDL, ApoB, LDL/HDL, and TC/HDL were better predictors in women . In addiOur study has several limitations. First, the studies did not adjust the values of the lipid markers with the confounding variables affecting the outcome under study. To avoid confounding bias, lifestyles, sociodemographic, and comorbidity variables should be considered and adjusted in future studies. Second, most of the studies have been carried out in the Asian continent, and very few have been found in other continents. Thus, it would be essential to analyze the value of these biomarkers in the risk of DFU in other latitudes. Third, high statistical heterogeneity was found due to the methodological and clinical differences between the studies. However, heterogeneity decreased when the sensitivity analysis was performed, which only included a low risk of bias studies. Finally, due to the lack of information in the studies, the values of sensitivity, specificity, and an optimal cutoff point of lipids for the risk of DFU were not estimated in a meta-analysis, so it should be addressed in future research.High values of LDL, TC, TG, and Lp(a) and low values of HDL are associated with a higher risk of developing DFU. Furthermore, we did not find a statistically significant association for VLDL, ApoA1, ApoB, and ApoB/ApoA1 ratio. However, primary studies are needed to define the optimal cutoff point for these biomarkers according to the profile of different diabetic populations worldwide.


Cutaneous tuberculosis (CTB) is a very rare disease and accounts for only 1–2% of cases of extrapulmonary tuberculosis (EPTB). Due to the variety of its clinical manifestations, the uncharacteristic appearance of its lesions, resembling other dermatoses in the early stages, and the limited experience of clinicians due to the rarity of CTB, diagnosis is very difficult. Particularly noteworthy is the fact that most cases of EPTB, including skin tuberculosis (TB), can be a manifestation of systemic involvement. In this paper, we present a case of an immunocompromised patient who was diagnosed with CTB almost a year after the first dermatological lesions were located on the lower extremities. At the same time, due to respiratory symptoms, a diagnosis of pulmonary TB (PTB) was made, and radiological and microbiological confirmations were obtained. Mycobacterium tuberculosis complex (MTBC). It is droplet-transmitted and most commonly manifests itself in the respiratory tract (pulmonary TB–PTB). However, it can cause disease in any system or organ (extrapulmonary TB–EPTB) [Tuberculosis (TB) is a systemic infection caused by TB–EPTB) . The disTB–EPTB) . In persTB–EPTB) . A diagnTB–EPTB) .In Poland, EPTB is rarely recorded, accounting for only 4.6% of all TB cases, and most commonly involves pleural TB .Cutaneous TB (CTB) is a very rare disease comprising only 1–2% of EPTB cases ,7. CTB mDue to the variety of its clinical manifestations and the non-specific occurrence of its lesions that resemble other types of skin disease at an early stage, the diagnosis of CTB is very difficult. In addition, the limited experience of clinicians, due to the rarity of CTB, means that they often do not suspect a tuberculous aetiology and do not diagnose the patient in this direction . ImportaIn this article, we describe the case of a patient with microbiologically confirmed CTB and lesions located on the lower limb. At the initial stage of infection, the lesions were diagnosed as the result of rheumatoid nodules; thus, the patient was treated with topical steroid therapy (ineffective).Mycobacterium tuberculosis complex strains, cultured from both sites, presented an identical phenotype and genotype, suggesting that the PTB was most likely the primary disease and source of the spreading infection.During the months-long diagnostic process, PTB and CTB were diagnosed. 2) of Caucasian ethnicity, with a high fever, dyspnoea, and acute respiratory distress syndrome, was admitted to the Lower Silesian Oncology, Pulmonology and Hematology Centre after computer tomography (CT) was performed at the one of the Polish rheumatology hospitals where he had been treated for years. A CT scan (unavailable) showed pleural thickening of the apexes of both lungs, with small thick-walled cavities. Small cavities (the largest was 29 mm) appeared at the apex of the left lung.A 64-year old non-smoking man , rheumatoid arthritis (RA), and ventilation disorders caused by a significant deformation of the chest. Because of evidence of spinal instability  at the age of 14, he was treated with a spinal column stabiliser .X-ray studies were repeated every year, mainly for a bone examination of his RA or post-medical osteoporosis (with the rheumatologic indication). The patient’s performance was constantly deteriorating. The X-ray alterations of an upper lobe of the lung were observed and interpreted by rheumatologist as a systemic manifestation of AS and nontuberculous fibrosis (probably an adverse drug reaction to the disease-modifying treatment of RA and AS).Previously (about 10 months ago), skin lesions (nodules and ulcers) were identified in various locations, primarily on the limbs. Topical therapy with steroids was ineffective, and the lesions were diagnosed as the results of rheumatoid nodules. Fatigue, anorexia, and weight loss were observed later. The patient was referred to the rheumatologic hospital by a rheumatologist because of increasing bone pain and dyspnoea, as well as hypergammaglobulinaemia, proteinuria, and high leukocytosis in laboratory tests. After haematological examinations, he was diagnosed with probable plasmocytic dyscrasia . As emergency medications, the patient received aggressive glucocorticoids and cyclophosphamide. CT was then performed for the dyspnoea (see above), and the presence of cavities led to the suspicion of tuberculosis. The patient was transferred to the Lower Silesian Oncology, Pulmonology and Hematology Centre under the care of a specialist in infectious diseases and clinical immunology.Upon physical examination in our centre, we observed local lymphangitis and oedema of the extremities with atypical lesions  A,B.Bronchoalveolar lavage (BAL) was performed in May 2021 to collect a sample of material for microbiological testing of the lesions in the lungs. The clinical specimens were cultured on solid Löwenstein–Jensen (L–J) and liquid growth media in the Bactec MGIT 960 system . After 9 days of incubation on a liquid medium and after 3 weeks on the L–J medium, the growth mycobacteria’s susceptibility to first-line TB drugs was observed. The critical concentrations for the specific drugs were as follows: isoniazid (INH), 0.2 μg/mL; rifampicin (RIF), 40 μg/mL; ethambutol (EMB), 2 μg/mL; streptomycin (STR), 4 μg/mL (for the L–J medium); and INH, 0.10 μg/mL; RIF, 1.00 μg/mL; EMB, 5.00 μg/mL; STR, 1.00 μg/mL; and pyrazinamide (PZA), 100 μg/mL (for the liquid medium). During that period, swabs from the wounds located on the lower extremities were also collected for microbiological tests .Mycobacterium tuberculosis strains, susceptible to first-line TB drugs, were cultured.After several weeks, loci MIRU-VNTR  analysis [The strains cultured from the BAL samples and wound swabs were sent to the National Reference Laboratory for Tuberculosis (NRLT) for genotyping. The genetic relationship between the isolated strains was investigated by spoligotyping  and 15-analysis ,10. A 10The clinical sequelae included anaemia, hypoalbuminaemia, and paraproteinaemia with renal symptoms, a weight loss of 5 kg, and finally multiple organ dysfunction syndrome. The patient died 2 months later.CTB is a special form of TB due to its very diverse clinical presentation and the mild and chronic course of the disease, resulting from the unfavourable conditions for the growth of mycobacteria in the skin, and other factors . The lesTherefore, when diagnosing CTB, special attention should be paid not only to the phenotype of the lesions, but also to all the factors predisposing the patient to infection. Otherwise, it is easy to overlook the actual cause of the disease.Apart from the difficulties associated with a wide range of differential diagnoses, there are significant problems with the microbiological confirmation of clinically suspected CTB. Therefore, in addition to standard microbiological procedures, it is mandatory to perform molecular tests that offer high sensitivity and specificity . The impTo summarise, the presented case of a patient with CTB and PTB is an example of the systemic comorbidities  associated with immunodeficiency . In such cases, the diagnostic procedures should focus on opportunistic infections and latent infection reactivation, including TB, which may have a different manifestation in each organ because of the primary disease. The list of skin conditions is open in this context, and even allergy-specific lesions may be associated with mycobacterial infection .


M = 45.17 SD = 15.08). Main results indicated adequate psychometric properties for the Short Dark Triad of Personality scale in the Argentinian context. In addition, the three traits of the dark triad were significantly related to hostile and benevolent sexism, which indicate that one of the variables to keep addressing in order to comprise and eventually reduce prejudice towards women would be the dark triad of personality. Main results are discussed, in order to strengthen the understanding of the relationships between the dark triad and ambivalent sexism.One of the main evaluation instruments of the dark side of personality has been the Short Dark Triad of Personality (SD3), that includes Machiavellianism, Narcissism and Psychopathy traits. Although other adaptations of this scale have been made in several countries, its psychometric properties have never been tested in Argentina. Different studies addressed that dark triad scores are related to different expressions of sexist prejudice. One of the issues that have been traditionally considered to understand intimate, yet unequal relationships between men and women, is prejudice toward women. Ambivalent sexism combines two types of sexist attitudes: hostile, and benevolent sexism. While hostile sexism involves attitudes of outright intolerance towards women, benevolent sexism is defined as a set of attitudes that comprises the perception of women in a positive emotional tone. The aim of the study was to analyze the Dark Triad of Personality scale in the Argentinian context and its relationships whit ambivalent sexism. A total of 1,198 individuals residing in different regions of Argentina participated, from different genders (woman = 59.5%), from 18 to 75 years old ( Gender inequalities are an existing phenomenon in general , and ArgDifferent theoretical and methodological frames converge on personality psychology . HoweverMachiavellianism-manipulation, self-interest, cynicism, opportunism and exploitation of others-, Narcissism-egoism, need to be admired, lack of empathy, self-admiration, and grandiosity-and Psychopathy-impulsivity, callousness, antisocial behaviors, lack of remorse or guilt– scale was developed by SRP-III; NPI; Mach-IV; In order to systematically gather evidence on these personality traits, the In a recent study To date, previous research has associated Machiavellianism with hostile sexual attitudes, with promiscuity, and sexual deceptions, such as the disclosure of sexual secrets, feigned love, induced intoxication to obtain sex, and endorsement of the use of force for sexual purposes . NeverthAlso, previous research indicate that gender violence is related to narcissistic  and antiM = 45.17; SD = 15.08); 59.5% (n = 713) were female, 7.3% (n = 87) finished primary school, 22% (n = 264) high school, 42.7% (n = 512) terciario education [comparable to an Associate’s Degree], and 28% (n = 335) university education. No cases were dismissed from the total sample due to missing values, according to A cross-sectional study was conducted and a geolocated online survey was administered, with a quota sampling , accordiShort scale of the Dark Triad of Personality  to 5 . There are three dimensions, and each one has nine items: Machiavellianism , Narcissism , and Psychopathy .The survey included the following material. ity SD3; : the oriity SD3; : First, Ambivalent sexism scale (ASI): the Argentinian adaptation  and Benevolent Sexism . The reliability levels in the present study were adequate for the total scale, as well as for the dimensions that compose it: benevolent sexism (α = 0.90) and hostile sexism (α = 0.92).aptation  of the Aory ASI;  was usedory ASI; . The invQuestionnaire of sociodemographic variables (ad-hoc): participants were asked about gender, age, province of residence and educational level.Participants received no compensation for participation and their consent was requested. They were also informed that data derived from this research will be used exclusively for academic-scientific purposes, under Argentinian National Law 25.326 on the protection of personal data and anonymity insurance. The survey could be fully answered in 15 min. The geolocated survey service has been configured to guarantee that the same IP cannot send two responses to the form. Likewise, an email address was offered for any questions regarding the research.software-version 21-and AMOS program were used. The descriptive statistics of the items-mean, standard deviation, kurtosis, asymmetry-were calculated and analyzed. The factor structure of the short scale of the dark triad of personality was verified through a confirmatory factor analysis. In addition, within each subscale-Machiavellianism, narcissism and psychopathy-, item discrimination was analyzed using the item-dimension correlation, and Cronbach’s Alpha if item is deleted. To test the internal consistency of each scale, Cronbach’s Alpha statistic was used. Then, a confirmatory factor analysis was carried out to find out if the responses of the people who participated were adjusted to the three-dimensional model that theoretically possesses the construct of the dark triad of personality. Likewise, for the analysis of the external validity of the scale, correlations were made between the dark triad of personality and ambivalent sexism using Pearson’s r statistic. Finally, a t-test was performed for independent samples, in order to verify if there were differences in the levels of the dark triad of personality according to gender.To carry out the analyses, SPSS A total of 27 items from the original SD3 scale  was testx < 1.5) (five items were eliminated due to excess of kurtosis), (b) the analysis of item-total correlation of each dimension-narcissism, psychopathy, Machiavellianism–(> 0.40) (five items were removed due to low correlation with their own factor), and (c) Cronbach’s alpha if item deleted-the elimination of any item increases the internal consistency of the scale-, a scale of 15 items was obtained, with five items for each dimension of the dark triad of personality. The internal consistency of Machiavellianism (α = 0.73), narcissism (α = 0.72), and psychopathy (α = 0.71) dimensions were adequate.In general, all the items contribute adequately to the set of each subscale, since they present an adequate correlation with the total scale, and the reliability of each subscale it is not improved by eliminating any element. According to (a) the levels of kurtosis and asymmetry of each item  and benevolent sexism (r = 0.296).Subsequently, the second hypothesis of the study was tested by addressing the relation between the dark triad of personality-Narcissism, Machiavellianism, and Psychopathy-and ambivalent sexism-hostile sexism and benevolent sexism-. Pearson’s correlation coefficient was used and, as seen in t = −3.562; p < 0.01) and Psychopathy  were identified. Likewise, males obtained higher scores in Machiavellianism  than females . Similarly, those who considered themselves masculine  obtained higher scores in Psychopathy than those who considered themselves feminine . However, no differences were found regarding Narcissism.On the other hand, statistically significant differences between men and women in terms of levels of Machiavellianism  in order to provide stronger evidence for the validity of these constructs. Second, participants were recruited from social media and directed to online survey platforms. While there is previous evidence supporting these kind of procedures , maybe mFurthermore, future research should analyze the relationship between dark personality traits and other variables associated with sexism, such as gender role ideology  or partnThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.PB and EE contributed to design the present study. JU and EE organized the database. PB, EE, and JU did the statistical analysis. PB and TG wrote the first draft of the article. PB, EE, JU, and TG wrote the different sections. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The allometric scaling of the brain size and neuron number across species has been extensively studied in recent years. With the exception of primates, parrots, and songbirds, larger brains have more neurons but relatively lower neuronal densities than smaller brains. Conversely, when considering within-population variability, it has been shown that mice with larger brains do not necessarily have more neurons but rather more neurons in the brain reflect higher neuronal density. To what extent this intraspecific allometric scaling pattern of the brain applies to individuals from other species remains to be explored. Here, we investigate the allometric relationships among the sizes of the body, brain, telencephalon, cerebellum, and optic tectum, and the numbers of neurons and non-neuronal cells of the telencephalon, cerebellum, and optic tectum across 66 individuals originated from an intercross between wild and domestic chickens. Our intercross of chickens generates a population with high variation in brain size, making it an excellent model to determine the allometric scaling of the brain within population. Our results show that larger chickens have larger brains with moderately more neurons and non-neuronal cells. Yet, absolute number of neurons and non-neuronal cells correlated strongly and positively with the density of neurons and non-neuronal cells, respectively. As previously shown in mice, this scaling pattern is in stark contrast with what has been found across different species. Our findings suggest that neuronal scaling rules across species are not a simple extension of the neuronal scaling rules that apply within a species, with important implications for the evolutionary developmental origins of brain diversity. The variation in brain size has been of long-standing interest to biologists due to the cognitive and behavioral phenotypes that such variation is thought to underlie. For example, numerous studies have attempted to determine the explanatory factors underlying brain size variation among species . AlthougParoedura picta) have significantly larger brains with more neurons (Poecilia reticulata) artificially selected for larger brains have proportionally more neurons in the brain than individuals with relatively smaller brains (Mus musculus), brain size is not a good proxy for the numbers of neurons  and wild (red junglefowl) chickens, we determine whether larger individuals have larger brains with more neurons and lower neuronal density. As mentioned above, domestic chickens have larger body sizes and brain sizes than their wild counterparts . Thus, aGallus gallus, with the difference that white leghorns  have been selected to lay eggs with maximum efficiency  between one male of red junglefowl and three females of white leghorns . Each inficiency . Of the ficiency . All indsensuAfter culling, the brains of all individuals were immediately extracted and the following regions dissected: telencephalon, cerebellum, optic tectum, and brain remainder  while the telencephalon and optic tectum had similar ranges of variation in mass (1.44-fold) see . Across p < 0.01, slope = 0.253; R2 = 0.463; p < 0.01; no slope difference; p < 0.01, slope = 0.247; R2 = 0.420; p < 0.01, slope = 0.379; R2 = 0.430; p < 0.01, slope = 0.171; R2 = 0.200; p’s < 0.05; no slope differences; Brain mass and body mass were positively correlated among all individuals  but not the cerebellum   (P. picta) (M. musculus) the size of the brain was not significantly explained by the size of the body  , brown t trutta) , and gec. picta)  have ovethe body . Apart fthe body . DespiteAmong our individuals, the numbers of neurons were significantly and positively correlated with the sizes of the brain regions examined . HoweverWe also note that for the telencephalon, the number of non-neuronal cells increased at a faster rate relative to the increase observed in the mass of the telencephalon. Conversely, the number of neurons in the telencephalon increased isometrically with the size of the telencephalon. This means that larger telencephalon contains disproportionate numbers of non-neuronal cells when compared to individuals with smaller telencephalon. For the optic tectum, however, both neurons and non-neuronal cells increased in number at similar rates relative to the increase observed in the size of the optic tectum. The finding that relative numbers of neurons and non-neuronal cells increase at different rates depending on the brain region analyzed aligns with what has been found across different species  and White Leghorn (domestic) chickens. It has been shown that domestication in the chicken appears to specifically affect the anatomy of the cerebellum . White LOverall, we conclude that within a population of highly variable chickens, larger individuals tend to have larger brains and more neurons. Among chickens, neuronal density was strongly and positively associated with neuron number, an opposite scaling pattern to that observed in interspecific analyzes . The extThe original contributions presented in this study are included in the article/This animal study was reviewed and approved by the local Ethical Committee of the Swedish National Board for Laboratory Animals.DW and RH: funding acquisition. FC, DS-H, RC, DW, and RH: data collection. FC: data analysis and writing—initial draft. FC, DS-H, DW, and RH: conceptualization and writing—final draft. All authors had full access to the data in the study, take responsibility for the integrity of the data, accuracy of the data analysis, revised the initial and final draft, and gave final approval for publication.


Numerous evidence has shown that patients with chronic fatigue syndrome (CFS) have changes in resting brain functional connectivity, but there is no study on the brain network effect of Tai Chi Chuan intervention in CFS. To explore the influence of Tai Chi Chuan exercise on the causal relationship between brain functional networks in patients with CFS, 21 patients with CFS and 19 healthy controls were recruited for resting-state functional magnetic resonance imaging (rs-fMRI) scanning and 36-item Short-Form Health Survey (SF-36) scale assessment before and after 1month-long training in Tai Chi Chuan. We extracted the resting brain networks using the independent component analysis (ICA) method, analyzed the changes of FC in these networks, conducted Granger causality analysis (GCA) on it, and analyzed the correlation between the difference causality value and the SF-36 scale. Compared to the healthy control group, the SF-36 scale scores of patients with CFS were lower at baseline. Meanwhile, the causal relationship between sensorimotor network (SMN) and default mode network (DMN) was weakened. The above abnormalities could be improved by Tai Chi Chuan training for 1 month. In addition, the correlation analyses showed that the causal relationship between SMN and DMN was positively correlated with the scores of Role Physical (RP) and Bodily Pain (BP) in CFS patients, and the change of causal relationship between SMN and DMN before and after training was positively correlated with the change of BP score. The findings suggest that Tai Chi Chuan is helpful to improve the quality of life for patients with CFS. The change of Granger causality between SMN and DMN may be a readout parameter of CFS. Tai Chi Chuan may promote the functional plasticity of brain networks in patients with CFS by regulating the information transmission between them. Chronic fatigue syndrome (CFS) is a complex disease with a 0.2 to 2.6% prevalence rate in modern society . PatientIn recent years, with the proposal of central sensitization mechanism and the discovery of central nervous system's injury symptoms in CFS –10, it hIn the treatment of CFS, exercise therapy is applied as the most common measure at present –19. NevePositively, what can support our hypothesis are the research with fMRI revealing that Tai Chi Chuan promotes the plasticity of brain function. Brain plasticity refers to the ability to change brain structure and function under the influence of the environment . More evAs mentioned earlier, there are many abnormal intrinsic FCs of RSNs in CFS patients, but there is no research studying the interaction between them. A study about Tai Chi Chuan intervention in CFS is needed accordingly. Furthermore, to move beyond the identification of regional activations toward the characterization of functional circuits is a key challenge in neuroscience. Therefore, Granger causality analysis (GCA), as a powerful method to achieve this, can not only evaluate the FC of brain networks but also examine abnormal relationships among RSNs in psychiatric patients to better understand the neurobiological basis of the disorders –37. In tIn this study, 21 CFS patients  and 19 healthy subjects  were recruited from Dongzhimen Hospital, Beijing University of Chinese Medicine. They were all right-handed, aged 25 to 65, with no previous practice history of Tai Chi Chuan and no difficulty answering and filling out the questionnaire. They had not taken psychotropic drugs for nearly a month, with no metal in the body and no contraindications for MRI examination. The experimental group met the following inclusion criteria: diagnosed as CFS of the 1994 Center for Disease Control and Prevention Case Definition ; the couThe 36-item Short-Form Health Survey (SF-36) was used to evaluate the health-related quality of life (HRQoL) of all subjects, which was regarded as the main index. All subjects made a self-report with an SF-36 scale before and after training in Tai Chi Chuan. This study adopted the Chinese version translated in 1991 by the Department of Social Medicine, Zhejiang University Medical College. The scale consists of eight subscales, namely Physical Functioning (PF), Role Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE), and Mental Health (MH). The score ranges from 0 to 100. The higher the score, the better the HRQoL.Before and after training in Tai Chi Chuan, all the subjects underwent an MRI scanning in Dongzhimen Hospital of Beijing University of Chinese Medicine with a MAGNETOM Prisma magnetic resonance scanner . Before the scan, the patients were told in detail about the scanning time, scanning purpose, and precautions. After getting used to the indoor environment of MRI, they were told to rest on their backs for 30 min and wait until the participants were completely calm before starting scanning. Safety indicators  were monitored before and after each scan to evaluate the safety of the test process.The two MRI scans adopted the same scanning sequence. The participants lay flat for 30 min to maintain complete calm. Then, they were required to stay still, think of nothing, keep eyes closed and refrain from falling asleep during scanning. In the process, earplugs were worn for noise isolation and the foam head holders were immobilized to minimize head movements. After that, the T1 structure image which is for 4 min and 10 s and the DTI image which is for 5 min and 10 s were continued.Scanning parameters: fMRI was applied with echo-planar imaging (EPI) sequence: Repetition time (TR), 2000 ms; Echo time (TE), 30 ms; Matrix, 64 × 64; Field of view (Fov), 225 × 225 mm; Slice thickness, 3.5 mm; Gap, 0.7 mm; Phase encode direction, A>>P; Flip Angle, 90°; Fat suppr, Fat sat. The three-dimensional structure imaging scan of the whole brain was scanned using T1W1 sequence: TR, 1900 ms; TE, 2.53 ms; Fov, 250 × 250 mm; Matrix, 256 × 256; Slice thickness, 1.0 mm.To eliminate the influence of different training durations and frequencies, the training time of Tai Chi Chuan in the experimental group and the healthy control group were designed in the same way. Both the experimental group and the healthy control group were given Tai Chi Chuan training twice a week for 1 h each time. The whole process was under the guidance of therapists, with the exercise learning and repeated posture control training. The course of treatment was 4 weeks, with eight training courses in total. For the rest of the time, each participant was asked to practice Tai Chi Chuan for 30 min every day. Training Tai Chi Chuan standard movements referred to the 24-style simplified version of the General Administration of Sport of China and the Tai Chi Chuan's standard movements in Chinese Traditional Health Care Sports and Health Preservation, national teaching materials for colleges and universities citation. We selected three experienced Tai Chi Chuan coaches for systematic training, and let them know the intervention methods of Tai Chi Chuan and the basic knowledge of related diseases. During the experiment, Tai Chi Chuan's teaching was recorded to ensure the practice quality. After each training, the participants were reminded to carry out family Tai Chi Chuan exercises, video feedback of each exercise, and telephone follow-up supervision training during the research process.http://rfmri.org/dpabi) (All data processing was completed by DPABI (g/dpabi) .The T1 images were converted into the BIDS dataset. Then, they were corrected for intensity non-uniformity with N4BiasFieldCorrection , which wFirst, the custom methodology of fMRIPrep  was usedIndependent component analysis was applied to extract the RSNs by GIFT software . The number of independent components in all data was calculated by the method of the minimum description length (MDL) technique. Randlnit and Bootstrap operations were applied to evaluate the independent components. Then, we selected the brain networks by combining the manual selection, goodness-of-fit method , and thep = 0.05 at the cluster level was applied.To analyze the changes of FC in these six brain networks before and after Tai Chi Chuan, the images of components were normalized to Z-scores with Fisher's r-to-z transformation for acquiring the entire brain Z-score map of each subject. Meanwhile, a repeated measures model, including condition effect and interaction effect, was used to investigate the Tai Chi Chuan-induced changes in the six brain networks. The significant thresholds were set as 0.005 and family-wise error (FWE) correction for multiple comparisons at t-test in each component to compute the single network imaging. An independent t-test was used for comparison between groups and a paired t-test was used for intragroup comparison. The P-value of the t-test was set as 0.05 which was corrected by the false discovery rate (FDR) for multiple comparisons. Finally, BrainNetViewer was used to display the result onto a 3D brain surface.All the selected components were filtered between 0.01 and 0.1 Hz for multivariate Granger causal modal to explore the characteristics of networks. Meanwhile, we used the generalized partial directed coherence (GPDC) as the measured parameter . The metP < 0.05.Compared to the healthy subjects, there was a significant decrease in the causal relationship between SMN and DMN in CFS patients. However, after 1 month-long training in Tai Chi Chuan, the causal relationship between SMN and DMN in CFS patients was enhanced. Given the relevance of SMN and DMN to sensorimotor function, which could be best reflected by RP and BP scores, we conducted a correlation analysis between the mean Granger causality value of SMN-DMN and RP and BP scores in CFS patients. Statistical analyses were conducted using SPSS 20.0, and the threshold was set at In this study, 21 CFS patients  and 19 healthy people  were recruited from Dongzhimen Hospital of Beijing University of Chinese Medicine. There were 6 males and 15 females in the experimental group, with an average age of 37.47 ± 12.14 years and an average body mass index (BMI) of 21.88 ± 3.49. The healthy control group consisted of 7 males and 12 females, with an average age of 33.31 ± 12.46 years and an average BMI of 22.98 ± 2.83. There is no statistical difference in sex, age, and BMI between the two groups. Refer to P < 0.05), while there was no significant difference in the scores of MH between the two groups (P > 0.05). After 1month-long training in Tai Chi Chuan, the scores of PF, RP, BP, GH, VT, MH, SF, and RE in SF-36 in the experimental group were significantly higher than those before the training (P < 0.05). There was no obvious change in the SF-36 scale score of the healthy control group after practicing Tai Chi Chuan (P > 0.05). Refer to By observing the scores on SF-36 scale, we found that at baseline, the scores of PF, RP, BP, GH, VT, SF, and RE in the experimental group were significantly lower than those in the healthy control group . Six resting brain networks were selected, namely executive control network (ECN), VN, SMN, DMN, SN, and RFPN . The speGCA indicated that the brain networks of patients with CFS showed different functional connection modes compared with healthy subjects.P < 0.05, False Discovery Rate Correction), which was mainly manifested in the weakening of the effective connection between SMN and DMN.As shown in For healthy subjects, after 1 month of Tai Chi Chuan training, VN became the network with the most output information. The information transmission modes in the baseline state of SMN-ECN and SMN-RFPN were changed to SMN-VN-ECN and SMN-VN-RFPN, both used VN as a relay station. Interestingly, the causal relationship between RFPN and VN was reversed compared to the baseline state. However, before and after Tai Chi Chuan training, healthy subjects did not show such a significant difference in the causal relationship of brain networks .P < 0.05, False Discovery Rate Correction)  .The results showed that the mean causal value of SMN-DMN was positively correlated with the scores of RP and BP . BesidesTai Chi Chuan was introduced as an exercise therapy, which has been proved to have the ability to promote brain plasticity . AccordiIn our results, the SF-36 scale score of patients was significantly lower than that of healthy controls, which is consistent with the previous results , 47, indCFS, as a complex disorder composed of various symptoms, is related to many brain functions such as sensory, motor, and cognition. Our results showed a change in the effective connection between SMN and DMN in CFS patients compared with the healthy control group, which was in line with previous studies –16. The Gratifyingly, after a month of training in Tai Chi Chuan, the SF-36 scale reflected the improvement of HRQoL of CFS patients, and the information transmission between SMN and DMN was stronger than before. Correlation analysis also showed that the change of effective connection strength between SMN and DMN had a positive correlation with the change in physiological function. A similar effect of Tai Chi Chuan has been described in another neuroimaging study  in whichRemarkably, the reversed and strengthened causal relationship between RFPN and VN in CFS patients who often suffer from cognitive disorders –66 was aThere are still a few inconsistencies compared with previous studies –73. A prThere are also several limitations in our research. First, the sample size is relatively small. Only 21 patients and 19 healthy people were included in our study. Second, the changes in RSNs related to cognitive function were found, but the indicators related to cognitive function were lacking. Third, GCA may not distinguish the direct causality caused by the action of the intermediate network, introducing a limited result in the brain analysis. Fourth, performing a double-blind trial on physiotherapy interventions is impossible, so there might be placebo effects. Last but not least, there's no similar large sample study before for us to refer to, and the results need to be repeated. Future research should increase the sample size, improve the analysis method, supplement the correlation analysis between the changes in brain networks and the improvement of cognition function, and compare the effect of conventional exercise therapy with Tai Chi Chuan.In conclusion, we recruited patients with CFS and healthy controls for fMRI scanning before and after 1-month-long training in Tai Chi Chuan. ICA and GCA were used to extract the RSNs and the changes of FC in these networks were also analyzed. Compared to the healthy control group, the causal relationship between SMN and DMN was weakened, which could be improved by Tai Chi Chuan. The findings suggest that the change of Granger causality between SMN and DMN may be a readout parameter of CFS. Tai Chi Chuan may promote the functional plasticity of brain networks in patients with CFS by regulating the information transmission between RSNs.The original contributions presented in the study are included in the article/The study involving human participants was reviewed and approved by Medical Ethics Committee of Dongzhimen Hospital of Beijing University of Chinese Medicine. The patients/participants provided their written informed consent to participate in this study.KL and YZ: conceptualization, methodology, and formal analysis. YL, KW, XH, and TX: data collection and research performance. YL and KW: writing the original draft. KL: revising the original draft. YZ and ZL: research supervision. All authors contributed to the article and approved the submitted version.This study was supported by the National Natural Science Foundation (Grant No. 82004437) and the Beijing Natural Science Foundation (Grant No. 7204277).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Lymphoid aggregates (LA) are occasionally seen in bone marrow biopsies (BMB) of myelodysplastic syndromes (MDS) patients. Our aim was to evaluate their incidence and association with prognosis.We compared BMB reports of MDS patients treated at the Tel Aviv Sourasky Medical Center (2011-2018), and controls , and examined the charts of the MDS patients (LA+ and LA-). Categorical, normally and non-normally distributed continuous variables were compared using Fisher’s exact, independent t and Mann-Whitney tests respectively. Adjusted  Cox proportional hazard model examined survival at 12 and 24 months.MDS patients (N=140) were older than controls ; 34 MDS (24.3%) and 5 controls (13.2%) had LA+ (P=0.141). CD20/CD3 staining suggested LA polyclonality. MDS/LA+ (vs MDS/LA-) patients were younger, with a trend  towards poor prognostic parameters: lower Hb, WBC, and platelets, higher LDH, BM cellularity, and IPSS-R score. The incidence of cardiovascular disease was similar, but MDS/LA+ had twice the incidence of DM . Similar trend for cancer . Twelve-month survival: 24/34 (70.6%) MDS/LA+; 88/106 (83.0%) MDS/LA- (p=0.140). This trend, seen in Kaplan-Meier curves, disappeared at 24 months. The hazard ratio for LA was 2.283 (p=0.055) for 12 months.These preliminary data suggest LA are relatively common (24%) in MDS BMB, and might indicate poor prognosis. This may reflect involvement of the immune system in MDS. Future studies will examine larger groups, to clarify the incidence, significance and the pathophysiology. Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized by ineffective hematopoiesis, cytopenia and a likelihood of leukemic transformation , 2. BoneClusters of lymphoid aggregates (LA) are occasionally observed in BMB of patients with non-lymphoproliferative disorders. We have noticed that, in addition to the known dysplastic features, LA are commonly reported as present in BMB of patients diagnosed with myelodysplastic syndromes (MDS). While this finding is probably not specific and is not a part of the MDS diagnostic or prognostic tools, it raises several questions, including the incidence of this finding, as well as its role in the pathogenesis and possibly disease prognosis.In many non-malignant, hematological or other conditions, including systemic autoimmune diseases and infectious disorders, such as HIV, hepatitis B or C, bacterial, mycobacterial and fungal infections, LA can be seen in BMB –16. ThesOccasionally in an otherwise “normal” BM, LA can be the harbinger of a lymphoproliferative disorder that will be diagnosed later . The preThe presence of LA in MDS BMB has received little attention so far. In the few publications, the incidence ranges from 2.5 to 25% of patients , 19–22. We report here a single-institute small-scale analysis, studying the characteristics, incidence and potential prognostic role of the presence of LA in the BMB reports of an MDS patient cohort.We reviewed the medical records of patients diagnosed, followed or treated at the Tel-Aviv Sourasky Medical Center, from January 2011 through December 2018. For this retrospective analysis patients had to fulfill the following criteria: MDS Diagnosis  with an Patients were excluded from the analysis if MDS diagnosis was only suspected but not yet proven, if a baseline BMB was not available or if only an aspirate had been performed. Patients were also excluded if they had another concurrent hematologic or neoplastic disease.The controls were consecutive patients undergoing BMB as a part of a workup for unexplained anemia (2015-2017), who had an available BMB report from the time of the evaluation  that had been interpreted as normal or non-diagnostic. Control patients were excluded if they had any current hematological or oncologic disease diagnosed or present in the BM or elsewhere in the body.First, we compared the MDS patient population with the non-MDS controls with a special focus on the presence or absence of LA, as well as other demographic parameters.The main analysis was a comparison between the two MDS patient subpopulations: MDS patients whose BMB was reported to include clusters of LA (LA+), and those MDS patients in whom LA were not reported (LA-). For the comparison, we used a categorical parameter – presence or absence of LA in the baseline BMB report.The two MDS patient subpopulations were compared with regard to several baseline parameters from chart reviews at the time of diagnosis: demographic characteristics, comorbidities, medications, lab values – especially hemoglobin (Hb), mean corpuscular volume (MCV), white blood cell (WBC) count, absolute neutrophil count (ANC), lymphocyte count, lactate dehydrogenase (LDH) – BM cellularity and percentage of blast cells, international prognostic scoring system (IPSS) and IPSS-R (IPSS revised) scores. We also assessed the BM lymphoid cell characteristics using the immunohistochemistry staining reports. This staining had been performed in the clinical pathology lab of our medical center, using the Benchmark ULTRA (Roche Diagnostics) automated device and protocol.The main outcome was survival, specifically, the number/percentage of patients alive in each group at 12 and at 24 months. We also looked at the flow cytometry pattern of the BM aspirates in the subset of the patients where the data were available. We chose to focus on the CD34+ cells (stem cells). We also examined the percentage of lymphocytes in the BM, as well as the percentage of BM T cells and B cells  and the percentage of lymphocytes that were T or B cells.Comparisons were made between MDS patients and non-MDS patients and between MDS patients with and without lymphoid aggregates as described in the text. Categorical variables are summarized with count & percentages and compared between groups using Fisher’s exact test. Continuous variables are summarized with means ± standard deviation if distribution is approximately normal or with medians  if normality cannot be assumed, and comparisons between groups were performed using independent t-test or Mann Whitney test respectively.A Kaplan Meir model was applied to compare the survival at 12 and 24 months.A Cox proportional hazard model was applied to evaluate the survival adjusted for age, gender, lymphocytes, WBC and diabetes at 12 and 24 months. P values <0.05 were considered as statistically significant. Analyses were carried out using SPSS 27.0.In total, 178 patients, 140 with myelodysplastic syndromes (MDS), and 38 controls, met the criteria, and entered the study Table 1.The MDS group (n=140), included 34 patients (24.3%), in whom the BM biopsy contained lymphoid aggregates (MDS/LA+), and 106 patients without LA (MDS/LA-). Comparing the whole MDS group to the controls demonstrates a higher percentage of LA in MDS patients than in the controls: , although it failed to reach statistical significance p=0.141, Table 1.In 21 BM biopsy samples, staining had been performed for CD20 and CD3, markers of B cells and T cells, respectively. In 18 of them, both markers stained positive  on these cells was similar for the MDS/LA+ and MDS/LA- groups Table 2.In The survival of the two analyzed groups, MDS/LA+ and MDS/LA-, is demonstrated in Finally, using the Cox proportional hazard model adjusted for the most relevant variables , at 12 months lymphoid aggregates were associated with a hazard ratio (HR) greater than 2 with borderline statistical significance  in the bone marrow biopsy (BMB) specimens of MDS patients. Our study confirms the relatively higher incidence of LA in BMB of MDS patients, compared with controls . Although specific clonality assays were not performed, the positivity of both CD3 and CD20, suggests that these LA are polyclonal. In MDS patients, the percentage of total lymphocytes, B cells and T cells (by flow cytometry) was similar, irrespective of the existence of lymphoid aggregates in the BM biopsy. MDS patients with LA (MDS/LA+) were younger, but had features of worse disease: lower values of all three hematologic cell lines, higher serum LDH, BM cellularity, as well as a higher IPSS-R score and a greater percentage in the higher risk (HR) category. However, despite this tendency of poor prognostic features in the MDS/LA+ group, none of these differences reached statistical significance. This may be due to the small number of analyzed patients in our study.Scores such as IPSS and IPSS-R take into account several factors, including cytopenias, BM blasts, and basic cytogenetics, and are therefore strong predictors of mortality. Most recently, the IPSS-M score has been proposed, with the inclusion of more detailed molecular genetics .Analyzing the survival, we found that there may be increased mortality for MDS/LA+ patients during the first 12 months from diagnosis as seen in If LA proves to be significant in continued studies with larger numbers of patients, then its incorporation into existing prognostic models  may provide added value.On average, MDS/LA+ patients had approximately twice the incidence of past cancer and diabetes as compared to MDS/LA- patients, but only diabetes mellitus achieved statistical significance. The importance of this association remains to be clarified . There wDo LA in the bone marrow of MDS patients have a role in the disease pathogenesis? The likely polyclonality of the aggregates themselves as well as the polyclonality seen in the lymphoid markers on the CD34+ cells, and in the BM in general, suggests a general immune response, and the relatively high incidence may suggest a biological role. It has been proposed that they represent an immunologic stimulation as a part of the pathobiology of MDS . Indeed,Our study has several limitations. The relatively small number of patients calls for caution in evaluating the results. It could also be the reason for the lack of statistical significance. The retrospective nature of this analysis is also a limitation. We assessed the BMB reports and while we had the analyses of CD20 and CD3 in a portion of the patients, and examined the flow cytometry in the cells, we performed no additional staining or molecular studies. It is also true that these data were not available for the BM of all patients. In this study, we refer to LA as a categorical parameter. We did not examine features of the aggregates like their number, size, and location within the BM. Also, because of the nature of this retrospective study, not all of the BMB specimens were of optimal quality.The control group did not include truly healthy people. They were patients referred for a BMB for evaluation of a hematological problem, usually anemia, and their BMB was interpreted as normal. Ideally, one would like to use healthy individuals with normal BMB as controls, but they do not undergo such invasive procedures.In addition, since the MDS patients were significantly older than the healthy controls, it might be argued that hematopoietic changes were related to clonal hematopoiesis with somatic mutations that have been found to exist in the elderly , 34. HowIn summary, despite these limitations, we believe that this preliminary study teaches us several relevant lessons. LA appears to be present with a high enough incidence (24%) to warrant investigation. In our series, MDS patients with LA tended to have more baseline poor prognostic features, albeit without statistical significance. Of special interest is the association with diabetes, which should be studied further . While tThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Helsinki Committee, Tel Aviv Sourasky Medical Center. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.RB collected the data, performed the initial analysis of the data, and wrote the first draft of the paper. JBE performed the assessment of bone marrow biopsies. CGS and SK performed and analyzed the flow cytometry of the BM aspirates. GS participated in data interpretation and writing the manuscript HO and MM designed the study, supervised the analysis, wrote the subsequent drafts of the manuscript. All authors contributed to the article and approved the submitted version.


Background/Aims: The relationship between the efficacy of metformin and the prognosis of patients with head and neck cancer (HNC) was still unclear. This study aims to clarify the prognostic value of metformin treatment using meta-analysis.Methods: Studies related to HNC prognosis and metformin were searched in Cochrane Library, Embase, LILACS, MEDLINE and PubMed databases. A meta-analysis was performed to evaluate the association between metformin therapy and the prognosis of HNC on overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS) and whether article quality, comorbidities, age, region or smoking had an influence on the prognosis of metformin treatment. Pooled hazard ratio (HR) and 95% confidence interval (CI) were analyzed to assess the effect.Results: Eleven eligible studies involving 14,694 participants were included. Metformin increased the OS , but failed on DFS  or DSS  in HNC patients. Subgroup analysis showed metformin was associated with improved OS , DFS  and DSS  in studies with higher Newcastle-Ottawa Scale (NOS) scores. Subgroup analysis of age indicated that patients younger than 65 years  were more likely to benefit from metformin treatment. Subgroup analysis of comorbidities showed metformin significantly improved patient outcomes in studies without adjusted for comorbidities , but not in studies that adjusted for comorbidities.Conclusions: Metformin improved the prognosis of HNC patients as an adjuvant therapy, especially in those with higher NOS scores. Age and comorbidities of HNC patients influenced the therapeutic effect of metformin. Further well-conducted investigations are needed. Head and neck cancer (HNC) is used to describe cancers that occur in the larynx, nasal cavity, oral cavity, paranasal sinuses, throat, as well as salivary glands. Most HNCs are squamous cell carcinomas . HNC is p = 0.413). However, this meta-analysis missed three studies . The inclusion criteria were defined as follows: 1) The population is patients with head and neck cancer; 2) Metformin is used as adjuvant therapy; 3) Metformin is associated with head and neck cancer; 4) Clinical research. The exclusion criteria were defined as follows: 1) Cell culture and animal experiments; 2) Article does not contain survival data; 3) Published not in English; 4) Data overlap.The literature retrieval and screening were conducted independently by two authors (Jiao and Sun). If there is an unidentified document between the two authors, the third author (Chen) will make a decision based on the inclusion criteria.An author (YJ) selected the required information from the selected studies: author, publication year, country, sample size, study design, stage/location, the mean or median age of metformin, outcomes, definition of metformin exposure, follow-up (months), adjusted variables, results and conclusions. If there was no original data required for meta-analysis in the article, we sent an email to the corresponding author or calculated from the data extracted from Kaplan-Meier curves using the method given by Jayne F Tierney . The secIt is worth noting that: first, in Yung-An Tsou’s article, the number of people in the metformin treatment group and the control group in the abstract was inconsistent with the number in the results. After communicating with the author, the correct value was confirmed . Second,Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of non-randomized studies . The qua2 statistics. I2 values of 25%, 50%, and 75% were considered as low, moderate, and high heterogeneity, respectively  was obvious. A sensitivity analysis was performed by deleting one study at a time to evaluate the impact of each study on heterogeneity. Alexandra E Quimby’s article was considered to be the main reason for the high heterogeneity. After excluding this article, the heterogeneity was reduced , and the results were not greatly affected .The heterogeneity of OS , DFS  and DSS .The average score of NOS was 7.18. Studies with NOS > 7.18 were considered to belong to the high-quality group, and studies with NOS < 7.18 were classified as low-quality group. Four of the 11 studies were classified into the high-quality group . In the p = 0.002; DSS, HR = 0.38, 95% CI: 0.22–0.65, p = 0.0004), but not in studies that adjusted for comorbidities.Subgroup analysis based on comorbidity showed that metformin significantly improved patient outcomes in studies without adjusted for comorbidities , DFS , and DSS  showed that although it was not statistically significant, metformin was associated with better prognosis only in Asian HNC patients.When analyzing populations in different regions, OS .Subgroup analysis with the 65-year-old showed a better prognosis in the metformin group in the population under 65-years-old , DFS , DSS .In addition, subgroup analysis of adjusted smoking indicated that although there was no statistically significant difference between the use and non-use of metformin on OS  suggested that there was no publication bias.The funnel plots  and Beggp = 0.05).This systematic review and meta-analysis investigated the effect of metformin on HNC patients concerning survival. Our study demonstrated that metformin significantly prolonged the survival of HNC patients for the study of OS analysis. Especially, the survival benefit showed more obscure in studies with high-quality and among patients without comorbidity. In addition, it was worth noting that the efficacy of metformin therapy seems to be better for Asian HNC patients, although there was no statistical significance, there was a corresponding trend , but not in studies that adjusted for comorbidities. This suggested that metformin use was associated with diabetes, and that HNC patients with previously diagnosed diabetes may have a better prognosis. However, the result made the impact of metformin on the prognosis of HNC patients confusing. Of the 11 studies, three were performed only in patients with type 2 diabetes (Many HNC patients used metformin because of type 2 diabetes mellitus. In a subgroup analysis of comorbidities, mainly diabetes, metformin significantly improved patient outcomes in studies without adjusted for comorbidities (OS, HR = 0.66, 95% CI: 0.51–0.85, diabetes , and allMany reviews showed that metformin adjuvant treatment significantly associated with a survival benefit for Asian cancer patients . SubgrouSmoking is an important factor affecting the prognosis of patients with HNC. Subgroup analysis by adjusted smoking suggested that there was a trend that those who accepted metformin therapy lived longer than those who did not.Several limitations of this study should be considered in this meta-analysis. First, only 11 cohort studies were included. Although we included more studies than that in the meta-analysis performed by Wang, it was still insufficient. Second, the influence of confounding factors on the results was beyond control. Third, measurement errors were unavoidable. Fourth, the dose and exposure time of metformin and the survival rate of HNC patients were unable to determine. The last, the effect of the interaction between metformin and other drugs or treatments on the outcome was unable to evaluate.This systematic review and meta-analysis showed that metformin had a significant improvement in overall survival of HNC patients, thus supporting metformin as an adjunct to the treatment of head and neck cancer. Especially, the efficacy of metformin in the high-quality group was more significant than that in the low-quality group. In a subgroup analysis of comorbidities, mainly diabetes, metformin significantly improved patient outcomes in studies without adjusted for comorbidities, but not in studies that adjusted for comorbidities. It is necessary to study the effect of metformin on the prognosis of HNC patients in the population without diabetes in the future. In addition, Asian HNC patients seemed to be more likely to benefit from the metformin therapy. However, the quantitative limitation of studies undermined the power of the analysis. There is a need for further studies with large sample sizes to investigate the relationship between metformin and the survival of HNC patients.