Corrigendum: BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

[This corrects the article DOI: 10.3389/fphar.2023.1265230.].

The Effect of Gut Microbiota-Targeted Interventions on Neuroinflammation and Motor Function in Parkinson's Disease Animal Models-A Systematic Review.

Gut microbiome-targeted interventions such as fecal transplant, prebiotics, probiotics, synbiotics, and antibiotic gut depletion are speculated to be of potential use in delaying the onset and progression of Parkinson's disease by rebalancing the gut microbiome in the context of the gut-brain axis. Our study aims to organize recent findings regarding these interventions in Parkinson's disease animal models to identify how they affect neuroinflammation and motor outcomes. A systematic literature search was applied in PubMed, Web of Science, Embase, and SCOPUS for gut microbiome-targeted non-dietary interventions. Studies that investigated gut-targeted interventions by using in vivo murine PD models to follow dopaminergic cell loss, motor tests, and neuroinflammatory markers as outcomes were considered to be eligible. A total of 1335 studies were identified in the databases, out of which 29 were found to be eligible. A narrative systematization of the resulting data was performed, and the effect direction for the outcomes was represented. Quality assessment using the SYRCLE risk of bias tool was also performed. Out of the 29 eligible studies, we found that a significant majority report that the intervention reduced the dopaminergic cell loss (82.76%, 95% CI [64.23%, 94.15%]) produced by the induction of the disease model. Also, most studies reported a reduction in microglial (87.5%, 95% CI [61.65%, 98.45%]) and astrocytic activation (84,62%, 95% CI [54.55%, 98.08%]) caused by the induction of the disease model. These results were also mirrored in the majority (96.4% 95% CI [81.65%, 99.91%]) of the studies reporting an increase in performance in behavioral motor tests. A significant limitation of the study was that insufficient information was found in the studies to assess specific causes of the risk of bias. These results show that non-dietary gut microbiome-targeted interventions can improve neuroinflammatory and motor outcomes in acute Parkinson's disease animal models. Further studies are needed to clarify if these benefits transfer to the long-term pathogenesis of the disease, which is not yet fully understood. The study had no funding source, and the protocol was registered in the PROSPERO database with the ID number CRD42023461495.

TANGO1 inhibitors reduce collagen secretion and limit tissue scarring.

Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring and fibrosis and compromise tissue function. Despite the widespread occurrence of fibrotic diseases and scarring, effective therapies are lacking. A promising approach would be to limit the amount of collagen released from hyperactive fibroblasts. We have designed membrane permeant peptide inhibitors that specifically target the primary interface between TANGO1 and cTAGE5, an interaction that is required for collagen export from endoplasmic reticulum exit sites (ERES). Application of the peptide inhibitors leads to reduced TANGO1 and cTAGE5 protein levels and a corresponding inhibition in the secretion of several ECM components, including collagens. Peptide inhibitor treatment in zebrafish results in altered tissue architecture and reduced granulation tissue formation during cutaneous wound healing. The inhibitors reduce secretion of several ECM proteins, including collagens, fibrillin and fibronectin in human dermal fibroblasts and in cells obtained from patients with a generalized fibrotic disease (scleroderma). Taken together, targeted interference of the TANGO1-cTAGE5 binding interface could enable therapeutic modulation of ERES function in ECM hypersecretion, during wound healing and fibrotic processes.

Oral frailty among dentate and edentate older adults in long-term care.

BACKGROUND: The objectives of this study were to compare oral frailty (OFr) among edentate and dentate older adults living in long-term care facilities (LTCF) and to clarify how edentulism and oral disease burden (ODB) of dentate older adults are associated with OFr. METHODS: The population of this study comprised 94 edentate and 209 dentate residents in LTCF in Helsinki, Finland, who had previously participated in a nutritional study. The participants underwent a clinical oral examination. The dentate residents were further divided into three ODB groups based on asymptotic dental score. The edentate and different ODB groups were compared with each other regarding demographics and oral and medical findings. OFr was defined as ≥ 2 of following: having a diet of soft/pureed food, residue of food in the oral cavity, inability to keep the mouth open during examination, unclearness of speech, dry mouth. The association between OFr and edentulousness and various levels of ODB was analyzed by a multivariate logistic model. RESULTS: Participants with low ODB had significantly less OFr than their edentate peers (p = 0.009). Furthermore, the edentate and dentate with high ODB had similar odds for OFr. CONCLUSIONS: Edentulousness and high ODB are equally harmful conditions and may predispose to OFr. This study suggests that maintaining healthy natural teeth and good oral health (low ODB) may protect against OFr. TRIAL REGISTRATION: The Ethics Committee of the Hospital District of Helsinki and Uusimaa approved the protocols for the nutritional status and oral healthcare studies and the merging of the data, including patient medical records (Register number HUS/968/2017).

BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.

Ophthalmic manifestations in children with tuberous sclerosis complex.

PURPOSE: To report on the ophthalmic findings in children with tuberous sclerosis complex (TSC) in southern Sweden, and to investigate the frequency of refractive errors, strabismus and cerebral visual impairment associated with this condition. METHODS: This was a retrospective cohort study including all paediatric patients with TSC in southern Sweden born between 1983 and 2020. Medical records were reviewed regarding retinal findings, visual acuity, refractive error, strabismus, full-field electroretinography results and cerebral visual impairment. RESULTS: Ophthalmological records were available for 50 of the 52 children in the region diagnosed with TSC. The mean age at the last visit was 12.4 (SD 7.2) years. Monocular visual acuity had been measured in 38 patients, and the median value did not deviate from that expected for their age in the better eye, but by -0.2 Snellen decimal acuity in the worse eye. Refractive errors were found in 62% of the patients, and strabismus in 16%. Retinal astrocytic hamartomas were found in 34% and achromatic patches in 34%. Ten of the patients on medication with vigabatrin were examined with full-field electroretinography and treatment had to be stopped or lowered in three (30%), due to a reduced response. Investigation of cerebral visual impairment had not been conducted in any of the children. CONCLUSION: Refractive errors and strabismus were common among children with TSC. None of the patients in this cohort had undergone investigation for cerebral visual impairment. The general awareness of cerebral visual impairment among ophthalmologists is poor and constitutes an important area for improvement.

The role of depression and antidepressant treatment in antihypertensive medication adherence and persistence: Utilising electronic health record data.

Higher blood pressure levels in patients with depression may be associated with lower adherence to antihypertensive medications (AHMs). Here, we use electronic health record (EHR) data from the Estonian Biobank (EstBB) to investigate the role of lifetime depression in AHM adherence and persistence. We also explore the relationship between antidepressant initiation and intraindividual change in AHM adherence among hypertension (HTN) patients with newly diagnosed depression. Diagnosis and pharmacy refill data were obtained from the National Health Insurance database. Adherence and persistence to AHMs were determined for hypertension (HTN) patients initiating treatment between 2009 and 2017 with a three-year follow-up period. Multivariable regression was used to explore the associations between depression and AHM adherence or persistence, adjusting for sociodemographic, genetic, and health-related factors. A linear mixed-effects model was used to estimate the effect of antidepressant treatment initiation on antihypertensive medication adherence, adjusting for age and sex. We identified 20,724 individuals with newly diagnosed HTN (6294 depression cases and 14,430 controls). Depression was associated with 6% lower probability of AHM adherence (OR = 0.943, 95%CI = 0.909-0.979) and 12% lower odds of AHM persistence (OR = 0.876, 95%CI = 0.821-0.936). Adjusting for sociodemographic, genetic, and health-related factors did not significantly influence these associations. AHM adherence increased 8% six months after initiating antidepressant therapy (N = 132; ß = 0.078; 95%CI = 0.025-0.131). Based on the EHR data on EstBB participants, depression is associated with lower AHM adherence and persistence. Additionally, antidepressant therapy may help improve AHM adherence in patients with depression.

Microwaved-Assisted Synthesis of Starch-Based Biopolymer Membranes for Novel Green Electrochemical Energy Storage Devices.

The investigated starch biopolymer membrane was found to be a sustainable alternative to currently reported and used separators due to its properties, which were evaluated using physicochemical characterization. The molecular dynamics of the biomembrane were analyzed using low-field nuclear magnetic resonance (LF NMR) as well as Raman and infrared spectroscopy, which proved that the chemical composition of the obtained membrane did not degrade during microwave-assisted polymerization. Easily and cheaply prepared through microwave-assisted polymerization, the starch membrane was successfully used as a biodegradable membrane separating the positive and negative electrodes in electric double-layer capacitors (EDLCs). The obtained results for the electrochemical characterization via cyclic voltammetry (CV), galvanostatic charge with potential limitation (GCPL), and electrochemical impedance spectroscopy (EIS) show a capacitance of 30 F g-1 and a resistance of 2 Ohms; moreover, the longevity of the EDLC during electrochemical floating exceeded more than 200 h or a cyclic ability of 50,000 cycles. Furthermore, due to the flexibility of the membrane, it can be easily used in novel, flexible energy storage systems. This proves that this novel biomembrane can be a significant step toward ecologically friendly energy storage devices and could be considered a cheaper alternative to currently used materials, which cannot easily biodegrade over time in comparison to biopolymers.

How Does Pruning Impact Long-Tailed Multi-Label Medical Image Classifiers?

Pruning has emerged as a powerful technique for compressing deep neural networks, reducing memory usage and inference time without significantly affecting overall performance. However, the nuanced ways in which pruning impacts model behavior are not well understood, particularly for long-tailed, multi-label datasets commonly found in clinical settings. This knowledge gap could have dangerous implications when deploying a pruned model for diagnosis, where unexpected model behavior could impact patient well-being. To fill this gap, we perform the first analysis of pruning's effect on neural networks trained to diagnose thorax diseases from chest X-rays (CXRs). On two large CXR datasets, we examine which diseases are most affected by pruning and characterize class "forgettability" based on disease frequency and co-occurrence behavior. Further, we identify individual CXRs where uncompressed and heavily pruned models disagree, known as pruning-identified exemplars (PIEs), and conduct a human reader study to evaluate their unifying qualities. We find that radiologists perceive PIEs as having more label noise, lower image quality, and higher diagnosis difficulty. This work represents a first step toward understanding the impact of pruning on model behavior in deep long-tailed, multi-label medical image classification. All code, model weights, and data access instructions can be found at https://github.com/VITA-Group/PruneCXR.

How Does Pruning Impact Long-Tailed Multi-label Medical Image Classifiers?

Pruning has emerged as a powerful technique for compressing deep neural networks, reducing memory usage and inference time without significantly affecting overall performance. However, the nuanced ways in which pruning impacts model behavior are not well understood, particularly for long-tailed, multi-label datasets commonly found in clinical settings. This knowledge gap could have dangerous implications when deploying a pruned model for diagnosis, where unexpected model behavior could impact patient well-being. To fill this gap, we perform the first analysis of pruning's effect on neural networks trained to diagnose thorax diseases from chest X-rays (CXRs). On two large CXR datasets, we examine which diseases are most affected by pruning and characterize class "forgettability" based on disease frequency and co-occurrence behavior. Further, we identify individual CXRs where uncompressed and heavily pruned models disagree, known as pruning-identified exemplars (PIEs), and conduct a human reader study to evaluate their unifying qualities. We find that radiologists perceive PIEs as having more label noise, lower image quality, and higher diagnosis difficulty. This work represents a first step toward understanding the impact of pruning on model behavior in deep long-tailed, multi-label medical image classification. All code, model weights, and data access instructions can be found at https://github.com/VITA-Group/PruneCXR.

Relationship between oral frailty, health-related quality of life, and survival among long-term care residents.

PURPOSE: We evaluated oral frailty (OFr) and its association with health-related quality of life (HRQoL), energy and protein intake, and survival among older long-term care residents. METHODS: This cross-sectional study with a 3-year follow-up for survival assessed 349 residents in long-term care facilities (73% female, mean age 82 years). We defined OFr with six signs (dry mouth, food residue on oral surfaces, unclear speech, inability to keep mouth open or pain expression during the clinical oral examination, diet pureed/soft) and OFr severity was categorized as Group 1, (mild) = 0-1 signs, Group 2 (moderate) = 2-4 signs, and Group 3 (severe) = 5-6 signs. We measured HRQoL with 15D instrument, and energy and protein intake by a 1- to 2-day food record. Mortality was retrieved from central registers on March 2021. RESULTS: Of the residents, 15% had 0-1, 67% 2-4 and 18% 5-6 OFr signs. HRQoL decreased linearly from Group 1 to Group 3. OFr correlated with such dimensions of HRQoL as mobility, eating, speech, excretion, usual activities, mental function, and vitality. We found no association between OFr categories and energy and protein intake. Survival decreased linearly from Group 1 to Group 3. CONCLUSIONS: OFr was common among older long-term care residents and OFr severity predicts poorer outcomes. The six oral signs denoting OFr may be used at the bedside to screen residents at risk for OFr.

Chemical Characteristics and Thermal Oxidative Stability of Novel Cold-Pressed Oil Blends: GC, LF NMR, and DSC Studies.

Plant oils contain a high content of unsaturated fatty acids. Studies of food products have revealed a considerable disproportion in the ratio of ω6 to ω3. This article presents information on the healthful qualities of eight new oil blends that contain a beneficial proportion of ω6 to ω3 fatty acids (5:1), as well as their degradation during heating at 170 and 200 °C. The fatty acid profile was analyzed by gas chromatography (GC), content of polar compounds and polymers of triacylglycerols by liquid chromatography (LC), water content was measured by the Karl Fischer method, and oxidative stability was measured by differential scanning calorimetry (DSC) and low-field nuclear magnetic resonance (LF NMR) methods. The results showed that during heating, the polar fraction content increased in samples heated at both analyzed temperatures compared to unheated oils. This was mainly due to the polymerization of triacylglycerols forming dimers. In some samples that were heated, particularly those heated to 200 °C, trimers were detected, however, even with the changes that were observed, the polar fraction content of the blends did not go beyond the limit. Despite the high content of unsaturated fatty acids, the analyzed blends of oils are characterized by high oxidative stability, confirmed by thermoanalytical and nuclear magnetic resonance methods. The high nutritional value as well as the oxidative stability of the developed oil blends allow them to be used in the production of food, in particular products that ensure an adequate supply of ω3 fatty acids.

Association of medication use with falls and mortality among long-term care residents: a longitudinal cohort study.

BACKGROUND: Falls in long-term care are common. The aim of our study was to explore how medication use is associated with incidence of falls, related consequences, and all-cause mortality among long-term care residents. METHODS: Five hundred thirty two long-term care residents aged 65 years or older participated in this longitudinal cohort study in 2018-2021. Data on medication use were retrieved from medical records. Polypharmacy was defined as use of 5-10 medications and excessive polypharmacy as use of > 10 medications. The numbers of falls, injuries, fractures, and hospitalizations were collected from medical records over 12 months following baseline assessment. Participants were followed for three years for mortality. All analysis were adjusted for age, sex, Charlson Comorbidity Index, Clinical dementia rating, and mobility. RESULTS: A total of 606 falls occurred during the follow-up. Falls increased significantly with the number of medications used. Fall rate was 0.84/person-years (pyrs) (95% CI 0.56 to 1.13) for the non-polypharmacy group, 1.13/pyrs (95% CI 1.01 to 1.26) for the polypharmacy group, and 1.84/pyrs (95% CI 1.60 to 2.09) for the excessive polypharmacy group. Incidence rate ratio for falls was 1.73 (95% CI 1.44 to 2.10) for opioids, 1.48 (95% CI 1.23 to 1.78) for anticholinergic medication, 0.93 (95% CI 0.70 to 1.25) for psychotropics, and 0.91 (95% CI 0.77 to 1.08) for Alzheimer medication. The three-year follow-up showed significant differences in mortality between the groups, the lowest survival rate (25%) being in the excessive polypharmacy group. CONCLUSION: Polypharmacy, opioid and anticholinergic medication use predicted incidence of falls in long-term care. The use of more than 10 medications predicted all-cause mortality. Special attention should be paid to both number and type of medications when prescribing in long-term care.

Surface guided electron FLASH radiotherapy for canine cancer patients.

BACKGROUND: During recent years FLASH radiotherapy (FLASH-RT) has shown promising results in radiation oncology, with the potential to spare normal tissue while maintaining the antitumor effects. The high speed of the FLASH-RT delivery increases the need for fast and precise motion monitoring to avoid underdosing the target. Surface guided radiotherapy (SGRT) uses surface imaging (SI) to render a 3D surface of the patient. SI provides real-time motion monitoring and has a large scanning field of view, covering off-isocentric positions. However, SI has so far only been used for human patients with conventional setup and treatment. PURPOSE: The aim of this study was to investigate the performance of SI as a motion management tool during electron FLASH-RT of canine cancer patients. METHODS: To evaluate the SI system's ability to render surfaces of fur, three fur-like blankets in white, grey, and black were used to imitate the surface of canine patients and the camera settings were optimized for each blanket. Phantom measurements using the fur blankets were carried out, simulating respiratory motion and sudden shift. Respiratory motion was simulated using the QUASAR Respiratory Motion Phantom with the fur blankets placed on the phantom platform, which moved 10 mm vertically with a simulated respiratory period of 4 s. Sudden motion was simulated with an in-house developed phantom, consisting of a platform which was moved vertically in a stepwise motion at a chosen frequency. For sudden measurements, 1, 2, 3, 4, 5, 6, 7, and 10 Hz were measured. All measurements were both carried out at the conventional source-to-surface distance (SSD) of 100 cm, and in the locally used FLASH-RT setup at SSD = 70 cm. The capability of the SI system to reproduce the simulated motion and the sampling time were evaluated. As an initial step towards clinical implementation, the feasibility of SI for surface guided FLASH-RT was evaluated for 11 canine cancer patients. RESULTS: The SI camera was capable of rendering surfaces for all blankets. The deviation between simulated and measured mean peak-to-peak breathing amplitude was within 0.6 mm for all blankets. The sampling time was generally higher for the black fur than for the white and grey fur, for the measurement of both respiratory and sudden motion. The SI system could measure sudden motion within 62.5 ms and detect motion with a frequency of 10 Hz. The feasibility study of the canine patients showed that the SI system could be an important tool to ensure patient safety. By using this system we could ensure and document that 10 out of 11 canine patients had a total vector offset from the reference setup position <2 mm immediately before and after irradiation. CONCLUSIONS: We have shown that SI can be used for surface guided FLASH-RT of canine patients. The SI system is currently not fast enough to interrupt a FLASH-RT beam while irradiating but with the short sampling time sudden motion can be detected. The beam can therefore be held just prior to irradiation, preventing treatment errors such as underdosing the target.

Comparison of two GP service provider models in older adults: a register-based follow-up study.

BACKGROUND: In Finland, there have been various strategies attempting to provide access to GPs. The 'restricted-List General Practitioner model' (rLGP) was launched in primary health care (PHC) in the city of Vantaa after the 'named General Practitioner model' (nGP) failed to provide sufficient access to GPs. This was done to improve access to GP appointments for those most needing care. AIM: To evaluate the impact of the transition from nGP to rLGP on access to non-urgent scheduled appointments among patients aged ≥75 years. DESIGN & SETTING: A register-based follow-up study in public PHC in Vantaa, Finland. METHOD: The study focused on patients aged ≥75 years who used PHC from 2004-2008. It looked at the number of non-urgent and urgent scheduled appointments, patient contacts, home visits, PHC emergency department appointments, and cancelled appointments, which were recorded 7 years before and after the transition from nGP to rLGP in 2011 and adjusted to patient-years. Non-urgent appointments were booked to the patient's own nGP or rLGP in public PHC, whereas urgent appointments could be to any GP. RESULTS: The number of non-urgent scheduled appointments to GPs was halved during the time of nGP, before launching the rLGP. Simultaneously, the number of urgent scheduled appointments more than tripled. The number of both started to plateau a year before the rLGP was launched. The number of both non-urgent and urgent scheduled appointments remained mainly at that level after rLGP was implemented. CONCLUSION: The rLGP model was unsuccessful in improving access to non-urgent scheduled appointments to GPs.

Case report: Bilateral damage to the immature optic radiation and secondary massive loss of retinal ganglion cells causing tunnel vision.

We describe the case of a 30-year-old woman, who needed a formal report on her visual impairment to seek support from society. She was born preterm, and during her neonatal period, she suffered from bilateral intraventricular hemorrhage (IVH) grade 3, a condition that can cause cerebral visual impairment (CVI) due to damage to the retro-geniculate visual pathways. Individuals with such brain damage of this severity are often restricted by cerebral palsy (CP) and intellectual disability, and thus have a limited ability to cooperate in the assessment of visual function. However, our patient was capable of providing reliable test results, and she manifested only a small island of central vision in each eye, with additional reduced visual acuities. She cooperated well in examinations involving MRI of the brain, optical coherence tomography (OCT) of retinal ganglion cells, and multi-focal visual evoked potentials, with each test providing information about potential limitations in the structural prerequisites for visual function. What distinguishes our case is the severity of the damage to the optic radiations and the massive secondary loss of most of her retinal ganglion cells (GCs). However, there is some measurable visual function, which may be due to developmental neuroplasticity during early development, when surviving GCs prioritize the central visual field. Despite her visual difficulties, she is a keen portrait painter. Our patient may be representative of, and a spokesperson for, other individuals with extensive brain damage of the same etiology, who are unable to perform perimetric tests and therefore run the risk of not being recognized as severely visually impaired, and consequently, not being given the best conditions for habilitation. OCT may serve as a helpful diagnostic tool. Aim: This study aims to describe visual behavior and practical applications of visual function in relation to structural prerequisites for visual function.