Histological Outcomes Research Articles

Muscle regeneration is not impaired by ablation of UCP-1-expressing cells

INTRODUCTION: Recently, cells expressing uncoupling protein 1 (UCP-1) have been proposed to impact muscle physiology. First, transplant of brown adipose tissue (which has high expression of UCP-1) enhanced regeneration in the injured mouse rotator cuff. Second, isolated UCP-1+ muscle fibroadipogenic progenitors (FAPs) treated to enhance UCP-1 expression improved injured mouse rotator cuff muscle pathology. However, it remains unknown whether endogenous UCP-1-expressing cells contribute to muscle regeneration. Therefore, the objective of this study was to assess whether mice that lack UCP-1-expressing cells demonstrate impaired muscle regeneration following toxin administration. METHODS: Experiments were performed using tibialis anterior (TA) and 5th toe extensor digitorum longus (EDL) muscle of wild type C57BL/6J (WT; n=22), and uncoupling protein 1 diphtheria Toxin A (UCP1-DTA; n=18) mice, which lack all UCP-1 expressing cells. All procedures were performed in accordance with the National Institute of Health’s Guide for the Use and Care of Laboratory Animals and were approved by Washington University School of Medicine IACUC. Muscle injury was induced using intramuscular injection of 50%v/v solution of glycerol. Regeneration was assessed at “early” (7 days post-injury (dpi)), “intermediate” (14 dpi) and “late” (21 dpi) stages. Outcome measures were cell population dynamics by flow cytometry, ex-vivo physiology testing and histological scoring as appropriate for each timepoint. RESULTS: Our preliminary data in early regeneration show that UCP1-DTA mice have significantly greater percentage of FAPs compared to WT mice (29.84 ± 1.24% higher cell population, p<0.0134), however no differences in muscle satellite (stem) cells between genotypes. Physiological and histological outcomes at intermediate and late-stage regeneration find a baseline deficit in muscle mass (23.69 ± 2.3% smaller, p<0.0001), type 2B fiber cross-sectional area (32.56 ± 4.8% smaller, p<0.0001) and normalized muscle active force generation (16.2 ± 3.3% lower force, p<0.0154) in UCP1-DTA compared with WT. However, mass and contractile forces recover to a similar extent between the genotypes following glycerol injection suggesting the phenotypic drivers of the reduced mass and contractile function do not affect muscle regeneration. CONCLUSIONS: Taken together, the data from this study point to a baseline growth deficit in mice lacking UCP-1-expressing cells. However, in two separate timepoints of regeneration (14 and 21dpi), we see that UCP1-DTA mice have similar recovery of mass and normalized contractile force to baseline values suggesting regeneration can proceed normally without UCP-1 expressing cells. However, further data collection will be needed at early-stage regeneration to help discern whether mice lacking UCP-1-expressing cells have initial changes in cell population dynamics given the increased FAP population at 7dpi. ACKNOWLEDGMENTS: This work was supported by R01AR075773 and R21AR071582 to GAM. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Clinical, Radiographic, and Histologic Outcomes of Regenerative Endodontic Treatment in Human Immature Teeth Using Different Biological Scaffolds: A Systematic Review and Meta-analysis.

Biological scaffolds such as blood clot (BC), platelet-rich plasma (PRP), platelet- rich fibrin (PRF), and platelet pellet (PP) are used in regenerative endodontic treatments (RETs). To systematically and quantitatively evaluate clinical, radiographic, and histologic outcomes of RET studies using different biological scaffolds. MEDLINE, Scopus, Cochrane library, and Embase were searched to identify studies on RET procedures with any scaffold type performed on immature non-vital human teeth, employing any type of biological scaffold. Clinical, radiographic, and histologic outcomes were extracted. Cochrane collaboration risk of bias tool and Newcastle-Ottawa scale were used for quality assessment. Random and fixed model meta-analysis was carried out with 95% confidence interval. Thirty-two studies were included in the qualitative analysis from the primarily retrieved 1895 studies. Only one study had high risk of bias and 71.8% of the studies had high quality. None of the studies reported any histologic findings. Thirty studies were included in meta-analysis. Clinical success rate of RET using either BC, PRP, or PRF was >99%. Furthermore, 32%, 23%, and 27% of BC, PRP, and PRF cases regained vitality, respectively. Periapical healing was seen in 67%, 75%, and 100% of BC, PRP, and PRF cases, respectively. There was no statistical difference between BC, PRP, or PRF regarding clinical success or any radiographic outcomes. There was no significant difference between BC, PRP, and PRF in terms of clinical and radiographic outcomes. When it is difficult or dangerous to induce bleeding in root canals, PRP and PRF may be employed instead.

Immune checkpoint markers and tumour mutation burden in Wilms tumour: a study of 59 cases

Wilms tumour (WT) is the most common renal tumour in children, and studies of immune checkpoint inhibitors (ICIs) treatment and markers are limited in number. In this study we investigated the ICIs' related immune landscape by examining the expression of PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) proteins by immunohistochemistry (IHC), tumour mutation burden (TMB), and correlations with histology and clinical outcome. Positive PD-L1 (SP263) expression was defined as modified combined positive score (CPS) ≥1. A total of 59 WTs (from 2000 to 2017), including eight (14.0%) with anaplasia, from 46 patients were analysed (45 primary and 14 metastatic). Thirteen WTs (13/59, 22%) were positive for PD-L1 (8 primary, 5 metastatic; CPS 1.11-3.42). Positive PD-L1 expression was associated with diffuse anaplasia (p<0.05) and significantly shorter progression-free survival (p<0.05) among WTs with favourable histology (n=39). CD8+ lymphocytes were present in all analysed WTs. A subset of CD8+ cells co-expressed PD-1, which was associated with favourable histology and treatment. MMR IHC stains identified two (2/18, 11%) WTs with isolated PMS2 loss. All six WTs analysed for TMB showed low mutation burden. We found CD8+ lymphocytes in all analysed WTs and identified a fraction of WT (17.8% of primary and 35.8% of metastatic) with positive PD-L1 CPS, suggesting potential response to ICIs in some patients.

Histological Outcome of Conjunctival Lesions at a Tertiary Hospital in North East Nigeria

Objective: The objective of this study was to determine the relative frequency of histologically diagnosed conjunctival lesions at a tertiary hospital over a 12-month period. Methods: It was a prospective study in which all patients who presented to the ophthalmology clinic with suspicious conjunctival lesions between January and December 2022 were recruited. Data recorded were age, sex, duration of the growth and the affected eye. All the patients underwent basic ocular examination and an examination of the growth to document its site and size. Lesions were excised in the operating theatre under anaesthesia. The excised tissue was preserved in a formalin bottle and sent for histology. Data were entered into Excel and analysed using SPSS version 20.0. Results: A total of 73 eyes were recruited during the period of study. There were 41 males (56.2%) with M:F ratio of 1.3:1. Mean age was 38.44 ± 19.07 years with a range of 2–77 years. Forty patients (54.8%) presented with lesions in the right eye and 33 (45.2%) in the left eye. Fifteen types of conjunctival lesions were diagnosed, including pterygium 37%, conjunctival intraepithelial neoplasia 2.7%, melanoma 2.7%, ocular surface squamous neoplasia 4.1% and squamous cell carcinoma 4.1%, respectively. Conclusion: Pterygium was the most common benign lesion in this study. When conjunctival lesions appear suspicious, it is of utmost importance for the surgeons to differentiate between benign, premalignant and malignant lesions as this may aid in prompt patient management as well as better outcomes.

Treatment with inhaled Argon: a systematic review of pre-clinical and clinical studies with meta-analysis on neuroprotective effect

Argon (Ar) has been proposed as a potential therapeutic agent in multiple clinical conditions, specifically in organ protection. However, conflicting data on pre-clinical models, together with a great variability in Ar administration protocols and outcome assessments, have been reported. The aim of this study was to review evidence on treatment with Ar, with an extensive investigation on its neuroprotective effect, and to summarise all tested administration protocols. Using the PubMed database, all existing pre-clinical and clinical studies on the treatment with Ar were systematically reviewed (registration: https://doi.org/10.17605/OSF.IO/7983D). Study titles and abstracts were screened, extracting data from relevant studies post full-text review. Exclusion criteria included absence of full text and non-English language. Furthermore, meta-analysis was also performed to assess Ar potential as neuroprotectant agent in different clinical conditions: cardiac arrest, traumatic brain injury, ischemic stroke, perinatal hypoxic-ischemic encephalopathy, subarachnoid haemorrhage. Standardised mean differences for neurological, cognitive and locomotor, histological, and physiological measures were evaluated, through appropriate tests, clinical, and laboratory variables. Invivo studies were evaluated for risk of bias using the Systematic Review Center for Laboratory Animal Experimentation tool, while invitro studies underwent assessment with a tool developed by the Office of Health Assessment and Translation. The systematic review detected 60 experimental studies (16 invitro, 7 exvivo, 31 invivo, 6 with both invitro and invivo) investigating the role of Ar. Only one clinical study was found. Data from six invitro and nineteen invivo studies were included in the meta-analyses. In pre-clinical models, Ar administration resulted in improved neurological, cognitive and locomotor, and histological outcomes without any change in physiological parameters (i.e., absence of adverse events). This systematic review and meta-analysis based on experimental studies supports the neuroprotective effect of Ar, thus providing a rationale for potential translation of Ar treatment in humans. Despite adherence to established guidelines and methodologies, limitations in data availability prevented further analyses to investigate potential sources of heterogeneity due to study design. This study was funded in part by Italian Ministry of Health-Current researchIRCCS and by Ministero della Salute Italiano, Ricerca Finalizzata, project no. RF 2019-12371416.

Shift from Pro- to Anti-Inflammatory Phase in Pelvic Floor Muscles at Postpartum Matches Histological Signs of Regeneration in Multiparous Rabbits.

Background and Objectives: Pelvic floor muscles (PFM) play a core role in defecation and micturition. Weakening of PFM underlies urogynecological disorders such as pelvic organ prolapse and stress urinary incontinence. Vaginal delivery damages PFM. Muscle trauma implies an inflammatory response mediated by myeloid cells, essential for subsequent recovery. Molecular signaling characterizing the pro-inflammatory phase shifts M1 macrophages to M2 macrophages, which modulate muscle repair. The present study aimed to evaluate histological characteristics and the presence of M1 and M2 macrophages in bulbospongiosus (Bsm) and pubococcygeus muscles (Pcm). Materials and Methods: Muscles from young nulliparous (N) and multiparous rabbits on postpartum days three (M3) and twenty (M20) were excised and histologically processed to measure the myofiber cross-sectional area (CSA) and count the centralized myonuclei in hematoxylin-eosinstained sections. Using immunohistochemistry, M1 and M2 macrophages were estimated in muscle sections. Kruskal-Wallis or one-way ANOVA testing, followed by post hoc tests, were conducted to identify significant differences (p < 0.05). Results: The myofiber CSA of both the Bsm and Pcm of the M3 group were more extensive than those of the N and M20 groups. Centralized myonuclei estimated in sections from both muscles of M20 rabbits were higher than those of N rabbits. Such histological outcomes matched significant increases in HLA-DR immunostaining in M3 rabbits with the CD206 immunostaining in muscle sections from M20 rabbits. Conclusions: A shift from the pro- to anti-inflammatory phase in the bulbospongiosus and pubococcygeus muscles of multiparous rabbits matches with centralized myonuclei, suggesting the ongoing regeneration of muscles.

TXNIP knockdown protects rats against bupivacaine-induced spinal neurotoxicity via the inhibition of oxidative stress and apoptosis

Bupivacaine (BUP) is an anesthetic commonly used in clinical practice that when used for spinal anesthesia, might exert neurotoxic effects. Thioredoxin-interacting protein (TXNIP) is a member of the α-arrestin protein superfamily that binds covalently to thioredoxin (TRX) to inhibit its function, leading to increased oxidative stress and activation of apoptosis. The role of TXNIP in BUP-induced oxidative stress and apoptosis remains to be elucidated. In this context, the present study aimed to explore the effects of TXNIP knockdown on BUP-induced oxidative stress and apoptosis in the spinal cord of rats and in PC12 cells through the transfection of adeno-associated virus-TXNIP short hairpin RNA (AAV-TXNIP shRNA) and siRNA-TXNIP, respectively. In vivo, a rat model of spinal neurotoxicity was established by intrathecally injecting rats with BUP. The BUP + TXNIP shRNA and the BUP + Control shRNA groups of rats were injected with an AAV carrying the TXNIP shRNA and the Control shRNA, respectively, into the subarachnoid space four weeks prior to BUP treatment. The Basso, Beattie & Bresnahan (BBB) locomotor rating score, % MPE of TFL, H&E staining, and Nissl staining analyses were conducted. In vitro, 0.8 mM BUP was determined by CCK-8 assay to establish a cytotoxicity model in PC12 cells. Transfection with siRNA-TXNIP was carried out to suppress TXNIP expression prior to exposing PC12 cells to BUP. The results revealed that BUP effectively induced neurological behavioral dysfunction and neuronal damage and death in the spinal cord of the rats. Similarly, BUP triggered cytotoxicity and apoptosis in PC12 cells. In addition, treated with BUP both in vitro and in vivo exhibited upregulated TXNIP expression and increased oxidative stress and apoptosis. Interestingly, TXNIP knockdown in the spinal cord of rats through transfection of AAV-TXNIP shRNA exerted a protective effect against BUP-induced spinal neurotoxicity by ameliorating behavioral and histological outcomes and promoting the survival of spinal cord neurons. Similarly, transfection with siRNA-TXNIP mitigated BUP-induced cytotoxicity in PC12 cells. In addition, TXNIP knockdown mitigated the upregulation of ROS, MDA, Bax, and cleaved caspase-3 and restored the downregulation of GSH, SOD, CAT, GPX4, and Bcl2 induced upon BUP exposure. These findings suggested that TXNIP knockdown protected against BUP-induced spinal neurotoxicity by suppressing oxidative stress and apoptosis. In summary, TXNIP could be a central signaling hub that positively regulates oxidative stress and apoptosis during neuronal damage, which renders TXNIP a promising target for treatment strategies against BUP-induced spinal neurotoxicity.

Phallus preservation and reconstruction: 5-year outcomes of national penile cancer centralisation in the Republic of Ireland

IntroductionPenile cancer is a rare urological malignancy with an age-standardised incidence of 0.8 per 100,000 person-years [1]. Given this low incidence it has been suggested that centralised care may improve patient outcomes in relation to phallus sparing surgery and nodal assessment [2]. We aim to assess the outcomes after 5-years of national centralisation of penile cancer care. MethodsA retrospective analysis of prospectively collected data was performed. All patients undergoing penile cancer surgery from January 2018 to December 2022 following centralisation of care were included. The primary outcome was proportion of phallus sparing procedures performed. Secondary outcomes were patient characteristics, histologic outcomes and procedures performed. Results124 patients underwent surgery in the study period. Mean age was 64.49 (±13.87). Overall, 82.3% of patients underwent phallus sparing surgery. This remained stable over the 5-year period from 2018 to 2022 ​at 92%, 85%, 76%, 79% and 78% respectively (p ​= ​0.534). 62.7% had reconstruction performed, including split-thickness skin graft neoglans formation, (57.8% [n ​= ​37]), preputial flap (32.8% [n ​= ​21]), glans resurfacing (4.7% [n ​= ​3]), shaft advancement flap (1.6% [n ​= ​1]), penile shaft skin graft (1.6% [n ​= ​1]), and partial penectomy with urethral centralisation (1.6% [n ​= ​1]). Phallus preservation was not affected by positive nodal status (OR 0.75 [95% CI 0.249–2.266], p ​= ​0.564) or T-stage ≥1b (OR 0.51 [95% CI 0.153–1.711], p ​= ​0.276). There has been a significant reduction in Nx nodal status from 64% in 2017 to 15% in 2021 (p ​= ​0.009). ConclusionCentralisation of treatment for rare malignancies such as penile cancer may improve oncologic outcomes and rates of phallus preservation. This study has shown centralisation to has a high rate of phallus preservation. Further long-term analysis of outcomes in Ireland is required.

A CT-based radiomics nomogram for predicting histologic grade and outcome in chondrosarcoma

ObjectiveThe preoperative identification of tumor grade in chondrosarcoma (CS) is crucial for devising effective treatment strategies and predicting outcomes. The study aims to build and validate a CT-based radiomics nomogram (RN) for the preoperative identification of tumor grade in CS, and to evaluate the correlation between the RN-predicted tumor grade and postoperative outcome.MethodsA total of 196 patients (139 in the training cohort and 57 in the external validation cohort) were derived from three different centers. A clinical model, radiomics signature (RS) and RN (which combines significant clinical factors and RS) were developed and validated to assess their ability to distinguish low-grade from high-grade CS with area under the curve (AUC). Additionally, Kaplan-Meier survival analysis was applied to examine the association between RN-predicted tumor grade and recurrence-free survival (RFS) of CS. The predictive accuracy of the RN was evaluated using Harrell’s concordance index (C-index), hazard ratio (HR) and AUC.ResultsSize, endosteal scalloping and active periostitis were selected to build the clinical model. Three radiomics features, based on CT images, were selected to construct the RS. Both the RN (AUC, 0.842) and RS (AUC, 0.835) were superior to the clinical model (AUC, 0.776) in the validation set (P = 0.003, 0.040, respectively). A correlation between Nomogram score (Nomo-score, derived from RN) and RFS was observed through Kaplan-Meier survival analysis in the training and test cohorts (log-rank P < 0.050). Patients with high Nomo-score tumors were 2.669 times more likely to suffer recurrence than those with low Nomo-score tumors (HR, 2.669, P < 0.001).ConclusionsThe CT-based RN performed well in predicting both the histologic grade and outcome of CS.

Sellar metastasis: A rare intraoperative finding – surgical treatment, strategies and outcome

ObjectiveThe sellar region, though uncommon for metastatic spread, may become more prevalent due to longer survival of patients with metastatic malignancies. Compression of adjacent vital anatomy can cause disabling symptoms and endocrine disturbances, leading to significant morbidity MethodsThis study analyzed sellar pathologies treated via endonasal approach from January 2011 to December 2021 to assess the incidence of sellar metastases. Patient demographics, presenting symptoms, radiological and histological findings, management, and outcomes were evaluated ResultsAmong 334 patients treated during the study period, eight (2.3 %) had metastases confirmed histopathologically, with one having a known malignant tumor history. Preoperative imaging suspected malignancy or metastasis in two cases. Diagnosis was unexpectedly confirmed in 57 % of cases. Subtotal resection was achieved in three cases, near-total resection in one. Mean follow-up was 2.4 years, with 71 % mortality ConclusionsThe sellar region can manifest metastatic disease, with sellar symptoms potentially indicating neoplastic disease onset. Rapid hormonal dysfunction or ophthalmoplegia suggests metastasis, even without a known primary. Further meta analysis of reported cases is necessary to determine the incidence and optimal treatment of these rare metastases.

Determination of the Effects of Ankaferd Wound Dressing on the Wound Healing Process in Rats.

The effects of a composite nanofiber wound dressing material consisting of a polyvinylidene alcohol and polyvinylidene pyrrolidone polymer mixture with a hemostatic agent doped with Ankaferd Blood Stopper (ABS) on the healing of experimentally induced dermal wounds in rats were examined. Rats were divided into 4 groups (n= 6). Histological material was examined on tissues taken from the wound site, whereas total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) analyses were performed on blood samples taken from the cardia. The material that was produced had hydrophilic properties, and both the ABS-doped and-undoped forms of the material positively affected wound healing. In the histopathological examinations, macroscopic evaluations revealed a statistically significant difference between the groups in terms of wound diameter, reepithelialization, and inflammation formation (p= 0.019). In parallel with wound healing and histological outcomes, TAS values increased in the ABS-doped groups, and TOS and OSI values decreased in the wound dressing groups (p < 0.05). It was concluded that the ABS-dopped dressing did not have a negative effect on wound healing, it accelerated healing, and it could be used effectively and safely to treat skin injuries. However, further studies are needed to evaluate the clinical and histopathological benefits and potential adverse effects of wound dressings produced using ABS-doped polymers on wound healing.

108 A Translational Approach to Suppress Local Inflammation in the Ischemic Penumbra and Deliver Local Anti-platelet Activity After Stroke

INTRODUCTION: Mechanical thrombectomy is the standard of care for ischemic stroke, but there is a significant mismatch between successful recanalization and clinical outcomes. Inflammation in the ischemic penumbra remains a target for neuroprotective interventions even in recanalized and non-recanalized patients. P-selectin (Psel) is a marker of endothelial cell activation and could be used to deliver therapeutics locally to the site of ischemic injury. METHODS: The fusion protein Pselectin-Crry was constructed using single chain antibody sequence linked to the extracellular region of mouse Crry. In-vivo testing using surface plasmon resonance for binding affinity to Psel, and zymosan assay for complement inhibitory activity. In-vivo studies were performed in C57bl/6 mice subjected to transient middle cerebral artery occlusion for 1 hour followed by administration of Psel-Crry 2 hours after reperfusion. Psel-Crry was labelled using far-red fluorescence and live-animal imaging was used to study brain-specific targeting. The modified Neurological Severity (NS) score was used for functional outcome along with survival, infarct volume and histological outcomes. RESULTS: Psel-Crry demonstrated dose-dependent complement inhibitory activity, and localized specifically to the stroke brain on in-vivo live imaging. Ex-vivo imaging of explanted brain showed Psel-Crry binding specifically to the injured hemisphere without off-target binding (Stroke vs. Sham, p &lt; 0.001). Psel-Crry resulted in 60% reduction in infarct volume at 3 days compare to vehicle (N = 8/group, p &lt; 0.05), reduction in NS scores compared to vehicle (Median 3 vs. 1.5, p &lt; 0.05), and improved 1-week survival (80% vs. 50%, p &lt; 0.05). Histological analyses demonstrated preservation of dendritic arborization in the ischemic penumbra with Psel-Crry treatment with concurrent significant reduction in microglial activation. CONCLUSIONS: Psel-Crry is a translational agent that can achieve local complement inhibitory effect and antiplatelet activity after stroke and has promise for potential use as ajuvant therapy in stroke.

Responses of Proton Pump Inhibitors and Potassium-Competitive Acid Blockers According to Outcomes of Symptom, Endoscopy, and Histology in Patients With Eosinophilic Esophagitis.

We aimed to examine the response rate to proton pump inhibitors (PPIs) and potassium-competitive acid blockers and the prevalence of topical corticosteroid (TCS) therapy as the second-line treatment for eosinophilic esophagitis (EoE). Acid-suppressive drugs such as PPIs and potassium-competitive acid blockers are often used to treat EoE. Treatment response is based on outcomes including symptoms, endoscopy, and histology; however, the detailed response rate to PPI/P-CAB is unknown. In total, 236 patients with histologically confirmed EoE who received PPI/P-CAB as the first-line treatment were included. We assessed the symptoms, endoscopic reference score (EREFS), and histology [eosinophils per high-power field (eos/hpf)] 8 weeks after PPI/P-CAB administration. Complete normalization was defined as the disappearance of symptoms, EREFS score 0, or 0-1 eos/hpf, and response as disappearance or improvement of symptoms, EREFS score ≤2, or <15 eos/hpf. The prevalence of TCS therapy in each response group was assessed. Complete normalization was achieved in 25%, 50%, 36%, and 8% of patients for symptoms, endoscopy, histology, and all 3 outcomes, respectively. The response rates were 81%, 87%, 87%, 75%, and 60% for symptoms, endoscopy, histology, and all 3 outcomes, respectively. TCS use was significantly lower (8%) in patients who achieved response of all 3 outcomes than in other groups and was dependent on the number of outcomes with nonresponse. Complete normalization of symptoms, endoscopy, and histology using PPI/P-CAB is uncommon. Based on treatment efficacy by response/nonresponse, TCS was the secondary treatment in cases with an increase in the number of nonresponse outcomes.

Single-Stage Lateral Sinus Floor Elevation Using Different Grafts: A Systematic Review of Controlled Clinical Trials.

To assess histologic and imaging outcomes related to new bone formation around implants, inserted simultaneously with sinus augmentation, and compare different types of grafts. This systematic review (SR) was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Cochrane Handbook for Systematic Reviews of Interventions. LILACS/BVS, MEDLINE/PubMed, Cochrane Library, and Embase databases, including gray literature and manual investigations, were searched to identify clinical trials reporting specific requirements. The present study needed human histologic and imaging data of bone formation around implants inserted into the maxillary sinus simultaneously with elevation and augmentation procedures. Study selection, risk of bias (Rob 2.0 or ROBINS-I), quality of evidence (GRADE), and data collection were performed by two independent reviewers. Of the 1,101 potentially eligible articles, 44 were retrieved, 12 were assessed for eligibility, and 5 were included (4 randomized and 1 controlled clinical trial). As a result, 130 grafted sinuses with 179 placed implants in 103 patients were analyzed. The patients were aged between 24 and 79 years and followed up between 6 and 15 months. The heterogeneity between studies did not allow the data to be combined for meta-analysis. All graft materials proved to be viable options for the intervention. The use of biphasic calcium phosphate was related to higher bone-to-implant contact. All of the assessed grafts are viable options for the addressed intervention. The use of some material is justified to maintain the sinus volume and allow bone formation in the apical implant site under the sinus membrane. Longer chair time and donor site morbidity should be considered when choosing autogenous bone. Synthetic biphasic materials can be selected for this intervention due to superior bone-to-implant contact compared to deproteinized bovine bone.

Differences Between the 2016 and 2022 Food and Drug Administration Guidance-Implications for Design and Interpretation of Clinical Trials in Ulcerative Colitis.

In 2022, the Food and Drug Administration (FDA) updated its draft guidance for drug development in ulcerative colitis, replacing the version from 2016. Several changes from the 2016 version merit further discussion as they impact clinical trial design and the interpretation of trial results. We compared both documents and critically appraised the changes and implications for future clinical trials. The 2022 guidance recommends full colonoscopy, rather than flexible sigmoidoscopy, to document disease activity in all involved segments of the colon. The concordance between the findings of the 2 procedures is very high and there is little evidence to support colonoscopy over sigmoidoscopy. The use of colonoscopy, rather than sigmoidoscopy, is also associated with a higher burden to trial participants who must undergo full bowel preparation, cost, and a potential for more adverse events. The definition of the Mayo endoscopic score of 0 was changed from the original publication to "normal appearance of mucosa," which suggests that endoscopic signs of prior disease, such as pseudopolyps and scarring, are incompatible with a score 0, even though they are not associated with active disease. The term "mucosal healing" has been abolished and histologic outcomes defined as exploratory. A welcome change is that shorter washout periods than 5 half-lives will be considered to reduce patient exposure to corticosteroids as bridging therapy. The 2022 FDA draft guidance includes changes which for the most part are not informed by empirical evidence, which may ultimately complicate interpretation of future trials and preclude comparisons with past trials.

Clinical and laboratory characteristics of early-onset and delayed-onset lupus nephritis patients: A single-center retrospective study

BackgroundLupus nephritis (LN) manifests systemic lupus erythematosus (SLE) and is characterized by various clinical and laboratory features. This study aimed to comprehensively evaluate the characteristics of LN patients according to the time of LN diagnosis: early-onset (LN diagnosed within one year from SLE diagnosis) vs. delayed-onset (LN diagnosed more than one year after SLE diagnosis).MethodsWe conducted a retrospective analysis of medical records from all SLE patients treated at the University Hospital in Kraków, Poland, from 2012 to 2022. We collected data on demographic, clinical, and laboratory characteristics, including histological findings, treatment modalities, and disease outcomes. Statistical analyses were performed to identify factors impacting LN development and prognosis.ResultsAmong 331 LN patients, early-onset was diagnosed in 207 (62.54%) and delayed-onset was documented in 122 cases (36.86%). In 2 (0.6%) LN cases, the time of first kidney manifestation in the SLE course was unknown. Delayed-onset LN had a higher female-to-male ratio and younger age at SLE diagnosis. This group was associated with more severe clinical manifestations. In turn, studied subgroups did not differ in internist comorbidities, kidney histopathology, and family history regarding autoimmune diseases. Delayed-onset LN exhibited a higher frequency of anti-dsDNA, anti-Smith, anti-Ro, anti-RNP, and anti-cardiolipin IgG autoantibodies. During a 14-year follow-up period, 16 patients died. Mortality rate and causes of death were comparable in both analyzed subgroups.ConclusionsMore severe clinical manifestations in delayed-onset LN prompt strict monitoring of non-LN SLE patients to diagnose and treat kidney involvement early. Also, recognizing the higher frequency of autoantibodies such as anti-dsDNA or anti-Smith in delayed-onset LN underscores the potential value of autoantibody profiling as a diagnostic and prognostic tool.

Histological Outcomes And Jak-Stat Signalling In Ulcerative Colitis Patients Treated With Tofacitinib.

Histological outcomes and JAK-STAT signaling were assessed in a prospective ulcerative colitis (UC) patient cohort after 8 weeks treatment with tofacitinib, an oral Janus kinase (JAK) inhibitor. Forty UC patients received tofacitinib 10mg twice daily for 8 weeks. Treatment response was defined as histo-endoscopic mucosal improvement (HEMI). Histological remission was defined as a Robarts Histopathology Index (RHI) ≤3 points and histological response as 50% decrease in RHI. Mucosal expression of JAK1-3, Tyrosine kinase 2 (TYK2) and total signal transducer and activator of transcription (STAT) 1-6 were assessed using immunohistochemistry (IHC). At baseline, the median RHI was 14 (interquartile range (IQR) 10-19). Twenty-six of 40 (65%) patients had severe endoscopic disease (endoscopic Mayo score 3) and 31/40 (78%) failed prior anti-TNF treatment. At week 8, 15 patients (38%) had HEMI, 23 patients (58%) histological remission and 34 (85%) histological response. RHI decreased by a median of 14 points (IQR 9-21) in responders (p<0.001) and by 6 points (IQR 0-13) in non-responders (p=0.002). STAT1, STAT3 and STAT5 expression levels decreased significantly in the whole cohort. Responders had lower week 8 STAT1 expression levels compared to non-responders (0.2%, IQR 0.1-2.8 vs 4.3%, IQR 1.2-11.9, p=0.001), suggesting more profound STAT1 blockade. A trend of higher baseline JAK2 expression was observed in tofacitinib non-responders (2.7%, IQR 0.1-7.7) compared to responders (0.4%, IQR 0.1-2.1). Tofacitinib treatment resulted in histological improvement in the majority of UC patients and a substantial decrease of STAT1, STAT3 and STAT5 expression. HEMI was associated with more profound suppression of STAT1.

Effect of TiO2 Abutment Coatings on Peri-Implant Soft Tissue Behavior: A Systematic Review of In Vivo Studies.

Establishing a proper soft tissue adhesion around the implant abutment is essential to prevent microbial invasion, inhibit epithelial downgrowth, and obtain an optimal healing process. This systematic review aims to evaluate the real potential of TiO2 coating on the behavior of peri-implant soft tissue health and maintenance. A specific aim was to evaluate clinically and histologically the effect of TiO2 abutment coating on epithelial and connective tissue attachment. Electronic database searches were conducted from 1990 to 2023 in MEDLINE/PubMed and the Web of Science databases. In total, 15 out of 485 publications were included. Eight studies involved humans, and seven were animal studies. Exposure time ranges from 2 days to 5 years. The peri-implant soft tissue evaluations included clinical assessment (plaque index (PI), peri-implant probing pocket depth (PPD), and bleeding on probing (BoP)), histological as well as histomorphometric analysis. The Office of Health Assessment and Translation (OHAT) Risk of Bias Rating Tool for Human and Animal Studies was used to evaluate the overall quality of the studies included in the review. The results showed some variation but remained within acceptable limits. Within the limitations of this systematic review, the present findings suggest that TiO2 coatings seem to influence soft tissue healing. TiO2-coated abutments with a roughness value between 0.2 and 0.5 μm enhance soft tissue health. Sol-gel-derived TiO2 coatings induced better soft tissue attachment than noncoated machined abutment surfaces. The anodized titanium abutments demonstrate comparable clinical and histological outcomes to conventional machined abutments. However, there was variation among the included studies concerning TiO2 coating characteristics and the measured outcomes used to evaluate the soft tissue response, and therefore, quantitative analysis was not feasible. Long-term in vivo studies with standardized soft tissue analysis and coating surface parameters are necessary before a definitive conclusion can be drawn. OSF Registration No.: 10.17605/OSF.IO/E5RQV.

Does progress in microfracture techniques necessarily translate into clinical effectiveness?

Multitudinous advancements have been made to the traditional microfracture (MFx) technique, which have involved delivery of various acellular 2nd generation MFx and cellular MFx-III components to the area of cartilage defect. The relative benefits and pitfalls of these diverse modifications of MFx technique are still not widely understood. To comparatively analyze the functional, radiological, and histological outcomes, and complications of various generations of MFx available for the treatment of cartilage defects. A systematic review was performed using PubMed, EMBASE, Web of Science, Cochrane, and Scopus. Patients of any age and sex with cartilage defects undergoing any form of MFx were considered for analysis. We included only randomized controlled trials (RCTs) reporting functional, radiological, histological outcomes or complications of various generations of MFx for the management of cartilage defects. Network meta-analysis (NMA) was conducted in Stata and Cochrane's Confidence in NMA approach was utilized for appraisal of evidence. Forty-four RCTs were included in the analysis with patients of mean age of 39.40 (± 9.46) years. Upon comparing the results of the other generations with MFX-I as a constant comparator, we noted a trend towards better pain control and functional outcome (KOOS, IKDC, and Cincinnati scores) at the end of 1-, 2-, and 5-year time points with MFx-III, although the differences were not statistically significant (P > 0.05). We also noted statistically significant Magnetic resonance observation of cartilage repair tissue score in the higher generations of microfracture (weighted mean difference: 17.44, 95% confidence interval: 0.72, 34.16, P = 0.025; without significant heterogeneity) at 1 year. However, the difference was not maintained at 2 years. There was a trend towards better defect filling on MRI with the second and third generation MFx, although the difference was not statistically significant (P > 0.05). The higher generations of traditional MFx technique utilizing acellular and cellular components to augment its potential in the management of cartilage defects has shown only marginal improvement in the clinical and radiological outcomes.

Multichannel bridges and NSC synergize to enhance axon regeneration, myelination, synaptic reconnection, and recovery after SCI

Regeneration in the injured spinal cord is limited by physical and chemical barriers. Acute implantation of a multichannel poly(lactide-co-glycolide) (PLG) bridge mechanically stabilizes the injury, modulates inflammation, and provides a permissive environment for rapid cellularization and robust axonal regrowth through this otherwise inhibitory milieu. However, without additional intervention, regenerated axons remain largely unmyelinated (<10%), limiting functional repair. While transplanted human neural stem cells (hNSC) myelinate axons after spinal cord injury (SCI), hNSC fate is highly influenced by the SCI inflammatory microenvironment, also limiting functional repair. Accordingly, we investigated the combination of PLG scaffold bridges with hNSC to improve histological and functional outcome after SCI. In vitro, hNSC culture on a PLG scaffold increased oligodendroglial lineage selection after inflammatory challenge. In vivo, acute PLG bridge implantation followed by chronic hNSC transplantation demonstrated a robust capacity of donor human cells to migrate into PLG bridge channels along regenerating axons and integrate into the host spinal cord as myelinating oligodendrocytes and synaptically integrated neurons. Axons that regenerated through the PLG bridge formed synaptic circuits that connected the ipsilateral forelimb muscle to contralateral motor cortex. hNSC transplantation significantly enhanced the total number of regenerating and myelinated axons identified within the PLG bridge. Finally, the combination of acute bridge implantation and hNSC transplantation exhibited robust improvement in locomotor recovery. These data identify a successful strategy to enhance neurorepair through a temporally layered approach using acute bridge implantation and chronic cell transplantation to spare tissue, promote regeneration, and maximize the function of new axonal connections.