What to do with an incidental finding of a fused sagittal suture: a modified Delphi study.

OBJECTIVE: As many as 5% of normocephalic children may have a prematurely fused sagittal suture, yet the clinical significance and best course of management of this finding remain unclear. Providers in the Synostosis Research Group were surveyed to create a multicenter consensus on an optimal treatment and monitoring algorithm for this condition. METHODS: A four-round modified Delphi method was utilized. The first two rounds consisted of anonymous surveys distributed to 10 neurosurgeons and 9 plastic surgeons with expertise in craniosynostosis across 9 institutions, and presented 3 patients (aged 3 years, 2 years, and 2 months) with incidentally discovered fused sagittal sutures, normal cephalic indices, and no parietal dysmorphology. Surgeons were queried about their preferred term for this entity and how best to manage these patients. Results were synthesized to create a treatment algorithm. The third and fourth feedback rounds consisted of open discussion of the algorithm until no further concerns arose. RESULTS: Most surgeons preferred the term "premature fusion of the sagittal suture" (93%). At the conclusion of the final round, all surgeons agreed to not operate on the 3- and 2-year-old patients unless symptoms of intracranial hypertension or papilledema were present. In contrast, 50% preferred to operate on the 2-month-old. However, all agreed to utilize shared decision-making, taking into account any concerns about future head shape and neurodevelopment. Panelists agreed that patients over 18 months of age without signs or symptoms suggesting elevated intracranial pressure (ICP) should not undergo surgical treatment. CONCLUSIONS: Through the Delphi method, a consensus regarding management of premature fusion of the sagittal suture was obtained from a panel of North American craniofacial surgeons. Without signs or symptoms of ICP elevation, surgery is not recommended in patients over 18 months of age. However, for children younger than 18 months, surgery should be discussed with caregivers using a shared decision-making process.

Cognitive Outcomes of Children With Sagittal Craniosynostosis Treated With Either Endoscopic or Open Calvarial Vault Surgery.

Importance: Several studies have reported a higher incidence of neurodevelopmental delays and cognitive deficits in patients with single-suture craniosynostosis; however, there are few studies examining the associations of repair type with cognitive outcomes. Objective: To measure differences in neuropsychological outcomes between school-age children who were treated for sagittal craniosynostosis and unaffected controls and explore differences in cognitive function among children with sagittal craniosynostosis who were previously treated with either endoscopic strip craniectomy or open calvarial vault surgery. Design, Setting, and Participants: This cohort study was performed between 2018 and 2022. Eligible participants included patients aged 5 to 17 years who had previously been seen as infants or toddlers (<3 years) at 1 of 3 surgical centers for craniosynostosis repair with either endoscopic surgery or open calvarial vault surgery. A separate cohort of unaffected controls were included for comparison. Data analysis was conducted from November 2023 to February 2024. Exposures: Open calvarial vault surgery or endoscopic repair for single-suture craniosynostosis. Main Outcomes and Measures: The primary outcome was the Differential Ability Scales-II (DAS-II) General Conceptual Ability (GCA) score, an index for overall intellectual ability. Secondary outcomes included DAS-II subscale scores (Verbal Ability, Nonverbal Reasoning, Spatial Ability, Working Memory, and Processing Speed), and Patient-Reported Outcomes Measurement Information System (PROMIS) cognitive function scores. Results: A total of 81 patients with sagittal craniosynostosis (59 male [73%]; 22 female [27%]) and 141 controls (81 male [57%]; 60 female [43%]) were included. Of the 81 participants with sagittal craniosynostosis, 46 underwent endoscopic repair and 35 underwent open repair. Median (range) age at time of follow-up assessment was 7.7 (5.0-14.8) years for children with sagittal craniosynostosis and median age at assessment was 8.5 (7.7-10.5) years for controls. After controlling for age at assessment, sex, and socioeconomic status, there was no statistically significant or clinically meaningful difference in GCA scores between children who underwent endoscopic repair (adjusted mean score, 100; 95% CI, 96-104) and open repair (adjusted mean score, 103; 95% CI, 98-108) (P > .99). We found no significant difference in PROMIS scores between repair types (median [range] for endoscopic repair 54 [31-68] vs median [range] for open repair 50 [32-63]; P = .14). When comparing the treatment groups with the unaffected controls, differences in subscale scores for GCA and working memory were observed but were within normal range. Conclusions and Relevance: In this cohort study, there were no statistically or clinically significant differences in cognitive outcomes among school-age children by and type of surgical procedure used to repair nonsyndromic sagittal craniosynostosis. These findings suggest primary care clinicians should be educated about different options for craniosynostosis surgery to ensure early referral of these patients so that all treatment options remain viable.

Preclinical assessment of MAGMAS inhibitor as a potential therapy for pediatric medulloblastoma.

Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and non-SHH group3 subtypes. MAGMAS (Mitochondrial Associated Granulocyte Macrophage colony-stimulating factor Signaling molecules) encode for mitochondrial import inner membrane translocase subunit and is responsible for translocation of matrix proteins across the inner membrane. We previously reported that a small molecule MAGMAS inhibitor, BT9, decreases cell proliferation, migration, and oxidative phosphorylation in adult glioblastoma cell lines. The aim of our study was to investigate whether the chemotherapeutic effect of BT9 can be extended to pediatric medulloblastoma. Methods: Multiple in vitro assays were performed using human DAOY (SHH activated tp53 mutant) and D425 (non-SHH group 3) cells. The impact of BT9 on cellular growth, death, migration, invasion, and metabolic activity were quantified using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. Survival following 50mg/kg BT9 treatment was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells. Results: Compared to control, BT9 treatment led to a significant reduction in medulloblastoma cell growth (DAOY, 24hrs IC50: 3.6uM, 48hrs IC50: 2.3uM, 72hrs IC50: 2.1uM; D425 24hrs IC50: 3.4uM, 48hrs IC50: 2.2uM, 72hrs IC50: 2.1uM) and a significant increase in cell death (DAOY, 24hrs p=0.0004, 48hrs p<0.0001; D425, 24hrs p=0.0001, 48hrs p=0.02). In DAOY cells, 3uM BT9 delayed migration, and significantly decreased DAOY and D425 cells invasion (p < 0.0001). Our in vivo study, however, did not extend survival in xenograft mouse model of group3 medulloblastoma compared to vehicle-treated controls. Conclusions: Our in vitro data showed BT9 antitumor efficacy in DAOY and D425 cell lines suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models.

Pediatric ping-pong skull fractures treated with vacuum-assisted elevation.

PURPOSE: Depressed ("ping-pong") skull fractures can be treated by different means, including observation, non-surgical treatments, or surgical intervention. The authors describe their experience with vacuum-assisted elevation of ping-pong skull fractures and evaluate variables associated with surgical outcomes. METHODS: The authors present a retrospective review of all ping-pong skull fractures treated with vacuum-assisted elevation at the Children's Hospital of Orange County in 2021-2022. Variables included patient age, mechanism of injury, fracture depth, bone thickness at the fracture site, and degree of elevation. RESULTS: Seven patients underwent vacuum-assisted elevation of ping-pong fractures at the bedside without the use of anesthesia. Fractures caused by birth-related trauma were deeper than those caused by falls (p < 0.001). There was no significant difference between groups in bone thickness at the fracture site (2.10 mm vs 2.16 mm, n.s). Six of the seven patients experienced significant improvement in fracture site depression, with four displaying a complete fracture reduction and two displaying a significant reduction. The degree of fracture reduction was modestly related to the depth of fracture, with the two deepest fractures failing to achieve full reduction. Age appeared to be related to fracture reduction, with the lowest reduction observed in one of the oldest patients in this sample. No complications were observed in any patient other than temporary mild swelling at the suction site, and no re-treatment or surgery for the fractures was required. CONCLUSION: Vacuum-assisted elevation of ping-pong skull fractures is a safe and effective noninvasive treatment option for infants that can be used under certain circumstances. The procedure can be done safely at the bedside and is a relatively quick procedure. It avoids the need for open surgical intervention, anesthesia, or hospital admission, and can lead to excellent outcomes.

Multicenter comparison of Chiari malformation type I presentation in children versus adults.

OBJECTIVE: Treatment for Chiari malformation type I (CM-I) often includes surgical intervention in both pediatric and adult patients. The authors sought to investigate fundamental differences between these populations by analyzing data from pediatric and adult patients who required CM-I decompression. METHODS: To better understand the presentation and surgical outcomes of both groups of patients, retrospective data from 170 adults and 153 pediatric patients (2000-2019) at six institutions were analyzed. RESULTS: The adult CM-I patient population requiring surgical intervention had a greater proportion of female patients than the pediatric population (p < 0.0001). Radiographic findings at initial clinical presentation showed a significantly greater incidence of syringomyelia (p < 0.0001) and scoliosis (p < 0.0001) in pediatric patients compared with adult patients with CM-I. However, presenting signs and symptoms such as headaches (p < 0.0001), ocular findings (p = 0.0147), and bulbar symptoms (p = 0.0057) were more common in the adult group. After suboccipital decompression procedures, 94.4% of pediatric patients reported symptomatic relief compared with 75% of adults with CM-I (p < 0.0001). CONCLUSIONS: Here, the authors present the first retrospective evaluation comparing adult and pediatric patients who underwent CM-I decompression. Their analysis reveals that pediatric and adult patients significantly differ in terms of demographics, radiographic findings, presentation of symptoms, surgical indications, and outcomes. These findings may indicate different clinical conditions or a distinct progression of the natural history of this complex disease process within each population, which will require prospective studies to better elucidate.

Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated. METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed. FINDINGS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants. INTERPRETATION: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study. FUNDING: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).

Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare.

Saracatinib/AZD0530 (SAR), a Src tyrosine kinase inhibitor, mitigates seizure-induced brain pathology in epilepsy models upon repeated oral dosing. However, repeated dosing is stressful and can be challenging in some seizing animals. To overcome this issue, we have incorporated SAR-in-Diet and compared serum pharmacokinetics (PK) and brain concentrations with conventional repeated oral dosing. Saracatinib in solution or in-diet was stable at room temperature for >4 weeks (97 ± 1.56%). Adult Sprague Dawley rats on SAR-in-Diet consumed ~1.7 g/day less compared to regular diet (16.82 ± 0.6 vs. 18.50 ± 0.5 g/day), but the weight gain/day was unaffected (2.63 ± 0.5 g/day vs. 2.83 ± 0.2 g/day). Importantly, we achieved the anticipated SAR dose range from 2.5-18.7 mg/kg of rat in response to varying concentrations of SAR-in-Diet from 54 to 260 ppm of feed, respectively. There was a strong and significant correlation between SAR-in-Diet dose (mg/kg) and serum saracatinib concentrations (ng/ml). Serum concentrations also did not vary significantly between SAR-in-Diet and repeated oral dosing. The hippocampal saracatinib concentrations derived from SAR-in-Diet treatment were higher than those derived after repeated oral dosing (day 3, 546.8 ± 219.7 ng/g vs. 238.6 ± 143 ng/g; day 7, 300.7 ± 43.4 ng/g vs. 271.1 ± 62.33 ng/g). Saracatinib stability at room temperature and high serum and hippocampal concentrations in animals fed on SAR-in-Diet are useful to titer the saracatinib dose for future animal disease models. Overall, test drugs in the diet is an experimental approach that addresses issues related to handling stress-induced variables in animal experiments.

A cyclophosphamide-induced immunosuppression Swiss Albino mouse model unveils a potential role for cow urine distillate as a feed additive.

BACKGROUND: Traditional and natural immunomodulators are increasingly used as supplements in animal feeds and as interventions in the prevention and treatment of disease in animals. OBJECTIVE: The aim of this study was to examine the immunomodulatory characteristics of distilled cow urine in vivo using two mouse models, a normal mouse model and an immunosuppressive mouse model. METHODOLOGY: We divided 144 Swiss Albino mice weighing between 15 g and 30 g, aged between two and three months, into two groups of 72 mice each. In the first group, we subdivided the animals into six subgroups of 12 each. In this group paramerters such as, body weight, organ weights of liver and kidney, haemagglutination titre, Jerne plaque-forming assay, and bone marrow cellularity were measured. We divided the second group into six subgroups for the assessment of delayed-type hypersensitivity (DTH). RESULTS: As compared to normal control mice, immunocompetent and immunosuppressed mice (given cow urine distillate) had significant increases in body weight, spleen weight, liver weight, total leucocyte count, lymphocyte count, serum protein, and globulin contents. In the treatment groups, the titre of antibodies, the number of antibody- producing cells, the cellularity of bone marrow, and foot pad thickness also increased. In the treatment group, both humoral and cellular immunity were altered compared to the control group, suggesting cow urine distillate to be a potential animal feed ingredient for immunoregulation. CONCLUSION: This study was able to demonstrate the experimental validity of natural compounds as immunomodulators that can be used in feed supplements for animals. Various compounds could be tested for immunomodulatory effects using this technique in experimental animals.

School-age anthropometric and patient-reported outcomes after open or endoscopic repair of sagittal craniosynostosis.

OBJECTIVE: Several studies have compared perioperative parameters and early postoperative morphology between endoscope-assisted strip craniectomy with orthotic therapy (endoscopic repair) and cranial vault remodeling (open repair). To extend these results, the authors evaluated school-age anthropometric outcomes after these techniques across three institutions. METHODS: School-aged children (age range 4-18 years) with previously corrected isolated sagittal craniosynostosis were enrolled. Upon inclusion, 3D photographs and patient-reported outcomes were obtained, and the cephalic index and head circumference z-scores were calculated. Analyses of covariance models controlling for baseline differences and a priori covariates were performed. RESULTS: Eighty-one participants (median [range] age 7 [4-15] years) were included. The mean (95% CI) school-age cephalic index was significantly higher in the endoscopic cohort, though within the normal range for both groups (endoscopic 78% [77%-79%] vs open 76% [74%-77%], p = 0.027). The mean change in the cephalic index from preoperation to school age was significantly greater in the endoscopic group (9% [7%-11%] vs open 3% [1%-5%], p < 0.001). Compared to preoperative measurements, mean school-age head circumference z-scores decreased significantly more in the open cohort (-1.6 [-2.2 to -1.0] vs endoscopic -0.3 [-0.8 to -0.2], p = 0.002). Patient-reported levels of stigma were within the normal limits for both groups. CONCLUSIONS: Endoscopic and open repair techniques effectively normalize school-age anthropometric outcomes. However, endoscopic repair produces a clinically meaningful and significantly greater improvement in the school-age cephalic index, with maintenance of head growth. These findings demonstrate the importance of early referral by pediatricians and inform treatment decisions.

Antineoplastic activity of plant-derived compounds mediated through inhibition of histone deacetylase: a review.

In the combat of treating cancer recent therapeutic approaches are focused towards enzymatic targets as they occupy a pivotal participation in the cascade of oncogenesis and malignancy. There are several enzymes that modulate the epigenetic pathways and chromatin structure related to cancer mutation. Among several epigenetic mechanisms such as methylation, phosphorylation, and sumoylation, acetylation status of histones is crucial and is governed by counteracting enzymes like histone acetyl transferase (HAT) and histone deacetylases (HDAC) which have contradictory effects on the histone acetylation. HDAC inhibition induces chromatin relaxation which forms euchromatin and thereby initiates the expression of certain transcription factors attributed with apoptosis, which are mostly correlated with the expression of the p21 gene and acetylation of H3 and H4 histones. Most of the synthetic and natural HDAC inhibitors elicit antineoplastic effect through activation of various apoptotic pathways and promoting cell cycle arrest at various phases. Due to their promising chemo preventive action and low cytotoxicity against normal host cells, bioactive substances like flavonoids, alkaloids, and polyphenolic compounds from plants have recently gained importance. Even though all bioactive compounds mentioned have an HDAC inhibitory action, some of them have a direct effect and others enhance the effects of the standard well known HDAC inhibitors. In this review, the action of plant derived compounds against histone deacetylases in a variety of in vitro cancer cell lines and in vivo animal models are articulated.

Mesenchymal Stromal Cells Facilitate Tip Cell Fusion Downstream of BMP-Mediated Venous Angiogenesis-Brief Report.

BACKGROUND: The goal of this study was to identify and characterize cell-cell interactions that facilitate endothelial tip cell fusion downstream of BMP (bone morphogenic protein)-mediated venous plexus formation. METHODS: High resolution and time-lapse imaging of transgenic reporter lines and loss-of-function studies were carried out to study the involvement of mesenchymal stromal cells during venous angiogenesis. RESULTS: BMP-responsive stromal cells facilitate timely and precise fusion of venous tip cells during developmental angiogenesis. CONCLUSIONS: Stromal cells are required for anastomosis of venous tip cells in the embryonic caudal hematopoietic tissue.

Use of intraoperative topical antibiotics to reduce intrathecal baclofen pump surgical site infections: a single institution's experience over 24 years.

OBJECTIVE: Patients requiring intrathecal baclofen (ITB) therapy are at high risk for surgical site infections (SSIs) given their poor functional status. After years of a nominal infection rate, there was an inexplicable increase in ITB pump infections at the authors' institution and multiple investigations offered no solution. Use of intraoperative topical antibiotics is well-documented in the orthopedic literature and was considered for ITB pump insertion. In this study, the authors investigated whether intraoperative vancomycin and tobramycin powder at the ITB pump site could reduce SSIs. METHODS: Operative and infection data were collected and analyzed retrospectively to determine the efficacy of this change. Patients were stratified into three cohorts (1998-2009, 2010-2012, and 2013-2021) to better understand the trends before and after implementation of intraoperative topical antibiotics. Each cohort had similar demographics. RESULTS: One hundred fifty-four patients underwent 272 ITB pump procedures between 1998 and 2021 (131 in 1998-2009, 49 in 2010-2012, and 92 in 2013-2021) for cerebral palsy (69.5%), spastic quadriparesis due to traumatic brain injury (7.1%), anoxic brain injury (6.5%), and other causes (16.9%). Infection rates were reduced from a high of 32% in 2010-2011 to 3.8% over the last 2.5 years (p = 0.0094). There were no adverse effects from the use of topical antibiotics. CONCLUSIONS: In the setting of an intractable rise in ITB pump infections, the addition of intraoperative topical antibiotics significantly reduced postoperative infections in a high-risk population. One could appreciate a significant drop each year in the rate of infections after the institution of intraoperative topical antibiotics. The reduction in SSIs significantly improved the long-term outcomes for these patients.

Cerebral revascularization surgery reduces cerebrovascular events in children with sickle cell disease and moyamoya syndrome: Results of the stroke in sickle cell revascularization surgery retrospective study.

BACKGROUND: Recent studies suggest that cerebral revascularization surgery may be a safe and effective therapy to reduce stroke risk in patients with sickle cell disease and moyamoya syndrome (SCD-MMS). METHODS: We performed a multicenter, retrospective study of children with SCD-MMS treated with conservative management alone (conservative group)-chronic blood transfusion and/or hydroxyurea-versus conservative management plus surgical revascularization (surgery group). We monitored cerebrovascular event (CVE) rates-a composite of strokes and transient ischemic attacks. Multivariable logistic regression was used to compare CVE occurrence and multivariable Poisson regression was used to compare incidence rates between groups. Covariates in multivariable models included age at treatment start, age at moyamoya diagnosis, antiplatelet use, CVE history, and the risk period length. RESULTS: We identified 141 patients with SCD-MMS, 78 (55.3%) in the surgery group and 63 (44.7%) in the conservative group. Compared with the conservative group, preoperatively the surgery group had a younger age at moyamoya diagnosis, worse baseline modified Rankin scale scores, and increased prevalence of CVEs. Despite more severe pretreatment disease, the surgery group had reduced odds of new CVEs after surgery (odds ratio = 0.27, 95% confidence interval [CI] = 0.08-0.94, p = .040). Furthermore, comparing surgery group patients during presurgical versus postsurgical periods, CVEs odds were significantly reduced after surgery (odds ratio = 0.22, 95% CI = 0.08-0.58, p = .002). CONCLUSIONS: When added to conservative management, cerebral revascularization surgery appears to reduce the risk of CVEs in patients with SCD-MMS. A prospective study will be needed to validate these findings.

Effectiveness of an oral health education intervention among 6-12-year-old children: A cluster randomized controlled trial.

OBJECTIVES: Literature on the effectiveness of theory-based oral health education on the oral hygiene of children is limited. We aimed to determine the effectiveness of an health behaviour theory-based school oral health education intervention on 1) oral hygiene and 2) oral health-related knowledge, attitude and practices among 6-12-year-old children in Kerala, India. METHODS: Cluster randomized controlled trial. Sixteen class divisions (clusters) were randomized into intervention and control groups of 225 and 228 children respectively. Primary and secondary outcomes were plaque score as measured using the simplified oral hygiene index (OHI-S) and oral health-related knowledge, attitude and practices respectively. The intervention group received structured oral health education classes for three months and materials including pamphlets. Children in the control group were not given the classes or materials. RESULTS: Post-intervention OHI-S scores in the intervention group and control groups were 1.65 and 2.17 respectively (difference = -0.52, 95%CI -0.86, -0.18). All the secondary outcomes improved in the intervention group compared to the control group. CONCLUSIONS: The intervention improved the oral hygiene status, oral health-related knowledge, attitude and practices of the children. Longer term follow-up and economic appraisal are needed to help policymakers plan and develop OHEI based on health behaviour theories.

Human papillomavirus related oropharyngeal cancer: identifying and quantifying topics of patient interest.

OBJECTIVE: As the incidence of human papillomavirus related oropharyngeal cancer continues to rise, it is increasingly important for public understanding to keep pace. This study aimed to identify areas of patient interest and concern regarding human papillomavirus and oropharyngeal cancer. METHOD: This study was a retrospective survey of search queries containing the keywords 'HPV cancer' between September 2015 and March 2021. RESULTS: There was 3.5-fold more interest in human papillomavirus related oropharyngeal cancer (15 800 searches per month) compared with human papillomavirus related cervical cancer (4500 searches per month). Among searches referencing cancer appearance, 96.8 per cent pertained to the head and neck region (3050 searches per month). Among vaccination searches, 16 of 47 (34.0 per cent; 600 searches per month) referenced human papillomavirus vaccines as being a cause of cancer rather than preventing cancer. CONCLUSION: The vast majority of online searches into human papillomavirus cancer pertain to the oropharynx. There are relatively few search queries on the topic of vaccination preventing human papillomavirus associated oropharyngeal cancer, which highlights the continued importance of patient education and awareness campaigns.

A critical appraisal of clinical practice guidelines for the diagnosis and management of benign paroxysmal positional vertigo.

BACKGROUND: Delays in the diagnosis and therapy of benign paroxysmal positional vertigo can greatly impact quality of life and increase healthcare costs for patients. This study aimed to appraise the quality of clinical practice guidelines for the diagnosis and management of benign paroxysmal positional vertigo. METHODS: A comprehensive database search of clinical practice guidelines was completed up to 30 October 2021. Four independent reviewers used the Appraisal of Guidelines for Research and Evaluation II instrument in the quality appraisal. RESULTS: The highest score was in 'clarity and presentation' (58.33 ± 22.7). The lowest score was in 'applicability' (13.96 ± 30.1). Overall, four clinical practice guidelines were 'low quality' and only one guideline was 'high quality'. CONCLUSION: This review identified a significant lack of quality in clinical practice guideline development for benign paroxysmal positional vertigo, highlighting the need for a more rigorous approach for future guideline development.

Fluorescein clearance kinetics in blood and bile indicates hepatic ischemia-reperfusion injury in rats.

Quantitative measurement of the degree of hepatic ischemia-reperfusion injury (IRI) is crucial for developing therapeutic strategies for its treatment. We hypothesized that clearance of fluorescent dye through bile metabolism may reflect the degree of hepatic IRI. In this study, we investigated sodium fluorescein clearance kinetics in blood and bile for quantifying the degree of hepatic IRI. Warm ischemia times (WITs) of 0, 30, or 60 min followed by 1 h or 4 h of reperfusion, were applied to the median and lateral lobes of the liver in Sprague-Dawley rats. Subsequently, 2 mg/kg of sodium fluorescein was injected intravenously, and blood and bile samples were collected over 60 min to measure fluorescence intensities. The bile-to-plasma fluorescence ratios demonstrated an inverse correlation with WIT and were distinctly lower in the 60-min WIT group than in the control or 30-min WIT groups. Bile-to-plasma fluorescence ratios displayed superior discriminability for short versus long WITs when measured 1 h after reperfusion versus 4 h. We conclude that the bile-to-blood ratio of fluorescence after sodium fluorescein injection has the potential to enable the quantification of hepatic IRI severity.NEW & NOTEWORTHY Previous attempts to use fluorophore clearance to test liver function have relied on a single source of data. However, the kinetics of substrate processing via bile metabolism include decreasing levels in blood and increasing levels in bile. Thus, we analyzed data from blood and bile to better reflect fluorescein clearance kinetics.

Effects of flumethrin on the germinative cells of engorged females of Rhipicephalus annulatus.

Chemical acaricides are widely used for the effective control of ticks in India. The synthetic pyrethroids, are one of the most popular chemical acaricides with selective neurotoxic potential. Flumethrin is a type II synthetic pyrethroid used extensively in veterinary practice in India. The present study was undertaken to evaluate the cytotoxic effects of flumethrin on the engorged females of Rhipicephalus annulatus using entomological parameters, histology, electron microscopy and relative quantification of receptors of dopamine and GABAB mRNAs. Adult immersion test (AIT) using flumethrin (100 ppm), revealed twenty per cent mortality of ticks, hundred per cent inhibition of fecundity and complete blocking of hatching of the laid eggs. Microscopic analysis of the structure of the ovaries after 24 h of treatment with flumethrin (90 ppm) revealed changes, viz., reduction in size with the presence of amorphous material inside stage I oocytes, wrinkled boundary and chromatin fragmentation of nucleus of stage II oocytes, vacuoles around the germinal vesicle, thickening of the nuclear membrane and chromatin clumping of stage III oocytes and reduction in size and shape of mature stage IV and V oocytes. Also, a large number of vacuoles were observed throughout the pedicel cell region of stage II and III oocytes. Ultrastructurally, irregular nuclear membrane, swelling as well as crystolysis of mitochondria and detachment of external and internal layers of the basal lamina of oocytes were the major structural alterations confirming direct damaging effects of flumethrin on the germinative cells. The relative quantification of the expression of dopamine D1, dopamine D2 and GABAB receptors by quantitative real-time PCR (qRT PCR), revealed the upregulation of dopamine D1 receptor and downregulation of receptors of dopamine D2 and GABAB in the ovary of treated ticks.

Inverse co-expression of EZH2 and acetylated H3K27 in prostatic tissue.

CONTEXT: Enhancer of Zeste 2 (EZH2), a methyltransferase and an upregulated gene is an adverse prognosticator in prostate cancer. It catalyzes histone H3 lysine 27 trimethylation (H3K27me3) leading to repressive chromatin status (heterochromatin). Following demethylation and acetylation of H3 protein (H3K27ac) the result is transcriptionally activated status (euchromatin), a key metastasis facilitator being targeted by ongoing clinical trials, as with palbociclib. Here, we performed the first immunohistochemical study of H3K27ac expression in prostatic tissue and cancer metastasis, and determined a possible correlation with EZH2 expression. METHODS: Tissue microarrays were made and immunohistochemistry was performed for EZH2 and H3K27ac. Slides were scanned and image data utilized a software-assisted, unbiased quantification method. The software captured diaminobenzidine positive regions, and tissue areas. RESULTS: Benign prostate tissue expressed almost no EZH2 but showed strong H3K27-Ac positivity. Tumor was EZH2 positive (p < 0.05 vs. benign) with strongest staining in lymph node metastasis. H3K27-Ac was decreased in tumors, yet paradoxically had stagewise and gradewise progressive increases (both p < 0.05), with the strongest staining in lymph nodes. The overall relationship of EZH2 and H3K27ac was weakly correlated (r = 0.28, p < 0.05). CONCLUSIONS: EZH2 and H3K27ac had an inverse correlation in benign versus (especially) low-grade and low-stage prostate cancers; however, in high-stage and high-grade cancers and metastases, H3K27ac increased significantly. Findings support EZH2 and H3K27ac as targets for cancer prevention in localized or low-grade prostate cancer, but we now note that their inverse relationship becomes uncoupled in advanced prostate cancer.