'The phenotypic conundrum of Trp748Ser variant in POLG gene: a report of two patients'.

We present two cases of a 23-years and 32-years old female respectively, who presented with recurrent seizures, ataxia, dysarthria, psychomotor slowing. Magnetic resonance imaging (MRI) of the brain in the first patient revealed T2/FLAIR hyperintensity in the bilateral thalamus and cerebellar white matter with diffusion restriction, with no contrast enhancement. In the second patient, magnetic resonance imaging of brain showed FLAIR hyperintensity in precuneus while CSF showed raised HSV IgG titre on first presentation leading to suspicion of infective etiology. The initial differential diagnosis included autoimmune, metabolic and demyelinating causes. However, routine laboratory investigations, cerebrospinal fluid analysis, and autoimmune panel and demyelination workup were inconclusive. Considering the possibility of a genetic-mediated metabolic disorder, genetic testing was carried out leading to the identification of the Trp748Ser variation in POLG gene associated with mitochondrial DNA depletion syndrome. These cases highlight the diagnostic challenges and complexities in identifying rare metabolic encephalopathy, emphasizing the importance of a multidisciplinary approach in such cases.

From Decay to Delight: A Case Report on Esthetic Rehabilitation in Early Childhood Caries.

Early childhood caries (ECC) continues to be a major global dental health concern for young children. This case report examines a young patient's transformation from decay to delight via comprehensive esthetic treatment. ECC in a four-year-old child resulted in significant dental caries and poor esthetics. In addition to space maintenance and orthodontic examination, essential treatments included dental extractions, stainless steel crowns, and composite restorations. The result showed that the child's smile and self-esteem had been successfully restored, as well as their oral health and function. This case emphasizes the value of early intervention, multidisciplinary teamwork, and individualized treatment plans in the management of early childhood caries and the restoration of pediatric patients' oral health.

Clinical Management of Dewey's Type 3 Anterior Crossbite in Angle Class I Malocclusion: A Case Report.

Anterior crossbite is a significant malocclusion characterized by the lingual eruption of one or more maxillary front teeth, often impeded by the mandibular deciduous counterparts. This clinical case study focused on a patient with an anterior crossbite involving the central and lateral incisors, detailing the diagnosis, treatment course, and outcomes. During the clinical evaluation, both aesthetic concerns related to attrition and occlusal malocclusion were identified. Diagnostic tests, including radiographs and extraoral and intraoral examinations, were conducted before initiating treatment. The treatment aimed to correct the anterior crossbite while enhancing function and aesthetics. Fixed orthodontic appliances were introduced to facilitate precise tooth movement. Throughout the first year, the alignment, crossbite correction, and occlusal refinement were meticulously documented through photographs. The treatment resulted in improved occlusal relationships, functional bite, and enhanced smile aesthetics. This case report underscores the importance of comprehensive and functional orthodontic treatment in effectively resolving anterior crossbite and providing optimal patient care.

C3 Selective Hydroxylation of Pyridines via Photochemical Valence Isomerization of Pyridine N-Oxides.

The C-H hydroxylation of the pyridine C3 position is a highly desirable transformation but remains a great challenge due to the inherent electronic properties of this heterocycle core which bring difficulties in chemical reactivity and regioselectivity. Herein we present an efficient method for formal C3 selective hydroxylation of pyridines via photochemical valence isomerization of pyridine N-oxides. This metal-free transformation features operational simplicity and compatibility with a diverse array of functional groups, and the resulting hydroxylated products are amenable to further elaboration to synthetically useful building blocks. The synthetic utility of this strategy is further demonstrated in the effective late-stage functionalization of pyridine-containing medicinally relevant molecules and versatile derivatizations of 3-pyridinols.

Smile Renewal: Incisor Restoration Using the Strip Crown Technique.

Aesthetics has been an important aspect of dentistry along with functionality for decades but its significance is at an all-time high. Hence among techniques that contribute toward this goal, strip crown has shown convincing results. However, its acceptance did not reach its potential, especially among general dentists which could be attributed to its technique-sensitive nature. This case report sheds light on the practicality and reliability of this technique along with various modifications made by authors while striving to improve the quality of treatment provided by the clinician.

The role of gut microbiota augmentation in managing non-alcoholic fatty liver disease: an in-depth umbrella review of meta-analyses with grade assessment.

Background and aim: Currently, there are no authorized medications specifically for non-alcoholic fatty liver disease (NAFLD) treatment. Studies indicate that changes in gut microbiota can disturb intestinal balance and impair the immune system and metabolism, thereby elevating the risk of developing and exacerbating NAFLD. Despite some debate, the potential benefits of microbial therapies in managing NAFLD have been shown. Methods: A systematic search was undertaken to identify meta-analyses of randomized controlled trials that explored the effects of microbial therapy on the NAFLD population. The goal was to synthesize the existing evidence-based knowledge in this field. Results: The results revealed that probiotics played a significant role in various aspects, including a reduction in liver stiffness (MD: -0.38, 95% CI: [-0.49, -0.26]), hepatic steatosis (OR: 4.87, 95% CI: [1.85, 12.79]), decrease in body mass index (MD: -1.46, 95% CI: [-2.43, -0.48]), diminished waist circumference (MD: -1.81, 95% CI: [-3.18, -0.43]), lowered alanine aminotransferase levels (MD: -13.40, 95% CI: [-17.02, -9.77]), decreased aspartate aminotransferase levels (MD: -13.54, 95% CI: [-17.85, -9.22]), lowered total cholesterol levels (MD: -15.38, 95% CI: [-26.49, -4.26]), decreased fasting plasma glucose levels (MD: -4.98, 95% CI: [-9.94, -0.01]), reduced fasting insulin (MD: -1.32, 95% CI: [-2.42, -0.21]), and a decline in homeostatic model assessment of insulin resistance (MD: -0.42, 95% CI: [-0.72, -0.11]) (P<0.05). Conclusion: Overall, the results demonstrated that gut microbiota interventions could ameliorate a wide range of indicators including glycemic profile, dyslipidemia, anthropometric indices, and liver injury, allowing them to be considered a promising treatment strategy.

Safety of combined ablative radiotherapy and immune checkpoint inhibitors in three phase I trials.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is safe and effective for treatment of extracranial metastatic disease, but its safety when combined with immune checkpoint inhibitors (ICI) has not yet been comprehensively reported. Here we report adverse events (AEs) associated with combined SBRT and ICI using prospectively-collected data on patients in three trials investigating multi-site SBRT combined with ICI. METHODS: Patients were included from three prospective trials of ICI (pembrolizumab; nivolumab/urelumab or nivolumab/cabiralizumab; nivolumab/ipilimumab) with SBRT to 1-4 sites. AEs were recorded prospectively using the CTCAE v4.0. Survival was analyzed using Kaplan-Meier method with a 90-day landmark. Association of patient characteristics with cumulative incidence of AEs was assessed using Fine-Gray regression. RESULTS: 213 patients were included, with a median follow-up of 10 months. Over the follow-up period, 50 % and 27 % of patients experienced at least one grade ≥ 2 or grade ≥ 3 AE, respectively. Cumulative incidences of grade ≥ 2 and grade ≥ 3 AEs at 6 months were 47 % and 23 %, respectively. Three grade 5 AEs rated "possibly" related to treatment occurred outside the 90-day dose-limiting toxicity window. Landmarked survival analysis of patients with or without grade ≥ 3 AEs showed no significant difference in progression-free or overall survival. Dual-agent ICI was significantly associated with grade ≥ 3 AE. CONCLUSION: This analysis features the largest prospectively evaluated cohort of patients treated with combination ablative SBRT and ICI to date and provides context for future trial design. We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints.

Quantification and Clinical Correlation of Posterior Cranial Fossa Cerebrospinal Fluid Volume in Primary Hemifacial Spasm Using Magnetic Resonance Imaging.

BACKGROUND AND OBJECTIVE: Primary hemifacial spasm (HFS) is caused by neurovascular conflict (NVC) at the root entry zone of the facial nerve. Whether reduction of posterior cranial fossa (PCF) cerebrospinal fluid (CSF) volume is a risk factor for HFS is not clear. The study aims at the radiologic assessment of PCF CSF volume and its clinical correlation. METHODS: A cross-sectional, hospital-based, case-control study was conducted, in which 50 cases of primary HFS and 50 age- and sex-matched controls were recruited. PCF CSF volume was quantified in 3-T brain magnetic resonance imaging. RESULTS: The mean age at presentation of cases was 50.7 ± 10.7 years (42-69 years) and controls was 52.4 ± 8.7 years (45-68 years). The mean duration of symptoms was 3.5 ± 1.3 years (1.5-8 years). About 52% of patients had grade 2 (mild) severity of HFS. The mean PCF CSF volume of patients was 13,725.1 ± 909.5 mm 3 and controls was 14,458.5 ± 973.5 mm 3 ( P < 0.001). The mean PCF CSF volume of females with HFS was 13,714.8 ± 852.5 mm 3 and female controls was 14,521.8 ± 973.5 mm 3 ( P = 0.006). PCF CSF volume was significantly associated with the presence of HFS ( P = 0.007), the severity of HFS ( P < 0.001), and the presence of NVC ( P = 0.02). CONCLUSION: PCF CSF volume was lesser in HFS patients and was associated with the presence of HFS, the severity of HFS, and the presence of NVC. Females with HFS had smaller PCF CSF volume. Small PCF CSF volume is a risk factor for HFS, particularly in females with HFS.

Sharing the Burden: The Case for Definitive Local Therapy in Place of Immune Checkpoint Blockade for Patients With a Low-Volume Burden of Metastatic Disease.

COMMENTARY: Sharing the burden of low-volume metastatic cancer between ICB and local treatments.

Scalp microbiome: a guide to better understanding scalp diseases and treatments.

The scalp microbiome represents an array of microorganisms important in maintaining scalp homeostasis and mediating inflammation. Scalp microbial dysregulation has been implicated in dermatologic conditions including alopecia areata (AA), dandruff/seborrheic dermatitis (D/SD), scalp psoriasis (SP) and folliculitis decalvans (FD). Understanding the impact of scalp microbial dysbiosis gives insight on disease pathophysiology and guides therapeutic decision making. Herein we review the scalp microbiome and its functional role in scalp conditions by analysis of metagenomic medical literature in alopecia, D/SD, SP, and other dermatologic disease.Increased abundance of Malassezia, Staphylococcus, and Brevibacterium was associated with SD compared to healthy controls. A higher proportion of Corynebacterium, actinobacteria, and firmicutes are present in AA patients, and lower proportions of Staphylococcus caprae are associated with worse clinical outcomes. Decreased prevalence of actinobacteria and Propionibacterium and increased firmicutes, staphylococcus, and streptococcus are associated with scalp psoriasis. Studies of central centrifugal cicatricial alopecia (CCCA) suggest scalp microbial composition contributes to CCCA's pro-inflammatory status. The most common organisms associated with FD include methicillin-resistant S. aureus and S. lugdunensis. Antifungals have been a mainstay treatment for these diseases, while other alternatives including coconut oils and shampoos with heat-killed probiotics have shown considerable potential efficacy by replenishing the scalp microbiome.

Point/Counterpoint #2: Current Clinical Considerations With Nonoperative Management of Rectal Cancer.

ABSTRACT: Locally advanced rectal cancer has historically been treated with multimodal therapy consisting of radiation therapy, chemotherapy, and total mesorectal excision. However, recent prospective trials and registry studies have demonstrated similar disease outcomes with nonoperative management for patients who experience an excellent clinical response to radiation and chemotherapy. This article reviews data regarding nonoperative management for rectal cancer, and highlights current challenges and limitations in a point-counterpoint format, in the context of two clinical cases.

A General Three-Component Alkyl Petasis Boron-Mannich Reaction.

Aryl amines are one of the most common moieties in biologically active molecules, and approximately 37% of drug candidates contain aromatic amines. Recent advancements in medicinal chemistry, coined "escaping from flatland", have led to a greater focus on accessing highly functionalized C (sp3)-rich amines to improve the physicochemical and pharmacokinetic properties of compounds. This article presents a modular and operationally straightforward three-component alkyl Petasis boron-Mannich (APBM) reaction that utilizes ubiquitous starting materials, including amines, aldehydes, and alkyl boronates. By adaptation of this transformation to high-throughput experimentation (HTE), it offers rapid access to an array of diverse C(sp3)-rich complex amines, amenable for rapid identification of drug candidates.

Three-dimensional saturated C(sp3)-rich bioisosteres for benzene.

Benzenes, the most ubiquitous structural moiety in marketed small-molecule drugs, are frequently associated with poor 'drug-like' properties, including metabolic instability, and poor aqueous solubility. In an effort to overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp3)-rich bioisosteric scaffolds relative to arenes. In the past two decades, we have witnessed an exponential increase in synthetic methods for accessing saturated bioisosteres of monosubstituted and para-substituted benzenes. However, until recent discoveries, analogous three-dimensional ortho-substituted and meta-substituted biososteres have remained underexplored, owing to their ring strain and increased s-character hybridization. This Review summarizes the emerging synthetic methodologies to access such saturated motifs and their impact on the application of bioisosteres for ortho-substituted, meta-substituted and multi-substituted benzene rings. It concludes with a perspective on the development of next-generation bioisosteres, including those within novel chemical space.

Adapting with the Pandemic: Modified Mohs Micrographic Surgery Using Rim and Deep Margin Technique.

The COVID-19 pandemic has changed many facets of medical care and has resulted in a rise in delayed treatments across all specialties, including cosmetic dermatology. Delayed care for squamous cell carcinomas (SCC) and basal cell carcinoma (BCC) is not only a burden for medical providers, but also confers a risk to patients, as delayed surgeries are associated with increased metastatic risk and tumor size. Mohs micrographic surgery (MMS) delayed by more than one year leads to increased risk of complications, including bleeding and impaired wound healing, especially in the elderly population. To decrease bleeding risks, we have developed a modified MMS technique known as the "rim and deep margin" technique. Here, we present additional cases using this technique to minimize bleeding and operative time for patients with an increased risk of morbidity. This technique has been used successfully in the past for large tumors and can now be used for patients who have faced delay of care, as evidenced by its success during the COVID-19 pandemic.

Hemisection: A Boon for the Hopeless Tooth.

If left untreated, an inflammatory periodontal disease eventually leads to attachment loss. This may have an impact on a multi-rooted tooth's bifurcation or trifurcation. The division of a tooth with two roots into two distinct parts is known as hemisection. Hemisection is the term used to describe the removal or separation of a two-rooted tooth's root and crown, most likely a mandibular molar. Compared to other treatment options, hemi-sectioning the affected tooth can help preserve the tooth's structure and alveolar bone. Careful selection of cases is essential for the long-term success of the procedure. In this case report, in contrast to the more common option of extracting the natural tooth, a treatment option is discussed for molars with extensive decay that threatens tooth loss. Therefore, this option should be discussed with patients when deciding on a course of treatment, and it may be a good substitute for extraction and implant therapy, particularly in cases of advanced endo-perio lesions.

Targeting aberrant fatty acid synthesis and storage in endocrine resistant breast cancer cells.

Background: Lipid metabolic reprogramming is an emerging characteristic of endocrine therapy (ET) resistance in estrogen receptor-positive (ER+) breast cancer. We explored changes in lipid metabolism in ER+ breast cancer cell lines following acquired resistance to common endocrine treatments and tested efficacy of an inhibitor in current clinical trials. Methods: We derived ER+ breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD). Parental and ET resistant cells were subjected to global gene expression and unbiased lipidomic profiling. Lipid storage changes were assessed via neutral lipid staining with Oil Red O (ORO). The impact of the fatty acid synthase (FASN) inhibitor TVB-2640 on the growth and lipid storage of these cell lines was evaluated. Additionally, 13 C 2 -acetate tracing was used to examine FASN activity in parental and ET resistant cells in the absence or presence of TVB-2640. Results: Compared to parental cells, lipid metabolism and processing pathways were notably enriched in ET resistant cells, which exhibited distinct lipidomes characterized by increased triglyceride and polyunsaturated FA (PUFA) species. ET-resistant cells displayed enhanced cytoplasmic lipid droplets. Increased FASN protein levels were observed in ET-resistant cells, and TVB-2640 effectively inhibited FASN activity. FASN inhibition reduced cell growth in some but not all cell lines and ET resistance types and did not correlate to lipid storage reduction. 13 C 2 -acetate tracing confirmed reduced palmitate synthesis and enhanced PUFA synthesis in ET-resistant cells, especially when combined with FulvR. Conclusion: ET resistant breast cancer cells exhibit a shift towards enhanced triglyceride storage and complex lipids enriched with PUFA acyl chains. While targeting FASN alongside ET may not fully overcome ET resistance in our models, focusing on the unique lipid metabolic dependencies, such as PUFA pathways, may present a promising alternative strategy for treating ET resistant breast cancer.

Radicular Cyst: The Sequelae of Untreated Caries.

A radicular cyst is characterized as an odontogenic cyst of inflammatory origin that develops from Malassez epithelial rests in the periodontal ligament as the consequence of dental pulp inflammation. The cyst commenced in the carious tooth and spread to the periodontal and periapical regions. The majority of these lesions appear as precise radiolucencies and encompass their entire apex. The cystic lesion, which is also called a root-end cyst or periapical cyst, is sometimes referred to as a true cyst because it is lined by fluid epithelium. There are several treatment options to address radicular cysts, including surgical and nonsurgical methods. In this case study, we described the clinical observation of the cyst. The cyst typically manifests in later life due to its prolonged etiology. The maxillary anterior region is the most frequently utilized site.