TB and HIV induced immunosenescence: where do vaccines play a role?

This paper tackles the complex interplay between Human Immunodeficiency virus (HIV-1) and Mycobacterium tuberculosis (M. tuberculosis) infections, particularly their contribution to immunosenescence, the age-related decline in immune function. Using the current literature, we discuss the immunological mechanisms behind TB and HIV-induced immunosenescence and critically evaluate the BCG (Bacillus Calmette-Guérin) vaccine's role. Both HIV-1 and M. tuberculosis demonstrably accelerate immunosenescence: M. tuberculosis through DNA modification and heightened inflammation, and HIV-1 through chronic immune activation and T cell production compromise. HIV-1 and M. tuberculosis co-infection further hastens immunosenescence by affecting T cell differentiation, underscoring the need for prevention and treatment. Furthermore, the use of the BCG tuberculosis vaccine is contraindicated in patients who are HIV positive and there is a lack of investigation regarding the use of this vaccine in patients who develop HIV co-infection with possible immunosenescence. As HIV does not currently have a vaccine, we focus our review more so on the BCG vaccine response as a result of immunosenescence. We found that there are overall limitations with the BCG vaccine, one of which is that it cannot necessarily prevent re-occurrence of infection due to effects of immunosenescence or protect the elderly due to this reason. Overall, there is conflicting evidence to show the vaccine's usage due to factors involving its production and administration. Further research into developing a vaccine for HIV and improving the BCG vaccine is warranted to expand scientific understanding for public health and beyond.

Hematological profile of OSMF patients with increasing severity.

Haematological profile of patients with oral sub mucous fibrosis (OSMF) and its correlation with the severity of OSMF is evaluated. The study comprised of sixty participants with clinical diagnoses. They were divided into smaller groups based on the OSMF stage. Sixty age and gender matched healthy controls were chosen among patients presenting for routine hematological examinations and free of systemic illnesses. Assessment of iron, hemoglobin, and red cell indices in all study participants was carried out. It was observed that the values of haematological tests like (Hb (g/dL), PCV, MCV (fl), MCH, MCHC, Iron (mg/dL) and Vitamin B12 (pg/Ml) was greater in normal subjects as compared to OSMF patients. Values were found to decrease further as the severity (staging) of OSMF increased among OSMF patients. The findings were statistically significant showing decrease in the values of different haematological parameters as the stage of OSMF progressed from stage I to stage III.

Immuno-histochemical evaluation of CD34 for OLP and OSMF.

Immuno-histochemical evaluation of CD34 in oral lichen planus (OLP) and Oral Submucous Fibrosis (OSMF) is of interest to dentist.20 specimens of normal oral mucosa (buccal mucosa/gingiva tissue) from patients who had extractions performed as part of orthodontic treatment comprised Group I, the control group. Group II comprised 30 individuals with a diagnosis of oral lichen planus. 30 OSMF cases with diagnoses is Group III. These 80 specimens were all given consideration when choosing for CD34immuno-histochemical staining. The CD34 was greater in all categories of OLP and OSMF when compared to normal controls. Maximum CD34 expression was observed in erosive OLP (147.41±17.60) followed by OSMF (116.01 ±11.72) and reticular OLP (105.01±11.62). Data was statistically significant (p<0.001).Immunohistochemistry of CD34 evaluation is a potential diagnostic marker for OLP and OSMF.

Modified Delphi Panel Consensus Recommendations for Management of Severe Aplastic Anemia.

Severe aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 adult and pediatric experts on aplastic anemia was assembled and, using the RAND/UCLA modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here we present the panel's recommendations to rule out inherited bone marrow failure (IBMF) syndromes, on supportive care prior to and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant versus medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision-making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA.

Paroxysmal nocturnal hemoglobinuria-related thrombosis in the era of novel therapies: a 2043-patient-year analysis.

ABSTRACT: Thrombophilia is one of the principal features of paroxysmal nocturnal hemoglobinuria (PNH) and constitutes the main cause of disease morbidity/mortality. Anticomplement treatment has revolutionized the natural history of PNH, with control of the hemolytic process and abolition of thrombotic events (TEs). However, no guidelines exist for the management of thromboembolic complications in this setting, with type and duration of anticoagulation depending on individual practices. Besides, a scarcity of data is present on the efficacy of direct oral anticoagulants (DOACs). Herein, we accrued a large real-world cohort of patients with PNH from 4 US centers to explore features, predictors of TE, and anticoagulation strategies. Among 267 patients followed up for a total of 2043 patient-years, 56 (21%) developed TEs. These occurred at disease onset in 43% of cases, involving more frequently the venous system, typically as Budd-Chiari syndrome. Rate of TEs was halved in patients receiving complement inhibitors (21 vs 40 TEs per 1000 patient-years in untreated cases, with a 2-year cumulative incidence of thrombosis of 3.9% vs 18.3%, respectively), and varied according to PNH granulocytes and erythrocytes clone size, type, disease activity parameters, as well as number (≥2 mutations, or less) and variant allelic frequency of PIGA mutations. Anticoagulation with warfarin (39%), DOACs (37%), and low-molecular weight heparin (16%) was administered for a median of 29 months (interquartile range [IQR], 9-61.8). No thrombotic recurrence was observed in 19 patients treated with DOACs at a median observation of 17.1 months (IQR, 8.9-45) whereas 14 cases discontinued anticoagulation without TE recurrence at a median time of 51.4 months (IQR, 29.9-86.8).

Insights on effects of Wnt pathway modulation on insulin signaling and glucose homeostasis for the treatment of type 2 diabetes mellitus: Wnt activation or Wnt inhibition?

Type 2 diabetes mellitus (T2DM) is a major worldwide chronic disease and can lead to serious diabetic complications. Despite the availability of many anti-diabetic agents in the market, they are unable to meet the long-term treatment goals. Also, they cause many side effects which justify the need for novel class of anti-diabetic drugs with newer mechanism of action. Wnt signaling is one of such novel target pathways which can be explored for metabolic disorders. Many key components of the Wnt signaling are involved in the regulation of glucose homeostasis. Polymorphism in the Transcription factor 7-like 2 (TCF7L2) gene, and mutations in the LRP5 (LDL Receptor Related Protein 5) gene lead to disturbed glucose metabolism and obesity. Despite of several years of research in this field, there is no concrete proof of concept available on whether Wnt activation or Wnt inhibition is the beneficial approach for the treatment of T2DM. Here, we have summarized the conclusions of relevant published research studies to give structured insights into possibilities to explore Wnt modulation as a novel target pathway for the treatment of T2DM. The review also highlights the present challenges and future opportunities towards the development of anti-diabetic small molecules targeting the Wnt signaling pathway.

Variability associated with maxillary infrazygomatic crest and palatal bone width, height, and angulation in subjects with different vertical facial growth types: a retrospective cone-beam computed tomography study.

OBJECTIVES: To assess the infrazygomatic crest (IZC) and palatal bone width, height, and angulation in patients with different vertical facial growth types as potential miniscrew insertion sites. MATERIALS AND METHODS: In this retrospective cone-beam computed tomography study, 162 subjects (81 males and 81 females, mean age 16.05 ± 0.65 years) were included. They were divided into three groups (hypodivergent, normodivergent, and hyperdivergent) based on the Frankfort mandibular plane angle. Ten buccal bone measurements were made at two different coronal sections: maxillary first molar mesiobuccal and distobuccal roots (bilaterally). Six palatal bone measurements were made on a sagittal section at the maxillary central incisors (bilaterally). A total of 32 measurements per subject were considered in the study. RESULTS: No significant difference was observed for the IZC (width and angle) at the maxillary first molar mesiobuccal root. A comparison of normodivergent and hyperdivergent groups for buccal width at the distobuccal root of the first molar showed significant differences. Palatal bone thickness at the level of 2 mm distal to the apex of the central incisor was significantly higher for the hyperdivergent group (10.43 mm) compared with the normodivergent (7.58 mm) and hypodivergent groups (7.83 mm). CONCLUSIONS: Hyperdivergent subjects tend to present a longer and deeper IZC and increased palatal bone thickness compared with other groups. The recommended insertion angle for the IZC mini-implant at 3 mm from the alveolar crest should be between 75.5° and 77°.

From Emergence to Endemicity: A Comprehensive Review of COVID-19.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), later renamed coronavirus disease 2019 (COVID-19), was first identified in Wuhan, China, in early December 2019. Initially, the China office of the World Health Organization was informed of numerous cases of pneumonia of unidentified etiology in Wuhan, Hubei Province at the end of 2019. This would subsequently result in a global pandemic with millions of confirmed cases of COVID-19 and millions of deaths reported to the WHO. We have analyzed most of the data published since the beginning of the pandemic to compile this comprehensive review of SARS-CoV-2. We looked at the core ideas, such as the etiology, epidemiology, pathogenesis, clinical symptoms, diagnostics, histopathologic findings, consequences, therapies, and vaccines. We have also included the long-term effects and myths associated with some therapeutics of COVID-19. This study presents a comprehensive assessment of the SARS-CoV-2 virology, vaccines, medicines, and significant variants identified during the course of the pandemic. Our review article is intended to provide medical practitioners with a better understanding of the fundamental sciences, clinical treatment, and prevention of COVID-19. As of May 2023, this paper contains the most recent data made accessible.

Implant abutment using hand drivers versus torque wrench.

The most frequent instrument used to begin tightening screws is a manually regulated screwdriver. Regarding manually regulated screwdrivers, predicted margins of error vary between fifteen percent to forty eight percent. Mechanical Torque restricting devices can consistently produce the requisite torques. As a result, devices like wrenches are needed to achieve the desirable values of torque. Hence, the present study was designed to evaluate the torque difference between handheld drivers and torque wrench and thereby its effect on the internal threads of implant surface.120 blocks was prepared from an autopolymerizing type of acrylic material each with a dimension of 1 inch. The centre of each block was affixed with analogue of dental impalnts with dimensions of 3.5 mm width and 13 mm length. With 60 specimens each, these models were split into two categories: hand torque specimens category and torque wrench specimens category. A stereomicroscope was used to look at the implant analog's internal threading architecture at a magnification of 100. At the bottom and top, four threads were spaced apart by a certain amount. Biowizard software was used for the assessment, and the results were recorded. Threads on the internal surface of dental implants were produced once more following torquing the implant's impression, and the stereomicroscope was used to quantify the separation between the 4 threads. Statistics were used to correlate the readings. All study participants' hand torque as well as torque wrench measurements were documented and statistical analysis was performed on them. When there was statistical analysis of the measurements then it was observed that mean values of torque in specimens included category of manual torque application was found out to be 33.6 ± 6.510 Ncm. On the other hand the mean values of torque in specimens included in category of torque application by torque wrench were found out to be 33.57 ± 3.472 Ncm. The outcome showed operator heterogeneity for both categories and operator variance when using a manual driver to generate torque. One independent - sample t test was used to contrast the mean data between the two categories, and P< 0.05 was chosen to determine whether the intergroup difference was meaningful. Because the torque values obtained with hand tightening were uneven, it may be concluded that different levels of hand torquing skill caused the torque to fluctuate. The torque wrench device displayed the desired torque data in the range that the manufacturer had advised. However, utilising manual drivers and a mechanical torque instrument did not cause any modifications to thread on the internal surface, and it rarely underwent significant deformation during the preliminary tightening torque readings. Thus, given that manually hand regulated drivers create a range of torques, it may be inferred that the employment of mechanical torque restricting instruments should be required.

Evaluation of the Impact of Different Instrumentation Techniques on the Incidence of Postoperative Pain in Patients Undergoing Root Canal Treatment.

BACKGROUND: Postoperative pain is a common concern in root canal treatment, and the choice of instrumentation technique can significantly impact patient comfort. This study aimed to evaluate the impact of different instrumentation techniques on the incidence of postoperative pain in patients undergoing root canal treatment. METHODS: A randomized controlled trial was conducted on 208 patients randomly assigned to four groups: step-back preparation, crown-down preparation, hybrid technique, and conventional instrumentation. Pain intensity was assessed using a verbal rating scale (VRS) at six, 12, 24, 48, and 72 hours postoperatively. Data were analyzed using appropriate statistical methods. RESULTS: The mean pain scores and standard deviations (SDs) were calculated for each instrumentation technique at different time intervals. At six hours, the step-back preparation group reported a mean pain score of 2.3 (SD = 0.8), the crown-down preparation group had a score of 2.8 (SD = 0.9), the hybrid technique group had a score of 2.5 (SD = 0.7), and the conventional instrumentation group had a score of 3.1 (SD = 0.1). The differences in pain scores between the groups were statistically significant at all time intervals (p < 0.05). CONCLUSION: The choice of instrumentation technique significantly influenced the incidence of postoperative pain in root canal treatment. The step-back preparation technique was associated with lower pain intensity than the crown-down preparation, hybrid technique, and conventional instrumentation. These findings highlight the importance of considering the instrumentation technique to optimize patient comfort during and after root canal treatment.

Correlation of Body Mass Index (BMI) with Saliva and Blood Glucose Levels in Diabetic and Non-Diabetic Patients.

Background: To compare and correlate the relationship between body mass index (BMI) and blood and salivary glucose (mean values) in patients with diabetes and non-diabetic control group patients. Materials and Methods: In the study, 100 patients were included, 50 patients each-patients with diabetes and non-diabetic control group. Each patient had their BMI measured as well as unstimulated whole saliva collected and blood drawn. Results: When compared to BMI, blood glucose (mean), and salivary glucose (mean) in healthy controls, BMI, blood glucose, and salivary glucose values in diabetic patients were considerably higher. Conclusion: Patients who have a higher BMI are more likely to develop diabetes.

Platelet-rich fibrin and titanium-prepared platelet-rich fibrin in endoperio lesion management.

Endo-perio lesions involve a variety of therapy choices that will lead to the best possible elimination of infection. Various therapy approaches have been investigated for curing of patients affected by endo-perio abnormalities. One of the second-generation platelet derivatives is plasma enriched with platelet (PRP).They may aid in the healing of wounds. Enhanced with platelets cells and several growth factors, platelet-rich fibrin (PRF) promotes repair and healing and regeneration of tissue at the periapical area. Platelet cell and leukocyte cell enriched fibrin, prepared in conjunction with titanium (T-PRF), is analogous to fibrin made using the traditional PRF process.The current study was undertaken to compare PRF against T-PRF in the therapy of endo-perio abnormalities using the basic information that was available.280 patients of all sexes between the ages of 18 years and 58 years make up the study's participants. They were divided into two categories. In category I study participants PRF was employed to fill the defect created due to pathology and in category II patients, a T-PRF was used, accompanied by suturing. The one walled, two walled, and three-wall walled infrabony abnormalities were quantified on the digital images acquired using the grid. After three months and six months, the probing periodontal pocket depth in mm and level of attachment (RAL) in mm were measured. In category one, mean change at 3 months was 3.21mm accounting for 33.79% change in PPD. On the other hand mean change at 6 months was 3.61mm accounting for 43.79% change in PPD. When there was evaluation in study participants in category two then it was observed that mean change at 3 months was 2.02mm accounting for 34.79% change in PPD. On the other hand mean change at 6 months was 3.62 mm accounting for 44.79% change in PPD. There was reduction of depth of periodontal pocket at both 3 months follow up and 6 months follow in both categories; however there was no statistical significant variation observed between the two categories regarding decrease in the depth of periodontal pocket on analysis of intergroup variations. It was concluded that there was increase in periodontal attachment and decrease in depth of periodontal pocket in both PRF and T-PRF however there was no statistical substantial variation observed between the two categories regarding increase in the attachment level or decrease in depth of periodontal when intergroup variations between PRF and T-PRF were considered.

Molecular patterns identify distinct subclasses of myeloid neoplasia.

Genomic mutations drive the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia. While morphological and clinical features have dominated the classical criteria for diagnosis and classification, incorporation of molecular data can illuminate functional pathobiology. Here we show that unsupervised machine learning can identify functional objective molecular clusters, irrespective of anamnestic clinico-morphological features, despite the complexity of the molecular alterations in myeloid neoplasia. Our approach reflects disease evolution, informed classification, prognostication, and molecular interactions. We apply machine learning methods on 3588 patients with myelodysplastic syndromes and secondary acute myeloid leukemia to identify 14 molecularly distinct clusters. Remarkably, our model shows clinical implications in terms of overall survival and response to treatment even after adjusting to the molecular international prognostic scoring system (IPSS-M). In addition, the model is validated on an external cohort of 412 patients. Our subclassification model is available via a web-based open-access resource ( https://drmz.shinyapps.io/mds_latent ).

Recent Advances in Local Anesthesia: A Review of Literature.

Even if local anesthetic is still the mainstay of pain management in dentistry, research will keep striving for novel and effective pain management techniques. The majority of research efforts are focused on improving anesthetic medications, delivery systems, and related methods. There are more recent technologies available that can assist the dentist in providing better pain relief with fewer unpleasant injections and fewer negative adverse effects. The purpose of the current review of the literature is to compile evidence that will convince dentists to employ modern local anesthetics, as well as other methods and techniques to reduce patient discomfort while administering anesthesia.

Using the Caries Assessment Spectrum and Treatment Index to Determine the Caries Incidence in Primary and Permanent Molars Among School Children of Kolkata: A Cross-Sectional Study.

INTRODUCTION: Caries in their early stages cannot be properly classified using the decayed, missing, and filled teeth (DMFT) index because it does not record precavitated lesions. Thus, the caries assessment spectrum and treatment (CAST) index is a good alternative as it is equipped to record the whole range of dental illnesses and count restored teeth as healthy ones. MATERIALS AND METHODS: The participants in this cross-sectional study included 300 children who were seven-to-eight years of age. We used the CAST index to assess the extent of caries in the deciduous and permanent molars of these children. For this, all the permanent and baby teeth, the primary and secondary permanent molars, as well as the first and second deciduous molars were examined to determine the prevalence of each carious stage. The correlation of the distribution of the CAST codes between the first and second molars, the second and first molars, the right and left sides of the dental bend, and the opposing jaws was analyzed using Spearman's rank correlation coefficient, while the cut-off for statistical significance was a p-value of 0.05. The quantitative analysis was conducted using IBM SPSS Experiences Version 20 for Windows. RESULTS: By comparing CAST codes in the right and left molars, we were able to observe how the development of caries in paired teeth might affect one another. The rank correlation value was found to be less than 0.5 only in the primary second molars (55/65 and 85/75), which were found exclusively in the deciduous first molars. Moreover, the r values for the neighboring deciduous and permanent molars were found to be below 0.3, i.e., 65/64 (0.497), 74/75 (0.327), and 84/85 (0.411), which indicated a weak connection between them. When comparing the teeth in different jaws, we found reasonable correlations (r = 0.33-0.49), with only 64/74 outliers (0.501). CONCLUSIONS: We found that, in the examined population, there was a well-established correlation between the stages of caries development in the deciduous molars on the left side of the mouth.

Antibody drug conjugates as targeted cancer therapy: past development, present challenges and future opportunities.

Antibody drug conjugates (ADCs) are promising cancer therapeutics with minimal toxicity as compared to small cytotoxic molecules alone and have shown the evidence to overcome resistance against tumor and prevent relapse of cancer. The ADC has a potential to change the paradigm of cancer chemotherapeutic treatment. At present, 13 ADCs have been approved by USFDA for the treatment of various types of solid tumor and haematological malignancies. This review covers the three structural components of an ADC-antibody, linker, and cytotoxic payload-along with their respective structure, chemistry, mechanism of action, and influence on the activity of ADCs. It covers comprehensive insight on structural role of linker towards efficacy, stability & toxicity of ADCs, different types of linkers & various conjugation techniques. A brief overview of various analytical techniques used for the qualitative and quantitative analysis of ADC is summarized. The current challenges of ADCs, such as heterogeneity, bystander effect, protein aggregation, inefficient internalization or poor penetration into tumor cells, narrow therapeutic index, emergence of resistance, etc., are outlined along with recent advances and future opportunities for the development of more promising next-generation ADCs.

A hypothesis on designing strategy of effective RdRp inhibitors for the treatment of SARS-CoV-2.

Vaccines are used as one of the major weapons for the eradication of pandemic. However, the rise of different variants of the SARS-CoV-2 virus is creating doubts regarding the end of the pandemic. Hence, there is an urgent need to develop more drug candidates which can be useful for the treatment of COVID-19. In the present research for the scientific hypothesis, emphasis was given on the direct antiviral therapy available for the treatment of COVID-19. In lieu of this, the available molecular targets which include Severe Acute Respiratory Syndrome Chymotrypsin-like Protease (SARS-3CLpro), Papain-Like Cysteine Protease (PLpro), and RNA-Dependent RNA Polymerase (RdRp) were explored. As per the current scientific reports and literature, among all the available molecular targets, RNA-Dependent RNA Polymerase (RdRp) was found to be a crucial molecular target for the treatment of COVID-19. Most of the inhibitors which are reported against this target consisted of the free amine group and carbonyl group which might be playing an important role in the binding interaction with the RdRp protein. Among all the reported RdRp inhibitors, remdesivir, favipiravir, and molnupiravir were found to be the most promising drugs against COVID-19. Overall, the structural features of this RNA-Dependent RNA Polymerase (RdRp) inhibitors proved the importance of pyrrolo-triazine and pyrimidine scaffolds. Previous computational models of these drug molecules indicated that substitution with the polar functional group, hydrogen bond donor, and electronegative atoms on these scaffolds may increase the activity against the RdRp protein. Hence, in line with the proposed hypothesis, in the present research work for the evaluation of the hypothesis, new molecules were designed from the pyrrolo-triazine and pyrimidine scaffolds. Further, molecular docking and MD simulation studies were performed with these designed molecules. All these designed molecules (DM-1, DM-2, and DM-3) showed the results as per the proposed hypothesis. Among all the designed molecules, DM-1 showed promising results against the RdRp protein of SARS-CoV-2. In the future, these structural features can be used for the development of new RdRp inhibitors with improved activity. Also, in the future lead compound DM-1 can be explored against the RdRp protein for the treatment of COVID-19.

Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria.

PURPOSE: Secondary myeloid neoplasms (sMNs) remain the most serious long-term complications in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, and early therapeutic interventions. PATIENTS AND METHODS: We studied a multicenter, retrospective cohort of 1,008 patients (median follow-up 8.6 years) with AA and PNH to assess clinical and molecular determinants of clonal evolution. RESULTS: Although none of the patients transplanted upfront (n = 117) developed clonal complications (either sMN or secondary PNH), the 10-year cumulative incidence of sMN in nontransplanted cases was 11.6%. In severe AA, older age at presentation and lack of response to immunosuppressive therapy were independently associated with increased risk of sMN, whereas untreated patients had the highest risk among nonsevere cases. The elapsed time from AA to sMN was 4.5 years. sMN developed in 94 patients. The 5-year overall survival reached 40% and was independently associated with bone marrow blasts at sMN onset. Myelodysplastic syndrome with high-risk phenotypes, del7/7q, and ASXL1, SETBP1, RUNX1, and RAS pathway gene mutations were the most frequent characteristics. Cross-sectional studies of clonal dynamics from baseline to evolution revealed that PIGA/human leukocyte antigen lesions decreased over time, being replaced by clones with myeloid hits. PIGA and BCOR/L1 mutation carriers had a lower risk of sMN progression, whereas myeloid driver lesions marked the group with a higher risk. CONCLUSION: The risk of sMN in AA is associated with disease severity, lack of response to treatment, and patients' age. sMNs display high-risk morphological, karyotypic, and molecular features. The landscape of acquired somatic mutations is complex and incompletely understood and should be considered with caution in medical management.