Impact of HLA-B*52:01-Driven Escape Mutations on Viral Replicative Capacity.

HLA-B*52:01 is strongly associated with protection against HIV disease progression. However, the mechanisms of HLA-B*52:01-mediated immune control have not been well studied. We here describe a cohort with a majority of HIV C-clade-infected individuals from Delhi, India, where HLA-B*52:01 is highly prevalent (phenotypic frequency, 22.5%). Consistent with studies of other cohorts, expression of HLA-B*52:01 was associated with high absolute CD4 counts and therefore a lack of HIV disease progression. We here examined the impact of HLA-B*52:01-associated viral polymorphisms within the immunodominant C clade Gag epitope RMTSPVSI (here, RI8; Gag residues 275 to 282) on viral replicative capacity (VRC) since HLA-mediated reduction in VRC is a central mechanism implicated in HLA-associated control of HIV. We observed in HLA-B*52:01-positive individuals a higher frequency of V280T, V280S, and V280A variants within RI8 (P = 0.0001). Each of these variants reduced viral replicative capacity in C clade viruses, particularly the V280A variant (P < 0.0001 in both the C clade consensus and in the Indian study cohort consensus p24 Gag backbone), which was also associated with significantly higher absolute CD4 counts in the donors (median, 941.5 cells/mm3; P = 0.004). A second HLA-B*52:01-associated mutation, K286R, flanking HLA-B*52:01-RI8, was also analyzed. Although selected in HLA-B*52:01-positive subjects often in combination with the V280X variants, this mutation did not act as a compensatory mutant but, indeed, further reduced VRC. These data are therefore consistent with previous work showing that HLA-B molecules that are associated with immune control of HIV principally target conserved epitopes within the capsid protein, escape from which results in a significant reduction in VRC.IMPORTANCE Few studies have addressed the mechanisms of immune control in HIV-infected subjects in India, where an estimated 2.7 million people are living with HIV. We focus here on a study cohort in Delhi on one of the most prevalent HLA-B alleles, HLA-B*52:01, present in 22.5% of infected individuals. HLA-B*52:01 has consistently been shown in other cohorts to be associated with protection against HIV disease progression, but studies have been limited by the low prevalence of this allele in North America and Europe. Among the C-clade-infected individuals, we show that HLA-B*52:01 is the most protective of all the HLA-B alleles expressed in the Indian cohort and is associated with the highest absolute CD4 counts. Further, we show that the mechanism by which HLA-B*52:01 mediates immune protection is, at least in part, related to the inability of HIV to evade the HLA-B*52:01-restricted p24 Gag-specific CD8+ T-cell response without incurring a significant loss to viral replicative capacity.

Evidence that miR-152-3p is a positive regulator of SETDB1-mediated H3K9 histone methylation and serves as a toggle between histone and DNA methylation.

SETDB1 is a histone methyltransferase that converts H3K9me2 to H3K9me3. SETDB1 activity and H3K9me3 are crucial for the formation of obligately silenced heterochromatin such as that of centromeres. Here we show that a microRNA, miR-152-3p, is involved in the regulation of SETDB1 protein levels, but surprisingly, miR-152-3p plays a positive regulatory role for SETDB1 expression. Inhibition of miR-152-3p by anti-miR treatment resulted in a robust reduction in SETDB1 protein levels, though SETDB1 mRNA levels were unaffected. This was also accompanied by a blockade of the biochemical pathway proceeding from H3K9me2 to H3K9me3 as evidenced by quantitative nucleosome ELISA assays that showed that H3K9me2 accumulates in cells treated with an anti-miR that targets miR-152-3p. In addition, the action of a miR-152-3p mimic increased flux of the reaction leading to H3K9me3. We also performed site-directed mutagenesis of three predicted miR-152-3p target recognition sequences to yield three precise deletions. Deletion of one of the three sites recapitulated the positive regulatory aspect of the action of miR-152-3p upon SETDB1 expression in a luciferase reporter assay. Previous studies have shown that miR-152-3p negatively regulates DNMT1, the sole maintenance DNA methyltransferase which is required for levels of 5-methylcytosine levels within DNA. Our results shown that miR-152-3p positively regulates the production of H3K9me3 by regulating the production of SETDB1. Therefore, our findings provide strong evidence that miR-152-3p can serve as a toggle switch that regulates the balance between DNA methylation and H3K9 histone methylation in constitutive heterochromatin.

Patient perspective: diagnosis and prognosis of acute spinal cord injuries.

STUDY DESIGN: Qualitative study. OBJECTIVES: The purpose of this study is to understand the patient perspective after diagnosis of an acute traumatic spinal cord injury (tSCI). Discussing the diagnosis and prognosis of a tSCI with a patient can be a challenging experience for both the patient and the physician. As such, this paper attempts to better understand the patient experience to improve communication when discussing this life-altering injury. SETTING: Vancouver General Hospital, Vancouver, British Columbia, Canada. METHODS: This study is a qualitative study utilizing grounded theory and semi-structured interviews. The interview transcripts were manually coded using manifest and latent content analysis. Major and minor codes were identified and discussed. RESULTS: In total, 17 interviews were conducted, fifteen individuals with tSCI who received acute care at Vancouver General Hospital (VGH) and eleven family members were interviewed. Patient participants were interviewed individually or in a paired interview with a participating family member. Patient participants had varying spinal cord injuries from AIS A-D. Two major themes were identified from the interviews. The first major theme was physician demeanor (general approach and attitude towards patients) and the second major theme was delivery of information (content, timing, and source). CONCLUSIONS: This study summarizes the preferences of patients who sustained a tSCI discussions regarding their diagnosis and prognosis in the acute care setting. The goal of this study is to help guide physician interactions at this difficult and vulnerable time for patients with hopes to improve patient care through effective communication.

Assessment of C-reactive Protein Level and Efficacy of Diclofenac Sodium and Mefenamic Acid in Relieving Pain in Mandibular Impacted Third Molar Surgery.

AIM: To compare the efficacy of diclofenac sodium and mefenamic acid in relieving pain in mandibular impacted third molar surgery and to assess the level of the C-reactive protein (CRP) level. MATERIALS AND METHODS: This study was conducted on 90 patients of impacted mandibular third molars. All patients were administered with 2% lignocaine with 1:80,000 adrenaline, and surgical removal of impacted third molar was done following the standardized surgical procedure by a single oral surgeon. Patients were divided into two groups of 45 each. In group I, patients were prescribed 50 mg diclofenac sodium and in group II patients were prescribed 500 mg mefenamic acid for three times a day for 3 days. The CRP level was again evaluated after 3 days of analgesics. Pain was assessed using the visual analog scale (VAS). RESULTS: The mean VAS was 2.58 in group I and 3.46 in group II, which was statistically considerable (p < 0.05). The mean CRP level postoperatively in group I was 15.7 and after 3 days was 27.2 in group I, whereas it was 25.1 postoperatively and 31.5 after 3 days in group II. CONCLUSION: Authors found that diclofenac sodium as useful as mefenamic acid. The CRP level was raised significantly following surgery, thus reflecting that it is an indicator of inflammation. CLINICAL SIGNIFICANCE: Diclofenac sodium can be used to relieve pain. The CRP level evaluation can be helpful to assess inflammation following surgery.

Impact of Oral Health Literacy on Periodontal Health among Low-income-group Workers of Dental Institutes in Patna, Bihar, India.

AIM: To evaluate the impact of oral health literacy (OHL) on the periodontal health among low-income-group workers of dental institutes. MATERIALS AND METHODS: A cross-sectional study was conducted on 137 class III and IV workers of dental college. Data collection was done by using a customized pro forma including demographics, REALD-30 for calculating OHL, and items on oral hygiene habits like toothpaste use, brushing frequency, and any other oral hygiene aid. Following which periodontal health status was determined, which was categorized into severe, moderate, and mild periodontitis (health). The analysis was done using the SPSS 11.5. Periodontal health status was associated with OHL scores, oral hygiene habits, and demographics using the chi-square test. The statistical significance level was set at 5% level. RESULTS: Among the 137 subjects, 25 participants reported health/mild periodontitis, 53 had moderate periodontitis, and 59 had severe periodontitis. Low OHL was observed in 52.5% and only 13.8% had high OHL. The participants who had low OHL, 56.94% (n = 41), were having severe disease, while the subjects who had better OHL, only 21.05% (n = 4) were found to have severe disease. CONCLUSION: The people with low socioeconomic classes can be reached effectively if the community involvement concept is used through the workers of dental institutions. But first efforts should be made to improve the OHL of these workers. CLINICAL SIGNIFICANCE: Improving OHL can be of great help to the clinicians and the community health workers because it helps them to make patient adherent to the treatment and the medications prescribed to them. Periodontitis affects people with low socioeconomic status and in the present study it was class III and IV workers. Improving OHL of this population will decrease the oral disease burden of India.

Assessment of the Role of Vitamin D in the Treatment of Oral Lichen Planus.

AIM: Lichen planus is an autoimmune disease that can affect the skin and mucous membranes, including the oral mucosa. Vitamin D plays a very important role in the bone health along with boosting immunity. This study was carried out to assess the role of vitamin D in the treatment of oral lichen planus. MATERIALS AND METHODS: A sample size of 450 was taken which included patients showing clinical presentation of oral lichen planus. The patients were equally divided into three different groups based on their vitamin D levels. The data were analyzed using SPSS version 26.0. RESULTS: The patients who were given the vitamin D supplementation showed the maximum improvement. The comparison of the data were found to be statistically significant. CONCLUSION: It was concluded that vitamin D played an important role in the treatment of oral lichen planus. CLINICAL SIGNIFICANCE: The role of vitamin D in lichen planus needs to be explored. This study may be useful in conducting further study to assess the role in vitamin D supplementation in the treatment of oral lichen planus.

A Comparative Assessment of the Management of Mandibular Angle Fractures Using 3D Plates and 2D Miniplates.

AIMS: The aim of this study was to compare 2D plates with 3D miniplate system in the management of mandibular angle fractures. MATERIALS AND METHODS: The study was conducted on 146 patients with mandibular angle fracture, who were equally divided into two groups of 73. Patients in group I were treated with 3D plating and in group II with 2D plating. In all cases, 2.0 mm titanium miniplates were used. The etiology of fracture, amount of mouth opening, and pain and sensory deficit were recorded. Clinical and radiographic assessment was done at 1, 3, and 6 months. RESULTS: The etiology of mandibular angle fracture is roadside accident (RSA) seen in 110 (75.3%) cases, fall in 24 (16.4%), and assault in 12 (2.6%) cases. There was significant (p < 0.05) mouth opening in group I at 1 month postoperatively (32.4 mm) as compared to group II (27.5 mm), at 3 months in group I (33.6 mm) as compared to group II (30.2 mm), and at 6 months in group I (36.4 mm) as compared to group II (31.6 mm). After 1 month, sensory deficit was present in six patients in group I and 10 patients in group II. After 3 months, group I had no patients and three patients in group II. Right angle fracture was found in 71 patients (group I-36, group II-35). Mandibular right angle fracture in 58 patients (group I-28, group II-30). CONCLUSION: The authors found that the 3D miniplate system is more useful in the management of cases of mandibular angle fracture as compared to 2D miniplates. CLINICAL SIGNIFICANCE: There has been increase in mandibular fractures in the last few years. Appropriate management with 3D miniplates may be useful in providing better treatment outcomes.

The Subacromial Balloon Spacer Versus Superior Capsular Reconstruction in the Treatment of Irreparable Rotator Cuff Tears: A Biomechanical Assessment.

PURPOSE: To compare the subacromial balloon spacer with superior capsular reconstruction (SCR) for the treatment of massive irreparable rotator cuff tears. METHODS: Eight male cadaveric shoulders were mounted on a custom shoulder simulator that permitted quasistatic deltoid and rotator cuff muscle loading. Four shoulder conditions were tested: intact, irreparable rotator cuff tear (torn), subacromial balloon spacer, and SCR. The primary outcomes were superior humeral head migration and functional shoulder abduction force, which were measured at 0°, 30°, 60°, and 90° of shoulder abduction. RESULTS: In comparison to the intact condition, the torn condition resulted in a significant increase in superior humeral head migration at 0° (P = .03) and 30° (P = .02) of abduction. Insertion of the subacromial balloon spacer restored the humeral head position such that it was not significantly different from the intact condition (P = .18). Similarly, SCR restored the humeral head position such that it was not significantly different from the intact condition (P = .99). No significant differences were found between the balloon and SCR (P = .99). The functional abduction force was significantly decreased after tear creation (P = .01); however, the subacromial balloon (P = .40) and SCR (P = .99) restored functional abduction force comparable to the intact shoulder state. CONCLUSIONS: On the basis of the results, both techniques function to decrease superior humeral head migration and to restore more normal glenohumeral joint position and forces during various abduction positions. No substantial differences were identified between techniques at time zero. CLINICAL RELEVANCE: The results of this laboratory study indicate that the balloon and SCR both provided mechanical effects that restored the humeral head position from the superiorly migrated location. As such, similar clinical effects can be expected at time zero in patients with massive rotator cuff tears.

The effect of the subacromial balloon spacer on humeral head translation in the treatment of massive, irreparable rotator cuff tears: a biomechanical assessment.

BACKGROUND: The current management of massive, irreparable rotator cuff tears is challenging, and no individual surgical technique has demonstrated clinical superiority. This study evaluated the role of a subacromial balloon spacer and its ability to depress the humeral head in the setting of a massive, irreparable rotator cuff tear. METHODS: Eight cadaveric shoulders were tested. The specimens were mounted onto a shoulder simulator that applied muscle loading. Five shoulder states were tested: intact; irreparable rotator cuff tear; and inflation of the subacromial balloon spacer with 10, 25, and 40 mL of saline solution on the irreparable rotator cuff tear. Humeral head migration was measured at 0°, 30°, 60°, and 90° of shoulder abduction. RESULTS: After creation of a massive, irreparable rotator cuff tear, in 0° of abduction, the humeral head migrated superiorly by a mean of 3.5 ± 0.7 mm compared with the intact shoulder state (P = .002). The subacromial balloon spacer inflated to 25 mL translated the humeral head inferiorly relative to the torn state by an average of 3.2 ± 0.6 mm (P = .001) for all abduction angles. The balloon inflated to 10 mL was ineffective at restoring humeral head position as it was still significantly superior than intact (P = .017). The balloon inflated to 40 mL was successful in depressing the humeral head; however, it over-translated the humeral head anteroinferiorly, such that it was significantly different from the intact condition (P < .001). Overall, the 25-mL balloon best restored the humeral head position. CONCLUSION: The results of this study demonstrate that the subacromial balloon spacer is most effective in depressing the humeral head and restoring the glenohumeral joint position when inflated to 25 mL.

Effectiveness of Homeopathic Medicines as Add-on to Institutional Management Protocol for Acute Encephalitis Syndrome in Children: An Open-Label Randomized Placebo-Controlled Trial.

BACKGROUND: Acute encephalitis syndrome (AES) is endemic to certain parts of India, with limited treatment options. In our initial exploratory comparative observational study of 151 patients with AES, there was significantly reduced mortality with adjunctive homeopathy compared to institutional management protocol (IMP). The present randomized placebo-controlled trial brings more statistical rigor to this research program. METHODS: This study was conducted at a pediatric unit from 2013 to 2015. Children aged > 6 months and ≤ 18 years and receiving IMP were randomized to receive adjunctive homeopathy (n = 325) or placebo as control (n = 323). The primary effectiveness analysis was based on Glasgow Outcome Scale (GOS). Morbidity was assessed using the Liverpool Outcome Score for Assessing Children at Follow-up. Analysis was by intention to treat. RESULTS: A total of 612 children were analyzed (Homeopathy [H] = 304; Control [C] = 308). The primary outcome, GOS, differed significantly between H and C groups. There was 14.8% death/neuro-vegetative state in the H group compared to 29.8% in the C group. Relative risk was 0.49 (95% confidence interval [CI]: 0.36 to 0.68), with absolute risk reduction of 15.0% (95% CI: 8.6 to 21.6%). Number needed to treat to prevent one additional death/neuro-vegetative state was 6.6 (95% CI: 4.6 to 11.6). Proportional-odds analysis also revealed a greater effect in the H group: odds ratio, 0.40 (95% CI: 0.27 to 0.60). The most frequently used medicines were Belladonna (n = 116), Stramonium (n = 33), Arsenicum album (n = 25), Sulfur (n = 18), Opium (n = 17), and Nux vomica (n = 10). CONCLUSION: Adjunctive homeopathic medicines may improve clinical outcomes associated with AES. Further randomized and controlled studies, using double-blinded trial design, are recommended to discover if the current findings may be corroborated.

Comparative genetic variability in HIV-1 subtype C nef gene in early age groups of infants.

Targeting properties of vertically transmitted viruses in early infancy is important to understand disease progression. To investigate genotypic characteristics of transmitted viruses, blood samples were obtained from infants aged 6 weeks-18 months, categorized in two age groups, acute (<6 months) and early (>6-18 months). Nef having an important role in pathogenesis was selected to explore the viral characteristics. A total of 57 PCR positive samples, amplified by nef gene were sequenced. Analysis showed that 50 sequences belonged to subtype C. In one sequence of acute age group, a long insertion of 10 residues (AAERMRRAEP) in variable region and a 13 residues deletion (ATNNADCAWLEAQ) around proteolytic cleavage region of gene in another sequence was observed. Insertions were also observed in sequences of early age group, however, they ranged from two to eight residues only. In one sequence of early age group, 3/4 arginines at positions 19, 21, 22 of arginine cluster were mutated to glutamine, alanine, and glutamine, respectively. Entropy analysis of two age groups revealed presence of several residues with statistically significant differences in their variability. Among these, 15 (R18,R23,R24; A66,L68,Q71; E74,E77,E78; V87,M92; R119, P144, E167, and C176) belonged to functional motifs, out of which, 12 were in acute age group, suggesting that variability was greater in this group. Prediction of HLA binding peptide motif revealed that epitope LTFGWCFKL was present in >80% study sequences. This epitope was also present in maximum number of HLA types circulating in India and vaccine candidate sequences, suggesting that it may be helpful in designing an epitope-based vaccine.

Novel, potent, orally bioavailable and selective mycobacterial ATP synthase inhibitors that demonstrated activity against both replicating and non-replicating M. tuberculosis.

The mycobacterial F0F1-ATP synthase (ATPase) is a validated target for the development of tuberculosis (TB) therapeutics. Therefore, a series of eighteen novel compounds has been designed, synthesized and evaluated against Mycobacterium smegmatis ATPase. The observed ATPase inhibitory activities (IC50) of these compounds range between 0.36 and 5.45µM. The lead compound 9d [N-(7-chloro-2-methylquinolin-4-yl)-N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-2,3-dichlorobenzenesulfonamide] with null cytotoxicity (CC50>300µg/mL) and excellent anti-mycobacterial activity and selectivity (mycobacterium ATPase IC50=0.51µM, mammalian ATPase IC50>100µM, and selectivity >200) exhibited a complete growth inhibition of replicating Mycobacterium tuberculosis H37Rv at 3.12µg/mL. In addition, it also exhibited bactericidal effect (approximately 2.4log10 reductions in CFU) in the hypoxic culture of non-replicating M. tuberculosis at 100µg/mL (32-fold of its MIC) as compared to positive control isoniazid [approximately 0.2log10 reduction in CFU at 5µg/mL (50-fold of its MIC)]. The pharmacokinetics of 9d after p.o. and IV administration in male Sprague-Dawley rats indicated its quick absorption, distribution and slow elimination. It exhibited a high volume of distribution (Vss, 0.41L/kg), moderate clearance (0.06L/h/kg), long half-life (4.2h) and low absolute bioavailability (1.72%). In the murine model system of chronic TB, 9d showed 2.12log10 reductions in CFU in both lung and spleen at 173µmol/kg dose as compared to the growth of untreated control group of Balb/C male mice infected with replicating M. tuberculosis H37Rv. The in vivo efficacy of 9d is at least double of the control drug ethambutol. These results suggest 9d as a promising candidate molecule for further preclinical evaluation against resistant TB strains.

Novel Aerosol Delivery Devices.

Delivery of medication to sites of action through airways has been used for centuries but has gained momentum in recent decades. Currently available modes of aerosol delivery offer advantages but still there are shortcomings. Delivery of active agents to sites of action is affected by many factors beyond the characteristics of the delivery devices, including the coordination between inhalation and actuation and dependence on the patient's inspiratory flow and breathing pattern. Recent advances in drug delivery focus around changes in the generation of particle size with better penetration to the targeted sites, easier activation of the device with inspiratory flow, ease of use including fewer steps in using the device, and better portability. Availability of computer chips allows for smart delivery devices to tailor delivery to the patient's breathing pattern and lung function. Further, smart devices can provide feedback to patients. Novel inhaler technologies, separately or in combination with new therapeutic agents, are in development not only for respiratory diseases but also for diseases of other systems. This article reviews some of the recent clinically relevant advances in aerosol delivery devices.

Precision Genome Editing Techniques in Gene Therapy: Current State and Future Prospects.

Precision genome editing is a rapidly evolving field in gene therapy, allowing for the precise modification of genetic material. The CRISPR and Cas systems, particularly the CRISPR-- Cas9 system, have revolutionized genetic research and therapeutic development by enabling precise changes like single-nucleotide substitutions, insertions, and deletions. This technology has the potential to correct disease-causing mutations at their source, allowing for the treatment of various genetic diseases. Programmable nucleases like CRISPR-Cas9, transcription activator-like effector nucleases (TALENs), and zinc finger nucleases (ZFNs) can be used to restore normal gene function, paving the way for novel therapeutic interventions. However, challenges, such as off-target effects, unintended modifications, and ethical concerns surrounding germline editing, require careful consideration and mitigation strategies. Researchers are exploring innovative solutions, such as enhanced nucleases, refined delivery methods, and improved bioinformatics tools for predicting and minimizing off-target effects. The prospects of precision genome editing in gene therapy are promising, with continued research and innovation expected to refine existing techniques and uncover new therapeutic applications.

Differences in the surgical management of degenerative lumbar spondylolisthesis based on self-reported sex: analysis of the CSORN prospective DLS study.

OBJECTIVE: Surgical treatment of degenerative lumbar spondylolisthesis (DLS) reliably improves patient-reported quality of life; however, patient population heterogeneity, in addition to other factors, ensures ongoing equipoise in choosing the ideal surgical treatment. Surgeon preference for fusion or decompression alone influences surgical treatment decision-making. Meanwhile, at presentation, patient-reported outcome measures (PROMs) differ considerably between females and males. The aims of this study were to determine whether there exists a difference in the rates of decompression and fusion versus decompression alone based on patient-reported sex, and to determine if widely accepted indications for fusion justify any observed differences or if surgeon preference plays a role. METHODS: This study is a retrospective cohort analysis of patients enrolled in the Canadian Spine Outcomes Research Network (CSORN) DLS study, a multicentered Canadian prospective study, investigating the surgical management and outcome of DLS. Decompression and fusion rates, patient characteristics, preoperative PROMs, and radiographic measures were compared between males and females before and after propensity score matching. RESULTS: In the unmatched cohort, female patients were more likely to undergo decompression and fusion than male patients. Females were more likely to have the recognized indications for fusion, including kyphotic disc angle, higher spondylolisthesis grade and slip percentage, and patient-reported back pain. Other radiographic findings associated with the decision to fuse, including facet effusion, facet distraction, or facet angle, were not more prevalent in females. After propensity score matching for demographic and radiographic characteristics, similar proportions of male and female patients underwent decompression and fusion and decompression alone. CONCLUSIONS: Although it remains unclear who should or should not undergo fusion, in addition to surgical decompression of DLS, female patients undergo fusion at a higher rate than their male counterparts. After matching baseline radiographic factors indicating fusion, this analysis showed that the decision to fuse was not biased by sex differences. Rather, the higher proportion of females undergoing fusion is largely explained by the radiographic and clinical indications for fusion, suggesting that specific clinical and anatomical features of this condition are indeed different between sexes.

Factors associated with increased length of stay in degenerative cervical spine surgery: a cohort analysis from the Canadian Spine Outcomes and Research Network.

OBJECTIVE: Postoperative length of stay (LOS) significantly contributes to healthcare costs and resource utilization. The primary goal of this study was to identify patient, clinical, surgical, and institutional variables that influence LOS after elective surgery for degenerative conditions of the cervical spine. The secondary objectives were to examine the variability in LOS and institutional practices used to decrease LOS. METHODS: This was a multicenter observational retrospective cohort study of patients enrolled in the Canadian Spine Outcomes and Research Network (CSORN) between January 2015 and October 2020 who underwent elective anterior cervical discectomy and fusion (ACDF) (1-3 levels) or posterior cervical fusion (PCF) (between C2 and T2) with/without decompression for degenerative conditions of the cervical spine. Prolonged LOS was defined as LOS greater than the median for the ACDF and PCF populations. The principal investigators at each participating CSORN healthcare institution completed a survey to capture institutional practices implemented to reduce postoperative LOS. RESULTS: In total, 1228 patients were included (729 ACDF and 499 PCF patients). The median (IQR) LOS for ACDF and PCF were 1.0 (1.0) day and 5.0 (4.0) days, respectively. Predictors of prolonged LOS after ACDF were female sex, myelopathy diagnosis, lower baseline SF-12 mental component summary score, multilevel ACDF, and perioperative adverse events (AEs) (p < 0.05). Predictors of prolonged LOS after PCF were nonsmoking status, education less than high school, lower baseline numeric rating scale score for neck pain and EQ5D score, higher baseline Neck Disability Index score, and perioperative AEs (p < 0.05). Myelopathy did not significantly predict prolonged LOS within the PCF cohort after multivariate analysis. Of the 8 institutions (57.1%) with an enhanced recovery after surgery (ERAS) protocol or standardized protocol, only 3 reported using an ERAS protocol specific to patients undergoing ACDF or PCF. CONCLUSIONS: Patient and clinical factors predictive of prolonged LOS after ACDF and PCF are highly variable, warranting individual consideration for possible mitigation. Perioperative AEs remained a consistent independent predictor of prolonged LOS in both cohorts, highlighting the importance of preventing intra- and postoperative complications.

Emergence of drug resistance-associated mutations in HIV-1 subtype C protease gene in north India.

A major cause of anti-retroviral therapy (ART) failure is the drug resistance-associated mutations in polymerase gene of HIV-1. Paucity of data regarding potential drug resistance to protease inhibitors (PIs) prompted us to carry out this study. Drug resistance (DR) genotyping of the entire protease gene was performed in 104 HIV-1 ART-naive and first-line ART-experienced patients. The DR pattern was analyzed using the Stanford HIV-DR database, International AIDS Society-USA mutation list and REGA algorithm version 8.0. Subtyping was done using Mega 4 and REGA HIV-1 subtyping tool-v2.01. Majority of our sequences 98 (96%) were subtype C and remaining four (3.92%) were subtype A1. In three (2.9%) DE patients, major DR-associated mutation at D30 N and M46I positions were detected. Approximately 70% polymorphisms as minor mutations were observed in protease gene, of which 14 distinct amino acids changes were linked to partial DR such as G16E, K20R, M36I, D60E, I62V, L63P, I64M, H69K, T74A/S, V77I, V82I, I85V, L89M, and I93L. The two major and several minor mutations detected in this study confer low/intermediate levels of resistance to most PIs independently or together. Our results conclude that resistance testing in HIV-1-infected patients should be performed before the initiation of PI therapy for better therapeutic outcome in this region. This information not only will shed light on the extent of current DR in HIV strains but also will aid in patient treatment and drug designing.

Effects of radiation and vitamin C treatment on metronidazole genotoxicity in mice.

The impact of exposure to low dose radiation (LDR) on human health is not clear. Besides, cross adaptation or sensitization with pharmaceutical agents may modify the risk of LDR. In the present study, we analyzed the interaction of radiation and metronidazole (MTZ) in inducing chromosome aberration (CA) and micronucleus (MN) in the bone marrow cells of Balb/C mice in vivo. Further, we evaluated the efficacy of vitamin C to reduce MTZ induced genotoxicity. We found that 10, 20 and 40mg/kg of MTZ induced dose dependent increase in the frequency of CA (r=0.9923, P<0.01) as well as MN (r=0.9823, P<0.05) in polychromatic erythrocytes. However, MTZ did not affect the ratio of polychromatic erythrocytes to normochromatic erythrocytes indicating lack of cytotoxicity. Supplementation with vitamin C prior to MTZ treatment significantly reduced the frequency of CA (P<0.001) as well as MN (P<0.001). Radiation (0.5Gy) exposure prior to MTZ treatment produced a less than additive (for CA) to additive (for MN) effects. However, radiation exposure following MTZ treatment produced additive (for CA) and synergistic (for MN) effects. Further, vitamin C pre-treatment also reduced the genotoxicity indices following the combined treatment of MTZ and radiation. Our findings suggest that MTZ may sensitize bone marrow cells to radiation exposure and enhances genotoxicity. We recommend more studies on the interaction of LDR and marketed pharmaceuticals to minimize possible harmful outcomes through appropriate precautionary measures.

Effect of Mycetoma in Lung Transplant Patients - a Single Center Experience.

BACKGROUND: Mycetomas are uncommon in lung transplant recipients. Prior studies have shown increased mortality associated with mycetoma in lung transplant recipients (LTR). We reviewed our center's experience in outcome of LTRs with pre -or post-transplant mycetoma. METHODS: We retrospectively reviewed electronic health records of LTRs performed at our institute between January 1, 2013 to December 31, 2020. RESULTS: Mycetoma was present in less than 1 percent of LTR patients (7/1086). Mean age at the time of the transplant was 65 years. Idiopathic pulmonary fibrosis (5/7), interstitial lung disease (1/7), and sarcoidosis (1/7) were underlying pulmonary diagnoses. Seventy-one percent (5/7) received single lung transplant and 29% received double lung transplant. Seventy-one percent had negative serum galactomannan vs 29% (2/7) of patients who had positive serum galactomannan (one post and one pre). Fifty-seven percent had positive bronchoalveolar aspergillus galactomannan (23% had negative). A total of 42% (3/7) were found to have mycetoma before transplant and 58% (4/7) had mycetoma post transplant. Chest computed tomography findings in all patients were consistent with mycetoma. CONCLUSIONS: In our cohort of patients, mycetoma was not found to be the primary cause of death if diagnosed pre transplant. Transplant recipients with mycetoma pre transplant did not develop invasive fungal infection or mycetoma post transplant. Careful evaluation of lung transplant candidates with mycetoma is critical. Further studies are needed to determine optimal duration of antifungal therapy and to determine if surgical resection may be needed to manage post-lung transplant mycetoma.

Multivariate Statistical 2D QSAR Analysis of Indenoisoquinoline-based Topoisomerase- I Inhibitors as Anti-lung Cancer Agents.

BACKGROUND: Indenoisoquinoline-based compounds have shown promise as topoisomerase-I inhibitors, presenting an attractive avenue for rational anticancer drug design. However, a detailed QSAR study on these derivatives has not been performed till date. OBJECTIVE: This study aimed to identify crucial molecular features and structural requirements for potent topoisomerase- 1 inhibition. METHODS: A comprehensive two-dimensional (2D) QSAR analysis was performed on a series of 49 indenoisoquinoline derivatives using TSAR3.3 software. A robust QSAR model based on a training set of 33 compounds was developed achieving favorable statistical values: r2 = 0.790, r2CV = 0.722, f = 36.461, and s = 0.461. Validation was conducted using a test set of nine compounds, confirming the predictive capability of the model (r2 = 0.624). Additionally, artificial neural network (ANN) analysis was employed to further validate the significance of the derived descriptors. RESULTS: The optimized QSAR model revealed the importance of specific descriptors, including molecular volume, Verloop B2, and Weiner topological index, providing essential insights into effective topoisomerase-1 inhibition. We also obtained a robust partial least-square (PLS) analysis model with high predictive ability (r2 = 0.788, r2CV = 0.743). The ANN results further reinforced the significance of the derived descriptors, with strong r2 values for both the training set (r2 = 0.798) and the test set (r2 = 0.669). CONCLUSION: The present 2D QSAR analysis offered valuable molecular insights into indenoisoquinoline-based topoisomerase- I inhibitors, supporting their potential as anti-lung cancer agents. These findings contribute to the rational design of more effective derivatives, advancing the development of targeted therapies for lung cancer treatment.