Septic Arthritis of the Knee Due to Chronic Osteomyelitis of the Femur in an Adult: A Case Report.

Introduction: Adult cases of septic arthritis due to concomitant persistent osteomyelitis are incredibly uncommon. This study describes a rare example of septic arthritis in an adult's knee joint caused by long-term femur osteomyelitis. A cement rod laced with antibiotics proved to be an effective treatment for the illness. Case Report: A case of septic knee arthritis caused by reactivated chronic osteomyelitis is described in this study. Initial radiographs revealed an osteolytic lesion, prompting further imaging, including a magnetic resonance imaging, which verified the diagnosis. To treat the infected intra-articular knee joint and ream the femoral intramedullary canal, we chose open debridement over arthroscopic surgery based on the patient's history, physical examination, and imaging data. To close the dead space and remove the infection, a cement rod impregnated with antibiotics was placed into the medullary cavity, in addition to administering long-term antibiotic treatment. This approach was successful in eradicating the infection. Following a period of rehabilitation, the patient regained the ability to walk independently. Conclusion: Cement rods infused with antibiotics are effective for delivering high doses of antibiotics locally while providing structural support to the bone. Over the last three decades, they have demonstrated encouraging outcomes in treating infections, and due to their affordability, simplicity, and effectiveness, they remain an excellent treatment option. Here, we highlight the use of colistin in making antibiotic-coated cement rods for the eradication of chronic, long-standing infection.

Targeting CERS6-AS1/FGFR1 axis as synthetic vulnerability to constrain stromal cells supported proliferation in Mantle cell lymphoma.

The interaction between stromal and tumor cells in tumor microenvironment is a crucial factor in Mantle cell lymphoma (MCL) progression and therapy resistance. We have identified a long non-coding RNA, CERS6-AS1, upregulated in MCL and associated with poor overall survival. CERS6-AS1 expression was elevated in primary MCL within stromal microenvironment and in a subset of MCL cells adhered to stromal layer. These stromal-adhered MCL-subsets exhibited cancer stem cell signatures than suspension counterparts. Mechanistically, we found that downregulating CERS6-AS1 in MCL reduced Fibroblast Growth Factor Receptor-1 (FGFR1), expression attributed to loss of its interaction with RNA-binding protein nucleolin. In addition, using in-silico approach, we have discovered a direct interaction between nucleolin and 5'UTR of FGFR1, thereby regulating FGFR1 transcript stability. We discovered a positive association of CERS6-AS1 with cancer stem cell signatures, and Wnt signaling. Building on these, we explored potential therapeutic strategies where combining nucleolin-targeting agent with FGFR1 inhibition significantly contributed to reversing cancer stem cell signatures and abrogated primary MCL cell growth on stromal layer. These findings provide mechanistic insights into regulatory network involving CERS6-AS1, nucleolin, and FGFR1 axis-associated crosstalk between tumor cells and stromal cell interaction and highlights therapeutic potential of targeting a non-coding RNA in MCL.

Mechanistic basis for rescuing hypertrophic cardiomyopathy with myosin regulatory light chain phosphorylation.

We investigated the impact of the phosphomimetic (Ser15 → Asp15) myosin regulatory light chain (S15D-RLC) on the Super-Relaxed (SRX) state of myosin using previously characterized transgenic (Tg) S15D-D166V rescue mice, comparing them to the Hypertrophic Cardiomyopathy (HCM) Tg-D166V model and wild-type (WT) RLC mice. In the Tg-D166V model, we observed a disruption of the SRX state, resulting in a transition from SRX to DRX (Disordered Relaxed) state, which explains the hypercontractility of D166V-mutated myosin motors. The presence of the S15D moiety in Tg-S15D-D166V mice restored the SRX/DRX balance to levels comparable to Tg-WT, thus mitigating the hypercontractile behavior associated with the HCM-D166V mutation. Additionally, we investigated the impact of delivering the S15D-RLC molecule to the hearts of Tg-D166V mice via adeno-associated virus (AAV9) and compared their condition to AAV9-empty vector-injected or non-injected Tg-D166V animals. Tg-D166V mice injected with AAV9 S15D-RLC exhibited a significantly higher proportion of myosin heads in the SRX state compared to those injected with AAV9 empty vector or left non-injected. No significant effect was observed in Tg-WT hearts treated similarly. These findings suggest that AAV9-delivered phosphomimetic S15D-RLC modality mitigates the abnormal Tg-D166V phenotype without impacting the normal function of Tg-WT hearts. Global longitudinal strain analysis supported these observations, indicating that the S15D moiety can alleviate the HCM-D166V phenotype by restoring SRX stability and the SRX ↔ DRX equilibrium.

Modified Osteotomy for TMJ Ankylosis in Paediatric Patients with Deficient Interpositional Temporalis Muscle Mass and Buccal Fat Pad - A case Series and Literature Review.

Ankylosis of the temporomandibular joint (TMJ) is a bony or fibrous fusion of the articular surfaces of the mandibular condyle and the glenoid fossa. Gap arthroplasty, Interpositional arthroplasty, Condyle reconstruction with autogenic or alloplastic grafts and total joint replacement are some common modalities of management. In this article, we discuss a series of three cases of unilateral TMJ ankylosis in paediatric patients, managed by gap arthroplasty using a modified osteotomy cut. The modification was adapted due to inadequate interpositionable temporalis muscle or buccal fat on the affected side and chances of adaptive remodelling of the CCG (Costochondral graft), if placed were rendered negative.

CCTG BR34: A Randomized Phase 2 Trial of Durvalumab and Tremelimumab With or Without Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.

INTRODUCTION: First-line therapy for patients with metastatic NSCLC includes checkpoint inhibitor monotherapy, dual checkpoint inhibition, or combination with chemotherapy. We compared outcomes with combination chemoimmunotherapy versus dual checkpoint inhibition as first-line treatment for patients with metastatic NSCLC. METHODS: This open-label, randomized clinical trial was conducted at 44 sites in Canada and Australia. Patients with treatment-naive, metastatic NSCLC without sensitizing EGFR or ALK alterations were randomized (1:1) to receive treatment with durvalumab plus tremelimumab with or without platinum-doublet chemotherapy. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate, and safety. RESULTS: A total of 301 patients were randomized. Median OS was 16.6 months (95% confidence interval [CI]: 12.6-19.1) with chemotherapy plus immunotherapy and 14.1 months (95% CI: 10.6-18.3) with immunotherapy (hazard ratio = 0.88, 90% CI: 0.67-1.16, p = 0.46). Median progression-free survival with chemotherapy plus immunotherapy was 7.7 months (95% CI: 5.5-8.5) and 3.2 months (95% CI: 2.7-5.1) with immunotherapy (hazard ratio = 0.67, 95% CI: 0.52-0.88). The overall response rate with chemoimmunotherapy was 42.4% and 29.3% with immunotherapy (adjusted OR = 1.69, 95% CI: 1.04-2.76). The percentage of patients with grade 3 or higher adverse events was 82% in the chemotherapy plus immunotherapy group and 70% in the immunotherapy group. Exploratory analyses of programmed death-ligand 1 expression and blood-based tumor mutation burden revealed no differential treatment effect on OS. CONCLUSIONS: The addition of chemotherapy to durvalumab plus tremelimumab in the first-line treatment of stage IV NSCLC did not improve survival compared with durvalumab plus tremelimumab alone. Further study is warranted to identify patients that benefit from initial immunotherapy alone versus combination chemotherapy plus immunotherapy as first-line treatment.

The alternative sigma factors, rpoN1 and rpoN2 are required for mycophagous activity of Burkholderia gladioli strain NGJ1.

Bacteria utilize RpoN, an alternative sigma factor (σ54) to grow in diverse habitats, including nitrogen-limiting conditions. Here, we report that a rice-associated mycophagous bacterium Burkholderia gladioli strain NGJ1 encodes two paralogues of rpoN viz. rpoN1 and rpoN2. Both of them are upregulated during 24 h of mycophagous interaction with Rhizoctonia solani, a polyphagous fungal pathogen. Disruption of either one of rpoNs renders the mutant NGJ1 bacterium defective in mycophagy, whereas ectopic expression of respective rpoN genes restores mycophagy in the complementing strains. NGJ1 requires rpoN1 and rpoN2 for efficient biocontrol to prevent R. solani to establish disease in rice and tomato. Further, we have identified 17 genes having RpoN regulatory motif in NGJ1, majority of them encode potential type III secretion system (T3SS) effectors, nitrogen assimilation, and cellular transport-related functions. Several of these RpoN regulated genes as well as certain previously reported T3SS apparatus (hrcC and hrcN) and effector (Bg_9562 and endo-ß-1,3-glucanase) encoding genes are upregulated in NGJ1 but not in ΔrpoN1 or ΔrpoN2 mutant bacterium, during mycophagous interaction with R. solani. This highlights that RpoN1 and RpoN2 modulate T3SS, nitrogen assimilation as well as cellular transport systems in NGJ1 and thereby promote bacterial mycophagy.

Diabetes and Cancer: Risk, Challenges, Management and Outcomes.

BACKGROUND: Diabetes mellitus and cancer are commonly coexisting illnesses, and the global incidence and prevalence of both are rising. Cancer patients with diabetes face unique challenges. This review highlights the relationship between diabetes and cancer and various aspects of the management of diabetes in cancer patients. METHODS: A literature search using keywords in PubMed was performed. Studies that were published in English prior to July 2021 were assessed and an overview of epidemiology, cancer risk, outcomes, treatment-related hyperglycemia and management of diabetes in cancer patients is provided. RESULTS: Overall, 8-18% of cancer patients have diabetes as a comorbid medical condition. Diabetes is a risk factor for certain solid malignancies, such as pancreatic, liver, colon, breast, and endometrial cancer. Several novel targeted compounds and immunotherapies can cause hyperglycemia. Nevertheless, most patients undergoing cancer therapy can be managed with an appropriate glucose lowering agent without the need for discontinuation of cancer treatment. Evidence suggests that cancer patients with diabetes have higher cancer-related mortality; therefore, a multidisciplinary approach is important in the management of patients with diabetes and cancer for a better outcome. CONCLUSIONS: Future studies are required to better understand the underlying mechanism between the risk of cancer and diabetes. Furthermore, high-quality prospective studies evaluating management of diabetes in cancer patients using innovative tools are needed. A patient-centered approach is important in cancer patients with diabetes to avoid adverse outcomes.

Time-Lapse Between Presentation and Treatment of Mandibular Fractures: Is There a Correlation With Sensory Loss Recovery or No Recovery?

ABSTRACT: A prospective cohort study composed of 43 patients treated for unilateral mandibular fracture. The primary study variables were the post-traumatic IAN neurosensory score and the score after fracture reduction in two different groups on the basis of time lapse between presentation and treatment and displacement of mandible fracture. Appropriate descriptive and bivariate statistics were computed. The sample was analyzed over a one year period. It was observed that the recovery percentage (80%) was good in Group-A (n = 20) patients as compared to Group-B (n = 23) patients (43.47%) with significant P value of 0.015. Patients with displacement of ≥9 mm have neurosensory deficit of 80% while fracture displacement ≥ 5 mm to 8 mm have the neurosensory deficit of 34.21% which is significant with P value of 0.049. With each millimeter increase of displacement of fracture segments, more neurosensory deficit will be manifested. Delay in seeking in the treatment increases the risk because of continued movement. Where the injury is more severe, excessive displacement with increased time lapse from injury to surgical intervention, there is a higher possibility neurosensory deficit or no recovery. Early management can reduce the risk of permanent neurosensory deficits.

Temporal evolution of submicron particles during extreme fireworks.

Evolution of submicron particles in terms of particle number concentration and mobility-equivalent diameter was measured during Diwali festival-specific intensive pyrotechnic displays in Varanasi over central Indo-Gangetic Plain (IGP). A scanning mobility particle sizer coupled with an optical particle sizer was used to fit in an overlapping size range, and particle number concentration was analyzed to have an insight into the new particle formation and subsequent evolution of particles from nucleation to accumulation mode. Further, variation in black carbon (BC) concentration and aerosol ionic composition was measured simultaneously. Frequent fluctuation in particle number concentration in and around Diwali festival was evidenced, primarily influenced by local emission sources and meteorology, with three distinct peaks in number concentrations (dN/dlogDp, 3.1-4.5 × 104 cm3) coinciding well with peak firework emission period (18:00-23:00 h). Submicron particle size distribution revealed a single peak covering a size range of 80-130 nm, and for all instances, number concentration maximum coincided with geometric mean minimum, indicating the emission primarily in the ultrafine range (< 0.1 µm). Interestingly, during peak firework emissions, besides rise in accumulation mode, an event of new particle formation was identified with increase in nucleation and small Aitken mode, before being dispersed to background aerosols. On an integral scale, a clear distinction was noted between a normal and an episodic event, with a definite shift in the formation of ultrafine particles compared with the accumulation mode. The BC diurnal profile was typical, with a prominent nocturnal peak (12.0 ± 3.9 µg m-3) corresponding to a decrease in the boundary layer height. A slight variation in maximum BC concentration (16.8 µg m-3) was noted in the night of the event coinciding well with firework emissions. An increase in some specific ionic species was also noted in combination with an increase in the overall cation to anion ratio, which was explained in terms of heterogeneous transformation of NOx and catalytic conversion of SO2. Graphical abstract Time-resolved evolution of particle size distribution during normal and episodic events.

Therapeutic potential of AAV9-S15D-RLC gene delivery in humanized MYL2 mouse model of HCM.

Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder characterized by ventricular hypertrophy, myofibrillar disarray, and fibrosis, and is primarily caused by mutations in sarcomeric genes. With no definitive cure for HCM, there is an urgent need for the development of novel preventive and reparative therapies. This study is focused on aspartic acid-to-valine (D166V) mutation in the myosin regulatory light chain, RLC (MYL2 gene), associated with a malignant form of HCM. Since myosin RLC phosphorylation is critical for normal cardiac function, we aimed to exploit this post-translational modification via phosphomimetic-RLC gene therapy. We hypothesized that mimicking/modulating cardiac RLC phosphorylation in non-phosphorylatable D166V myocardium would improve heart function of HCM-D166V mice. Adeno-associated virus, serotype-9 (AAV9) was used to deliver phosphomimetic human RLC variant with serine-to-aspartic acid substitution at Ser15-RLC phosphorylation site (S15D-RLC) into the hearts of humanized HCM-D166V mice. Improvement of heart function was monitored by echocardiography, invasive hemodynamics (PV-loops) and muscle contractile mechanics. A significant increase in cardiac output and stroke work and a decrease in relaxation constant, Tau, shown to be prolonged in HCM mice, were observed in AAV- vs. PBS-injected HCM mice. Strain analysis showed enhanced myocardial longitudinal shortening in AAV-treated vs. control mice. In addition, increased maximal contractile force was observed in skinned papillary muscles from AAV-injected HCM hearts. Our data suggest that myosin RLC phosphorylation may have important translational implications for the treatment of RLC mutations-induced HCM and possibly play a role in other disease settings accompanied by depressed Ser15-RLC phosphorylation. KEY MESSAGES: HCM-D166V mice show decreased RLC phosphorylation and decompensated function. AAV9-S15D-RLC gene therapy in HCM-D166V mice, but not in WT-RLC, results in improved heart performance. Global longitudinal strain analysis shows enhanced contractility in AAV vs controls. Increased systolic and diastolic function is paralleled by higher contractile force. Phosphomimic S15D-RLC has a therapeutic potential for HCM.

Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain.

Myosin regulatory light chain (RLC) phosphorylation is important for cardiac muscle mechanics/function as well as for the Ca2+ -troponin/tropomyosin regulation of muscle contraction. This study focuses on the arginine to glutamine (R58Q) substitution in the human ventricular RLC (MYL2 gene), linked to malignant hypertrophic cardiomyopathy in humans and causing severe functional abnormalities in transgenic (Tg) R58Q mice, including inhibition of cardiac RLC phosphorylation. Using a phosphomimic recombinant RLC variant where Ser-15 at the phosphorylation site was substituted with aspartic acid (S15D) and placed in the background of R58Q, we aimed to assess whether we could rescue/mitigate R58Q-induced structural/functional abnormalities in vitro. We show rescue of several R58Q-exerted adverse phenotypes in S15D-R58Q-reconstituted porcine cardiac muscle preparations. A low level of maximal isometric force observed for R58Q- versus WT-reconstituted fibers was restored by S15D-R58Q. Significant beneficial effects were also observed on the Vmax of actin-activated myosin ATPase activity in S15D-R58Q versus R58Q-reconstituted myosin, along with its binding to fluorescently labeled actin. We also report that R58Q promotes the OFF state of myosin, both in reconstituted porcine fibers and in Tg mouse papillary muscles, thereby stabilizing the super-relaxed state (SRX) of myosin, characterized by a very low ATP turnover rate. Experiments in S15D-R58Q-reconstituted porcine fibers showed a mild destabilization of the SRX state, suggesting an S15D-mediated shift in disordered-relaxed (DRX)↔SRX equilibrium toward the DRX state of myosin. Our study shows that S15D-phosphomimic can be used as a potential rescue strategy to abrogate/alleviate the RLC mutation-induced phenotypes and is a likely candidate for therapeutic intervention in HCM patients.

Optic nerve head three-dimensional shape analysis.

We present a method for optic nerve head (ONH) 3-D shape analysis from retinal optical coherence tomography (OCT). The possibility to noninvasively acquire in vivo high-resolution 3-D volumes of the ONH using spectral domain OCT drives the need to develop tools that quantify the shape of this structure and extract information for clinical applications. The presented method automatically generates a 3-D ONH model and then allows the computation of several 3-D parameters describing the ONH. The method starts with a high-resolution OCT volume scan as input. From this scan, the model-defining inner limiting membrane (ILM) as inner surface and the retinal pigment epithelium as outer surface are segmented, and the Bruch's membrane opening (BMO) as the model origin is detected. Based on the generated ONH model by triangulated 3-D surface reconstruction, different parameters (areas, volumes, annular surface ring, minimum distances) of different ONH regions can then be computed. Additionally, the bending energy (roughness) in the BMO region on the ILM surface and 3-D BMO-MRW surface area are computed. We show that our method is reliable and robust across a large variety of ONH topologies (specific to this structure) and present a first clinical application.

Bilateral congenital mucous extravasation phenomenon: A rare case with literature review.

The purpose of this paper is to discuss a rare case of bilateral congenital mucous extravasation phenomenon on buccal mucosa near commissure of mouth. The lesions were noted at birth, subsequently enlarged to interfere with feeding. The lesion frequently ruptured, regressed, and again enlarged to interfere with normal function. The lesions were surgically removed under general anesthesia at 11 months of age and the diagnosis was confirmed by histopathological examination. Postoperative follow-up after 14 months showed no recurrence.

Waugh's Syndrome: Report of Two Children with Intussusception.

Waugh's syndrome (WS) is the rare association of intussusception and intestinal malrotation. We present two such cases in a 5-month-old infant and a 9-year-old girl. Both patients presented with intussusception and were diagnosed with malrotation during workup and surgical exploration. We conclude that the possibility of intestinal malrotation must be taken into consideration while managing children with intussusception.

Cardiac contractility, motor function, and cross-bridge kinetics in N47K-RLC mutant mice.

We have investigated the physiology and mechanical profiles of skinned papillary muscle fibers from transgenic mice expressing the N47K mutation in the myosin regulatory light chain (RLC), shown to cause hypertrophic cardiomyopathy in humans. The results were compared with wild-type (WT) mice, both expressing the human ventricular RLC. Rate constants of a cross-bridge (XB) cycle were deduced from tension transients induced by sinusoidal length changes during maximal Ca2+ activation, and were studied as a function of MgATP, MgADP, and Pi concentrations. N47K mutant showed slower XB cycles but higher actin-activated ATPase activity compared with WT. Consequently, N47K exhibited larger tension than WT. K0 (ADP association constant) and K4 (equilibrium constant of force generation) were larger in N47K, and K1 (ATP association constant) was slightly larger in N47K vs. WT, demonstrating stronger nucleotide binding and force generation abilities of the mutant, but no changes in rigor acto-myosin binding were observed. Tension per XB was similar among groups, but N47K exhibited more XB distribution in the attached state. Larger values of tension and higher ATPase in N47K suggested that more cross-bridges participated in tension production in the mutant myocardium compared with WT. In vivo analysis of heart function, performed in ~ 12.5-month-old mice by echocardiography and invasive hemodynamics, demonstrated a significant decrease in dP/dtmax -end-diastolic volume relationship, indicating a depression of ventricular contractility in N47K mice. Our findings suggest that the N47K mutation exerts its action through direct alterations of myosin motor function that ultimately result in pathological hypertrophic remodeling in N47K hearts.

Orofacial trauma in rural India: A clinical study.

PURPOSE: Orofacial trauma is becoming a leading medical problem worldwide. Most of the studies pertaining to orofacial trauma have been done in urban areas but very little scientific literature is available for rural areas. METHODS: A prospective medical institute-based study of orofacial injury patients was carried out from May 2013 to April 2016 (36 Months). Data regarding incidence, age and sex distribution, causes, types and site of injury, treatment modalities and trauma associated complications were collected and analysed. RESULTS: A total of 784 patients were studied. Males outnumbered females by a ratio of 2.9:1. Age range was 9 months-75 years with the peak incidence in the age-group of 18-34 years. Most injuries were caused by road-side accidents (72.7%), followed by assault and falls in 11.6% and 8% respectively. Soft tissue injuries and mandibular fractures were the most common type of injuries. Head/neck (50.29%) and limb injuries (27.2%) were the most prevalent associated injuries. Surgical debridement and soft tissue suturing was the most common emergency procedure. Closed reduction was performed in 61% of patients and open reduction and internal fixation in 30% of cases and 9% were managed conservatively. Complications occurred in 6.88% of patients, mainly due to infection and malocclusion. The mean duration of hospital stay was (10.12 ± 6.24) days. CONCLUSION: This study highlights the importance of department of dental surgery along with other disciplinaries in the management of orofacial injuries. Road-side accident remains the major etiological factor of orofacial injuries in our setting.

Bimaxillary Oral Focal Mucinosis.

Oral focal mucinosis is considered as oral counterpart of cutaneous focal mucinosis. The preoperative diagnosis of mucinosis is almost impossible because of its rarity and clinical similarity to other lesions of various etiologies. The histological diagnosis of oral mucinosis is important to better understand the etiopathogenesis, treatment modalities, and any recurrence of the lesion besides differentiating from the other soft tissue lesions.The purpose of this paper is to report the first case of bimaxillary involvement with dome-shaped elevated, rounded, asymptomatic, normally colored swelling in left posterior palatal mucosa and left mandibular posterior region in a 25-year old woman who was diagnosed as oral focal mucinosis histopathologically.

Transoral approach alone in single miniplate osteosynthesis of angle fracture - our experience.

AIM: The aim of this study was to determine the outcome of transoral approach alone to treat the mandibular angle fracture using single 2.0 mm miniplate. MATERIALS AND METHODS: In this study, 28 patients were included and treated with 2.0 mm single miniplate osteosynthesis at upper border along Champy's line of osteosynthesis using transoral approach alone. RESULTS: All the cases were treated successfully with 2.0 mm single miniplate with common complications such as infection (two cases) and plate exposure (one case) in a total of two cases. CONCLUSION: Use of single miniplates by transoral approach alone for superior border osteosynthesis is effective and simple approach without need of extra armamentarium.

A new simplified technique for intermaxillary fixation by loop-designed wire.

In the treatment of maxillofacial fractures, Inter-maxillary fixation (IMF) is an important. The upper and lower arch bars or Ivy eyelet wiring is secured by wires and IMF is done with the help of box wiring. Here, we present a new type of IMF technique, using 26-gauze stainless steel 'loop-design' wire, which is a simple, quick, economical and minimally invasive technique without using arch bars. Typical indications for its use are minimally displaced fractures, deep bite cases, stabilization of fracture during open reduction and internal fixation, orthognathic surgeries and in tumor resection surgeries.