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Major progress has been made in the last five years to reduce the suffering and death caused by malaria infection worldwide. In the absence of effective preventative tools, such as vaccines, chemotherapy is a principal option to treat malaria. To date, Artemisinin-based combination therapy (ACT) is used as the most effective treatment strategy against malaria infection, which made a significant impact in reducing overall mortality and morbidity. Nevertheless, the current armamentarium of anti-malarial drugs is far from satisfactory as they have unacceptable toxic sideeffects, along with resistance to the conventional treatment regime, emphasizing the need to identify new compounds and alternative treatment strategies to stay one step ahead in this evolutionary arms race between host and parasites. Developing a vaccine would be the most desirable remedy for eliminating this deadliest parasitic disease. Furthermore, immunotherapy can also be the future to treat the inflammatory disease caused by the intracellular pathogen of the genus Plasmodium. In this pursuit, regulation of pro-inflammatory and anti-inflammatory pathways in a correct manner by maintaining optimal Treg/Th17 balance may be the key to successful immunotherapeutic treatment against malaria. In this chapter, the history and mechanism of action of some important anti-malarial drugs have been narrated, along with the future possibilities of potential therapeutic approaches against malaria.

Th9, a new subgroup of CD4

Proximal femur fractures in geriatric patients are associated with substantial mortality. Management of intracapsular proximal femur fractures has been based on age, displacement, cognition, and pre-injury mobility. However, over the last decade, there has been a tendency to offer arthroplasty rather than internal fixation for these patients irrespective of displacement, to allow early mobilisation and negate the higher rate of reoperation due to failed internal fixation. There are no previous investigations analysing whether the severity of fracture displacement is related to different patient characteristics.This study examines whether patients sustaining undisplaced or displaced intracapsular proximal femur fractures represent different patient groups with different pre-injury characteristics and post-operative mortality, irrespective of treatment modality.A retrospective series of 329 consecutive patients over the age of 55 years who sustained intracapsular proximal femur fractures, who underwent surgical management at a district general hospital over a period of 2 years (2012-2013) were identified using the national hip fracture database. Demographics, American Society of Anaesthesiologist (ASA) grade, pre-injury outdoor mobility status, cognitive status, and admission serum investigations, fracture displacement, type of surgery, and mortality rates at short term (2 years)long-term (7-9 years) were reviewed.There were 109 male and 220 female patients with a minimum follow-up of 7 years. The mean age at surgery was 81.6 years (range 55-103 years). There were 63 (19.1%) undisplaced fractures (Garden 12) and, 265 (80.5%) displaced fractures (Garden 34). The median survival in this cohort was 2.95 years (95% CI 2.3-3.6). Mortality rates were 77.4% (n=257) at long-term (7-9 years) follow-up. Admission patient characteristics showed no statistically significant difference between displaced and undisplaced fracture groups. This included ASA, pre-operative cognition, and mobility status. Fracture displacement was not an independent predictor of mortality at short or long term.In patients sustaining intracapsular proximal femur fractures, the degree of displacement is not a caveat for a different patient group. Fracture displacement is not predicted by the pre-injury level of function and does not predict short or long-term mortality.

Introduction Our study analyses the influence of the COVID-19 pandemic on perioperative death in elderly patients undergoing surgery for fractures who test positive for the virus during their admission in a rural hospital setting in the UK. Methods One hundred and fifty-six consecutive patients with age more than 75 years, who underwent surgery for fractures in Glangwili General Hospital during the second wave of the pandemic between 20th November 2020 and 20th January 2021, were included in this study. The 28-day mortality rate was estimated, and the results were compared to a matched cohort of patients from a similar duration before the pandemic (20th November 2019 to 20th January 2020). Results A total of 41 out of 156 patients were tested positive for COVID-19 in this study cohort. The overall 28-day mortality rate was 8.9% (n=15 patients) in comparison to 4% (n=8) in the comparative cohort of 196 patients from the pre-pandemic era. Of the 41 patients who tested positive for COVID-19, 11 patients died within 28 days of surgery, resulting in a mortality rate of 26.8% with a relative risk of 7.7(p=0.0461). Furthermore, 91% (n=10) of COVID-19-positive patients who died had an underlying cardiac disease and/or proximal femoral fractures. The 28-day mortality rate in those tested negative for COVID-19 was 3.5% (n=4). Conclusion There is a significantly increased risk of death in the perioperative period on contracting COVID-19, in patients who are 75 years of age or older, especially those with associated cardiac comorbidities and who have sustained proximal femoral fractures.

Myeloid derived suppressor cells (MDSCs) are a group of heterogeneous cell populations that can suppress T cell responses. Various aspects of MDSCs in regulating immune responses in several cancer and infectious diseases have been reported till date. But the role and regulation of MDSCs have not been systematically studied in the context of malaria. This study depicts the phenotypic and functional characteristics of splenic MDSCs and how they regulate Th-17 mediated immune response during Experimental Cerebral Malaria (ECM). Flow cytometric analysis reveals that MDSCs in the spleen and bone marrow expand at 8 dpi during ECM. Among subtypes of MDSCs, PMN-MDSCs show significant expansion in the spleen but M-MDSCs remain unaltered. Functional analysis of sorted MDSCs from spleens of Plasmodium berghei ANKA (PbA) infected mice shows suppressive nature of these cells and high production of Nitric oxide (NO). Besides, MDSCs were also found to express various inflammatory markers during ECM suggesting the M1 type phenotype of these cells. In-vivo depletion of MDSCs by the use of Anti Gr-1 increases mice survival but doesn't significantly alter the parasitemia. Previously, it has been reported that Treg/Th-17 balance in the spleen is skewed towards Th-17 during ECM. Depletion of MDSCs was found to regulate Th-17 percentages to homeostatic levels and subvert various inflammatory changes in the spleen. Among different factors, IL-6 was found to play an important role in the expansion of MDSCs and expression of inflammatory markers on MDSCs in a STAT3-dependent manner. These findings provide a unique insight into the role of IL-6 in the expansion of the MDSC population which causes inflammatory changes and increased Th-17 responses during ECM.

A wide number of disorders, including pathologies outside the hip, can cause and refer pain to hip. However, determining the cause of a painful hip can be a major challenge to orthopedic surgeons. Failure to diagnose and appropriately investigate pathologies of the hip in adults may result in delayed management and prolonged patient morbidity. A systematic approach to investigating the etiology of hip pain in adults (e.g., history, careful clinical and radiographic examination), will help identify the majority of clinically important pathologies which can cause hip pain. Conservative treatment and selective use of injection therapies has proven quite successful for the treatment of most causes of hip pain.

Objective: The purpose of this study is to analyze the epidemiological characteristics of operated pelvic and acetabular fractures at our institution and to compare them with epidemiological data from different parts of the world. Methods: This is a retrospective study of trauma data at Khoula Hospital from January 2010 to December 2016. Epidemiological data including age, gender, mode of trauma, presence of injuries, fracture classification, surgical approach, and associated complications were analyzed. Results: A total of 209 patients with a diagnosis of pelvis and acetabular fracture were included in this study. Young age group (mean: 35) and male gender (68%) were predominately affected. The main leading cause of the injury was road traffic accidents (96%). There were a total of 179 (86%) acetabular fractures and 30 (14%) pelvic fractures. Fracture of the posterior wall of the acetabulum was the most common pattern (39%), followed by transverse fracture (27%). Anterior–posterior compression type was clearly the most common type of pelvis fracture (40%). Six patients had postoperative sciatic nerve palsy, five patients had venous thromboembolism, and nine patients had wound infection. Conclusion: The great majority of the patients were victims of road traffic accidents, male, and young adults. The posterior wall fracture was the most common pattern, as shown in other studies as well. However, we identified some epidemiological differences in comparison with some studies from some other parts of the world. These include a higher contribution of road traffic accidents as a mode of injury and a high female-to-male ratio.

Splenomegaly, a major symptom in Plasmodium infection, is extensively studied for its immunopathological role in mice malaria model infected with Plasmodium berghei ANKA. The status of autophagic regulation in hosts in malaria pathogenesis remains unreported till date. This study demonstrated the autophagy, proteasomal degradation and NRF2-KEAP1 antioxidant pathway status in the host during Plasmodium infection taking murine spleen as our organ of interest. Initial staining and autophagic gene expression indicate a possibility of autophagic pathway activation. Although the conversion of LC3A to LC3B and lysosome-autophagosome fusion increases, the final degradation step remains incomplete. Resultant upregulation of p62 and its altered phosphorylated status enhances its binding to keap1 causing NRF2 translocation to the nucleus. NRF2 act as transcription factor upregulating p62 level itself leading to an autoinduction loop of p62 expression. Interestingly, enhancement of P62 interaction with proteasome subunit RPT1 indicates a possible role in transporting ubiquitinated cargo to proteasome complex. Ubiquitination level increased with subsequent upregulation of all three modes of proteasomal degradation i.e trypsin-like, caspase-like and especially chymotrypsin-like. Sqstm1/p62 plays a critical central role in regulating autophagy, proteasomal degradation, and NRF2-KEAP1 pathway. The incomplete autophagic flux in the final step may be a key therapeutic target, as autophagic degradation and subsequent pathogenic peptide presentation is of utmost necessity for downstream immune response.

Splenic plasmacytoid dendritic cells (pDC) possess the capability to harbor live replicative Plasmodium parasite. Isolated splenic pDC from infected mice causes malaria when transferred to naive mice. Incomplete autophagic degradation might cause poor antigen processing and poor immune response. Induction of autophagic flux by rapamycin treatment led to better prognosis by boosting pDC centered immune response against the pathogen. Splenic pDC from rapamycin-treated infected mice, caused less parasitemia in naive mice. The downregulation of adhesion with unaltered phagocytic potential of the cells post autophagic induction restricted excessive parasite burden within them. Rapamycin-treated pDC played a better role in antigen presentation. They showed higher expression of co-stimulatory molecules CD80, CD86, DEC205, MHCI. Rapamycin-treated pDC induced CD28 expression on CD8+ T cells and suppressed FasL level. This cells also influenced differentiation of effector, memory T cell population. The increase in IL10: TNFα ratio, Treg: Th17 ratio and lowering of myeloid DC: plasmacytoid DC ratio was observed. It shifted the overaggressive inflammation mediated Th1 pathway that is reported to incur host damage, to a better well-balanced cytokine profile exhibiting Th2 pathway. Autophagic flux induction within pDC proved to be beneficial in combating malarial pathogenicity.

Splenic red pulp macrophages play a critical role infiltration of infected RBC and elimination of pathogens during malarial infection. However, the efficiency of pathogenic processing and the intricate pathway followed by them to boost the downstream immune response has not been studied in details. We checked the status of autophagic regulation within the cells both before and after the infection and also modulated the autophagic flux with either its inducer or inhibitor. We found that the upregulation of autophagic gene and the corresponding pathway is correlated with better parasite clearance and survivability, with an enhanced downstream immune response. It also increases their phagocytic potential with better Lysosomal associated protein I and II synthesis. The autophagolysosome formation increases as well, and more vacuole bound LC3B protein are detected. Chemokine synthesized from Red Pulp macrophage helps in mediating the induction for recruiting neutrophil and CD4 + T cells to the splenic red pulp region. The skewing of M1 macrophage polarity is observed post autophagic induction with a better costimulatory molecule like CD80, CD86 expression and antigen presenting molecule MHC I, MHC II is observed. This study shows the possibility of an alternative or adjuvant therapy regimen for the malarial patient by inducing the autophagic pathway that targets the red pulp macrophages. This might be helpful for better pathogen degradation and processing. The subsequent clearance of parasite will result in a better outcome for the patients.

Lipoma arborescens (LA) is an uncommon intra-articular tumor of the synovium that can affect any joint in the body. A few cases of bilateral knee LA with osteoarthritis (OA) have been studied in the literature. We report the first patient with bilateral knee LA associated with advanced OA changes, who was operated upon with staged bilateral total knee replacement (TKR). Our case was complicated by immediate postoperative hematoma and wound complications on both sides. We describe the possible postoperative challenges that we encountered after TKR for knee OA combined with LA.