Sustained depression of B cell counts in lupus nephritis after treatment with rituximab and/or belimumab is associated with fewer disease flares.

OBJECTIVE: To study the risk of lupus nephritis flare (LNF) or severe lupus flare (SLF) as a function of B cell count kinetics in lupus nephritis (LN) patients after they achieve at least a partial renal response (PRR) with induction treatment that includes rituximab (RTX) and/or belimumab (BLM). METHODS: We performed a retrospective analysis of a cohort of 19 patients with severe LN that received a B cell agent (BCA), RTX and/or BLM, as part of an initial treatment regimen for an LN flare and had subsequent CD19+ B cell measurements in peripheral blood. We then characterized the follow-up periods, after B cell depressions occurred and PRR were achieved, by the corresponding trajectories of B cell counts (BCC). Time periods with sustained low BCC were type 1 (T1) episodes, while those with repletion of BCC>100 cells/µL were called type 2 (T2) episodes. Time periods with rapid BCC repletion, defined as >50 cells/µL in ≤6 months, were called T2b episodes. Corresponding C3, C4, and anti-dsDNA levels were recorded for each episode. The time from PRR until an event, either a LNF or SLF, or to censoring, either at the end of the study period or the end of available patient follow-up, was assessed for each episode type. Kaplan-Meier survival analysis was used to compare time to flare between T1 and T2 episodes. RESULTS: There were 26 episodes of B cell depression. Seventeen (65%) were T1 and 9 (35%) were T2. Compared to T1 episodes, T2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio (HR) = 9.0, 95% CI for HR = 2.2-36.7); this risk was even larger for T2b vs T1 episodes. Median BCC was 14 cells/µL in T1 and 160 cells/µL in T2 episodes. Both C3 and C4 levels significantly increased over the duration of the episode in T1 episodes only. CONCLUSION: Sustained low BCC was associated with prolonged serologic and clinical response, whereas repletion, and particularly rapid repletion, of B cells after treatment with BCA was associated with subsequent disease flare.

Recent advances in the diagnosis and management of typhoid fever in Africa: A review.

Typhoid fever, a classical disease of enteric origin caused by Salmonella species of bacteria, is among the most important diseases threatening public health in Africa. The African continent is a marker for both low resources within the healthcare system and poor disease control policy formulations in managing endemic infectious diseases. Since the colonial era, the Widal serological test has been used to confirm typhoid fever in Africa, however recent studies recommend blood culture, and when blood culture cannot be obtained, clinical findings, laboratory Widal test confirmation, and ruling out other febrile illnesses as confirmatory pathway to diagnose typhoid fever in Africa. Managing typhoid fever relies on antimicrobials. In 1980s chloramphenicol was the medication of choice. Years later, amoxicillin and co-trimoxazole were adopted. However, the instantaneous rise of resistant strains of Salmonella enterica confers an important challenge to treat the burdensome enteric fever. The current treatment algorithm of typhoid fever in Africa relies significantly on the use of fluoroquinolones, macrolides, and cephalosporins. Developed nations have successfully addressed and controlled typhoid fever via improvement in accessing safe water and food, better sanitary and hygienic behaviours, and vaccines development. Nevertheless, there is significant evidence to infer improvement in the diagnosis management of typhoid fever over the last few decades, and efforts are underway to control the disease spread in Africa. This review aims to provide an overview of the latest developments in typhoid fever diagnosis and management in Africa and provide key recommendations for a coordinated approach to mitigate typhoid in the continent.

Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice.

Advancement in both bioengineering and cell biology of the liver led to the establishment of the first-generation humanized liver chimeric mouse (HLCM) model in 2001. The HLCM system was initially developed to satisfy the necessity for a convenient and physiologically representative small animal model for studies of hepatitis B virus and hepatitis C virus infection. Over the last two decades, the HLCM system has substantially evolved in quality, production capacity, and utility, thereby growing its versatility beyond the study of viral hepatitis. Hence, it has been increasingly employed for a variety of applications including, but not limited to, the investigation of drug metabolism and pharmacokinetics and stem cell biology. To date, more than a dozen distinctive HLCM systems have been established, and each model system has similarities as well as unique characteristics, which are often perplexing for end-users. Thus, this review aims to summarize the history, evolution, advantages, and pitfalls of each model system with the goal of providing comprehensive information that is necessary for researchers to implement the ideal HLCM system for their purposes. Furthermore, this review article summarizes the contribution of HLCM and its derivatives to our mechanistic understanding of various human liver diseases, its potential for novel applications, and its current limitations.

Anesthesia and Alzheimer's: A review.

As early as 1955, it was Bedford who provided description of cognitive changes in elderly patients following anesthesia and surgery. Reports of individuals with catastrophic, non-stroke-related decline in cognitive functions following anesthesia and surgery lead to a perception in the lay population that anesthesia and surgery have the potential to greatly exaggerate the progression of dementia, particularly Alzheimer's disease (AD). There is a concern that anesthesia and surgery could cause irreversible impairment, leading to AD. This could also explain the accelerated decline in patients with mild cognitive impairment. We seek to explore the relevant literature to determine whether a correlation exists and then propose a possible pathophysiologic mechanism.

Distinct protein signatures of acute myeloid leukemia bone marrow-derived stromal cells are prognostic for patient survival.

Mesenchymal stromal cells (MSC) support acute myeloid leukemia (AML) cell survival in the bone marrow (BM) microenvironment. Protein expression profiles of AML-derived MSC are unknown. Reverse phase protein array analysis was performed to compare expression of 151 proteins from AML-MSC (n=106) with MSC from healthy donors (n=71). Protein expression differed significantly between the two groups with 19 proteins over-expressed in leukemia stromal cells and 9 over-expressed in normal stromal cells. Unbiased hierarchical clustering analysis of the samples using these 28 proteins revealed three protein constellations whose variation in expression defined four MSC protein expression signatures: Class 1, Class 2, Class 3, and Class 4. These cell populations appear to have clinical relevance. Specifically, patients with Class 3 cells have longer survival and remission duration compared to other groups. Comparison of leukemia MSC at first diagnosis with those obtained at salvage (i.e. relapse/refractory) showed differential expression of 9 proteins reflecting a shift toward osteogenic differentiation. Leukemia MSC are more senescent compared to their normal counterparts, possibly due to the overexpressed p53/p21 axis as confirmed by high ß-galactosidase staining. In addition, overexpression of BCL-XL in leukemia MSC might give survival advantage under conditions of senescence or stress and overexpressed galectin-3 exerts profound immunosuppression. Together, our findings suggest that the identification of specific populations of MSC in AML patients may be an important determinant of therapeutic response.

Impact of bistrand abasic sites and proximate orientation on DNA global structure and duplex energetics.

Bistrand lesions embedded within a single helical turn of tridecameric deoxyoligonucleotide duplexes represent a model system for exploring the impact of clustered lesions that occur in vivo and pose a significant challenge to cellular repair machineries. Such investigations are essential for understanding the forces that dictate lesion-induced mutagenesis, carcinogenesis, and cytotoxicity within a context that mimics local helical perturbations caused by an ionizing radiation event. This study characterizes the structural and energy profiles of DNA duplexes harboring synthetic abasic sites (tetrahydrofuran, F) as models of clustered bistrand abasic (AP) lesions. The standard tridecameric dGCGTACCCATGCG·dCGCATGGGTACGC duplex is employed to investigate the energetic impact of single and bistrand AP sites by strategically replacing one or two bases within the central CCC/GGG triplet. Our combined analysis of temperature-dependent UV and circular dichroism (CD) profiles reveals that the proximity and relative orientation of AP sites within bistrand-damaged duplexes imparts a significant thermodynamic impact. Specifically, 3'-staggered lesions (CCF/GFG) exert a greater destabilizing effect when compared with their 5'-counterpart (FCC/GFG). Moreover, a duplex harboring the central bistrand AP lesion (CFC/GFG) is moderately destabilized yet exhibits distinct properties relative to both the 3' and 5'-orientations. Collectively, our energetic data are consistent with structural studies on bistrand AP-duplexes of similar sequence in which a 3'-staggered lesion exerts the greatest perturbation, a finding that provides significant insight regarding the impact of orientation on lesion repair processing efficiency.

How Can We Identify Extraprostatic Extension (EPE) Before Surgery? The Use of a Preoperative Prostate MRI EPE Scoring System to Assess Postprostatectomy Locally Advanced Prostate Cancer.

Background: Distinguishing between organ-confined disease and extraprostatic extension (EPE) is crucial for the treatment of patients with prostate cancer. EPE is associated with an increased risk of biochemical recurrence, positive surgical margins, and metastatic disease. An MRI-based EPE scoring system was developed by Mehralivand in 2019; however, it has not been adopted in the Urology community. The purpose of this study is to evaluate the association of MRI-based EPE scoring with the pathologic EPE (pEPE) after radical prostatectomy. Methods: We conducted a retrospective review on a prospectively collected database of male patients who underwent a prostate MRI with EPE scoring by a trained genitourinary radiologist and subsequent robotic radical prostatectomy at our institution from September 2020 to December 2022. The associations between MRI EPE (mEPE) score and the presence of EPE on surgical pathology (pEPE) were examined using multivariable logistic regression. Results: A total of 194 patients met inclusion criteria with a median age of 63 years and prostate specific antigen (PSA) 7 ng/mL. Among those with mEPE score 3, 96% had pEPE. Those patients with an mEPE score ≥2 had an increased risk of pEPE compared with those with mEPE score 0 (odds ratio 3.79; 95% confidence interval 1.28-11.3) Furthermore, those with an mEPE score 3 were significantly more likely to have pEPE compared with those with mEPE score 0, 1 and 2 independently. Conclusion: MRI EPE is a straightforward tool that strongly correlates with the presence of pEPE. If validated prospectively, this scoring system could assist in counseling patients regarding nerve-sparing approach.

Application of SHAP for Explainable Machine Learning on Age-Based Subgrouping Mammography Questionnaire Data for Positive Mammography Prediction and Risk Factor Identification.

Mammography is considered the gold standard for breast cancer screening. Multiple risk factors that affect breast cancer development have been identified; however, there is an ongoing debate regarding the significance of these factors. Machine learning (ML) models and Shapley Additive Explanation (SHAP) methodology can rank risk factors and provide explanatory model results. This study used ML algorithms with SHAP to analyze the risk factors between two different age groups and evaluate the impact of each factor in predicting positive mammography. The ML model was built using data from the risk factor questionnaires of women participating in a breast cancer screening program from 2017 to 2021. Three ML models, least absolute shrinkage and selection operator (lasso) logistic regression, extreme gradient boosting (XGBoost), and random forest (RF), were applied. RF generated the best performance. The SHAP values were then applied to the RF model for further analysis. The model identified age at menarche, education level, parity, breast self-examination, and BMI as the top five significant risk factors affecting mammography outcomes. The differences between age groups ranked by reproductive lifespan and BMI were higher in the younger and older age groups, respectively. The use of SHAP frameworks allows us to understand the relationships between risk factors and generate individualized risk factor rankings. This study provides avenues for further research and individualized medicine.

Low Peripheral B-Cell Counts in Patients With Systemic Rheumatic Diseases Due to Treatment With Belimumab and/or Rituximab Are Associated With Low Antibody Responses to Primary COVID-19 Vaccination.

Background: Immunosuppressive agents inhibit COVID-19 vaccine antibody (Ab) responses in patients with systemic rheumatic diseases. Rituximab may fully block Ab responses when B cells become undetected. The effect of detected but low number of B cells due to treatment with a B-cell agent (belimumab and/or rituximab) has not been established. Purpose: We sought to examine whether there is an association between a low number of B cells due to treatment with belimumab and/or rituximab and impaired primary COVID-19 vaccination spike Ab responses in patients with systemic rheumatic diseases. Methods: We retrospectively examined Ab responses to COVID-19 vaccinations, especially in relation to B-cell counts after treatment with belimumab and/or rituximab, in 58 patients with systemic rheumatic diseases: 22 on and 36 not on B-cell agents. We used Kruskal-Wallis and Mann-Whitney U tests for comparison of Ab values between the groups and Fisher exact test for relative risk calculations. Results: Median (interquartile range) postvaccination Ab responses were lower in patients on versus those not on B-cell agents: 3.91 (0.77-20.00) versus 20.00 (14.32-20.00), respectively. Among patients on belimumab and/or rituximab, Ab responses of less than 25% of the assay's upper limit were exclusively observed in those with B-cell counts lower than 40/µL. Patients with B-cell counts lower than 40/µL exhibit a relative risk of 6.092 (95% CI: 2.75-14.24) for Ab responses of less than 25% of the upper limit compared with patients not on B-cell agents. This relative risk remained significant, even after excluding patients with undetected B cells. Conclusion: This retrospective study found an association between low B-cell counts (less than 40/µL) and decreased Ab responses to primary COVID-19 vaccination in patients with systemic rheumatic diseases treated with belimumab and/or rituximab. Despite the small number of patients studied, these findings add to the accumulating evidence on the importance of B-cell count in predicting spike Ab responses to COVID-19 vaccination.

FAAH inhibition ameliorates breast cancer in a murine model.

Breast cancer is the leading cancer among females worldwide. Disease outcome depends on the hormonal status of the cancer and whether or not it is metastatic, but there is a need for more efficacious therapeutic strategies where first line treatment fails. In this study, Fatty Acid Amide Hydrolase (FAAH) inhibition and endocannabinoids were examined as therapeutic alternatives. FAAH is an integral membrane enzyme that hydrolyzes endocannabinoids, rendering them inactive, and FAAH inhibition is predicted to increase cancer cell death. To test this, breast cancer cells were probed for FAAH expression using Western blot analysis, treated with FAAH inhibitors, exogenous endocannabinoids, and combinations of the two treatments, and assessed for viability. High levels of FAAH were observed in different breast cancer cell lines. FAAH inhibition was more effective than exogenous endocannabinoid treatment, and the combination of FAAH inhibitors and endocannabinoids was the most effective in inducing apoptosis of breast cancer cells in vitro. In addition, in vivo FAAH inhibition reduced breast cancer growth in immunodeficient mice. FAAH inhibition is a promising approach, and tremendous progress has been made in the field to validate this mechanism as an alternative to chemotherapy. Further research exploring the therapeutic potential and impact of FAAH expression on cancer cells is warranted.

Olfactory conditioning in the third instar larvae of Drosophila melanogaster using heat shock reinforcement.

Adult Drosophila melanogaster has long been a popular model for learning and memory studies. Now the larval stage of the fruit fly is also being used in an increasing number of classical conditioning studies. In this study, we employed heat shock as a novel negative reinforcement for larvae and obtained high learning scores following just one training trial. We demonstrated heat-shock conditioning in both reciprocal and non-reciprocal paradigms and observed that the time window of association for the odor and heat shock reinforcement is on the order of a few minutes. This is slightly wider than the time window for electroshock conditioning reported in previous studies, possibly due to lingering effects of the high temperature. To test the utility of this simplified assay for the identification of new mutations that disrupt learning, we examined flies carrying mutations in the dnc gene. While the sensitivity to heat shock, as tested by writhing, was similar for wild type and dnc homozygotes, dnc mutations strongly diminished learning. We confirmed that the learning defect in dnc flies was indeed due to mutation in the dnc gene using non-complementation analysis. Given that heat shock has not been employed as a reinforcement for larvae in the past, we explored learning as a function of heat shock intensity and found that optimal learning occurred around 41 °C, with higher and lower temperatures both resulting in lower learning scores. In summary, we have developed a very simple, robust paradigm of learning in fruit fly larvae using heat shock reinforcement.

Cavernous Gastric Hemangioma as an Unusual Cause of Upper Gastrointestinal Bleeding in a Young Woman.

Gastric hemangiomas (GHs) are extremely rare vascular lesions of mesodermal origin that may occur in isolation or in conjunction with underlying congenital pathology. Due to the scarcity of these tumors, there is no standardized diagnostic method; however, many have found the combination of endoscopic investigation and radiographic imaging to be most effective, with the presence of phleboliths on computerized tomography as being pathognomonic for GHs. Surgical treatment for symptomatic lesions is curative with no reports of recurrence. We describe a 21-year-old woman who presented with epigastric pain and one episode of 250 mL hematemesis earlier that morning. Under the impression of an upper gastrointestinal bleed due to peptic ulcer disease, esophagogastroduodenoscopy was performed which revealed a 5-cm blood clot-like mass similar in appearance to that of a II-b peptic ulcer, but the presence of a bridging fold led to the suspicion of a possible submucosal tumor. Dynamic computerized tomography scan showed similar findings, and the patient was referred for surgical intervention. Laparoscopic distal gastrectomy was performed with the final diagnosis of cavernous GH made via histological evaluation. The patient was discharged 9 days later with no complications. This case puts emphasis on the importance of considering cavernous GH as a potential cause of severe upper GI bleeding especially in those with atypical demographic profile and history.

Is Alzheimer's disease an infectious neurological disease? A review of the literature.

INTRODUCTION: Alzheimer's disease (AD) is a leading cause of dementia around the globe. Its pathogenesis is characterized primarily by the extracellular deposition of amyloid ß peptides and intracellular neurofibrillary tangles. Despite the significant investments in neurological research, the exact molecular mechanism of AD pathogenesis is still not fully elucidated. Several studies converge on a hypothesis that pathogenic microbes might play a role in AD progression. Although this hypothesis has been considered relatively weak for decades, it has recently received considerable attention due to increasing evidence on the association between microorganisms and AD. There is a lack of experimental and scientific arguments conveying that these microorganisms engender cognitive and neuropathological deficits and modifications specific to AD, challenging the theory that it could be an infectious neurological disease. This review focuses on recent advances in the infection hypothesis and provides an overview of new findings portraying the significance of pathogenic microbes in AD and the challenges confronting the validity of the hypothesis. METHODOLOGY: Data were collected from medical journals published on PubMed, Ovid MEDLINE, ScienceDirect, and Embase bibliographical databases with a predefined search strategy. All articles considering neurological disorders, especially AD associated with infectious diseases, were included. RESULTS: This work focused on providing an overview of new findings around the relationship between microorganisms and AD, challenges facing the validity of the theory, and recommendations on how the scientific community can best develop alternative approaches to address the pathophysiology of AD. CONCLUSION: While many studies reinforce the suspicion of an infectious etiology of AD, it is important to note that it is yet not validated how microorganisms' presence in the brain can develop AD due to the limited available evidence. Certainly, ground-breaking work is mandatory in this field of research, and these reports so far warrant a thorough investigation into how a chronic infection may remain silent while progressing its neuroinflammation. Amid this uncertainty arises the hope that many researchers will take on this challenge and join this endeavor to benefit AD patients worldwide.

Ebola virus outbreak returns to the Democratic Republic of Congo: An urgent rising concern.

On April 23, 2022, the Ministry of Health of the Democratic Republic of the Congo announced an EVD outbreak after discovering 2 confirmed cases and identifying 267 contacts. With collaboration from the WHO, the MoH are taking many interventions to prevent further expansion of this outbreak. Forty-six years ago, the Ebola virus was first discovered in 1976 near the Ebola River in the DRC. Since then, 13 outbreaks of EVD have occurred in the DRC and, in 2020, it witnessed the second largest EVD outbreak in the world, resulting in 3481 cases and 2299 mortalities. This article discusses the epidemiology of the current DRC outbreak by examining the etiology of EVD, the number of affected cases, and the subsequent case index. Considering these data, this paper discusses measures taken by the MoH, WHO, CDC, and UNICEF to mitigate the Ebola outbreak, such as supporting local teams to provide essential care, training medical staff, and raising awareness for vaccination. Finally, by comparing the gravity of the situation to current measures, this article provides recommendations for individuals and governments to protect themselves and mitigate future outbreaks.

The syndemic burden of HIV/AIDS in Africa amidst the COVID-19 pandemic.

INTRODUCTION: The human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) has long affected millions of individuals across the globe. Historically, the prevalence of this disease is particularly noted within the African continent. Before the coronavirus disease 2019 (COVID-19) pandemic, many African countries struggled to effectively manage the increasing burden associated with HIV/AIDS. There is now a need to reassess this in a COVID-19 pandemic context so that the impact of COVID-19 on HIV/AIDS healthcare within Africa can be adequately evaluated. METHODS: Data collection was performed on the PubMed, Ovid MEDLINE and Embase bibliographical databases with a predefined search strategy. Searches were performed in blind duplicate and all articles considering COVID-19 and HIV/AIDS within African healthcare were considered. RESULTS: The COVID-19 pandemic has severely exacerbated the many issues surrounding HIV/AIDS care within many African countries. These impacts are noticeable in medical, psychological, and socio-political contexts. CONCLUSIONS: Before efforts are made to improve the provision of HIV/AIDS and COVID-19 care within Africa, it is important that this issue is brought to the attention of the scientific and clinical community so that the continent can receive the necessary support and aid.

Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses.

Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I-stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1α-XBP1-controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1-PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.

Threats and outbreaks of cholera in Africa amidst COVID-19 pandemic: a double burden on Africa's health systems.

Every year, about 4 million cases and 143,000 deaths due to cholera are recorded globally, of which 54% were from Africa, reported in 2016. The outbreak and spread of cholera have risen exponentially particularly in Africa. Coupled with the recent emergence of the Coronavirus Pandemic (COVID-19) in Africa, the local health systems are facing a double burden of these infectious diseases due to their cumulative impact. In this paper, we evaluate the dual impact of cholera and COVID-19 in Africa and suggest plausible interventions that can be put in place to cushion its impact.

Robotics and urologic reconstructive surgery.

Minimally invasive surgery has made a profound impact on how urologists approach the challenges in reconstruction of the urinary tract. The advent of laparoscopic approaches to reconstructive urology have demonstrated comparable outcomes to open surgery with improved morbidity. The recent adoption of robotic surgery has seen further advancements such as improved visibility and, freedom of movement, and an easier technical learning curve. With these advantages, more reconstructive urology procedures are being performed robotically. Herein, we review reconstructive urology procedures for which robotics have been applied.

Repeated Plastic Stentings of Common Hepatic Duct for Portal Vein Aneurysm Compression in a Patient Unsuitable for Surgery.

Portal vein aneurysms are rare vascular malformations with unclear etiologies and optimal treatment guidelines. Although Doppler ultrasonography is the most commonly used diagnostic tool, there is no gold standard imaging modality. Despite recommendations of surgical treatment for symptomatic aneurysms, there are limited options in the management of portal vein aneurysm-related complications in patients unfit for surgical intervention. We describe an 85-year-old man who presented with abdominal pain and low-grade fever with clinical signs consistent with cholangitis. Endoscopic retrograde cholangiopancreatography revealed a common hepatic duct stricture and concomitant intraductal ultrasonography identified adjacent aneurysmal portal vein dilatation. The final diagnosis of portal vein aneurysm was made using contrast computerized tomography scan. The patient was considered unsuitable for surgery due to his advanced age and multiple comorbidities. Instead, an endoscopic biliary plastic stent was inserted as a therapeutic alternative, which successfully achieved complete resolution of symptoms 3 days after the procedure. The patient was regularly followed at the outpatient clinic with repeated stent replacements every 3 to 4 months. After a follow-up of over 3.5 years, the patient remained symptom-free without signs of portal vein aneurysm compression. The result suggests that repeated stent replacements may be a therapeutic option for biliary compression by portal vein aneurysm in patients contraindicated for surgical intervention.