Barriers and enablers for implementation of digital-linked diagnostics models at point-of-care in South Africa: stakeholder engagement.

The integration of digital technologies holds significant promise in enhancing accessibility to disease diagnosis and treatment at point-of-care (POC) settings. Effective implementation of such interventions necessitates comprehensive stakeholder engagements. This study presents the outcomes of a workshop conducted with key stakeholders, aiming to discern barriers and enablers in implementing digital-connected POC diagnostic models in South Africa. The workshop, a component of the 2022 REASSURED Diagnostics symposium, employed the nominal group technique (NGT) and comprised two phases: Phase 1 focused on identifying barriers, while Phase 2 centered on enablers for the implementation of digital-linked POC diagnostic models. Stakeholders identified limited connectivity, restricted offline functionality, and challenges related to load shedding or rolling electricity blackouts as primary barriers. Conversely, ease of use, subsidies provided by the National Health Insurance, and 24-h assistance emerged as crucial enablers for the implementation of digital-linked POC diagnostic models. The NGT workshop proved to be an effective platform for elucidating key barriers and enablers in implementing digital-linked POC diagnostic models. Subsequent research endeavors should concentrate on identifying optimal strategies for implementing these advanced diagnostic models in underserved populations.

Cardiovascular disturbances in COVID-19: an updated review of the pathophysiology and clinical evidence of cardiovascular damage induced by SARS-CoV-2.

Severe acute respiratory coronavirus-2 (SARS-Co-2) is the causative agent of coronavirus disease-2019 (COVID-19). COVID-19 is a disease with highly variable phenotypes, being asymptomatic in most patients. In symptomatic patients, disease manifestation is variable, ranging from mild disease to severe and critical illness requiring treatment in the intensive care unit. The presence of underlying cardiovascular morbidities was identified early in the evolution of the disease to be a critical determinant of the severe disease phenotype. SARS-CoV-2, though a primarily respiratory virus, also causes severe damage to the cardiovascular system, contributing significantly to morbidity and mortality seen in COVID-19. Evidence on the impact of cardiovascular disorders in disease manifestation and outcome of treatment is rapidly emerging. The cardiovascular system expresses the angiotensin-converting enzyme-2, the receptor used by SARS-CoV-2 for binding, making it vulnerable to infection by the virus. Systemic perturbations including the so-called cytokine storm also impact on the normal functioning of the cardiovascular system. Imaging plays a prominent role not only in the detection of cardiovascular damage induced by SARS-CoV-2 infection but in the follow-up of patients' clinical progress while on treatment and in identifying long-term sequelae of the disease.

Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach.

Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.

Design of 225Ac-PSMA for targeted alpha therapy in prostate cancer.

The first alpha emitting radiopharmaceutical, 223RaCl2, radium dichloride, was approved 10 years ago into the clinical armament of treating bone metastases in metastatic castration-resistant prostate cancer (mCRPC). In addition to this, the first beta-emitting radionuclide Lu-177 chelated with a prostate-specific membrane antigen (PSMA) compound, got last year its marketing approval for the third line treatment of mCRPC. Therefore, there is great excitement about combining alpha-emitters and prostate cancer targeting PSMA compounds. This review describes the clinical history of alpha-emitting PSMA in treating mCRPC. Here, we present the potential, current status, and opportunities for 225Ac-PSMA therapy. The work reviews the basic concepts, current treatment outcome, and toxicity, and areas requiring further investigations such as dosimetric aspects in clinical studies covering more than 400 patients. In general, approximately two-thirds of the patients benefit from this third-line therapy. There is also successful evidence of using 225Ac-PSMA in the second-line of prostate cancer management. The future potential of 225Ac-PSMA therapy and targeted alpha therapy (TAT) of cancer in general is enormous. According to our overview the clinical experience with 225Ac-PSMA therapy to date has shown great benefit and physicians dedicated to theragnostics are anxiously waiting for new applications. Hopefully, this review helps in deeper understanding of the strengths and limitations of TAT and may help in creating effective therapy protocols.

Prognostic Value of PSMA PET/CT in Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed in the majority of prostate cancer (PCa). PSMA has an enzymatic function that makes metabolic substrates such as folate available for utilization by PCa cells. Intracellular folate availability drives aggressive tumor phenotype. PSMA expression is, therefore, a marker of aggressive tumor biology. The large extracellular domain of PSMA is available for targeting by diagnostic and therapeutic radionuclides, making it a suitable cellular epitope for theranostics. PET imaging of radiolabeled PSMA ligands has several prognostic utilities. In the prebiopsy setting, intense PSMA avidity in a prostate lesion correlate well with clinically significant PCa (csPCa) on histology. When used for staging, PSMA PET imaging outperforms conventional imaging for the accurate staging of primary PCa, and findings on imaging predict post-treatment outcomes. The biggest contribution of PSMA PET imaging to PCa management is in the biochemical recurrence setting, where it has emerged as the most sensitive imaging modality for the localization of PCa recurrence by helping to guide salvage therapy. PSMA PET obtained for localizing the site of recurrence is prognostic, such that a higher lesion number predicts a less favorable outcome to salvage radiotherapy or surgical intervention. Systemic therapy is given to patients with advanced PCa with distant metastasis. PSMA PET is useful for predicting response to treatments with chemotherapy, first- and second-line androgen deprivation therapies, and PSMA-targeted radioligand therapy. Artificial intelligence using machine learning algorithms allows for the mining of information from clinical images not visible to the human eyes. Artificial intelligence applied to PSMA PET images, therefore, holds great promise for prognostication in PCa management.

[18F]F-Poly(ADP-Ribose) Polymerase Inhibitor Radiotracers for Imaging PARP Expression and Their Potential Clinical Applications in Oncology.

Including poly(ADP-ribose) polymerase (PARP) inhibitors in managing patients with inoperable tumors has significantly improved outcomes. The PARP inhibitors hamper single-strand deoxyribonucleic acid (DNA) repair by trapping poly(ADP-ribose)polymerase (PARP) at sites of DNA damage, forming a non-functional "PARP enzyme-inhibitor complex" leading to cell cytotoxicity. The effect is more pronounced in the presence of PARP upregulation and homologous recombination (HR) deficiencies such as breast cancer-associated gene (BRCA1/2). Hence, identifying HR-deficiencies by genomic analysis-for instance, BRCA1/2 used in triple-negative breast cancer-should be a part of the selection process for PARP inhibitor therapy. Published data suggest BRCA1/2 germline mutations do not consistently predict favorable responses to PARP inhibitors, suggesting that other factors beyond tumor mutation status may be at play. A variety of factors, including tumor heterogeneity in PARP expression and intrinsic and/or acquired resistance to PARP inhibitors, may be contributing factors. This justifies the use of an additional tool for appropriate patient selection, which is noninvasive, and capable of assessing whole-body in vivo PARP expression and evaluating PARP inhibitor pharmacokinetics as complementary to the currently available BRCA1/2 analysis. In this review, we discuss [18F]Fluorine PARP inhibitor radiotracers and their potential in the imaging of PARP expression and PARP inhibitor pharmacokinetics. To provide context we also briefly discuss possible causes of PARP inhibitor resistance or ineffectiveness. The discussion focuses on TNBC, which is a tumor type where PARP inhibitors are used as part of the standard-of-care treatment strategy.

Insights into Peptidoglycan-Targeting Radiotracers for Imaging Bacterial Infections: Updates, Challenges, and Future Perspectives.

The unique structural architecture of the peptidoglycan allows for the stratification of bacteria as either Gram-negative or Gram-positive, which makes bacterial cells distinguishable from mammalian cells. This classification has received attention as a potential target for diagnostic and therapeutic purposes. Bacteria's ability to metabolically integrate peptidoglycan precursors during cell wall biosynthesis and recycling offers an opportunity to target and image pathogens in their biological state. This Review explores the peptidoglycan biosynthesis for bacteria-specific targeting for infection imaging. Current and potential radiolabeled peptidoglycan precursors for bacterial infection imaging, their development status, and their performance in vitro and/or in vivo are highlighted. We conclude by providing our thoughts on how to shape this area of research for future clinical translation.

The SARS-COV-2 Seroprevalence among Oncology Patients.

Patients with cancer are presumed to be vulnerable to an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe clinical outcomes due to the immunocompromised state mediated by their underlying malignancies and therapy. The aim of this study was to estimate the SARS-CoV-2 seroprevalence, following second to fourth waves in solid tumour patients attending the Steve Biko Academic Hospital (SBAH) for diagnosis and treatment of cancer. We used the single-prick COVID-19 IgG/IgM Rapid Test Cassettes to detect SARS-CoV-2 IgG/IgM antibodies in 760 patients with solid tumours who were asymptomatic and who had never tested positive for coronavirus disease 2019 (COVID-19). Out of the 760 patients, 277 were male (36.4%), 483 were female (63.6%), and the mean age was 55 years (range 18−92). The estimated total seroprevalence was 33.2%. The seroprevalence status of the COVID-19 IgG/IgM antibodies rose significantly from the second wave (11.3%) to the third (67.38%) and then the fourth (69.81%) waves with roughly similar counts. A significant number of the seropositive patients were asymptomatic to COVID-19 (96%). There was a higher rate of seropositivity in cancer patients with hypertension (p < 0.05). Patients with breast, gynaecologic, and prostate cancers exhibited increased SARS-CoV-2 seropositivity. Although oncology patients may be susceptible to SARS-CoV-2 infection, our data indicate that these patients remained asymptomatic throughout various waves with an overall COVID-19 IgG/IgM antibody seropositivity of 33.16%, suggesting no risk of severe or fatal cases of COVID-19.

PSMA Theranostics: Science and Practice.

Prostate cancer (PCa) causes significant morbidity and mortality in men globally. While localized PCa may be managed with curative intent by surgery and/or radiation therapy, the management of advanced hormone resistant metastatic disease (mCRPC) is more challenging. Theranostics is a principle based on the ability to use an organ specific ligand and label it to both a diagnostic and a therapeutic agent. The overexpression of prostate specific membrane antigen (PSMA) on prostate cancer cells creates a unique opportunity for development of targeted radionuclide therapy. The use of both beta and alpha emitting particles has shown great success. Several clinical trials have been initiated assessing the efficacy and safety profile of these radionuclide agents. The results are encouraging with PSMA directed radioligand therapy performing well in patients who have exhausted all other standard treatment options. Future studies need to assess the timing of introduction of these radionuclide therapies in the management schema of mCRPC. Drugs or therapies are not without side effects and targeted radionuclide therapies presents a new set of toxicities including xerostomia and myelosuppression. New therapeutic strategies are being explored to improve outcomes while keeping toxicities to a minimum. This review aims to look at the various PSMA labelled tracers that form part of the theragnostic approach and subsequently delve into the progress made in the area of radionuclide therapy.

Pattern of Prostate Cancer Recurrence Assessed by 68Ga-PSMA-11 PET/CT in Men Treated with Primary Local Therapy.

Imaging plays a vital role in detecting the recurrence of prostate cancer (PCa) to guide the choice of salvage therapy. Gallium-68 prostate-specific membrane antigen positron-emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) is useful for detecting PCa recurrence. We assessed the pattern of PCa recurrence stratified by serum prostate-specific antigen level and type of primary local treatment in men with biochemical recurrence (BCR) after primary local therapy with radical prostatectomy or external beam radiotherapy (EBRT) using 68Ga-PSMA-11 PET/CT. We reviewed patients imaged with 68Ga-PSMA-11 PET/CT for the localization of the site of PCa recurrence. We determined the site and number of lesions due to PCa recurrence at different PSA levels. A total of 247 men (mean age of 65.72 ± 7.51 years and median PSA of 2.70 ng/mL (IQR = 0.78-5.80)) were included. 68Ga-PSMA-11 PET/CT detected the site of recurrence in 81.4% of patients with a median number of lesions per patient of 1 (range = 1-5). 68Ga-PSMA-11 PET/CT positivity was 43.6%, 75.7%, 83.3%, 90.0%, and 95.8% at PSA levels of <0.5, 0.5-1.0., 1.1-2.0, 2.1-5.0, and 5.0-10.0, respectively. The most common site of recurrence was in the prostate gland/bed at all PSA levels. Pelvic, extra-pelvic, and combined pelvic and extra-pelvic sites of recurrence were seen in 118, 50, and 33 patients, respectively. The risk of extra-pelvic recurrence increases with rising PSA levels. 68Ga-PSMA-11 PET/CT has a high lesion detection rate for biochemical recurrence of PCa in patients previously treated with primary local therapy.

Radionuclide Imaging of Invasive Fungal Disease in Immunocompromised Hosts.

Invasive fungal disease (IFD) leads to increased mortality, morbidity, and costs of treatment in patients with immunosuppressive conditions. The definitive diagnosis of IFD relies on the isolation of the causative fungal agents through microscopy, culture, or nucleic acid testing in tissue samples obtained from the sites of the disease. Biopsy is not always feasible or safe to be undertaken in immunocompromised hosts at risk of IFD. Noninvasive diagnostic techniques are, therefore, needed for the diagnosis and treatment response assessment of IFD. The available techniques that identify fungal-specific antigens in biological samples for diagnosing IFD have variable sensitivity and specificity. They also have limited utility in response assessment. Imaging has, therefore, been applied for the noninvasive detection of IFD. Morphologic imaging with computed tomography (CT) and magnetic resonance imaging (MRI) is the most applied technique. These techniques are neither sufficiently sensitive nor specific for the early diagnosis of IFD. Morphologic changes evaluated by CT and MRI occur later in the disease course and during recovery after successful treatment. These modalities may, therefore, not be ideal for early diagnosis and early response to therapy determination. Radionuclide imaging allows for targeting the host response to pathogenic fungi or specific structures of the pathogen itself. This makes radionuclide imaging techniques suitable for the early diagnosis and treatment response assessment of IFD. In this review, we aimed to discuss the interplay of host immunity, immunosuppression, and the occurrence of IFD. We also discuss the currently available radionuclide probes that have been evaluated in preclinical and clinical studies for their ability to detect IFD.

COVID-19 Is a Multi-Organ Aggressor: Epigenetic and Clinical Marks.

The progression of coronavirus disease 2019 (COVID-19), resulting from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be influenced by both genetic and environmental factors. Several viruses hijack the host genome machinery for their own advantage and survival, and similar phenomena might occur upon SARS-CoV-2 infection. Severe cases of COVID-19 may be driven by metabolic and epigenetic driven mechanisms, including DNA methylation and histone/chromatin alterations. These epigenetic phenomena may respond to enhanced viral replication and mediate persistent long-term infection and clinical phenotypes associated with severe COVID-19 cases and fatalities. Understanding the epigenetic events involved, and their clinical significance, may provide novel insights valuable for the therapeutic control and management of the COVID-19 pandemic. This review highlights different epigenetic marks potentially associated with COVID-19 development, clinical manifestation, and progression.

DNA Oncogenic Virus-Induced Oxidative Stress, Genomic Damage, and Aberrant Epigenetic Alterations.

Approximately 20% of human cancers is attributable to DNA oncogenic viruses such as human papillomavirus (HPV), hepatitis B virus (HBV), and Epstein-Barr virus (EBV). Unrepaired DNA damage is the most common and overlapping feature of these DNA oncogenic viruses and a source of genomic instability and tumour development. Sustained DNA damage results from unceasing production of reactive oxygen species and activation of inflammasome cascades that trigger genomic changes and increased propensity of epigenetic alterations. Accumulation of epigenetic alterations may interfere with genome-wide cellular signalling machineries and promote malignant transformation leading to cancer development. Untangling and understanding the underlying mechanisms that promote these detrimental effects remain the major objectives for ongoing research and hope for effective virus-induced cancer therapy. Here, we review current literature with an emphasis on how DNA damage influences HPV, HVB, and EBV replication and epigenetic alterations that are associated with carcinogenesis.

Hepatoepigenetic Alterations in Viral and Nonviral-Induced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major public health concern and one of the leading causes of tumour-related deaths worldwide. Extensive evidence endorses that HCC is a multifactorial disease characterised by hepatic cirrhosis mostly associated with chronic inflammation and hepatitis B/C viral infections. Interaction of viral products with the host cell machinery may lead to increased frequency of genetic and epigenetic aberrations that cause harmful alterations in gene transcription. This may provide a progressive selective advantage for neoplastic transformation of hepatocytes associated with phenotypic heterogeneity of intratumour HCC cells, thus posing even more challenges in HCC treatment development. Epigenetic aberrations involving DNA methylation, histone modifications, and noncoding miRNA dysregulation have been shown to be intimately linked with and play a critical role in tumour initiation, progression, and metastases. The current review focuses on the aberrant hepatoepigenetics events that play important roles in hepatocarcinogenesis and their utilities in the development of HCC therapy.

Prostate Cancer: Epigenetic Alterations, Risk Factors, and Therapy.

Prostate cancer (PCa) is the most prevalent urological cancer that affects aging men in South Africa, and mechanisms underlying prostate tumorigenesis remain elusive. Research advancements in the field of PCa and epigenetics have allowed for the identification of specific alterations that occur beyond genetics but are still critically important in the pathogenesis of tumorigenesis. Anomalous epigenetic changes associated with PCa include histone modifications, DNA methylation, and noncoding miRNA. These mechanisms regulate and silence hundreds of target genes including some which are key components of cellular signalling pathways that, when perturbed, promote tumorigenesis. Elucidation of mechanisms underlying epigenetic alterations and the manner in which these mechanisms interact in regulating gene transcription in PCa are an unmet necessity that may lead to novel chemotherapeutic approaches. This will, therefore, aid in developing combination therapies that will target multiple epigenetic pathways, which can be used in conjunction with the current conventional PCa treatment.

Overexpression of recombinant HIV-1 Subtype C Tat and Nef in a Salmonella vaccine vector.

Tat and Nef are very important regulatory proteins of HIV-1. They enhance viral replication and down-regulate expression of MHC Class I molecules, respectively. The antigens are now considered to be targets for HIV vaccine development. The expression of Tat and Nef in Salmonella vaccines has not previously been investigated. In this study, HIV-1 Subtype C tat and nef genes were cloned into an expression plasmid and their expression investigated in Salmonella. Very high-level expression of the two HIV-1 antigens was demonstrated in the recombinant Salmonella. The antigens were also successfully purified in bulk from the bacterium.Salmonella can therefore potentially be used to overexpress HIV-1 antigens and used as a possible delivery system in HIV-1 vaccine development.