PD-1/PD-L1 inhibitor treatment and its impact on clinical imaging in non-small cell lung cancer: a systematic review and meta-analysis of immune-related adverse events.

Background: In the contemporary era of cancer treatment, lung cancer (LC) holds the unenviable position of being the primary contributor to cancer-induced mortality worldwide. Although immunotherapy has expanded the therapeutic landscape for metastatic non-small cell lung cancer (NSCLC), the advent of immune checkpoint inhibitors has been accompanied by a concomitant increase in immune-related adverse events (irAEs). Timely detection of irAEs is pivotal for efficacious management and enhanced patient outcomes. Diagnostic imaging, encompassing x-ray and CT scans, can facilitate the identification and supervision of irAEs, thereby ensuring the prompt recognition of associated patterns and alterations for expeditious treatment. Methods: The present inquiry undertook a systematic exploration of multiple databases, incorporating a diverse array of studies such as randomized controlled trials and observational analyses. Patient demographics, imaging outcomes, and risk of bias were extracted from the data. Meta-analysis was executed utilizing R Statistical Software, with the results of the risk of bias assessment summarized accordingly. Findings: The analysis unveiled a higher prevalence of irAEs in patients receiving first-line treatment for NSCLC compared to those receiving subsequent treatments, with a statistically significant distinction observed for both high- and low-grade irAEs (p < 0.001). Pneumonitis, thyroiditis, and colitis emerged as the most frequently reported irAEs, whereas hepatitis and pancolitis were less commonly documented. This investigation signifies a crucial advancement in elucidating the function of imaging in the treatment of NSCLC with PD-1/PD-L1 inhibitors and emphasizes the imperative for ongoing research in this domain.

The effect of conjugated linoleic acids on inflammation, oxidative stress, body composition and physical performance: a comprehensive review of putative molecular mechanisms.

Conjugated linoleic acids (CLAs) are polyunsaturated fatty acids primarily found in dairy products and ruminant animal products such as beef, lamb, and butter. Supplementation of CLAs has recently become popular among athletes due to the variety of health-promoting effects, including improvements in physical performance. Preclinical and some clinical studies have shown that CLAs can reduce inflammation and oxidative stress and favorably modulate body composition and physical performance; however, the results of previously published clinical trials are mixed. Here, we performed a comprehensive review of previously published clinical trials that assessed the role of CLAs in modulating inflammation, oxidative stress, body composition, and select indices of physical performance, emphasizing the molecular mechanisms governing these changes. The findings of our review demonstrate that the effect of supplementation with CLAs on inflammation and oxidative stress is controversial, but this supplement can decrease body fat mass and increase physical performance. Future well-designed randomized clinical trials are warranted to determine the effectiveness of (1) specific doses of CLAs; (2) different dosing durations of CLAs; (3) various CLA isomers, and the exact molecular mechanisms by which CLAs positively influence oxidative stress, inflammation, body composition, and physical performance.

Collodion baby with ectropion in a Syrian newborn: a case report study.

Collodion baby is a rare congenital disorder and a very intense disorder in which the baby suffers from several complications, such as trans-epidermal water loss. Only ∼270 cases of collodion babies have been reported in the literature since 1892. This disease may later develop one of a spectrum of diseases including lamellar ichthyosis, which the patient may had Congenital lamellar ichthyosis with ectropion, which was clinically distinguished by the collodion baby phenotype at birth. Case presentation: The authors are reporting the first case in Syria, a 20-day-old white Syrian male newborn, vaginally delivered at 38 weeks of pregnancy, with normal conditions, and congenital lamellar ichthyosis was shown by physical examination, as parchment-like scales were covering the newborn's skin, which was starting to detach and showing the "collodion baby" appearance. Ophthalmologic examination revealed a bilateral ectropion of the upper eyelids with tarsal eversion. A treatment of Tobramycin 0.3% eye ointment was prescribed four times a day, with a viscotears liquid gel eye drops 4 times a day, and vaseline petroleum jelly to be applied three times daily. At 2-month follow-up, a significant improvement was noted. Conclusion: Ichthyosis have a wide range of disorders that involve the skin and have inherited and acquired forms. As a result, keratolytic and systemic retinoids can have significant benefits in restoring skin function.

Evaluation of the impact of different disinfectants on new coronavirus and human health.

A new health threat was appeared in 2019 known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19). The new coronavirus distributed all over the world and caused millions of deaths. One way to incomplete the process of COVID-19 transfer from one person to another is using disinfectants. A narrative review study was done on manuscript published documents about the stability of the virus, different types of disinfectants and the effects of disinfectants on SARS-CoV2 and environment from 2005 to 2022 based on Searched databases included Google Scholar, Springer, PubMed, Web of Science and Science Direct (Scopus). All relevant studies published 2005 until 2022 gathered. According to the databases, 670 articles were retrieved. Thirty studies were screened after review and 30 full-text articles entered into the analysis process. Finally, 14 articles were selected in this study. New coronavirus could survive until 9 days in room temperature; the surviving time decreases if temperature increases. The virus can survive in various plastic, glass, and metal surfaces for hours to days. Disinfectants, such as alcohol, isopropanol, formaldehyde, glutaraldehyde, and ethanol, can kill 70-90% viruses in up to 30 s but should be noted that these disinfectants are recognized by Occupational Safety and Health Administration (OSHA) as a potential carcinogen. According to the different reports, increased duration and level of disinfectant exposure can have negative impacts on human and animal health including upper and lower respiratory tract irritation, inflammation, edema, ulceration, and allergic reactions.

Vitamin D and Swimming Exercise Prevent Obesity in Rats under a High-Fat Diet via Targeting FATP4 and TLR4 in the Liver and Adipose Tissue.

The prevalence of obesity has risen in the last decades, and it has caused massive health burdens on people's health, especially metabolic and cardiovascular issues. The risk of vitamin D insufficiency is increased by obesity, because adipose tissue alters both the requirements for and bioavailability of vitamin D. Exercise training is acknowledged as having a significant and long-term influence on body weight control; the favorable impact of exercise on obesity and obesity-related co-morbidities has been demonstrated via various mechanisms. The current work illustrated the effects of vitamin D supplementation and exercise on obesity induced by a high-fat diet (HFD) and hepatic steatosis in rats and explored how fatty acid transport protein-4 (FATP4) and Toll-like receptor-4 antibodies (TLR4) might be contributing factors to obesity and related hepatic steatosis. Thirty male albino rats were divided into five groups: group 1 was fed a normal-fat diet, group 2 was fed an HFD, group 3 was fed an HFD and given vitamin D supplementation, group 4 was fed an HFD and kept on exercise, and group 5 was fed an HFD, given vitamin D, and kept on exercise. The serum lipid profile adipokines, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were analyzed, and the pathological changes in adipose and liver tissues were examined. In addition, the messenger-ribonucleic acid (mRNA) expression of FATP4 and immunohistochemical expression of TLR4 in adipose and liver tissues were evaluated. Vitamin D supplementation and exercise improved HFD-induced weight gain and attenuated hepatic steatosis, along with improving the serum lipid profile, degree of inflammation, and serum adipokine levels. The expression of FATP4 and TLR4 in both adipose tissue and the liver was downregulated; it was noteworthy that the group that received vitamin D and was kept on exercise showed also improvement in the histopathological picture of this group. According to the findings of this research, the protective effect of vitamin D and exercise against obesity and HFD-induced hepatic steatosis is associated with the downregulation of FATP4 and TLR4, as well as a reduction in inflammation.

Systematic review and meta-analysis of randomized, controlled trials on the effects of soy and soy products supplementation on serum adiponectin levels.

BACKGROUND AND AIMS: Our aim in this meta-analysis was to determine the effect of soy and soy product supplementation on serum adiponectin levels. METHOD: A systematic search was conducted using Medline (PubMed and Web of Science), Scopus, and Cochrane Library for eligible trials up to August 2020. A random-effects model was used to pool calculated effect sizes. RESULTS: Seven trials were included in the overall analysis. Our analysis showed that soy and soy product supplementation did not significantly affect adiponectin concentrations (WMD = -0.77 µg/ml, 95% CI: -0.61, 2.15, P = 0.27) in comparison with a placebo. The between-study heterogeneity was high (I2: 68.2%, P = 0.004). Subgroup analysis, based on participants' health status and duration of the supplementation, could not detect the potential source of the observed heterogeneity. In addition, subgroup analysis showed that the effect was not statistically significant in all subgroups. CONCLUSION: Overall, soy and soy product supplementation did not change the circulatory adiponectin levels. In addition, the results were not affected by the participant's health status and duration of supplementation. However, further studies are needed to confirm the present results.

Apigenin alleviates resistance to doxorubicin in breast cancer cells by acting on the JAK/STAT signaling pathway.

BACKGROUND: Breast cancer is the most frequent cancer among women. Despite the effectiveness of Doxorubicin (DOX) as a chemotherapeutic for the treatment of breast cancer, the therapy-resistance remains unsolvable. Apigenin is a natural dietary flavonoid with potential anticancer activities. Our study's intention was to evaluate the effect of Apigenin on DOX resistance in MCF-7 cells. METHODS: DOX-resistant MCF-7 cell line (MCF-7R) was developed by treating MCF-7 cells with increasing concentrations of DOX (0-100 µM). The viability of cell lines was assayed using MTT method. Quantitative polymerase chain reaction method was performed to measure multidrug-resistance 1 (MDR1) gene expression level. The expression of MDR1, Janus kinase 2 (JAK2) and Signal transducer and activator of transcription 3 (STAT3) proteins were determined by western blotting. RESULTS: MCF-7R cell line showed resistance to DOX in comparison to MCF-7 cells. Apigenin had a significant effect on the reduction of viability of both MCF-7 and MCF-7R cell lines. However, DOX-resistance in the MCF-7 cell line was considerably decreased due to the co-treatment of MCF-7R cells with Apigenin. This natural compound also downregulated the expression of MDR1 at mRNA and protein levels both in resistant and non-resistant cells. Apigenin significantly prohibited the phosphorylation and activation of JAK2 and STAT3 proteins both in MCF-7 and MCF-7R cell lines. CONCLUSIONS: The present results suggested, for the first time, Apigenin as an ideal therapeutic for ameliorating DOX resistance in breast cancer. These data also proposed a novel mechanism for the anti-resistance activity of Apigenin by regulating the JAK2/STAT3/MDR1 axis.

Osteoporosis treatment by mesenchymal stromal/stem cells and their exosomes: Emphasis on signaling pathways and mechanisms.

Osteoporosis is the loss of bone density, which is one of the main problems in developed and developing countries and is more common in the elderly. Because this disease is often not diagnosed until a bone fracture, it can become a life-threatening disease and cause hospitalization. With the increase of older people in a population, this disease's personal and social costs increase year by year and affect different communities. Most current treatments focus on pain relief and usually do not lead to bone tissue recovery and regeneration. But today, the use of stem cell therapy is recommended to treat and improve this disease recovery, which helps restore bone tissue by improving the imbalance in the osteoblast-osteoclast axis. Due to mesenchymal stromal/stem cells (MSCs) characteristics and their exosomes, these cells and vesicles are excellent sources for treating and preventing the progression and improvement of osteoporosis. Due to the ability of MSCs to differentiate into different cells and migrate to the site of injury, these cells are used in tissue regenerative medicine. Also, due to their contents, the exosomes of these cells help regenerate and treat various tissue injuries by affecting the injury site's cells. In this article, we attempted to review new studies in which MSCs and their exosomes were used to treat osteoporosis.

Various types of electrochemical biosensors for leukemia detection and therapeutic approaches.

Leukemia often initiates following dysfunctions in hematopoietic stem cells lineages. Various types of leukemia, including acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), acute promyelocytic leukemia (APL), and human T-cell leukemia/lymphoma virus type 1 (HTLV-1) can thus call for different diagnosis and treatment options. One of the most important subjects in leukemia is the early detection of the disease for effective therapeutic purposes. In this respect, biosensors detecting the molecules of deoxyribonucleic acid (DNA) as analytes are called genosensors or DNA biosensors. Electrochemical sensors, as the most significant approach, also involve reacting of chemical solutions with sensors to generate electrical signals proportional to analyte concentrations. Biosensors can further help detect cancer cells in the early stages of the disease. Moreover, electrochemical biosensors, developed based on various nanomaterials (NMs), can increase sensitivity to the detection of leukemia-related genes, e.g., BCR/ABL as a fusion gene and promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα). Therefore, the present review reflects on previous studies recruiting different NMs for leukemia detection.

The role of Pycnogenol in the control of inflammation and oxidative stress in chronic diseases: Molecular aspects.

The prevalence of chronic diseases has increased significantly with the rising trend of sedentary lifestyles, reduced physical activity, and dietary modifications in recent decades. Inflammation and oxidative stress play a key role in the pathophysiology of several chronic diseases, such as type II diabetes, cardiovascular diseases, and hepatic conditions. Therefore, reducing inflammation and oxidative stress may be beneficial in the prevention and treatment of various chronic disorders. Since chronic diseases are not completely curable, various methods have been proposed for their control. Complementary therapies and the use of natural antioxidant and antiinflammatory compounds are among these novel approaches. Pycnogenol (PYC) is a natural compound that could control inflammation and oxidative stress. Furthermore, some previous studies have shown that PYC could effectively reduce inflammation through signaling the downstream of insulin receptors, inhibiting the phosphorylation of the serine residues of insulin receptor substrate-1, reducing pro-inflammatory cytokines and oxidative stress indices through the stimulation of antioxidant pathways, increasing free radical scavenging activities, preventing lipid peroxidation, and protecting the erythrocytes in glucose-6-phosphate dehydrogenase-deficient individuals, although these effects have not been fully proved. The present study aimed to comprehensively review the evidence concerning the positive physiological and pharmacological properties of PYC, with an emphasis on the therapeutic potential of this natural component for enhancing human health.

Cancer combination therapies by angiogenesis inhibitors; a comprehensive review.

Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion. The deregulation mainly arises from the potentiated pro-angiogenic factors secretion and can also target immune cells' biological events, such as migration and activation. Owing to this fact, angiogenesis blockade therapy was established to fight cancer by eliminating the nutrient and oxygen supply to the malignant cells by impairing the vascular network. Given the dominant role of vascular-endothelium growth factor (VEGF) in the angiogenesis process, the well-known anti-angiogenic agents mainly depend on the targeting of its actions. However, cancer cells mainly show resistance to anti-angiogenic agents by several mechanisms, and also potentiated local invasiveness and also distant metastasis have been observed following their administration. Herein, we will focus on clinical developments of angiogenesis blockade therapy, more particular, in combination with other conventional treatments, such as immunotherapy, chemoradiotherapy, targeted therapy, and also cancer vaccines. Video abstract.

Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons.

The main breakthrough in tumor immunotherapy was the discovery of immune checkpoint (IC) proteins, which act as a potent suppressor of the immune system by a myriad of mechanisms. After that, scientists focused on the immune checkpoint molecules mainly. Thereby, much effort was spent to progress novel strategies for suppressing these inhibitory axes, resulting in the evolution of immune checkpoint inhibitors (ICIs). Then, ICIs have become a promising approach and shaped a paradigm shift in tumor immunotherapies. CTLA-4 plays an influential role in attenuation of the induction of naïve and memory T cells by engagement with its responding ligands like B7-1 (CD80) and B7-2 (CD86). Besides, PD-1 is predominantly implicated in adjusting T cell function in peripheral tissues through its interaction with programmed death-ligand 1 (PD-L1) and PD-L2. Given their suppressive effects on anti-tumor immunity, it has firmly been documented that ICIs based therapies can be practical and rational therapeutic approaches to treat cancer patients. Nonetheless, tumor inherent or acquired resistance to ICI and some treatment-related toxicities restrict their application in the clinic. The current review will deliver a comprehensive overview of the ICI application to treat human tumors alone or in combination with other modalities to support more desired outcomes and lower toxicities in cancer patients. Video Abstract.

Role of Acute Myeloid Leukemia (AML)-Derived exosomes in tumor progression and survival.

Acute myeloid leukemia (AML) is a quickly aggressive hematopoietic disorder that progress due to the accumulation and clonal expansion of immature myeloid cells. Despite the latest developments in AML treatment, repeated relapses and drug resistance remain one of the major challenges in treatment of leukemia. Currently, it is well known that the components of the tumor microenvironment such as cellular and non-cellular elements play a critical function in treatment failures of AML, also they are most common cause of complications including suppression of hematopoiesis. Exosomes are membrane-bound extracellular vesicles (EVs) that transfer signaling molecules and have attracted a large amount of attention due to their important role in inter-cellular communication in health and disease. Exosomes participate in the survival and chemoresistance of many leukemia through transferring their rich cargos of molecules including miRNAs, growth factors, and cytokines. The key producers of exosomes that mainly participate to AML pathogenesis are bone marrow mesenchymal stem cell (BMSCs) and AML cell themselves. These cells release an enormous number of exosomes that affect several target cells such as natural killer (NK) and hematopoietic stem cells to the development of leukemia proliferation and progression. In the present study, a comprehensive review of the literature has been done to briefly discuss the biology of exosomes and highlight the role of exosomes derived from AML in the progress of acute myeloid leukemia.

Mesenchymal stromal/stem cells and their exosomes application in the treatment of intervertebral disc disease: A promising frontier.

Today, the application of mesenchymal stromal/stem cells (MSCs) and their exosomes to treat degenerative diseases has received attention. Due to the characteristics of these cells, such as self-renewability, differentiative and immunomodulatory effects, their use in laboratory and clinical studies shows promising results. However, the allogeneic transplantation problems of MSCs limit the use of these cells in the clinic. Scientists propose the application of exosomes to use from the therapeutic effect of MSCs and overcome their defects. These vesicles change the target cell behaviour and transcription profile by transferring various cargo such as proteins, mi-RNAs, and lipids. One of the degenerative tissue diseases in which MSCs and their exosomes are used in their treatment is intervertebral disc disease (IDD). Different factors such as genetics, nutrition, ageing, and environmental factors play a significant role in the onset and progression of this disease. These factors affect the cellular and molecular properties of the disc, leading to tissue destruction. Nucleus pulposus cells (NPCs) are among the most important cells involved in the pathogenesis of disc degeneration. MSCs exert their therapeutic effects by differentiating, reducing apoptosis, increasing proliferation, and decreasing senescence in NPCs. In addition, the use of MSCs and their exosomes also affects the annulus fibrosus and cartilaginous endplate cells in disc tissue and prevents disc degeneration progression.

Immunotherapy of multisystem inflammatory syndrome in children (MIS-C) following COVID-19 through mesenchymal stem cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new type of coronavirus causing coronavirus 2019 (COVID-19) that was first observed in Wuhan, China, in Dec. 2019. An inflammatory immune response targeting children appeared during the pandemic, which was associated with COVID-19 named multisystem inflammatory syndrome in children (MIS-C). Characteristics of MIS-C include the classic inflammation findings, multi-organ dysfunction, and fever as the cardinal feature. Up to now, no specific therapy has been identified for MIS-C. Currently, considerable progress has been obtained in the MIS-C treatment by cell therapy, specially Mesenchymal stem cells (MSCs). Unique properties have been reported for MSCs, such as various resources for purification of cell, high proliferation, self-renewal, non-invasive procedure, tissue regenerator, multidirectional differentiation, and immunosuppression. As indicated by a recent clinical research, MSCs have the ability of reducing disease inflammation and severity in children with MIS-C. In the present review study, the benefits and characteristics of MSCs and exosomes are discussed for treating patients with MIS-C.

Imaging evaluation of lung cancer treated with PD-1/PD-L1 inhibitors.

Immunotherapy (PD-1/PD-L1 inhibitors) has attracted attention for lung cancer treatment and recasted the administration of immunotherapeutics to patients who have advanced/metastatic diseases. Whether in combination or as monotherapy, these medications have become common therapies for certain patients with lung cancer. Moreover, their usage is expected to expand widely in the future. This review aims to discuss the imaging evaluation of lung cancer response to PD-1/PD-L1 therapy with focus on new radiological criteria for immunotherapy response. Abnormal radiological responses (pseudoprogression, dissociative responses, and hyperprogression) and immune-related adverse events are also described.

Any day, split halfway: Flexibility in scheduling high-dose cisplatin-A large retrospective review from a high-volume cancer center.

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m2 × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m2 × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates.

Prevalence of erectile dysfunction in Egyptian males with metabolic syndrome.

Objectives: Determination of the potential effect of metabolic syndrome (MetS) on erectile function in Egyptian men and description of the sociodemographic characteristics of these men.Materials and methods: A cohort of 615 patients presenting to urology department aged between 30 and 75 years were prospectively assessed and divided into two groups. Group I (n = 325) diagnosed with MetS and mean age of 56.07 ± 8.51 years. Group II (n = 290) subjects with no MetS and mean age 54.97 ± 8.14 years. Patients filled the IIEF questionnaire, medical, personal history, and BMI data were tabulated. Metabolic syndrome was determined when three or more of the five risk factors were present according to the NCEP.Results: In Group I (79.4%) of the patients had erectile dysfunction (ED). Of these, 20.3% had mild, 22.5% had moderate, and 36.6% had severe ED and 30% of patients without MetS had ED. Of these, 17.2% had mild, 5.9% had moderate, and 6.9% had severe ED (p < .001; odds ratio 5.549; 95% CI 3.101-9.928). Patients with metabolic syndrome had lower IIEF-EF domain scores. Logistic regression analysis revealed that DM, dyslipidemia, age, and HTN were the most important criteria for ED in the MetS group (p < .01). While in the group without MetS, DM, HTN, HDL, and age were the most important risk factors (p < .01), and TG and BMI were less important.Conclusions: MetS is a potential risk factor for ED in Egyptian men. Patients with MetS should be questioned about ED. The diabetic patients are most risky for ED.

Use of malaria rapid diagnostic tests by community health workers in Afghanistan: cluster randomised trial.

BACKGROUND: The World Health Organisation (WHO) recommends parasitological diagnosis of malaria before treatment, but use of malaria rapid diagnostic tests (mRDTs) by community health workers (CHWs) has not been fully tested within health services in south and central Asia. mRDTs could allow CHWs to diagnose malaria accurately, improving treatment of febrile illness. METHODS: A cluster randomised trial in community health services was undertaken in Afghanistan. The primary outcome was the proportion of suspected malaria cases correctly treated for polymerase chain reaction (PCR)-confirmed malaria and PCR negative cases receiving no antimalarial drugs measured at the level of the patient. CHWs from 22 clusters (clinics) received standard training on clinical diagnosis and treatment of malaria; 11 clusters randomised to the intervention arm received additional training and were provided with mRDTs. CHWs enrolled cases of suspected malaria, and the mRDT results and treatments were compared to blind-read PCR diagnosis. RESULTS: In total, 256 CHWs enrolled 2400 patients with 2154 (89.8%) evaluated. In the intervention arm, 75.3% (828/1099) were treated appropriately vs. 17.5% (185/1055) in the control arm (cluster adjusted risk ratio: 3.72, 95% confidence interval 2.40-5.77; p < 0.001). In the control arm, 85.9% (164/191) with confirmed Plasmodium vivax received chloroquine compared to 45.1% (70/155) in the intervention arm (p < 0.001). Overuse of chloroquine in the control arm resulted in 87.6% (813/928) of those with no malaria (PCR negative) being treated vs. 10.0% (95/947) in the intervention arm, p < 0.001. In the intervention arm, 71.4% (30/42) of patients with P. falciparum did not receive artemisinin-based combination therapy, partly because operational sensitivity of the RDTs was low (53.2%, 38.1-67.9). There was high concordance between recorded RDT result and CHW prescription decisions: 826/950 (87.0%) with a negative test were not prescribed an antimalarial. Co-trimoxazole was prescribed to 62.7% of malaria negative patients in the intervention arm and 15.0% in the control arm. CONCLUSIONS: While introducing mRDT reduced overuse of antimalarials, this action came with risks that need to be considered before use at scale: an appreciable proportion of malaria cases will be missed by those using current mRDTs. Higher sensitivity tests could be used to detect all cases. Overtreatment with antimalarial drugs in the control arm was replaced with increased antibiotic prescription in the intervention arm, resulting in a probable overuse of antibiotics. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01403350 . Prospectively registered.

Cost-effectiveness of malaria diagnosis using rapid diagnostic tests compared to microscopy or clinical symptoms alone in Afghanistan.

BACKGROUND: Improving access to parasitological diagnosis of malaria is a central strategy for control and elimination of the disease. Malaria rapid diagnostic tests (RDTs) are relatively easy to perform and could be used in primary level clinics to increase coverage of diagnostics and improve treatment of malaria. METHODS: A cost-effectiveness analysis was undertaken of RDT-based diagnosis in public health sector facilities in Afghanistan comparing the societal and health sector costs of RDTs versus microscopy and RDTs versus clinical diagnosis in low and moderate transmission areas. The effect measure was 'appropriate treatment for malaria' defined using a reference diagnosis. Effects were obtained from a recent trial of RDTs in 22 public health centres with cost data collected directly from health centres and from patients enrolled in the trial. Decision models were used to compare the cost of RDT diagnosis versus the current diagnostic method in use at the clinic per appropriately treated case (incremental cost-effectiveness ratio, ICER). RESULTS: RDT diagnosis of Plasmodium vivax and Plasmodium falciparum malaria in patients with uncomplicated febrile illness had higher effectiveness and lower cost compared to microscopy and was cost-effective across the moderate and low transmission settings. RDTs remained cost-effective when microscopy was used for other clinical purposes. In the low transmission setting, RDTs were much more effective than clinical diagnosis (65.2% (212/325) vs 12.5% (40/321)) but at an additional cost (ICER) of US$4.5 per appropriately treated patient including a health sector cost (ICER) of US$2.5 and household cost of US$2.0. Sensitivity analysis, which varied drug costs, indicated that RDTs would remain cost-effective if artemisinin combination therapy was used for treating both P. vivax and P. falciparum. Cost-effectiveness of microscopy relative to RDT is further reduced if the former is used exclusively for malaria diagnosis. In the health service setting of Afghanistan, RDTs are a cost-effective intervention compared to microscopy. CONCLUSIONS: RDTs remain cost-effective across a range of drug costs and if microscopy is used for a range of diagnostic services. RDTs have significant advantages over clinical diagnosis with minor increases in the cost of service provision. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov under identifier NCT00935688.