Long-term outcomes by bone marrow B-cell depletion from the R2W trial of bortezomib with cyclophosphamide and rituximab in Waldenstrom macroglobulinaemia.

There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrom macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-specific flow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enroled into this phase II trial and randomised (2:1) to receive cyclophosphamide and rituximab with either bortezomib (BRC) or fludarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BRC (N = 41). An ORR of 97.6% (95%CI:87.1-99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-, 3- and 5-year progression-free survival (PFS) rates of 92.7% (95%CI:79.0-97.6), 80.5% (95%CI:64.8-89.7) and 65.5% (95%CI:48.8-77.9). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02-11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR = 0.06, 95%CI:0.01-0.47, p < 0.001), and remained independently associated after adjusting for baseline risk stratification or investigator-assessed response. BRC is a tolerable, highly efficacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes.

Laboratory practice is central to earlier myeloma diagnosis: Utilizing a primary care diagnostic tool and laboratory guidelines integrated into haematology services.

Treatment advances have greatly improved survival, but myeloma is among the worst of all cancers for delayed diagnosis, causing serious morbidities and early deaths. This delay is largely because the symptom profile of myeloma has very low specificity, and in primary care, myeloma is rare. However, initiating the journey to diagnosis simply requires considering myeloma and sending blood to test for monoclonal immunoglobulin. Laboratory tests reliably detect monoclonal immunoglobulin, which is present in 99% of myeloma cases, so why do health care systems have such a problem with delayed diagnosis? The Myeloma UK early diagnosis programme has brought together diverse expertise to investigate this problem, and this article was prepared by the programme's working group for laboratory best practice. It reviews evidence for test requesting, analysis and reporting, for which there is large variation in practice across the United Kingdom. It presents a 'GP Myeloma diagnostic tool' and how it can be integrated into laboratory practice alongside a laboratory best practice tool. It proposes improved requesting and integration with haematology services for reporting and interpretation. Here the laboratory has a central role in creating efficient and cost-effective pathways for appropriate and timely bone marrow examination for myeloma diagnosis.

Determinants of durable humoral and T cell immunity in myeloma patients following COVID-19 vaccination.

OBJECTIVE: To describe determinants of persisting humoral and cellular immune response to the second COVID-19 vaccination among patients with myeloma. METHODS: This is a prospective, observational study utilising the RUDYstudy.org platform. Participants reported their second and third COVID-19 vaccination dates. Myeloma patients had an Anti-S antibody level sample taken at least 21 days after their second vaccination and a repeat sample before their third vaccination. RESULTS: 60 patients provided samples at least 3 weeks (median 57.5 days) after their second vaccination and before their third vaccination (median 176.0 days after second vaccine dose). Low Anti-S antibody levels (<50 IU/mL) doubled during this interval (p = .023) and, in the 47 participants with T-spot data, there was a 25% increase negative T-spot tests (p = .008). Low anti-S antibody levels prior to the third vaccination were predicted by lower Anti-S antibody level and negative T-spot status after the second vaccine. Independent determinants of a negative T-spot included increasing age, previous COVID infection, high CD4 count and lower percentage change in Anti-S antibody levels. CONCLUSIONS: Negative T-spot results predict low Anti-S antibody levels (<50 IU/mL) following a second COVID-19 vaccination and a number of biomarkers predict T cell responses in myeloma patients.

Leaching characteristics and potential risk of heavy metals from drip irrigation pipes and mulch substrate in agricultural ecosystems.

Drip irrigation is a valuable method for optimising water and fertiliser usage, motivating its increasing use. However, the ecological effects of drip irrigation fertilisation have not been sufficiently evaluated, limiting its effective and widespread use. Within this context, we aimed to determine the effects and potential ecological risks of using polyethylene irrigation pipes and mulch substrate under various drip irrigation conditions as well as burning of waste pipes and mulch substrate. Laboratory simulations of field conditions were used to determine the distribution, leaching, and migration pattern of heavy metals (Cd, Cr, Cu, Pb, and Zn) from plastic drip irrigation pipes and agricultural mulch substrate into various solutions. Maize samples obtained from drip-irrigated fields were analysed to determine the presence of heavy metal residues and assess the risk of heavy metal contamination. Heavy metal leaching from pipes and mulch substrate was high under acidic conditions, while the migration of heavy metals from plastic products was low in alkaline water-soluble fertiliser solutions. After combustion, heavy metal leaching from pipes and mulch residues increased considerably, with the migration capacity of Cd, Cr, and Cu increasing by >10-fold. Heavy metals in plastic pipes migrated primarily to the residue (bottom ash), whereas those from mulch substrate migrated to the fly ash component. Under experimental conditions, the migration of heavy metals from plastic pipes and mulch substrate had a negligible effect on the heavy metal content in aqueous environments. Although heavy metal leaching increased, the effect on water quality under actual irrigation conditions was relatively minor (in the order of 10-9). Thus, the use of plastic irrigation pipes and mulch substrate did not result in significant heavy metal contamination and potential risk to the agriculture ecosystem. Our study findings provide evidence for the effective application and widespread promotion of drip irrigation and fertiliser technology.

11ß-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial.

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regenerates active glucocorticoid, we investigated whether 11ß-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn't met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.

Exposure Routes and Health Risks Associated with Pesticide Application.

Pesticides play an important role in agricultural development. However, pesticide application can result in both acute and chronic human toxicities, and the adverse effects of pesticides on the environment and human health remain a serious problem. There is therefore a need to discuss the application methods for pesticides, the routes of pesticide exposure, and the health risks posed by pesticide application. The health problems related to pesticide application and exposure in developing countries are of particular concern. The purpose of this paper is to provide scientific information for policymakers in order to allow the development of proper pesticide application technics and methods to minimize pesticide exposure and the adverse health effects on both applicators and communities. Studies indicate that there are four main pesticide application methods, including hydraulic spraying, backpack spraying, basal trunk spraying, and aerial spraying. Pesticide application methods are mainly selected by considering the habits of target pests, the characteristics of target sites, and the properties of pesticides. Humans are directly exposed to pesticides in occupational, agricultural, and household activities and are indirectly exposed to pesticides via environmental media, including air, water, soil, and food. Human exposure to pesticides occurs mainly through dermal, oral, and respiratory routes. People who are directly and/or indirectly exposed to pesticides may contract acute toxicity effects and chronic diseases. Although no segment of the general population is completely protected against exposure to pesticides and their potentially serious health effects, a disproportionate burden is shouldered by people in developing countries. Both deterministic and probabilistic human health risk assessments have their advantages and disadvantages and both types of methods should be comprehensively implemented in research on exposure and human health risk assessment. Equipment for appropriate pesticide application is important for application efficiency to minimize the loss of spray solution as well as reduce pesticide residuals in the environment and adverse human health effects due to over-spraying and residues. Policymakers should implement various useful measures, such as integrated pest management (IPM) laws that prohibit the use of pesticides with high risks and the development of a national implementation plan (NIP) to reduce the adverse effects of pesticides on the environment and on human health.

Environmental monitoring and potential health risk assessment from Pymetrozine exposure among communities in typical rice-growing areas of China.

Pymetrozine is one of the most commonly used insecticides in China. This study was conducted to analyse Pymetrozine's potential exposures through various environmental routes beyond the treatment areas. The aim was to estimate the potential health risk for communities due to non-dietary exposures to Pymetrozine in soil and paddy water. Data on registration of pesticides in China, government reports, questionnaires, interviews and literature reviews as well as toxicological health investigations were evaluated to determine the hazard and dose-response characteristics of Pymetrozine. These were based on the US EPA exposure and human health risk assessment methods and exposure data from soil and paddy water samples collected between 10 and 20 m around the resident's location. The exposure doses from dermal contact through soil and paddy water were estimated. The potential cancer risk from the following exposure routes was evaluated: ingestion through soil; dermal contact exposure through soil; dermal contact exposure through paddy water. The potential total cancer risk for residents was estimated to be less than 1 × 10-6. These were relatively low and within the acceptable risk levels. The potential hazard quotient (HQ) from acute and lifetime exposure by dermal contact through paddy water and soil and acute and lifetime exposure by soil ingestion for residents was less than 1, indicating an acceptable risk level. This study suggested that there were negligible cancer risk and non-cancer risks based on ingestion and dermal contact routes of exposure to residents.

Natural dynamics and residues of pymetrozine for typical rice-growing areas of China.

Pymetrozine has replaced toxic organophosphate pesticides previously used for controlling pests of rice crops in China. Existing data on its environmental behavior are usually related to studies on artificial plots that do not adequately address the natural dynamics and residues in actual field conditions. Therefore, studies under field conditions were carried out to investigate the natural dynamics and residues of pymetrozine in two typical rice-growing areas in China - Hunan and Guangxi provinces. Samples of paddy soil and water were collected in relation to spraying events in the study areas. The quick, easy, cheap, effective, rugged and safe (QuEChERS) method was used to extract pymetrozine residues from the samples by a Waters ACQUITY UPLC (Milford, MA, USA) system interfaced with a triple-quadrupole mass spectrometer (Xevo TQ-D, Waters Corp., USA). The initial deposition of pymetrozine in paddy soils was higher than in paddy waters in both areas. The decay of pymetrozine followed an exponential trend consistent with the first order kinetics. The half-life of pymetrozine in paddy water was determined to be 3.0 and 3.8 days, whereas the half-life in soil was 3.8 and 3.5 days in the Guangxi and Hunan samples, respectively. The decline rates of pymetrozine in paddy soil and paddy water in this field study were faster than those conducted under non-field conditions reported in previous studies. Compared to other pesticides used in China as reported in previous studies, the environmental persistence of pymetrozine in both paddy water and soils in Guangxi and Hunan provinces is very low. This has important implications for the use of pymetrozine in agricultural systems globally.

Bedside and laboratory diagnostic testing in myasthenia.

Myasthenia gravis (MG) and congenital myasthenic syndromes (CMS) are a group of disorders with a well characterised autoimmune or genetic and neurophysiological basis. We reviewed the literature from the last 20 years assessing the utility of various neurophysiological, immunological, provocative and genetic tests in MG and CMS. Diagnostic sensitivity of repetitive nerve stimulation test ranges between 14 and 94% and specificity between 73 and 100%; sensitivity of single-fibre EMG (SFEMG) test ranges between 64 and 100% and specificity between 22 and 100%; anti-acetylcholine receptor (AChR) antibody sensitivity ranges from 13 to 97% and specificity ranges from 95 to 100%. Overall, SFEMG has the highest sensitivity while positive anti-AChR antibodies have the highest specificity. Newer testing strategies that have been investigated over the last couple of decades include ocular vestibular-evoked myogenic potentials, otoacoustic emissions and disease-specific circulating miRNAs in serum for autoimmune myasthenia, as well as next-generation sequencing for genetic testing of CMS. While there has been significant progress in developing newer testing strategies for diagnosing MG and CMS over the last couple of decades, more research is needed to assess the utility of these newer tools regarding their sensitivity and specificity.

Immune response to COVID-19 vaccination is attenuated by poor disease control and antimyeloma therapy with vaccine driven divergent T-cell response.

Myeloma patients frequently respond poorly to bacterial and viral vaccination. A few studies have reported poor humoral immune responses in myeloma patients to COVID-19 vaccination. Using a prospective study of myeloma patients in the UK Rudy study cohort, we assessed humoral and interferon gamma release assay (IGRA) cellular immune responses to COVID-19 vaccination post second COVID-19 vaccine administration. We report data from 214 adults with myeloma (n = 204) or smouldering myeloma (n = 10) who provided blood samples at least three weeks after second vaccine dose. Positive Anti-spike antibody levels (> 50 iu/ml) were detected in 189/203 (92.7%), positive IGRA responses were seen in 97/158 (61.4%) myeloma patients. Only 10/158 (6.3%) patients were identified to have both a negative IGRA and negative anti-spike protein antibody response. In all, 95/158 (60.1%) patients produced positive results for both anti-spike protein serology and IGRA. After adjusting for disease severity and myeloma therapy, poor humoral immune response was predicted by male gender. Predictors of poor IGRA included anti-CD38/anti-BCMA (B-cell maturation antigen) therapy and Pfizer-BioNTech vaccination. Further work is required to understand the clinical significance of divergent cellular response to vaccination.

Probabilistic health risk assessment of chlorpyrifos exposure among applicators on rice farms in Ghana.

Human health risk assessments of exposures to non-carcinogenic occupational and environmental toxicants have mostly been undertaken using the Hazard Quotient (HQ) approach, which largely ignores variabilities in both exposures and associated adverse health outcomes, unlike probabilistic approaches. Chlorpyrifos is a neurotoxic insecticide that is commonly applied by farmers in Ghana with limited research on associated health risks among applicators. The objective of this study was to assess health risks associated with chlorpyrifos exposure among applicators on rice farms in Ghana, using advanced probabilistic approaches that incorporate variability in both exposure doses and adverse response doses obtained from human epidemiological studies. Urine samples obtained from the applicators were analyzed for 3,5,6-trichloro-2-pyridinol (TCP)from which Absorbed Daily Dose (ADD) and Lifetime Average Daily Dose (LADD) levels of chlorpyrifos were estimated. The scientific literature was searched to identify human epidemiological data from studies that have reported chlorpyrifos adverse effects and their corresponding exposure levels. Equivalent ADD and LADD of chlorpyrifos were estimated from the human epidemiological data to obtain chlorpyrifos Toxicant Sensitivity Distributions (TSDs). Using the applicators' chlorpyrifos dose distribution and TSDs, adverse health risks among the applicators were characterized using the probabilistic approaches, Overall Risk Probability (ORP) and Monte Carlo Simulation (MCS). The probabilities of chlorpyrifos adverse health effects occurring under the chronic exposure scenarios ranged from 1 to 8%, while those for acute exposure scenarios ranged from 31 to 34%. This study indicates that while the risks of chronic adverse health effects from chlorpyrifos exposure among the applicators were low, acute health risks were high.

Using quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify low level monoclonal proteins.

Mass spectrometry has recently been proposed as a novel sensitive screening tool for monoclonal gammopathies. In a small study we have tested the ability of quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify low level monoclonal immunoglobulins not currently detected by the initial serum protein electrophoresis (SPEP) screen. QIP-MS positively identified the primary monoclonal immunoglobulins in all 11 patient samples alongside additional monoclonal immunoglobulins in a subset of patient samples. We conclude that QIP-MS has clinical utility as a first-line screening tool for monoclonal gammopathy investigation, identifying monoclonality in patients with higher sensitivity and resolution compared to the current standard methods.

Health Risk Assessment for Exposure to Nitrate in Drinking Water in Central Java, Indonesia.

Since 2005, over 30 epidemiological studies have evaluated the association between nitrate in drinking water and adverse health outcomes. Conditions that lead to nitrate pollution in water, such as open defecation, the proximity of septic tanks to water sources, and the use of inorganic fertilizer, are rampant in Indonesia, which has experienced little research evaluating nitrate in drinking water. We conducted a health risk assessment for exposure to nitrate in drinking water and evaluated the nitrate concentration in key water sources in two villages of rural Central Java, Indonesia. The nitrate concentrations in the drinking water ranged from 3.55 mg/L to 26.75 mg/L as NO3-. Daily nitrate intake estimates, calculated at 50% and 95% exposure to the maximum nitrate concentration of the drinking water in both villages, were above the levels associated with birth defects, colorectal cancer, and thyroid conditions observed in other studies. There was a large variation in nitrate concentrations between and within the villages at different water sources. Further research into whether these health outcomes exist in rural Central Java, Indonesia will be required to better understand this risk.

Agriculture Development, Pesticide Application and Its Impact on the Environment.

Pesticides are indispensable in agricultural production. They have been used by farmers to control weeds and insects, and their remarkable increases in agricultural products have been reported. The increase in the world's population in the 20th century could not have been possible without a parallel increase in food production. About one-third of agricultural products are produced depending on the application of pesticides. Without the use of pesticides, there would be a 78% loss of fruit production, a 54% loss of vegetable production, and a 32% loss of cereal production. Therefore, pesticides play a critical role in reducing diseases and increasing crop yields worldwide. Thus, it is essential to discuss the agricultural development process; the historical perspective, types and specific uses of pesticides; and pesticide behavior, its contamination, and adverse effects on the natural environment. The review study indicates that agricultural development has a long history in many places around the world. The history of pesticide use can be divided into three periods of time. Pesticides are classified by different classification terms such as chemical classes, functional groups, modes of action, and toxicity. Pesticides are used to kill pests and control weeds using chemical ingredients; hence, they can also be toxic to other organisms, including birds, fish, beneficial insects, and non-target plants, as well as air, water, soil, and crops. Moreover, pesticide contamination moves away from the target plants, resulting in environmental pollution. Such chemical residues impact human health through environmental and food contamination. In addition, climate change-related factors also impact on pesticide application and result in increased pesticide usage and pesticide pollution. Therefore, this review will provide the scientific information necessary for pesticide application and management in the future.

Epidemiology of soil-transmitted helminth infections in Semarang, Central Java, Indonesia.

Soil-transmitted helminth (STH) infections are endemic in Indonesia. However, prevalence data for many parts of the country are incomplete. The aim of this study was to determine human STH prevalence and knowledge and practices relating to STH risk behaviour, to provide a current view of the status of STH infection in rural communities in Central Java. A cross-sectional survey of 16 villages was conducted in Semarang, Central Java in 2015. Demographic and household data together with information about knowledge and practices relating to STH and hygiene were elicited through face-to-face interviews. Stool samples were collected and examined using the flotation method. Children (aged 2-12 years) also had their haemoglobin (Hb) levels, height and weight data collected, and BMI estimated. Data were analysed using univariate logistic regression analysis. A total of 6,466 individuals with a mean age of 33.5 years (range: 2-93) from 2,195 households were interviewed. The overall prevalence of STH was 33.8% with Ascaris lumbricoides (roundworm) the predominant nematode identified (prevalence = 26.0%). Hookworm and Trichuris trichiura (whipworm) were found in 7.9% and 1.8% of participants, respectively. Females were at increased odds of infection with A. lumbricoides (adjusted OR 1.14, 95% CI [1.02-1.29], p = 0.02). Adults in age groups 51-60 and over 60 years had the highest odds of being infected with hookworm (adjusted OR 3.01, 95% CI [1.84-4.91], p<0.001 and adjusted OR 3.79, 95% CI [2.30-6.26], p<0.001, respectively) compared to 6-12 year olds. Farmers also had higher odds of being infected with hookworm (adjusted OR 2.36, 95% CI [1.17-4.76], p = 0.02) compared to other occupation categories. Poverty (OR 2.14, 95% CI [1.77-2.58], p<0.001), overcrowding (OR 1.35, 95% CI [1.27-1.44], p<0.001), goat ownership (OR 1.61, 95% CI [1.10-2.41], p = 0.02) and the presence of dry floor space in the home (OR 0.73, 95% CI [0.58-0.91], p = 0.01) were all household factors significantly associated with an increased odds of infection. Infection with STH was not significantly associated with the gastrointestinal illness (p>0.05), BMI or Hb levels; however, one third of all 2-12 year olds surveyed were found to be anaemic (i.e. Hb concentrations below 110g/l or 115g/l for children under 5 and 5 years or older, respectively), with a greater proportion of school-age children at risk. Knowledge and behaviour related to hygiene and gastrointestinal diseases varied widely and were generally not associated with STH infection. The study revealed that STH infection remains endemic in Central Java despite ongoing deworming programs. Current control efforts would benefit from being re-evaluated to determine a more effective way forward.

Experience from the first UK inter-regional specialist multidisciplinary meeting in the diagnosis and management of IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a complex multisystem fibro-inflammatory disorder, requiring diagnostic differentiation from malignancy and other immune-mediated conditions, and careful management to minimise glucocorticoid-induced toxicity and prevent progressive organ dysfunction. We describe the experience of the first inter-regional specialist IgG4-RD multidisciplinary team meeting (MDM) incorporating a broad range of generalists and specialists, held 6-weekly via web-link between Oxford University Hospitals NHS Foundation Trust and University College London Hospitals NHS Foundation Trust. Over 3 years, there were 206 discussions on 156 patients. Of these, 97 (62%) were considered to have definite or possible IgG4-RD; 67% had multi-organ involvement and 23% had a normal serum IgG4. The average number of specialist opinions sought prior to MDM was four per patient. Management was changed in the majority of patients (74%) with the treatment escalation recommended in 61 cases, including 19 for rituximab. Challenges arose from delays and misdiagnosis, cross-specialty presentation and the management of sub-clinical disease. Our cross-discipline IgG4-RD MDM enabled important diagnostic and management decisions in this complex multisystem disorder, and can be used as a model for other centres in the UK.