Laboratory evaluation of twelve portable devices for medicine quality screening

BackgroundPost-market surveillance is a key regulatory function to prevent substandard and falsified (SF) medicines from being consumed by patients. Field deployable technologies offer the potential for rapid objective screening for SF medicines.Methods and findingsWe evaluated twelve devices: three near infrared spectrometers (MicroPHAZIR RX, NIR-S-G1, Neospectra 2.5), two Raman spectrometers (Progeny, TruScan RM), one mid-infrared spectrometer (4500a), one disposable colorimetric assay (Paper Analytical Devices, PAD), one disposable immunoassay (Rapid Diagnostic Test, RDT), one portable liquid chromatograph (C-Vue), one microfluidic system (PharmaChk), one mass spectrometer (QDa), and one thin layer chromatography kit (GPHF-Minilab). Each device was tested with a series of field collected medicines (FCM) along with simulated medicines (SIM) formulated in a laboratory. The FCM and SIM ranged from samples with good quality active pharmaceutical ingredient (API) concentrations, reduced concentrations of API (80% and 50% of the API), no API, and the wrong API. All the devices had high sensitivities (91.5 to 100.0%) detecting medicines with no API or the wrong API. However, the sensitivities of each device towards samples with 50% and 80% API varied greatly, from 0% to 100%. The infrared and Raman spectrometers had variable sensitivities for detecting samples with 50% and 80% API (from 5.6% to 50.0%). The devices with the ability to quantitate API (C-Vue, PharmaChk, QDa) had sensitivities ranging from 91.7% to 100% to detect all poor quality samples. The specificity was lower for the quantitative C-Vue, PharmaChk, & QDa (50.0% to 91.7%) than for all the other devices in this study (95.5% to 100%).ConclusionsThe twelve devices evaluated could detect medicines with the wrong or none of the APIs, consistent with falsified medicines, with high accuracy. However, API quantitation to detect formulations similar to those commonly found in substandards proved more difficult, requiring further technological innovation.     

Lessons learnt from the implementation of a colorectal cancer screening programme for lynch syndrome in a tertiary public hospital

BackgroundLynch syndrome (LS) is the first cause of inherited colorectal cancer (CRC), being responsible for 2–4% of all diagnoses. Identification of affected individuals is important as they have an increased lifetime risk of multiple CRC and other neoplasms, however, LS is consistently underdiagnosed at the population level. We aimed to evaluate the yield of LS screening in CRC in a single-referral centre and to identify the barriers to its effective implementation.MethodsLS screening programme included individuals with CRC < 70 years, multiple CRC, or endometrial cancer at any age. Mismatch repair (MMR) protein immunohistochemistry (IHC) analysis was performed in routine practice on the surgical specimen and, if MLH1 IHC was altered, MLH1 gene promoter methylation was analysed. Results were collected in the CRC multidisciplinary board database. LS suspected individuals (altered MMR IHC without MLH1 promoter methylation) were referred to the Cancer Genetic Counselling Unit (CGCU). If accepted, a genetic study was performed. Two checkpoints were included: review of the pathology data and verification of patient referral by a genetic counsellor.ResultsBetween 2016 and 2019, 381 individuals were included. MMR IHC analysis was performed in 374/381 (98.2 %) CRC cases and MLH1 promoter methylation in 18/21 (85.7 %). Seventeen of the 20 LS suspected individuals were invited for referral at the CGCU. Two cases were not invited and the remaining patient died of cancer before completion of tumour screening. Fifteen individuals attended and a genetic analysis was performed in 15/20 (75 %) LS suspected individuals. Ten individuals were diagnosed with LS, in concordance with the IHC profile (2.7 % of the total cohort). This led to cascade testing in 58/75 (77.3 %) of the available adult relatives at risk, identifying 26 individuals with LS.ConclusionsEstablishing a standardized institutional LS screening programme with checkpoints in the workflow is key to increasing the yield of LS identification.     

A comparative field evaluation of six medicine quality screening devices in Laos

BackgroundMedicine quality screening devices hold great promise for post-market surveillance (PMS). However, there is little independent evidence on their field utility and usability to inform policy decisions. This pilot study in the Lao PDR tested six devices’ utility and usability in detecting substandard and falsified (SF) medicines.Methodology/principal findingsObservational time and motion studies of the inspections by 16 Lao medicine inspectors of 1) the stock of an Evaluation Pharmacy (EP), constructed to resemble a Lao pharmacy, and 2) a sample set of medicines (SSM); were conducted without and with six devices: four handheld spectrometers (two near infrared: MicroPHAZIR RX, NIR-S-G1 & two Raman: Progeny, Truscan RM); one portable mid-infrared spectrometer (4500a), and single-use paper analytical devices (PAD). User experiences were documented by interviews and focus group discussions.Significantly more samples were wrongly categorised as pass/fail with the PAD compared to the other devices in EP inspections (p<0.05). The numbers of samples wrongly classified in EP inspections were significantly lower than in initial visual inspections without devices for 3/6 devices (NIR-S-G1, MicroPHAZIR RX, 4500a). The NIR-S-G1 had the fastest testing time per sample (median 93.5 sec, p<0.001). The time spent on EP visual inspection was significantly shorter when using a device than for inspections without devices, except with the 4500a, risking missing visual clues of samples being SF. The main user errors were the selection of wrong spectrometer reference libraries and wrong user interpretation of PAD results. Limitations included repeated inspections of the EP by the same inspectors with different devices and the small sample size of SF medicines.Conclusions/significanceThis pilot study suggests policy makers wishing to implement portable screening devices in PMS should be aware that overconfidence in devices may cause harm by reducing inspectors’ investment in visual inspection. It also provides insight into the advantages/limitations of diverse screening devices in the hands of end-users.     

European guidelines for quality assurance in cervical cancer screening: recommendations for cervical cytology terminology

There are many different systems of cytology classification used in the member states of the European Union (EU) and many different languages. The following short annexe to Chapter 3 of the European Guidelines for Quality Assurance in Cervical Cancer Screening provides a framework that will allow different terminologies and languages to be translated into standard terminology based on the Bethesda system (TBS) for cytology while retaining the cervical intraepithelial neoplasia (CIN) classification for histology. This approach has followed extensive consultation with representatives of many countries and professional groups as well as a discussion forum published in Cytopathology (2005;16:113). This article will describe the reporting of specimen adequacy, which is dealt with in more detail elsewhere in Chapter 3 of the guidelines, the optional general categorization recommended in TBS, the interpretation/cytology result and other comments that may be made on reports such as concurrent human papillomavirus testing and the use of automation review and recommendations for management. The main categories in TBS will be described in the context of CIN, dyskaryosis and dysplasia terminologies so that all may be translated into the same framework. These guidelines should allow European countries to adapt their terminology in such a way as to make their screening programmes comparable with each other as well as with programmes elsewhere in the world.     

European guidelines for quality assurance in cervical cancer screening: recommendations for cytology laboratories.

The quality of a cervical cytology laboratory depends on adequate handling and staining of the samples, screening and interpretation of the slides and reporting of the results. These guidelines give an overview of procedures recommended in Europe to manage the balance between best patient care possible, laboratory quality assurance and cost effectiveness and will be published as a chapter 4 in the European Guidelines for Quality Assurance in Cervical Cancer Screening. The laboratory guidelines include protocols for personnel and organisation, material requirements, handling and analysing cervical samples, recording of results, quality management and communication. The section on quality management is comprehensive and includes protocols for all aspects of internal and external quality assurance. The guidelines are extensively referenced and as far as possible the recommendations are evidence-based.     

European guidelines for quality assurance in cervical cancer screening: recommendations for clinical management of abnormal cervical cytology, part 1

The current paper presents the first part of Chapter 6 of the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening. It provides guidance on how to manage women with abnormal cervical cytology. Throughout this article the Bethesda system is used for cervical cytology terminology, as the European guidelines have recommended that all systems should at least be translated into that terminology while cervical intraepithelial neoplasia (CIN) is used for histological biopsies (Cytopathology 2007; 18 :213–9). A woman with a high‐grade cytological lesion, a repeated low‐grade lesion or with an equivocal cytology result and a positive human papillomavirus (HPV) test should be referred for colposcopy. The role of the colposcopist is to identify the source of the abnormal cells and to make an informed decision as to whether or not any treatment is required. If a patient requires treatment the colposcopist will decide which is the most appropriate method of treatment for each individual woman. The colposcopist should also organize appropriate follow‐up for each woman seen. Reflex testing for high‐risk HPV types of women with atypical squamous cells (ASC) of undetermined significance with referral for colposcopy of women who test positive is a first option. Repeat cytology is a second possibility. Direct referral to a gynaecologist should be restricted to special circumstances. Follow‐up of low‐grade squamous intraepithelial lesion is more difficult because currently there is no evidence to support any method of management as being optimal; repeat cytology and colposcopy are options, but HPV testing is not sufficiently selective, unless for older women. Women with high‐grade squamous intraepithelial lesion (HSIL) or atypical squamous cells, cannot exclude HSIL (ASC‐H) should be referred without triage. Women with glandular lesions require particular attention. In a subsequent issue of Cytopathology, the second part of Chapter 6 will be presented, with recommendations for management and treatment of histologically confirmed intraepithelial neoplasia and guidance for follow‐up of special cases such as women who are pregnant, postmenopausal or immunocompromised.     

Prospects for crop production under drought: research priorities and future directions

The efficient use of water supplies requires a systems approach that encompasses all aspects of making water available and its use within society that must recognise global issues. Increasing the efficiency of water use within agricultural systems is an essential priority in many regions including the Mediterranean. This review examines the research priorities, the prospects for crop and soil management and plant breeding and biotechnology that are needed to achieve high stable yield under drought in the Mediterranean. Research must combine the latest genomics resources including quantitative genetics, genomics and biomathematics with an ecophysiological understanding of the interactions between crop plant genotypes and the growing environment to better inform crop improvement.     

European guidelines for quality assurance in cervical cancer screening: recommendations for collecting samples for conventional and liquid-based cytology.

The current paper presents an annex in the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening. It provides guidance on how to make a satisfactory conventional Pap smear or a liquid-based cytology (LBC) sample. Practitioners taking samples for cytology should first explain to the woman the purpose, the procedure and how the result will be communicated. Three sampling methods are considered as acceptable for preparing conventional Pap smears: (i) the cervical broom; (ii) the combination of a spatula and an endocervical brush; and (iii) the extended tip spatula. Smear takers should take care to sample the entire circumference of the transformation zone, to quickly spread the cellular material over a glass slide, and to fix the preparation within a few seconds to avoid drying artefacts. According to local guidelines, one of these three methods may be preferred. Sampling with a cotton tip applicator is inappropriate. Similar procedures should be followed for sampling cells for LBC, but only plastic devices may be used. The collected cells should be quickly transferred into a vial with fixative liquid according to the instructions of the manufacturer of the LBC system. Subsequently, the slide or vial and the completed request form are sent to the laboratory for cytological interpretation.     

Evaluation of docosahexaenoic acid deficiency as a preventable risk factor for recurrent affective disorders: Current status, future directions, and dietary recommendations

Major recurrent affective disorders, including major depressive disorder (MDD) and bipolar disorder, represent a growing public health crisis in the United States. Evidence from cross-national and cross-sectional epidemiological surveys, comparative peripheral and central composition studies, and placebo-controlled intervention trials suggest that n-3 fatty acid deficiency may contribute to the pathoaetiology of affective disorders. These data are reviewed with the objective of estimating a daily docosahexaenoic acid (DHA, 22:6n-3) intake value that is projected to be efficacious in mitigating vulnerability. It is proposed that daily DHA intake sufficient to increase erythrocyte DHA composition to a level found in healthy subjects from Japan (7%), where the lifetime prevalence rates of MDD and bipolar disorder are several fold lower than the US, represents an appropriate target. To achieve this target, preliminary DHA intervention trials indicate that a daily dose of 400–700 mg/d in children and 700–1000 mg/d in adults would be required. Based on the results of placebo-controlled intervention trials, a higher daily DHA dose in the order of 1000–1500 mg/d in a 2:1 eicosapentaenoic acid (EPA, 20:5n-3):DHA ratio may be optimal for the treatment of established affective disorders. These recommendations are intended to guide future dose-ranging placebo-controlled DHA intervention trials in patients with established affective disorders, as well as in asymptomatic subjects at elevated risk for developing affective disorders. Such early intervention studies are currently feasible and will ultimately be required to definitively evaluate whether DHA is a required nutrient for the prevention of affective disorders.     

Rice-maize systems of South Asia: current status, future prospects and research priorities for nutrient management

Rice (Oryza sativa L.) and maize (Zey mays) are grown in 3.5 million hectares (Mha) in Asia that includes 1.5 Mha in South Asia. These crops are grown in sequence on the same land in the same year either in double–or triple-crop systems to meet the rice demand of a rapidly expanding human population and maize demand of livestock and poultry. The objective of this review is to provide a comprehensive overview of the current state of technical knowledge on agro-ecosystems and adaptation, area and distribution, yield potential and yield gaps, and nutrient management for rice-maize (R-M) systems in South Asia. Rice-maize systems are emerging all around South Asia but in particular are developing quite rapidly in Bangladesh and South and North India. Yield potential of rice and maize, as estimated by ORYZA2000 and Hybrid Maize models, reaches up to 15 and 22 t ha^-1, respectively. However, data from several environments in India reveal gaps between potential and attainable yields of maize of upto 100% and between attainable and actual yields of upto 25–50%. Nutrient demand of R-M system is high due to high nutrient removal by high-yielding maize. Nutrient balance studies for these highly–productive and nutrient-extractive systems are scarce in South Asia. The review outlines principles of nutrient management for R-M systems, and identifies development, refinement, and dissemination of the integrated plant nutrition system technologies based on site-specific nutrient management principles as priorities for future research to increase yield, profitability, and sustainability of R-M systems.