CIA2 and CIA2-LIKE are required for optimal photosynthesis and stress responses in Arabidopsis thaliana.

Chloroplast-to-nucleus retrograde signaling is essential for cell function, acclimation to fluctuating environmental conditions, plant growth and development. The vast majority of chloroplast proteins are nuclear-encoded, and must be imported into the organelle after synthesis in the cytoplasm. This import is essential for the development of fully functional chloroplasts. On the other hand, functional chloroplasts act as sensors of environmental changes and can trigger acclimatory responses that influence nuclear gene expression. Signaling via mobile transcription factors (TFs) has been recently recognized as a way of communication between organelles and the nucleus. In this study, we performed a targeted reverse genetic screen to identify dual-localized TFs involved in chloroplast retrograde signaling during stress responses. We found that CHLOROPLAST IMPORT APPARATUS 2 (CIA2) has a functional plastid transit peptide, and can be located both in chloroplasts and the nucleus. Further, we found that CIA2, along with its homolog CIA2-like (CIL) are involved in the regulation of Arabidopsis responses to UV-AB, high light and heat shock. Finally, our results suggest that both CIA2 and CIL are crucial for chloroplast translation. Our results contribute to a deeper understanding of signaling events in the chloroplast-nucleus cross-talk.

Arabidopsis annexin 5 is involved in maintenance of pollen membrane integrity and permeability.

In Arabidopsis, a dry stigma surface enables a gradual hydration of pollen grains by a controlled release of water. Occasionally the grains may be exposed to extreme precipitations that cause rapid water influx and swelling, eventually leading to pollen membrane rupture. In metazoans, calcium- and phospholipid-binding proteins, referred to as annexins, participate in the repair of plasma membrane damages. It remains unclear, however, how this process is conducted in plants. Here, we examined whether plant annexin 5 (ANN5), the most abundant member of the annexin family in pollen, is involved in the restoration of pollen membrane integrity. We analyzed the cellular dynamics of ANN5 in pollen grains undergoing hydration in favorable or stress conditions. We observed a transient association of ANN5 with the pollen membrane during in vitro hydration that did not occur in the pollen grains being hydrated on the stigma. To simulate a rainfall, we performed spraying of the pollinated stigma with deionized water that induced ANN5 accumulation at the pollen membrane. Interestingly, calcium or magnesium application affected pollen membrane properties differently, causing rupture or shrinkage of pollen membrane, respectively. Both treatments, however, induced ANN5 recruitment to the pollen membrane. Our data suggest a model in which ANN5 is involved in the maintenance of membrane integrity in pollen grains exposed to osmotic or ionic imbalances.

Clinical significance of self-descriptive apathy assessment in patients with neurological form of Wilson's disease.

BACKGROUND AND AIM: Apathy is one of the neuropsychiatric symptoms of Wilson's disease (WD) which typically affects the brain's fronto-basal circuits. Lack of agreed diagnostic criteria and common use of self-description assessment tools lead to underestimation of this clinical phenomenon. The aim of this study was to investigate whether subjective and informant-based clinical features of apathy in patients with WD enable clinicians to make a valid diagnosis. METHODS: Multiple aspects of goal-oriented behavior were assessed in 30 patients with the neurological form of WD and 30 age-matched healthy participants using two questionnaires, the Lille Apathy Rating Scale (LARS) and the Dysexecutive Questionnaire (DEX). Both included a self-descriptive and a caregiver/proxy version. Cognitive functioning was estimated with the use of Addenbrooke's Cognitive Examination-Revised. RESULTS: Patients obtained significantly worse scores on all clinical scales when more objective measures were considered. Features of apathy and executive dysfunction were revealed in patients' caregiver versions of LARS and DEX, which may indicate poor self-awareness of patients with WD. Roughly 30% of participants were likely to present with clinically meaningful symptoms, independent of cognitive dysfunction. CONCLUSIONS: Methods relying on self-description appear inferior to informant-based scales when diagnosing apathy. More objective criteria and measurement tools are needed to better understand this clinical syndrome.

Similarities, reliability and gaps in assessing the quality of conduct of systematic reviews using AMSTAR-2 and ROBIS: systematic survey of nutrition reviews.

BACKGROUND: AMSTAR-2 ('A Measurement Tool to Assess Systematic Reviews, version 2') and ROBIS ('Risk of Bias in Systematic Reviews') are independent instruments used to assess the quality of conduct of systematic reviews/meta-analyses (SR/MAs). The degree of overlap in methodological constructs together with the reliability and any methodological gaps have not been systematically assessed and summarized in the field of nutrition. METHODS: We performed a systematic survey of MEDLINE, EMBASE, and the Cochrane Library for SR/MAs published between January 2010 and November 2018 that examined the effects of any nutritional intervention/exposure for cancer prevention. We followed a systematic review approach including two independent reviewers at each step of the process. For AMSTAR-2 (16 items) and ROBIS (21 items), we assessed the similarities, the inter-rater reliability (IRR) and any methodological limitations of the instruments. Our protocol for the survey was registered in PROSPERO (CRD42019121116). RESULTS: We found 4 similar domain constructs based on 11 comparisons from a total of 12 AMSTAR-2 and 14 ROBIS items. Ten comparisons were considered fully overlapping. Based on Gwet's agreement coefficients, six comparisons provided almost perfect (> 0.8), three substantial (> 0.6), and one a moderate level of agreement (> 0.4). While there is considerable overlap in constructs, AMSTAR-2 uniquely addresses explaining the selection of study designs for inclusion, reporting on excluded studies with justification, sources of funding of primary studies, and reviewers' conflict of interest. By contrast, ROBIS uniquely addresses appropriateness and restrictions within eligibility criteria, reducing risk of error in risk of bias (RoB) assessments, completeness of data extracted for analyses, the inclusion of all necessary studies for analyses, and adherence to predefined analysis plan. CONCLUSIONS: Among the questions on AMSTAR-2 and ROBIS, 70.3% (26/37 items) address the same or similar methodological constructs. While the IRR of these constructs was moderate to perfect, there are unique methodological constructs that each instrument independently addresses. Notably, both instruments do not address the reporting of absolute estimates of effect or the overall certainty of the evidence, items that are crucial for users' wishing to interpret the importance of SR/MA results.

Photosystem II 22kDa protein level - a prerequisite for excess light-inducible memory, cross-tolerance to UV-C and regulation of electrical signalling.

It is well known that PsbS is a key protein for the proper management of excessive energy in plants. Plants without PsbS cannot trigger non-photochemical quenching, which is crucial for optimal photosynthesis under variable conditions. Our studies showed wild-type plants had enhanced tolerance to UV-C-induced cell death (CD) upon induction of light memory by a blue or red light. However, npq4-1 plants, which lack PsbS, as well as plants overexpressing this protein (oePsbS), responded differently. Untreated oePsbS appeared more tolerant to UV-C exposure, whereas npq4-1 was unable to adequately induce cross-tolerance to UV-C. Similarly, light memory induced by episodic blue or red light was differently deregulated in npq-4 and oePsbS, as indicated by transcriptomic analyses, measurements of the trans-thylakoid pH gradient, chlorophyll a fluorescence parameters, and measurements of foliar surface electrical potential. The mechanism of the foliar CD development seemed to be unaffected in the analysed plants and is associated with chloroplast breakdown. Our results suggest a novel, substantial role for PsbS as a regulator of chloroplast retrograde signalling for light memory, light acclimation, CD, and cross-tolerance to UV radiation.

Support for Metastatic Breast Cancer Patients-a Systematic Review.

Our study objective was to evaluate existing evidence on different types of support received by metastatic breast cancer patients as well as the need for support expressed by such patients. We searched Medline and EMBASE up to January 2019 for survey studies that aimed to assess any type of support among women of any age, with metastatic breast cancer diagnosis. Two reviewers independently screened titles and abstracts, then full texts of retrieved records against inclusion/exclusion criteria, and extracted the data and assessed the quality of included studies with AXIS tool. From a total of 2876 abstracts, we selected 100 potentially eligible full-text articles, and finally, we included 12 records reporting on 11 studies. Due to the variability of methods used to measure and define support, it was not possible to quantitatively synthesize data; therefore, we synthesized them narratively. The quality of the included studies was moderate. We found that most patients are satisfied with the received psychosocial, emotional, informational, and medical support. In the analysis of any support received from a certain type of group of people, we found that the majority of patients reported receiving sufficient support from their family, friends, and healthcare providers. Ten studies showed a high need for informational support. If asked about the need for psychosocial, medical, and sexual support, women also declared the need for such support. Our review revealed that the patients generally receive support from their community but they express high need for information and treatment choice. PROSPERO CRD42019127496.

Evidence for the Involvement of Electrical, Calcium and ROS Signaling in the Systemic Regulation of Non-Photochemical Quenching and Photosynthesis.

In contrast to the function of reactive oxygen species, calcium, hormones and small RNAs in systemic signaling, systemic electrical signaling in plants is poorly studied and understood. Pulse amplitude-modulated Chl fluorescence imaging and surface electrical potential measurements accompanied by pharmacological treatments were employed to study stimuli-induced electrical signals in leaves from a broad range of plant species and in Arabidopsis thaliana mutants. Here we report that rapid electrical signals in response to a local heat stimulus regulate systemic changes in non-photochemical quenching (NPQ) and PSII quantum efficiency. Both stimuli-induced systemic changes in NPQ and photosynthetic capacity as well as electrical signaling depended on calcium channel activity. Use of an Arabidopsis respiratory burst oxidase homolog D (RBOHD) mutant (rbohD) as well as an RBOH inhibitor further suggested a cross-talk between ROS and electrical signaling. Our results suggest that higher plants evolved a complex rapid long-distance calcium-dependent electrical systemic signaling in response to local stimuli that regulates and optimizes the balance between PSII quantum efficiency and excess energy dissipation in the form of heat by means of NPQ.

Abscisic Acid Insensitive 4 transcription factor is an important player in the response of Arabidopsis thaliana to two-spotted spider mite (Tetranychus urticae) feeding.

Plants growing in constantly changeable environmental conditions are compelled to evolve regulatory mechanisms to cope with biotic and abiotic stresses. Effective defence to invaders is largely connected with phytohormone regulation, resulting in the production of numerous defensive proteins and specialized metabolites. In our work, we elucidated the role of the Abscisic Acid Insensitive 4 (ABI4) transcription factor in the plant response to the two-spotted spider mite (TSSM). This polyphagous mite is one of the most destructive herbivores, which sucks mesophyll cells of numerous crop and wild plants. Compared to the wild-type (Col-0) Arabidopsis thaliana plants, the abi4 mutant demonstrated increased susceptibility to TSSM, reflected as enhanced female fecundity and greater frequency of mite leaf damage after trypan blue staining. Because ABI4 is regarded as an important player in the plastid-to-nucleus retrograde signalling process, we investigated the plastid envelope membrane dynamics using stroma-associated fluorescent marker. Our results indicated a clear increase in the number of stroma-filled tubular structures deriving from the plastid membrane (stromules) in the close proximity of the site of mite leaf damage, highlighting the importance of chloroplast-derived signals in the response to TSSM feeding activity.

Neuropsychological characteristics of encephalopathy in Susac's Syndrome - Case report.

Susac's Syndrome (SS) is a rare, autoimmune angiopathy characterized by hearing loss, retinal artery occlusions and encephalopathy, which is usually expressed in multifocal neurological signs and symptoms, confusion state and cognitive impairment. There have been few descriptions of neuropsychological assessment of SS. We present a case study of 29-year-old woman who developed full SS. During the post-acute stage of disease, she was admitted to neurorehabilitation ward to improve her cognitive-behavioral and motor functioning. The initial assessment revealed attention, memory and executive dysfunctions, as well as behavioral changes including impulsivity, affective dysregulation and reduced self-awareness of disease deficits. After five weeks recovery process supported by rehabilitation program, improvement was observed, although some cognitive-behavioral deficits were still present in the follow-up assessment.

Assessment of the implementation of the infectious diseases screening programmes among pregnant women in the Lesser Poland region and comparison with similar programmes conducted in other European Union countries.

OBJECTIVES: The aim of the study was to assess the level of implementation of recommendations of the Ministry of Health regarding infectious disease screening during pregnancy. MATERIAL AND METHODS: The study included 477 patients who were admitted to the delivery room between December 2015 and February 2016. Data on screening test results were collected based on medical records covering the period before the admission. RESULTS: The Human Immunodeficiency Virus (HIV) screening was conducted in 410 (86%). 460 (96%) of patients were screened for Hepatitis B Virus (HBV) and 427 (89.5%) for Hepatitis C Virus (HCV). Syphilis screening covered 465 (97.5%) of patients. Immunoglobulin M (IgM) titer against Rubella Virus (RV) was assessed in 218 (45%) patients and immunoglobulin G (IgG) in 319 (66.9%). Screening for Toxoplasma gondii based on assessment of IgM titer was conducted in 440 (92%) patients while IgG titter was assessed in 413 (86.6%). 343 (71.9%) patients had obtained vaginal swabs for Group B Streptococci (GBS) while the anal swabs were taken only from 268 (56.2%) patients. CONCLUSIONS: Coverage of screening for syphilis and HBV was similar to the countries with highest prevalence of conducting such screening, on the other hand RV screening place as among countries with lowest prevalence. There is an increasing trend in conducting HIV screening. Screening for HCV and toxoplasmosis is at satisfactory level and Poland is one of a few European countries offering such screening. The screening for GBS is insufficient which result in excessive use of intrapartum antibiotic prophylaxis.

Isochorismate synthase 1 is required for thylakoid organization, optimal plastoquinone redox status, and state transitions in Arabidopsis thaliana.

Isochorismate synthase 1 (ICS1) is a crucial enzyme in the salicylic acid (SA) synthesis pathway, and thus it is important for immune defences. The ics1 mutant is used in experiments on plant-pathogen interactions, and ICS1 is required for the appropriate hypersensitive disease defence response. However, ICS1 also takes part in the synthesis of phylloquinone, which is incorporated into photosystem I and is an important component of photosynthetic electron transport in plants. Therefore, photosynthetic and molecular analysis of the ics1 mutant in comparison with wild-type and SA-degrading transgenic NahG Arabidopsis thaliana plants was performed. Photosynthetic parameters in the ics1 mutant, when compared with the wild type, were changed in a manner observed previously for state transition-impaired plants (STN7 kinase recessive mutant, stn7). In contrast to stn7, deregulation of the redox status of the plastoquinone pool (measured as 1-q p) in ics1 showed significant variation depending on the leaf age. SA-degrading transgenic NahG plants targeted to the cytoplasm or chloroplasts displayed normal (wild-type-like) state transition. However, ics1 plants treated with a phylloquinone precursor displayed symptoms of phenotypic reversion towards the wild type. ics1 also showed altered thylakoid structure with an increased number of stacked thylakoids per granum which indicates the role of ICS1 in regulation of state transition. The results presented here suggest the role of ICS1 in integration of the chloroplast ultrastructure, the redox status of the plastoquinone pool, and organization of the photosystems, which all are important for optimal immune defence and light acclimatory responses.

Evidence for light wavelength-specific photoelectrophysiological signaling and memory of excess light episodes in Arabidopsis.

Although light is essential for photosynthesis, excess light can damage the photosynthetic apparatus and deregulate other cellular processes. Thus, protective integrated regulatory responses that can dissipate excess of absorbed light energy and simultaneously optimize photosynthesis and other cellular processes under variable light conditions can prove highly adaptive. Here, we show that the local and systemic responses to an excess light episode are associated with photoelectrophysiological signaling (PEPS) as well as with changes in nonphotochemical quenching and reactive oxygen species levels. During an excess light incident, PEPS is induced by quantum redox changes in photosystem II and in its proximity and/or by changes in glutathione metabolism in chloroplasts. PEPS is transduced, at least in part, by bundle sheath cells and is light wavelength specific. PEPS systemic propagation speed and action potential are dependent on ASCORBATE PEROXIDASE2 function. Excess light episodes are physiologically memorized in leaves, and the cellular light memory effect is specific for an excess of blue (450 nm) and red (650 nm) light of similar energy. It is concluded that plants possess a complex and dynamic light training and memory system that involves quantum redox, reactive oxygen species, hormonal, and PEPS signaling and is used to optimize light acclimation and immune defenses.

[The value of self-report methods in neuropsychological diagnostics of patients after brain injury]. / Wartosc pomiaru samoopisowego w diagnostyce neuropsychologicznej pacjentów z uszkodzeniem mózgu.

Self-report methods are commonly applied in medicine and psychology. However, their diagnostic value in assessment of patients with acquired brain damage can be limited due to a number of various difficulties encountered by these patients, including cognitive disorders, fatigue, similarity of psychopathological and somatic symptoms, psychological reaction to the disease and limited or lack of insight (anosognosia). In our article we highlight the most important limitations of application of popular frequently used questionnaires in evaluation of brain-injured patients. We also discuss the possible ways of adjusting self-report techniques to requirements of diagnostic process in this clinical population. Proposed modifications refer to, among others, specific construction of diagnostic tools (appropriate content and number of questions, methods of measuring responses), collecting information from relatives, using questionnaires along with more objective measures, and controlling conditions in which the assessment is carried out. Although relying only on self-report methods can be misleading, for an aware clinician it is still an important source of data on patient's subjective opinion and on the way they experience their symptoms.

SARS-CoV-2 infection impairs NK cell functions via activation of the LLT1-CD161 axis.

Introduction: Natural killer (NK) cells plays a pivotal role in the control of viral infections, and their function depend on the balance between their activating and inhibitory receptors. The immune dysregulation observed in COVID-19 patients was previously associated with downregulation of NK cell numbers and function, yet the mechanism of inhibition of NK cell functions and the interplay between infected cells and NK cells remain largely unknown. Methods: In this study we show that SARS-CoV-2 infection of airway epithelial cells can directly influence NK cell phenotype and functions in the infection microenvironment. NK cells were co-cultured with SARS-CoV-2 infected epithelial cells, in a direct contact with A549ACE2/TMPRSS2 cell line or in a microenvironment of the infection in a 3D ex vivo human airway epithelium (HAE) model and NK cell surface expression of a set of most important receptors (CD16, NKG2D, NKp46, DNAM-1, NKG2C, CD161, NKG2A, TIM-3, TIGIT, and PD-1) was analyzed. Results: We observed a selective, in both utilized experimental models, significant downregulation the proportion of CD161 (NKR-P1A or KLRB1) expressing NK cells, and its expression level, which was followed by a significant impairment of NK cells cytotoxicity level against K562 cells. What is more, we confirmed that SARS-CoV-2 infection upregulates the expression of the ligand for CD161 receptor, lectin-like transcript 1 (LLT1, CLEC2D or OCIL), on infected epithelial cells. LLT1 protein can be also detected not only in supernatants of SARS-CoV-2 infected A549ACE2/TMPRSS2 cells and HAE basolateral medium, but also in serum of COVID-19 patients. Finally, we proved that soluble LLT1 protein treatment of NK cells significantly reduces i) the proportion of CD161+ NK cells, ii) the ability of NK cells to control SARS-CoV-2 infection in A549ACE2/TMPRSS2 cells and iii) the production of granzyme B by NK cells and their cytotoxicity capacity, yet not degranulation level. Conclusion: We propose a novel mechanism of SARS-CoV-2 inhibition of NK cell functions via activation of the LLT1-CD161 axis.

Novel application of the MSSCP method in biodiversity studies.

Analysis of 16S rRNA sequence diversity is widely performed for characterizing the biodiversity of microbial samples. The number of determined sequences has a considerable impact on complete results. Although the cost of mass sequencing is decreasing, it is often still too high for individual projects. We applied the multi-temperature single-strand conformational polymorphism (MSSCP) method to decrease the number of analysed sequences. This was a novel application of this method. As a control, the same sample was analysed using random sequencing. In this paper, we adapted the MSSCP technique for screening of unique sequences of the 16S rRNA gene library and bacterial strains isolated from biofilms growing on the walls of an ancient gold mine in Poland and determined whether the results obtained by both methods differed and whether random sequencing could be replaced by MSSCP. Although it was biased towards the detection of rare sequences in the samples, the qualitative results of MSSCP were not different than those of random sequencing. Unambiguous discrimination of unique clones and strains creates an opportunity to effectively estimate the biodiversity of natural communities, especially in populations which are numerous but species poor.

Evaluation of the prevalence of folic acid supplementation before conception and through the first 12 weeks of pregnancy in Polish women at high risk of fetal anomalies.

OBJECTIVES: Local and international organizations recommend folic acid (FA) supplementation in the periconceptional period. This study aimed to analyse the prevalence of periconceptional supplementation with FA in women at high risk of fetal anomalies refferred for first trimester screening. MATERIAL AND METHODS: Our analysis involved 1,455 women at high risk of fetal anomalies refferred for first trimester screening. FA supplementation was assessed by face-to-face interviews conducted by doctors performing first trimester screening for aneuploidy. RESULTS: FA supplementation before pregnancy was reported by 46.8% of the women and during the first trimester by 57.2% of those studied. Women used FA supplementation more frequently if they had a history of at least one miscarriage (OR 2.2, 95% CI 1.70-2.83; p < 0.001), a history of assissted reproductive techniques (OR 2.25, 95% CI 1.18-4.31; p = 0.014), or were aged between 30 and 34 (OR 2.87, 95% CI 1.47-5.58; p = 0.002). Among 122 women with a history of fetal defects only 50% confirmed FA supplementation before pregnancy and 62.2% during pregnancy (p = 0.488). A similar frequency of FA supplementation was noted among women with epilepsy, diabetes, and hypertension. Less frequent taking of FA was noted among women at least third and subsequent pregnancies (p < 0.001). In the current pregnancy, neural tube defects (NTDs) were less frequent by 86% in the group of women with FA supplementation than in the non-supplementation group (1 case vs 6 cases, respectively) and for other fetal defects by 62.5% (24 vs 40 cases, respectively). CONCLUSIONS: We found an unsatisfactory compliance with recommendations for the use of folic acid supplementation during periconceptional period among women at high risk of fetal defects and folate deficiency, that could have negative effects on the health of child and mother. The study results show the need to increase the awareness of FA supplementation during periconceptional period especially in women with high risk of fetal anomalies.

Predictors of Higher Quality of Systematic Reviews Addressing Nutrition and Cancer Prevention.

Systematic reviews/meta-analyses (SR/MAs) are considered a reliable source of information in healthcare. We aimed to explore the association of several characteristics of SR/MAs addressing nutrition in cancer prevention and their quality/risk of bias (using assessments from AMSTAR-2 and ROBIS tools). The analysis included 101 SR/MAs identified in a systematic survey. Associations of each specified characteristic (e.g., information about the protocol, publication year, reported use of GRADE, or other methods for assessing overall certainty of evidence) with the number of AMSTAR-2 not met ('No' responses) and the number of ROBIS items met ('Probably Yes' or "Yes' responses) were examined. Poisson regression was used to identify predictors of the number of 'No' answers (indicating lower quality) for all AMSTAR-2 items and the number of 'Yes' or 'Probably Yes' answers (indicating higher quality/lower concern for bias) for all ROBIS items. Logistic regression was used to identify variables associated with at least one domain assessed as 'low concern for bias' in the ROBIS tool. In multivariable analysis, SR/MAs not reporting use of any quality/risk of bias assessment instrument for primary studies were associated with a higher number of 'No' answers for all AMSTAR-2 items (incidence rate ratio (IRR) 1.26, 95% confidence interval (CI) 1.09-1.45), and a lower number of 'Yes' or 'Probably Yes' answers for all ROBIS items (IRR 0.76, 95% CI 0.66-0.87). Providing information about the protocol and search for unpublished studies was associated with a lower number of 'No' answers (IRR 0.73, 95% CI 0.56-0.97 and IRR 0.75, 95% CI 0.59-0.95, respectively) and a higher number of 'Yes' or 'Probably Yes' answers (IRR 1.43, 95% CI 1.17-1.74 and IRR 1.28, 95% CI 1.07-1.52, respectively). Not using at least one quality/risk of bias assessment tool for primary studies within an SR/MA was associated with lower odds that a study would be assessed as 'low concern for bias' in at least one ROBIS domain (odds ratio 0.061, 95% CI 0.007-0.527). Adherence to methodological standards in the development of SR/MAs was associated with a higher overall quality of SR/MAs addressing nutrition for cancer prevention.

Are systematic reviews addressing nutrition for cancer prevention trustworthy? A systematic survey of quality and risk of bias.

CONTEXT: The last 30 years have yielded a vast number of systematic reviews and/or meta-analyses addressing the link between nutrition and cancer risk. OBJECTIVE: The aim of this survey was to assess overall quality and potential for risk of bias in systematic reviews and meta-analyses (SRMAs) that examined the role of nutrition in cancer prevention. DATA SOURCES: MEDLINE, Embase, and the Cochrane Library databases were searched (last search performed November 2018). STUDY SELECTION: Studies identified as SRMAs that investigated a nutritional or dietary intervention or exposure for cancer prevention in the general population or in people at risk of cancer and in which primary studies had a comparison group were eligible for inclusion. Screening, data extraction, and quality assessment were conducted independently by 2 reviewers. DATA EXTRACTION: Altogether, 101 studies were randomly selected for analysis. The methodological quality and risk of bias were evaluated using the AMSTAR-2 and ROBIS tools, respectively. RESULTS: Most SRMAs included observational studies. Less than 10% of SRMAs reported a study protocol, and only 51% of SRMAs assessed the risk of bias in primary studies. Most studies conducted subgroup analyses, but only a few reported tests of interaction or specified subgroups of interest a priori. Overall, according to AMSTAR-2, only 1% of SRMAs were of high quality, while 97% were of critically low quality. Only 3% had a low risk of bias, according to ROBIS. CONCLUSIONS: This systematic survey revealed substantial limitations with respect to quality and risk of bias of SRMAs. SRMAs examining nutrition and cancer prevention cannot be considered trustworthy, and results should be interpreted with caution. Peer reviewers as well as users of SRMAs should be advised to use the AMSTAR-2 and/or ROBIS instruments to help to determine the overall quality and risk of bias of SRMAs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42019121116.

Cladribine tablets versus other disease-modifying oral drugs in achieving no evidence of disease activity (NEDA) in multiple sclerosis-A systematic review and network meta-analysis.

INTRODUCTION: Assuming full control of the relapsing-remitting multiple sclerosis (RRMS) is the main target for practitioners. Disease control could be defined as no clinical relapse, absence of 3-month confirmed disability progression expressed on the Expanded Disability Status Scale (EDSS), as well as no disease activity on magnetic resonance imaging (MRI). NEDA-3 (no evidence of disease activity) is a composite endpoint used primarily in clinical trials, comprising these 3 measurements of disease activity. The aim of this study is to compare cladribine tablets (CT) with oral disease-modifying drugs (DMDs) - fingolimod (FTY), dimethyl fumarate (DMF), and teriflunomide (TERI) - with regard to NEDA-3 and its clinical (relapse and disability progression) and MRI (no new T1 Gd+ lesions or no new T2 lesions or no enlargement of existing lesions) components occurrence during a 24-month follow-up. METHODS: In June 2018, a systematic review of MEDLINE, Embase and Cochrane database was performed. Due to the lack of head-to-head trials directly comparing cladribine tablets to oral drugs of interest, an indirect network meta-analysis (NMA) was applied, with placebo as a common comparator. NMA was performed with Bayesian approach and Markov chain Monte Carlo (MCMC) method for estimating posterior distributions. Additional data used in the analysis were taken from conference abstracts or post hoc analyses of pooled data from the clinical studies. RESULTS: Six randomised clinical trials (RCTs) presenting NEDA, with active treatment compared to placebo, were included in the NMA: CLARITY (CT), FREEDOMS and FREEDOMS II (FTY), CONFIRM and DEFINE (DMF) and TEMSO (TERI). The rate of NEDA-3 was significantly higher in cladribine tablets vs DMF: OR (odds ratio)=1.76 (95% CrI [credible intervals]: 1.02-3.03) and TERI: OR=2.78 (95% CrI: 1.60-4.83), but not vs FTY. For the MRI NEDA results were as follows - cladribine tablets vs DMF: OR=1.87 (95% CrI: 1.18-2.97); cladribine tablets vs TERI: OR=6.59 (95% CrI: 4.32-10.09); cladribine tablets vs FTY: OR=1.58 (95% CrI: 1.10-2.29). The comparison of clinical NEDA did not reach significance vs either DMF or TERI and evaluation vs FTY was not possible because of lack of data. CONCLUSIONS: Cladribine in the form of tablets was significantly more effective in achieving NEDA-3 than DMF and TERI, but there was no significant difference vs FTY. Cladribine tablets was more effective than all oral comparators considering the MRI NEDA. For clinical NEDA, the superiority vs DMF and vs TERI was not confirmed, and vs FTY evaluation was not possible.