The growing threat posed by antimicrobial resistance (AMR) continues to attract scientific and policy attention ,2. A numRochford and others recently called for an international inter-agency effort to strengthen global governance of AMR . They suFollowing previous observations in Ethiopia of a possible reduction in childhood mortality resulting from antibiotic interventions tackling trachoma, the New England Journal of Medicine published details of a multi-country cluster-randomised trial in Sub-Saharan Africa, providing twice-yearly mass administration of azithromycin vs placebo to children aged 1 to 59 months . A totalLancet Infectious Diseases highlighted that the mortality reduction was highest in Niger at 18.1%  while there were non-significant reductions of 5.7%  in Malawi and 3.4%  in Tanzania [An editorial in the Tanzania , the nutat risk of wasting (<-1 WHZ) this further increased to 35% [Epidemiological data has shown that malnutrition increases the risk of infectious morbidity and mortality in childhood. Our examd to 35% . Our finWe acknowledge that the relationship between infection and malnutrition is complex  offer nutritional education, to tackle low awareness or cultural barriers ; 2) provMobile phone-based  tools have potential to support the delivery of such holistic interventions as well as to collect data on nutritional and infection indicators to guide the targeting of interventions and enable smarter AMR management . While hWe strongly recommend that nutrition be considered as an essential element of strategies to provide antibiotic stewardship and security. Active and preventative, patient-centred nutritional interventions within primary health care and communities have a key role to play in addressing the global challenge of AMR, supported by further research to unpick the complex relationship between nutrition, infection and AMR.


New England Journal of Medicine [Lancet published a systematic review and meta-analysis of cardiovascular outcome trials for the three widely marketed SGLT2 inhibitors: canagliflozin, empagliflozin and dapagliflozin [Coincident with the recent reporting of the Dapagliflozin Effect on Cardiovascular Events (DECLARE) trial in the Medicine , the LanWhile able to reduce hospitalization for heart failure, kidney disease progression and cardiovascular death, sodium–glucose linked cotransporter-2 (SGLT2) inhibitors are not generally regarded as agents that reduce the atherosclerotic components of MACE: myocardial infarction and stroke. The meta-analysis of the SGLT2 inhibitor cardiovascular outcome trials suggests, however, that for this drug class myocardial infarction and stroke should be viewed separately [The observed difference in hazard ratios among myocardial infarction, stroke and amputation suggest that a primary anti-atherosclerotic effect of the SGLT2 inhibitors is unlikely since such an effect would have been expected to reduce myocardial infarction and stroke similarly, as is the case with cholesterol lowering  and anti2 needed to maintain viability. As such, its likelihood can be reduced by either augmenting O2 supply or reducing its demand. Nitrates, for instance, are thought to improve symptoms in patients with flow-limiting coronary artery disease primarily by reducing preload that, in turn, leads to a diminution in left ventricular volume, wall tension and O2 demand [Infarction occurs when the demands of the myocardium exceed the supply of O2 demand . Nicoran2 demand . Through2 demand . AccordiIn conclusion, we view the meta-analysis-based finding of a statistically significant reduction in myocardial infarction risk in diabetic individuals treated with SGLT2 inhibitors as real, and consistent with the known effects of this drug class on cardiac preload.


Rationale. In recent years, significant advances have been made on the subject of MRI examination techniques, which have opened new avenues of research regarding the spinal involvement in amyotrophic lateral sclerosis (ALS).Objective. Our objective was to compile and analyze the available literature data, concerning the MRI of the cervical spine in ALS, detailing the metrics and their significance in diagnosis and follow-up.Methods and results. We have conducted an extensive search on the subject using literature data published over the last fifteen years, correlating it with our own experience.In ALS, there is a permanent interest in developing new biomarkers that might be sensitive to spatial and temporal patterns of neurodegeneration, which will permit early diagnosis and hopefully lead to new therapeutic approaches. Both diffusion tensor imaging (DTI) and spinal cord morphometry  reflect different aspects of the disease and correlate with clinical deterioration. Newer approaches like inhomogeneous magnetization transfer (ihMTR) and multiparametric analysis seem to have better sensitivity, are more appropriate for follow-up, and lend themselves to prognostic conclusions.Discussion. We conclude that MRI is a constantly expanding field, a unique non-invasive tool with immense potential in evaluating the in vivo evolution of the neurodegenerative ALS process, both structurally and functionally, with high hopes for the future.Abbreviations: ALS - amyotrophic lateral sclerosis, UMN - upper motor neuron, LMN - lower motor neuron, EMG – electromyography, CST - cortico-spinal tract, FLAIR – fluid-attenuated inversion recovery, MND - motor neuron disease, DTI - Diffusion tensor imaging, FA - fractional anisotropy, MD - mean diffusivity, ihMTR - inhomogeneous magnetization transfer, fMRI - functional MRI Amyotrophic lateral sclerosis (ALS) is a progressive disease characterized by the combined degeneration of lower and upper motor neurons  leading inexorably to severe neurological deficits and death.1)(2). The diagnosis of ALS is especially challenging during the early stages, and the cases where a patient has to be reevaluated at 6-12 months for a clear verdict are not rare. The diagnostic delay is on average one year from the first clinical signs, which leads to the fact that most patients are included in trials after their disease has already advanced significantly (3). The current Awaji diagnostic criteria (Table 1) have a sensitivity of only 70-80% and, although they have proven superior to the revised El Escorial Criteria, there is a constant desire to improve them (4). Cervical spine MRI is currently used for satisfying criteria 1B2—i.e., to exclude “other disease processes that might explain the observed clinical and electrophysiological signs”. While this aspect will never fade, the current aspiration is to extend its use to criteria 1A2 and 1A3, in order to be able to use MRI to gather “evidence of UMN degeneration“  and “progressive spread of signs within a region or to other regions”, respectively.Despite extensive ongoing research, the diagnosis remains a clinical one, with substantial support from electrophysiological studies, mainly electromyography (EMG) (5)(6). There is hope that by studying patients in the early clinical stages, perhaps even in the preclinical phase, we could get new insights into ALS pathogenesis and, hopefully, new therapeutic approaches.There is increasing interest in developing biomarkers that might be sensitive to spatial and temporal patterns of neurodegeneration, capable to discriminate between different clinical forms and prognostic categories (7–9).While LMNs are relatively easy to assess both clinically and through EMG, UMNs are clinically limited to the modification of reflexes and a positive Babinski sign, both having low specificity and both at risk of being concealed through advanced LMN deterioration. Also, the paraclinical means of assessing UMN at the spinal level are scarce, consisting mainly of transcranial magnetic stimulation. In the last ten years, magnetic resonance imaging (MRI) has been progressing in this direction, the expectations being that it will soon become the main biomarker for corticospinal tracts degeneration. .T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequences. The changes are generally more pronounced in the case of advanced disease (11).ALS is known to be associated with signal anomalies of the CST on both brain and spinal MRI, usually in the form of hyperintensity on 12). The sensitivity and specificity of these changes are very low and have failed to become significant in the diagnosis or patient follow-up (13). The same study that found anomalies in 96% of ALS patients, found anomalies in 68% of controls (12)(14).T2/FLAIR hyperintensity of the CST is a usual finding in ALS at all levels, but especially in the posterior limb of the internal capsule, in some studies being identified in up to 96% of patients (15).ALS patients with CST hyperintensity and prominent UNM involvement are significantly younger, have faster progression rate and shorter survival period compared to those without CST hyperintensity. The reason and the underlying mechanism are unknown (The standard protocols remain useful for the exclusion of other pathologies that could mimic motor neuron disease (MND) such as external compression of the spinal cord, syringomyelia, myelitis, intramedullary tumors.Diffusion-weighted imaging (DWI) is an MRI technique which acquires information about the Brownian translation motion of water molecules in tissues. Diffusion tensor imaging (DTI) is derived from the DWI data and calculates tensors that can be used to describe fiber bundles in the white matter and produce tractography images. The diffusion tensor is characterized through measures such as fractional anisotropy (FA), which describes how strongly directional the water displacement is within the tissue and mean diffusivity (MD), which reflects the average displacement distance independent of orientation. The normal white matter will restrict diffusion parallel to the main fiber direction (leading to higher FA and lower MD), whereas white matter damage will cause diffusivity to be less restricted (with lower FA and higher MD) (10).Over the past ten years, interest in the diffusion anomalies of the spinal cord has been growing, with exciting results.10). The DTI parameters were well correlated with scores for disease severity , forced vital capacity and mean finger and foot tapping speed (16). The differences in FA between ALS patients and controls tend to be more pronounced as we examine the lower cervical segments, supporting the dying back hypothesis of neurodegeneration (5)(17).Studies have repeatedly shown altered water diffusion in the CST of ALS patients, with decreased FA and increased MD (18).Baseline measurements were not associated with their changes over time. No correlation was found between the longitudinal changes of cord average MD and FA and the concomitant change in the cord area. Cord MRI changes did not differ between rapidly and non-rapidly progressing patients (19). Also, the presence of multiple fiber populations (crossing fibers within a single voxel) confounds the results (10).Tensor metrics are sensitive to a variety of factors. A known problem is that axonal loss and swelling, demyelination, reactive gliosis and the presence of cell debris from degenerated fibers can lead to a ‘‘pseudonormalization’’ of mean diffusivity values, which would reduce fractional anisotropy (20).The spinal findings contrast with DTI studies of the CST at the cerebral level where alterations along the CST correlate with the clinical progression measured through ALSFRS-R decline, leading to the hope that DTI-based metrics can be considered as a possible noninvasive follow-up marker for for the progression of the disease (13)(18).Progressive loss of fibers in the lateral columns and motor neurons in the anterior horns has led to the idea that progressive spinal atrophy could be a feature of ALS and this was proven through MRI imaging. Agosta et al. found that cross-sectional area decreases over time on longitudinal spinal cord imaging in ALS and this fact has been replicated in multiple research papers (18)(21).Although not all studies agree, the area of the spinal cord seems to be the most sensitive MRI parameter to detect longitudinal disease progression and and correlates significantly with clinical deterioration (6). New data from 2018 suggests that early atrophy of the cervical spinal cord may predict the progression of respiratory distress and could be considered a primary endpoint in neuroprotection studies (22).In a 2017 study, spinal cord measurements were predictive of survival, with cervical spine atrophy at C3–C4 and C5–C6 levels correlating with shorter survival. The MRI parameters were more predictive from this point of view compared to the clinical variables (6).The spinal cord cross-sectional area seems to be a more reliable marker for longitudinal neurodegeneration than DTI metrics (6)(17). New techniques such as inhomogeneous magnetization transfer (ihMTR) are correlated with ECG and manage to cancel the artifacts generated by the heart movements.Imaging the spinal cord is challenging itself because of the spatial inhomogeneity of the magnetic field in this region, the small size of the spinal cord, the physiological respiratory and cardiac movements (6)(18). This becomes even more significant when applied to complex research protocols in which periods are prolonged (16). There are constant efforts in this direction to shorten the duration of the exam without compromising quality, especially by developing multi-slice and multi-angle capabilities for both DTI and ihMTR, providing multiple pure cross-sectional spine slices within a single acquisition (16).Another limitation is the supine position required during MRI. ALS patients with swallowing or respiratory difficulties are often unable to lie down motionless for a long time in the scanner. This is a known universal selection bias in ALS which constantly prevents the inclusion or follow-up of these patients (18)(23). This is usually due to disability progression, severely affected patients becoming unable to come for scheduled visits or to repeat MRI scans, or death (21).Afterwards, there are the classical difficulties in gathering large cohorts in a disease with a medium incidence of 2-3/100.000 and high study dropout rates which are usually 25-30% but can reach 75% .With Inhomogeneous magnetization transfer (ihMTR) is a new technique, with protocols still being refined. It has a high specificity for myelin due to its unique architecture, consisting of multiple sheaths of lipid bilayers (24). The ihMTR technique is magnetic field independent and has been successfully applied for 1.5T and 3T (16)(24).16).ihMTR decreases were found to be systematically more important and more statistically significant than DTI and conventional magnetization transfer metric variations suggesting a marked sensitivity of the technique to microstructural changes of the tissue. This technique will therefore be of great interest when performing longitudinal follow-up on patients with ALS to monitor spatial and temporal tissue demyelination . Iron deposits may be a promising biomarker early in the disease and although out of reach yet, they are considered worthy of future study.Functional MRI (fMRI) of the brain has been used extensively in ALS research. To date, no spinal fMRI study has been published in these patients, presumably due to the technical challenges combined with the challenges of gathering and following up an ALS cohort. However, as the technology becomes more widely available, spinal cord fMRI should show promise as a marker in ALS (13).6)(25).Just as importantly, the current dominant concept is that the best approach to spinal MRI in ALS, at least for the time being, are multiparametric studies, either linking clinical data with different MRI parameters, or various MRI markers between themselves. The results so far are encouraging, at least two studies showing the ability of multiparametric analysis of predicting survival (6).Also, there is the relatively recent idea that MRI parameters referring to white matter and grey matter degeneration should be considered together since they mirror the complexity of pathological changes happening in vivo . It is hoped that spinal cord MRI could be an effective biomarker and would be widely disposable and noninvasive (6). It is likely that the early detection of ALS patients and their inclusion in clinical trials along with multidisciplinary care would lead to better disease outcomes (4).MRI been shown to be useful in the assessment of both white and grey matter in ALS patients, showing damage to the CST, non-motor areas and the spinal cord (10). As of now, they are yet unsuitable for longitudinal follow-up and remain useful only in trials. The normal range of DTI metrics values is wide and in the current phase, we cannot assign a patient as normal or abnormal, outside of transversal or longitudinal comparison.DTI has demonstrated pervasive anomalies of FA and MD in the CST of ALS patients, which tend to correlate with disease severity and may have a particular niche in the detection of occult UMN involvement, thereby expanding the trial inclusion pool (6). It also correlates well with disease progression and could be considered a primary endpoint in therapeutic studies (22).Spinal cord atrophy , reflecting both the loss of LMNs and depopulation of the CST, seems to be a more reliable marker for longitudinal studies than DTI (Multiparametric approaches are likely to improve the sensitivity of spinal MRI methods and generate valuable predictive data, at least for the near future.With multiple research avenues appearing on the horizon, the increasing usage of improved 3T machines, functional MRI and new protocols such as ihMTR, the future does not look as bleak as it used to.The authors declare that there is no conflict of interest.


The additional precipitation is diagnosed to fall primarily as rain, but the physical and dynamical constraints governing the transition to a rain-dominated Arctic are unknown. Here we use actual precipitation, snowfall, rainfall output of 37 global climate models in standardised 21st-century simulations to demonstrate that, on average, the main contributor to additional Arctic (70–90°N) rainfall is local warming (~70%), whereas non-local (thermo)dynamical processes associated with precipitation changes contribute only 30%. Surprisingly, the effect of local warming peaks in the frigid high Arctic, where modest summer temperature changes exert a much larger effect on rainfall changes than strong wintertime warming. This counterintuitive seasonality exhibits steep geographical gradients, however, governed by non-linear changes in the temperature-dependent snowfall fraction, thereby obscuring regional-scale attribution of enhanced Arctic rainfall to climate warming. Detailed knowledge of the underlying causes behind Arctic snow/rainfall changes will contribute to more accurate assessments of the (possibly irreversible) impacts on hydrology/run-off, permafrost thawing, ecosystems, sea ice retreat, and glacier melt.The Arctic region is warming two to three times faster than the global mean, intensifying the hydrological cycle in the high north. Both enhanced regional evaporation and poleward moisture transport contribute to a 50–60% increase in Arctic precipitation over the 21 Secondly, changes in local temperature (of the lowest atmospheric layers), which govern whether or not the precipitation that starts off as snow will melt into rain on its way to the surface. Changes in precipitation and their underlying causes can be characterized as ‘remote’ because they depend primarily on non-local climate mechanisms, whereas changes in local temperature directly determine the transformation of snow to rain. Since the scale, magnitude and duration of various impacts of Arctic precipitation trends depend crucially on whether the additional precipitation will fall as snow or rain5, it is imperative to accurately determine the underlying causes behind the steep increase in projected Arctic rainfall, including its dependence on local warming.Changes in Arctic rainfall are dominated by two distinct processes. Firstly, changes in total precipitation, which in turn can be attributed to atmospheric moisture transports (mainly from lower latitudes) converging over the Arctic 6) (see Suppementary Information). In the Arctic, the largest temperature increases are projected to occur during the cold winters, and to a much lesser extent in the already fairly mild summers7. Moreover, projected increases in Arctic precipitation exhibit a strong seasonal signature, peaking in late autumn and winter4. Hence, the impact of local warming on rainfall changes will strongly and non-linearly depend on the background climate , and on the season.The relation between changes in Arctic rainfall and both temperature and precipitation is surprisingly complex, however. Obviously, higher temperatures lead to a lower snowfall fraction and thus more rain, but the rate of increase depends crucially on the ambient atmospheric temperature. In very cold conditions, temperature increases will hardly affect the snowfall fraction, which will stay close to 1. Similarly, in temperatures sufficiently far above 0 °C where snowfall fractions are close to zero, warming also will not lead to substantial increases in liquid precipitation. The largest impact on the snowfall fraction, and thus on temperature-induced rainfall changes, will occur in the temperature range close to 0 °C (ref.8), the melting of snow and sea ice through heat transfer by rainfall penetrating into the snow pack9, hydrological changes12  and the melting of permafrost13 (and consequent release of greenhouse gases14), all of which occur more efficiently during rainfall. Moreover, more rain will lead to ecological changes associated with icing , and with run-off affecting marine biochemistry16 and Arctic ecosytems18, to enhanced glacier melt19, and to economic impacts through more frequent icing conditions20 and to permafrost melting impacts on infrastructures and indigenous people21.To what extent impacts of increased Arctic rainfall can be attributed to local warming or to remote (thermo)dynamical processes is key to fully understand the causes, magnitude and irreversability of the various impacts and to develop appropriate adaptation strategies. Potential impacts include the snow-covered surface reflectivity  precipitation is projected to strongly increase over the next century . In the  absence of this process, Arctic rainfall would still increase simply because the extra precipitation would transform into rain at the same rate  as today (30%). Increases in total precipitation are to a considerable extent associated with changes in (remote) climate variables through changes in moisture transport, sea-ice related surface evaporation and cloud microphysical processes4. In any case, the sharp increase in snowfall being transformed into rain causes Arctic mean snowfall to hardly increase in the near-future and even decline after the year 2035. As a result, the combined models project that rainfall will become the dominant form of Arctic precipitation around the year 2080 (in the RCP8.5 scenario).Here we apply 37 state-of-the-art global climate models in standardised scenario simulations st-century warming under RCP8.5 forcing4). Apparently the increases in total precipitation and  absolute increases in rainfall are such that the fractional contribution of local warming induced rainfall is largely model independent and therefore a robust feature of Arctic climate change. However, considering annual and Arctic means averages out strong spatial and seasonal variations in rainfall changes and in the associated climate processes.While all 37 climate models agree that Arctic rainfall will increase over the next century, the magnitude of the simulated changes is much less robust among models Fig. . The inc4, potentially amplifying the temperature effect on rainfall changes. Interestingly, the maximum values over the central Arctic Ocean can be attributed largely to summer conditions , one in the North Atlantic and the other on the North Pole, exhibit totally opposing seasonal cycles . In too cold  or too mild (subarctic summer) conditions, temperature changes do not lead to substantial changes in the snowfall fraction  or to more generic changes in total precipitation , jet stream dynamics, surface evaporation and cloud formation processes3). Climate models are consistent in their projections of the relative contribution of local temperature on Arctic average rainfall changes, but superimposed on these are huge spatial and seasonal variations. During winter over the Arctic Ocean and the adjacent continents, changes in rainfall are effectively decoupled from local warming owing to minute changes in snowfall fraction in these very cold climates. Hence, in such deep-freeze conditions, additional rainfall can be attributed mainly to large-scale precipitation changes, and local warming rates are not a good predictor of rainfall changes.This links to the issue whether changes in Arctic rainfall – and thereby snowfall3) – uncertainty than those in local temperature23. Addressing the magnitude, extent and potential irreversability of the various impacts of projected strong increases in Arctic rainfall  will benefit from improved insights into the underlying causes, in particular the spatial/seasonal dependence of the attribution of rainfall to local warming, the associated accuracy in the projections and the effect on seasonally varying snowfall rates.The intuitive notion that strong Arctic warming always leads to considerable increases in rainfall is inaccurate, even though on average  local warming does explain the major part (~70%) of the increase in rainfall. Our findings also link to the uncertainty in future projections of Arctic rainfall and snowfall: local, seasonal and temporal variability in precipitation potentially exhibits a different – and likely larger  forcing scenario, for which the combined greenhouse, aerosol and other radiative forcings in the year 2100 totals 8.5 W m−2 (ref.7). We use all models for which the coverage of surface air temperature, precipitation and snowfall output was complete and without obvious errors (other than that no selection of models was made); one ensemble member per model (the first) was used. 21st-century trends in Arctic temperature, precipitation and its solid and liquid components are defined as differences between the means over the periods 2091–2100 and 2006–2015 (refs5), with all uncertainties throughout the paper being evaluated as the standard deviations of the model ensemble. Note that annual means of thermal contribution fractions  state-of-the-art global climate modelsons Figs  were evaSupplementary Information


BRCA1 and BRCA2 genes), such as specific screening policies and new therapeutic strategies involving PARP inhibitors or platinum-based chemotherapy.Patients who are carriers of inherited mutations in essential component of DNA repair pathways have a significantly higher lifetime risk for developing cancer compared to the population of reference. Recent advances in DNA next-generation sequencing technology have allowed screening for carriers of those mutations, allowing development of promising risk-reduction strategies and providing the rationale to personalize the therapeutic approach for these patients. New intriguing scenarios are opening nowadays for the management of prostate cancer in patients with germline or somatic mutations in components of DNA repair pathways (e.g.,  BRCA1 and BRCA2 are tumor suppressor genes with essential functions in the maintenance of genome stability  evaluated a tailored PC screening in 1522 men with BRCA1/2 germline mutation, proposing annual PSA tests and a prostate biopsy if PSA >3 ng/mL  is evaluating the role of prostate MRI in male BRCA carriers, regardless of the PSA values.p = 0.009). BRCA carriers had higher rate of lymph-nodes involvement, higher Gleason score, developed distant metastasis earlier and had a shorter survival. Overall, the independent prognostic value of this mutation at the multivariate analysis strongly suggests the need of a timely management in BRCA carriers  carrying genomic defects in DNA-repair pathways , an overwhelming genome instability condition which drives cancer cells to die  polymerase (PARP) inhibitors in BRCA-associated breast and ovarian cancers  are currently being investigated in several tumor types. In the case of BRCAness PCs, phase I clinical trials  investigated the activity of Olaparib in 50 mCRPC patients who had shown progression disease after one or two treatments, including docetaxel , fatigue and gastrointestinal side effects. The striking results in BRCA1/2 and ATM gene-mutated mCRPC patients led the US Food and Drug Administration (FDA) to approve this breakthrough therapy with Olaparib for this population, although efficacy and safety results of the phase II trial need to be confirmed in larger trials. Noteworthy, it could be reductive to restrict treatment with Olaparib to patients with BRCA or ATM mutations only since this drug showed to be effective in additional 25% of patients who are very likely carriers of unknown defects in homologous recombination.The Part B of TOPARP study (NCT01682772) (TOPARP-B) aims to validate the role of Olaparib in BRCA2 or ATM carriers and to provide additional efficacy data in presence of less common mutations in other genes involved in DNA repair such as FANC, CDK12, RAD51, PALB2, ATR, CHEK1, CHEK2, DSS1, MRE11, XRCC2/3, and ETS gene fusions (TMPRSS2-ERG) which have been previously linked to PARP inhibitors sensitivity ; medical records were reviewed for 390 mPC patients with known gDDRm status. Data suggested that mPC patients with inherited mutations in DDR genes, including those with BRCA2 mutations, can achive similar benefit from standard of care therapies in terms of both response rate and PFS compared to patients without mutations [38].Additional clinical trials are testing efficacy and safety of PARP inhibitors in combination with chemotherapy, radiotherapy or biological agents in several disease setting, including the localized disease. Phase II clinical trials are evaluating the combination of olaparib with abiraterone vs. placebo in mCRCP (NCT01972217), the combination of veliparib with abiraterone vs. abiraterone (NCT01576172) or the association of niraparib with enzalutamide (NCT02500901).Another study evaluated the combination of veliparib (ABT-888) plus temozolamide in 26 mCRPC patients pre-treated with docetaxel: the authors demonstrated a very modest efficacy of the combination therapy with 12% of the patients achieving a PSA response >30% within 3 months  to platinum chemotherapy in advanced prostate cancer (Cheng et al., Additionaly, the retrospective multicentre analysis from Pomerantz et al confirmed that mCRPC carriers of BRCA2 mutations have a higher likelihood of positive response to carboplatin-based chemotherapy than non-carriers (Pomerantz et al., It is clear that the studies evaluating the efficacy of platinum-based therapies in selected subgroup of patients with defects in DNA-repair genes are necessary, but the detection of mutations in DNA-repair genes could represent a predictive biomarker able to drive the therapeutic strategy. Despite the number of agents efficacious in mCRPC patients, today no robust available biomarkers are able to predict the response to a specific class of agents. Growing retrospective data could suggest a reduced activity of new hormone agents compared to chemotherapeutic agents in presence of the splice variant of androgen receptor AR-V7 (Antonarakis et al., Carcinogenesis is mediated by the accumulation of inherited or acquired genetic aberrations that promote the tumor growth advantage. DNA-repair defects can lead to an increase in genetic changes in cells resulting in an improved risk of developing cancer. The identification of the carriers of these genomic aberrations allows not only to identify people who have cancer susceptibility but also to define cancer subtypes with a different sensitivity to the treatments. It is likely that DNA sequencing will change the therapeutic approach to prostate cancer in the next years, improving molecular classification of this tumor and therefore the personalized therapeutic approach. Molecular characterization of prostate cancer seems to be promising to define also cancer prognosis.In order to maximize the efficacy of cancer therapies avoiding unnecessary side effects, identification and prospective validation of predictive biomarkers are strongly advocated. In this context there is the need of carefully designed clinical trials which will be able to guide the tailored therapeutic approach and thus the clinical decision making process.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Only 30% (n = 12/40) of studies that reported a significant association between food and global gastrointestinal symptoms used a validated symptom-reporting tool. Of the thirty (75%) studies that reported at least one significant association between individual gastrointestinal symptoms and dietary intake, only four (13%) used a validated symptom tool. Guidelines to ensure that validated symptom-reporting tools are matched with fit-for-purpose dietary assessment methods are needed to minimise discrepancies in the alignment of food and symptom tools, in order to progress functional gastrointestinal disorder research.Food ingestion is heavily implicated in inducing symptoms of irritable bowel syndrome (IBS) and functional dyspepsia (FD), which affect over one-third of adults in developed countries. The primary aim of this paper was to assess the alignment of dietary assessment and symptom-reporting capture periods in diet-related studies on IBS or FD in adults. Secondary aims were to compare the degree of alignment, validity of symptom-reporting tools and reported significant associations between food ingestion and symptoms. A five-database systematic literature search resulted in 40 included studies, from which data were extracted and collated. The food/diet and symptom capture periods matched exactly in 60% ( More than one-third of adults in developed countries have chronic unexplained gastrointestinal (GI) symptoms that are classified as a functional GI disorder (FGID) ,2. FGIDsTo measure changes in symptoms, FGID research relies on clinician or researcher-reported change on a symptom scale or a patient-defined judgment of improvement . OutcomeAlthough IBS and FD induce symptoms in different parts of the digestive tract, dietary intake is implicated in both the induction and management of symptoms of both FGIDs ,12. By dGastrointestinal motility, visceral sensitivity, immune regulation, inflammation, gut barrier function and microbiome can all be influenced by dietary intake . Each ofAssessing food and nutrient intakes is critical to understanding diet–disease relationships and managing diet-related components of health conditions . AccuratThe assessment methods most commonly used to prospectively examine dietary intake are 24 hour (h) recalls, weighed food records and estimated food records. Diet histories, food-frequency questionnaires (FFQ) and short assessment screeners are the main methods of examining intake retrospectively. Within each method, considerable variation exists depending on whether the validated tool has been modified for use in the population group, the frequency and duration of implementation, and the skills and experience of researchers . The cosGiven these potential inadequacies, the aim of this systematic review was to investigate dietary assessment methodology in functional gastrointestinal research by critically assessing the alignment of the dietary assessment capture period and FGID symptom-reporting period in studies that examined relationships and reported on significant associations between dietary intake and FD or IBS symptoms. A systematic literature search was conducted in five databases  for studies that examined associations between FGID symptoms and food or food components in adults (18 years and older). The search terms related to the following three domains (i) symptoms of functional dyspepsia OR irritable bowel syndrome OR presumed gastroduodenal symptoms  and (ii) a dietary factor, nutrient, food or food component and (iii) a dietary assessment method. The search strategy is described in detail in The primary outcome was the alignment of the symptom-reporting timeframe and the dietary intake capture period of the dietary assessment tool. The secondary outcome was the proportions of studies with full, partial or no overlap between dietary intake and symptom assessment that reported significant associations between food ingestion and FGID symptoms. The participants, interventions, comparisons, outcomes and study design (PICOS) used to systematically review relationship between food ingestion and symptom reporting in functional gastrointestinal disorders is shown in Studies were included if (i) participants were adults (18 years or older) who were reported as being diagnosed with IBS or FD using Rome criteria (I or II or III or IV) and had a negative upper endoscopy or colonoscopy and (ii) the paper reported on at least one FGID  symptom and (iii) the paper reported on a dietary factor, either nutrient, food or food component and the method of assessing the dietary factor and (iv) the paper reported on the relationship between at least one dietary intake factor and at least one FGID symptom. The review considered experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, pre–post studies, prospective and retrospective cohort studies, case control studies and analytical cross-sectional studies.Studies were excluded if participants were children or adolescents under 18 years old, if the ROME criteria was not reported as being used for diagnosis of the FGID, if they did not exclude participants who had a positive upper endoscopy for FD  or colonoscopy for IBS (to rule out the presence of inflammatory bowel disease or cancer) or did not have a separate study arm for participants with only FGID diagnosis. Studies were excluded if they reported on eating but did not report on a dietary factor and the relationship between the dietary factor/s and FGID symptoms. Study types that were excluded were letters to editor, conference abstracts, reviews, case reports, and research theses.www.covidence.org). Two reviewers independently assessed relevance for inclusion by screening titles and abstracts against inclusion criteria (GD and MP). Conflicts were resolved by a third reviewer and full texts of included abstracts were retrieved (KD). The full texts of retrieved studies were subsequently assessed by two independent reviewers (KD and GD) to determine whether they met inclusion criteria. Conflicts were resolved by a third reviewer (TB).Data extraction and reporting of results was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist  Supplem. All stuData were extracted from included studies using a purpose-built excel spreadsheet tool developed by the authors, with the following variables extracted: study location (Country); study design; year and duration of study; participant characteristics ; dietary assessment method/s; dietary outcomes; food intake/consumption or administration method or variable; FGID diagnosis; FGID symptoms, FGID symptom-reporting tool or method. The tool was piloted on the first five studies, with minor amendments made before finalising extraction of data from all included studies.The dietary instrument/s reported were extracted into the spreadsheet, along with the individual FGID symptoms reported (either by participants or as study outcome measures) and whether the instrument was reported as being validated (V) or modified from a validated instrument (m-V). The timeframe or sequence of symptom/s reporting and collection was also extracted, and whether the tool was a self-report tool or researcher-administered tool. Dietary assessment methods were categorised using the features shown in A method was considered to be validated if the paper stated that a validated dietary assessment method had been use in it’s original format with a comparable study population. If validation was not mentioned, this was recorded as not reported (NR). The timeframe/sequence of dietary data collection was also extracted.The reported relationship between dietary intake and FGID symptoms was categorised by the effect type, based on the analysis and study type. Categories were: “group by time” effect for significant differences in symptom responses to food between the control and intervention group (or between intervention arms) over the intervention period; “group” effect for significant difference in symptom responses to food between groups cross-sectionally or for retrospectively collected data; “time” effect for a significant difference in a cohort over the intervention period; “not significant if the study reported no significant group or time effect”; “not measured”; and “not applicable”.Two researchers (GD and KD) extracted data independently and compared extracted data, with inconsistencies rechecked to achieve consensus or referred to a third reviewer for adjudication (TB).Study quality appraisal was conducted to ensure that findings from respective studies could be contextualized. Articles meeting inclusion criteria were assessed for study quality, using the Academy of Nutrition and Dietetics Quality Criteria Checklist for Primary Research standardized tool . This 10Descriptive statistics were used to analyse the study characteristics and results of included studies. For the study characteristics, mean and range calculations were applied to discrete data. Counts, sums and proportions were applied to summarise and analyse categorical data, and to generate frequency tables. Tables, graphs and numerical summary tools were used to characterise the data and to identify and display patterns when comparing dietary intake capture data and symptom-reporting data. The protocol for this review was registered with the International Prospective Register of Systematic Reviews , with registration number CRD42018105776XXX.Search strategy implementation  identifiThe results of this review have been divided into sections. Firstly, the study characteristics, dietary assessment methods, symptom-reporting data and study quality of the 40 included studies are described in A total of 10,997  participants were involved in the studies, including control group participants. As shown in Critical appraisal resulted in twenty-two included studies being rated as positive study quality ,56,59,60Of the 40 included studies, 29 studies assessed diet and symptoms in IBS patients ,56,59,60n = 22), bloating (n = 18) and gas or wind (n = 18). Symptoms reported or collected only in IBS studies were overall GI symptoms (n = 11) and bowel specific symptoms including urgency, constipation, diarrhoea and borborygmi  were used in all studies to determine the patient’s diagnosis, as indicated in the study inclusion criteria and displayed in rborygmi .n = 8), nausea (n = 6) and bloating (n = 5). The symptoms that were reported only in FD studies were postprandial fullness/distress (n = 8), epigastric pain (n = 4) and hunger (n = 1)  .n = 10 studies), validated for a capture period of the previous 10 days; the Gastrointestinal Symptom Rating Scale (GSRS) (n = 3), validated for capture over the previous seven days; the Birmingham IBS Symptom Score (n = 2 studies), validated over a capture period of the previous four weeks; and the “adequate relief” question, validated for use over the previous week (n = 4). The only individual symptom assessment instrument reported as being validated was the validated Bristol Stool Form (BSF), which was used in three studies. Non-validated visual assessment scales were used in 11 studies, and other non-validated symptom rating scales were used in eight studies.The most commonly used instruments for the assessment of global symptomology were the IBS-SSS  [Visual analogue scales (VASs) for individual symptoms were the single symptom assessment method used in five studies ,49,50,511 study) . Other i1 study) ,46,52, a1 study) ,29,33,54The reporting period was highly variable between studies: with daily reporting ranging from three days  and 42 dn = 13 studies [n = 2) over a period of seven days [n = 12) [Prospective dietary assessment methods included food diaries of between two and 42 days duration  ,54,56,58[n = 12) ,32,44,56[n = 12) ,57,59,60The dietary assessment and symptom-reporting capture periods matched exactly in 15 out of 27 prospective studies . Of the Twenty five out of the 33 studies (76%) that reported on dietary intake and global gastrointestinal symptoms reported at least one significant association. Of these, 12 (36%) used a validated symptom-reporting tool, 11 (33%) used non-validated tools and three (9%) were not capture period aligned . Of the In comparing the alignment of dietary assessment and symptom-reporting capture periods, this systematic review is a novel addition to the FGID literature. Over 80% of included studies assessed dietary factors that would be expected to induce symptoms within a timeframe from minutes to hours after consumption, but the majority of these involved dietary assessment methods suited to a longer capture period. Additionally, validated tools were routinely used to measure global IBS and FD but not available for individual FGID symptom assessment. In combination, these results highlight the need for validated symptom-reporting tools that are matched with fit-for-purpose dietary assessment methods.Although diet is now routinely implicated in symptom induction for both IBS and FD ,12, onlyThe use of Rome criteria for the diagnosis of the FGID was an inclusion criterion, and all 40 studies employed the most current version at the time of study implementation. The recent release of the Rome IV criteria is the likely reason that no studies reported using these diagnostic criteria . There wValidated instruments were used to assess global IBS and FD symptomology over capture periods ranging from one to four weeks in less than half of the included studies, and the only individual symptom-reporting tool reported as being validated was the Bristol Stool Form, used in 8% of studies. To date, individual symptom-rating scales are not validated in the same manner as the overall symptom-reporting instruments . HoweverAs expected, food diaries and weighed food records were more common in studies that investigated symptom induction or change in symptoms prospectively over time in relation to a dietary intervention. Food frequency questionnaires were generally used in studies that retrospectively investigated presence of symptoms over previous weeks or months. Food frequency questionnaires are considered suitable for assessing changes in dietary intake over time, and for ranking consumption between individuals, but lack the sensitivity to be used in studies focused on symptom induction . The incThe small proportion (17%) of studies that assessed habitual diet were suited to the use of the FFQ dietary assessment method. As food chemical intolerance symptom induction can take several weeks to become evident, FFQs may also be useful in studies investigating this dietary factor. The remaining studies assessed dietary factors that would be expected to induce symptoms within a much shorter timeframe (minutes to hours) after consumption. For example, FODMAPs  and fibrAn important additional consideration in reviewing dietary assessment tools used in functional gastrointestinal disorder research is the limitations of the food composition database linked to the dietary assessment tool. A common limitation of these country-specific food composition databases is the absence or lack of specific information on fibre  and fermentable carbohydrates  . Gaps inAlthough the capture periods for food and symptom reporting matched or overlapped in 90% (n = 36) of studies, only 30% of studies that reported on global gastrointestinal symptoms and 13% that reported on individual gastrointestinal symptoms that identified an association with food ingestion used a validated symptom tool. Therefore, guidelines to ensure validated symptom-reporting tools are matched with fit-for-purpose dietary assessment methods are needed to minimise discrepancies in the alignment of food and symptom tools in order to progress functional gastrointestinal disorder research. (i)An explicit explanation of hypothesised relationship between food and FGID symptoms;(ii)A clear differentiation between assessment of global symptomology and presence or induction of individual symptom;(iii)The selection of symptom-reporting tools be based on whether the study is investigating symptom induction versus presence (or retrospective assessment) of symptoms;(iv)The use of symptom-reporting tools that have been validated for use over the timeframe they were implemented (wherever possible);(v)The selection of appropriate dietary assessment methodologies and the implementation of these methods by researchers with dietary assessment expertise;(vi)The explicit explanation of the rationale for selected dietary assessment methodology, including the hypothesised association with symptom induction and the food composition database (and included nutrients) used for nutrient analysis;(vii)For dietary protocol implementation studies, more detailed reporting of dietary intake assessment than reporting of adherence alone;(viii)Protocols for the assessment of symptom induction in free-living settings, including dietary assessment methods that have a low participant and research burden but high specificity and sensitivity;(ix)The reporting of both significant and non-significant findings to reduce reporting bias.Recommendations that would be addressed include:This review summarises the body of research from studies aimed at assessing food and symptom relationships in IBS or FD. The findings indicate that the dietary assessment tools and symptom-reporting instruments used in these studies are often mismatched. The recommendations produced from this review are aimed at ensuring validated symptom-reporting tools are matched with fit-for-purpose dietary assessment methods to minimise discrepancies in the alignment of food and symptom tools. The implementation of these recommendations in future research will improve the determination of relationships between food ingestion and the presence or induction of FGID symptoms.This study is the first to report on the alignment of symptom reporting and dietary intake assessment methods in FGID research, addressed through studies that focused on the two most common FGIDs, IBS and FD. The findings will facilitate a more structured integration of dietary assessment into FGID research. Limitations associated with the review process are related to an inadequate description of methods in included studies and the need to subsequently extract and categorise this incomplete data. Examples of such limitations include the inadequate description of dietary assessment methods in dietary protocol studies and the reporting of only significant results rather than both significant and non-significant results, particularly in intervention studies with a control group. Recommendations to improve or reduce the impact of these limitations have been outlined in this review. It is also acknowledged that the wide range and large number of dietary factors and symptoms reported within studies increased the likelihood of at least one significant association being identified. Another consideration in FGID research is that study participants are likely to have made dietary changes prior to study participation, which may affect the assessment of usual dietary intake. For example, the reported intake in an FFQ (over previous three months) may not be sensitive to foods that have been reduced or eliminated by those with FGIDs prior to that dietary assessment capture period. It is important to take these factors into consideration when assessing study findings, along with the reported misalignment of dietary assessment and symptom-reporting instruments.


To test the effectiveness of a comprehensive team-based intervention to improve human papillomavirus (HPV) vaccination completion rates and reduce missed opportunities to vaccinate in rural Oregon.Stepped-wedge cluster randomized trial.Forty family physicians and pediatricians who are members of the Oregon Rural Practice-based Research Network.Tailored to individual practice needs, components will include (1) practice facilitation with clinicians, nurses, front office staff, and others who have patient contact to redesign patient care and communication strategies to optimize HPV vaccine series completion; (2) workflow mapping adapted to practice context to support HPV vaccine delivery; (3) a practice improvement model designed to firmly establish reminder and recall systems and then standing orders; (4) education for patients and parents that underscores HPV vaccination is safe, effective, and an important approach for reducing cancer risk; and (5) partnering with community organizations to plan and implement a social marketing campaign on HPV vaccination.Initiation and completion of the HPV vaccine series as well as reduction in rates of missed opportunities to vaccinate derived from Oregon Immunization Program data.NCT03604393: .Trial was registered on July 11, 2018. The first participant was enrolled on September 11, 2018.ClinicalTrials.govPRS,  Given the low rates and wide range of HPV vaccine initiation and completion in rural settings, a critical need exists to support primary care practices and their communities toward improving HPV vaccination rates and identify successful strategies for future intervention.The human papillomavirus (HPV) types in the current 9 valent vaccine account for about 73% to 88% of cancers of the cervix, vagina, and anus and for approximately 55–65% of cancers of the vulva, penis, and oropharynx , 2. AbouIn 2006, the US Food and Drug Administration approved a vaccine to protect against HPV-16 and HPV-18 , which aUnfortunately, the US National Immunization Survey (NIS) indicates many fail to complete the vaccine series . Among fMany barriers have contributed to low HPV vaccination rates, including factors at the system  and individual levels . One systematic review of 76 published studies  identifiMore rigorous research is needed to understand how to optimize HPV vaccination rates, especially in rural underserved communities. Toward this end, we developed a research proposal funded by the American Cancer Society (RSG-18-022-01-CPPB) to test, using a stepped-wedge cluster randomized design, a multi-component intervention to improve HPV vaccine completion rates and reduce missed opportunities to vaccinate. Table Oregon Rural Practice-based Research Network (ORPRN) is based at Oregon Health & Science University (OHSU) with a mission of improving the health of rural Oregonians by promoting knowledge transfer between communities and clinicians . ORPRN h> 40,000 people) that see adequate numbers of patients aged 11–17 years. Based on our sample size estimate, we will need 40 practices for the study. We will overenroll to 45 to account for an attrition rate of 11%. We received over 60 letters of support from rural practices that expressed interest in participating. Practice enrollment is currently underway. Community organizations established for at least 1 year and co-located in communities of participating primary care practices will also be eligible to take part. These will include Accountable Care Organizations (ACOs), which are healthcare organizations tasked with providing high-quality, low-cost care to their Medicaid and Medicare beneficiaries. In Oregon, the ACOs for the Medicaid population are 16 Coordinated Care Organizations (CCOs) [In this study, we will enroll eligible ORPRN primary care clinics located in rural communities  .The study has four specific aims described below. Figure To address aim 1, we will use data on vaccine initiation and completion rates from OIP’s immunization registry, ALERT Immunization Information System (IIS), to identify 12–15 practices with both high and low HPV vaccine initiation and completion rates in rural Oregon family medicine and pediatric practices. After practices are enrolled, we will conduct direct observations using expert qualitative investigators (authors MD and RG) to assess practice systems and workflows associated with high and low vaccination rates. An iterative sampling framework will inform practice recruitment—we anticipate enrolling, using a 2:1 ratio, higher performing clinics relative to lower performing clinics. Additional study measures for aim 1  Community Advisory Council (CAC), patient and family advisory groups, or local public health programs. Together, the practice and community group will plan and implement an evidence-based community-level intervention , 27 desiStudy measures for aim 3 will include pre- and post-community partner group interviews on the acceptability of HPV vaccination and patient/parent surveys to assess child and parents’ knowledge about cancer risk reduction and the HPV vaccine series, where and how information about HPV and cancer risk reduction via vaccination was sought, as well as demographic information.To address aim 4, we will create a practice and community HPV vaccine improvement toolkit for use by practices and community partners. The toolkit will be disseminated throughout Oregon by ORPRN, OIP, and the American Cancer Society through publication and as an online resource. Determining the toolkit’s direct impact on HPV vaccination completion rates is beyond the scope of this study. However, OIP will track the number of electronic downloads of the toolkit and be able to link this to rates of HPV vaccine completion as an indirect assessment of improvements in vaccine completion rates due to the toolkit. Our national dissemination plan will include five key activities: (1) presenting the final toolkit and project at the National Immunization Conference, which brings together a variety of partners to explore science, policy, education, and planning issues related to immunization; (2) distributing the toolkit on the National VFC/AFIX Group listserv through OIP’s partnership. Subscribers to this listserv represent more than 260 state and local immunization program and immunization registry staff from the USA; (3) distributing the toolkit on the Oregon Immunization Partners listserv, which currently has 2900 public and private providers; (4) distributing the toolkit on the Oregon Public Clinic listserv, which includes more than 1100 public providers from health departments, federally qualified health centers, school-based health centers, and tribal practices; and (5) Putting the toolkit on the OIP website hosted by the state health department. The OIP website is a critical resource utilized by over 2000 providers, ACOs, Health Systems, payers, and members of the public.With OIP, we identified specific HPV series initiation and completion rates from 2017 at the level of the county as well as the practices, and we have obtained county and practice-weighted population estimates for 13–17 year-olds , MenACWY , and HPV. As shown in Fig. Rural areas experience unique challenges regarding HPV vaccination and this phenomena is understudied in the current literature. Access to primary care can be challenging in rural areas and preventive care in these regions is often underutilized , 31. LowOur proposed study is innovative in at least nine important ways: 1) It is based in one of only two practice-based research network in the USA with a priority focus on rural primary care research; (2) it will involve tailored interventions for both pediatric and family medicine practices, allowing for specialty comparisons of staffing, workflow, and community linkages to deliver HPV vaccine; (3) ORPRN and OIP will collaborate to provide a descriptive baseline assessment of Oregon immunization rates and missed opportunities within rural practices, fostering a robust understanding of the gaps in meeting population health goals at practice and community levels (aim 1); (4) the practice-based intervention (aim 2) is designed to reduce burdens that busy primary care providers face using a team-based care approach with engaged, activated parents and adolescents; (5) the practice-based intervention (aim 2) is flexible enough to allow practices to tailor efforts that work best for them and they will not be burdened by data collection as the ALERT IIS system will provide vaccination data on all enrolled practices at 3-month intervals; (6) our interventions are designed to change primary care practice structure, communication strategies, and behavior through team-based care quality improvement (QI) efforts  the use of the ALERT IIS as a data source for intervention studies, (2) comparing Medicaid and ALERT IIS data sources, (3) rates of HPV vaccinations of males and females in rural pediatric and family medicine practices, (4) urban/rural differences based on the practice location to see if these differences exist within practices, (5) urban/rural differences at the population and practice levels, (6) facilitators and barriers for both initiation and completion of HPV vaccines in rural pediatric and family medicine practices, (7) rates of missed opportunities to vaccinate for HPV according to youth gender, (8) effectiveness of a multi-component primary care-based intervention on completion of the HPV vaccine series and reduce missed opportunities to vaccinate, (9) characteristics of practices with high uptake and low uptake of the primary care-based quality improvement intervention, (10) contribution of evidence-based social marketing campaigns as a supplement to practice-based interventions to improve HPV vaccination, and (11) components and dissemination of a toolkit designed to help primary care practices improve HPV vaccination. In conclusion, there is a critical need to conduct this study, which started in July of 2018. We look forward to undertaking this important work and what we will learn from it.