Oral and pharynx cancer represent a serious global problem, reaching an incidence of half a million cases annually. The role of tobacco and alcohol have been studied and proven to be one of its risk factors. We also know that mouthwashes contain a variable percentage of alcohol, so there is a reasonable concern about their role in carcinogenesis. To answer the PICOS  question: "Do patients (Population) who use alcohol-based mouthwashes (Intervention) compared to those who do not use them (Comparison) have higher acetaldehyde levels in saliva or higher risk of oral cancer development? (Outcomes)" Meta-analyses, systematic reviews, randomized and non-randomized clinical trials, case-control studies, and prospective and retrospective cohort studies were included (Study). Two independent authors conducted literature screening through MEDLINE, Scopus and the Cochrane Library, and they also conducted article and data extraction to undertake quality analyses. The main outcome measures were salivary acetaldehyde levels or the risk of oral cancer development. The most relevant data was extracted and the risk of bias from the studies included was also evaluated. Out of 497 potentially eligible papers, 8 studies were included in the qualitative analysis which include a total of 43,499 subjects: two meta-analyses, a clinical trial, three case-control studies and two cohort studies. One study  found a relationship between alcohol mouthwash and oral cancer, two studies  found this relationship when a high frequency of mouthwash was present, three studies  failed to find this relationship and 2 studies (n = 58) found a temporary increase of acetaldehyde levels in saliva after alcohol mouthwash. It cannot be guaranteed that the use of mouthwash represents an independent risk factor for the development of head and neck cancer. However, the risk does increase when it occurs in association with other carcinogenic risk factors. Key words:Oral Cancer, Oropharyngeal Neoplasms, Mouthwashes, Mouth rinse, Ethanol, Acetaldehyde, alcohol. There is an estimated incidence of oral and pharynx cancer of half a million per year resulting in 250.000 deaths annually in United States.Most of them are squamous cell carcinoma of the oral cavity (SCC). The main risk factors for head and neck cancer are tobacco and alcohol; the risk increases when both factors are present. Approximately 70% of cancers in this region could be explained by exposure to one or both factors . Currently, poor oral hygiene and chronic infection from Human Papillomavirus (HPV) could be added to the main risk factors of oropharyngeal cancer, highlighted in young patients ,4.This risk from alcohol consumption increases ten times in heavy drinkers compared to abstainers or irregular drinkers . The totAlthough there is a short period of exposure time to alcohol, this seems to increase the permeability of the oral mucosa to potential carcinogens, as well as, specific Nitrosamines of tobacco .Many mouth rinses contain alcoholic concentrations between 5 - 27%. This is usually used as a solubilizer, stabilizer, preservative, anti-plaque efficacy enhancer and as a way to obtain a distinctive flavor. On the other hand, in a similar way to the alcoholic solutions ingested, mouthwashes with alcoholic concentrations between 18 - 27% also potentiate the effect of the essential oils to achieve a high penetration in soft tissues (in 30 seconds)  ,7. This The mechanism for the acetaldehyde production of ethanol can come from the metabolism of ethanol itself through oral microflora or conversion by the epithelial cells. It has been shown that poor oral hygiene increases the production of acetaldehyde, in addition to other factors (smoking and heavy drinking), producing a carcinogenic potential in the oral cavity and upper airways ,7.During the last thirty years, there has been an attempt to find a possible association between the use of mouthwash with alcohol and its relationship with oral cancer. However, epidemiologically, there has been no conclusive evidence. Few epidemiological studies are found in the literature and they have contradictory results .Many of the commercially available mouth rinses contain considerable amounts of ethanol. Most of the adult population use this type of mouth rinse, so it could be transcendent in public health to certify its possible carcinogenic potential.et al.  . A meta-- Selection criteriaInclusion criteria were based on the following PICOS question: patients with no age, gender or medical condition restrictions (Patient); alcohol-based mouthwashes use (Intervention); no mouthwashes use (Comparison); oral cancer or the acetaldehyde levels in saliva (Outcome). Meta-analyses, systematic reviews, randomized and non-randomized clinical trials, case-control studies and prospective and retrospective cohort studies were included. Just articles published in the last 10 years were included and no language restrictions were applied.Animal studies, case series, case reports and technical notes were excluded. Studies of digestive tract cancer not including the oral area or based on alcohol sugars were also excluded.The main outcome variable was the level of acetaldehyde in saliva. The secondary outcome variable was the risk of oral cancer development.- Search strategiesAn electronic search in Pubmed (MEDLINE), Scopus and the Cochrane Library  databases was conducted until April 13th, 2018. Even though the search was initially limited to the last 10 years, the first studies began in 2006, so in the end, articles published between 2006 and April 13th, 2018 were included.The search strategy was:  OR ) OR ) OR ) OR ) OR )) OR .- Study selection and data selection processAfter eliminating duplicate studies, two independent examiners  selected the studies by first screening the titles and abstracts of the articles to determine their eligibility. The full text of the selected articles were then evaluated according to selection criteria. Any discrepancies were resolved by a third reviewer (CGE). The excluded articles and the reasons for their exclusion were recorded in this final stage Fig. . Two Coh- Data extractionThe data was extracted from the articles selected by one of the authors (MUB). After analyzing all the selected articles, the following data were identified: 1) the author or authors, 2) year of publication, 3) country of origin, 4) design of the study, 6) details of the participants, 7) intervention, 8) comparison, 9) outcomes and 10) follow-up. If the included studies had a homogeneous methodology, a meta-analysis of the data would be possible.- Risk of bias in individual studiesAs part of the data extraction process, two reviewers  independently assessed the risk of bias in the included studies.For cohorts and case-control studies, the risk of bias was assessed according to the Newcastle-Ottawa Scale (NOS)  Table 1Table 1. For clinical trial or meta-analysis studies, the quality evaluation system was SIGN , a categ- Study selection and descriptionThe flow chart for the selected articles used in this systematic review can be seen in Fig. 18 articles were excluded according to the selection criteria. The exclusion reasons were: literary reviews -18, lettFinally, 8 studies were included in the qualitative analysis  5,28-34-3428-34.- Risk of bias assessmentAs shown in Both clinical trial  and one - Data extraction: qualitative synthesisAmong all the studies, a total of 43,499 subjects were included. In one of the meta-analysis   the numb) of the other included articles in the present study, 21,754 were male and 7,469 were female. The age ranged between 22 and 75 years old. The descriptive variables of the included studies can be found in et al.  also had an increased risk of upper airway cancer , as well as those using it more than once per day .et al. (p<0.0001) and although it is a positive OR, there was no significant difference if the use of mouthwash was once a day  or less than 1 use/day . All this data was obtained in centers located in Latin America . However, in both cases no differences were found between the group that brushes their teeth ≥2 times/day and the group that never brushes it . These results were obtained when patients were analyzed without considering possible confounding factors such as smoking and alcohol. The tobacco and alcohol habit modified the risk of cancer according to the use of mouthwash ; no significant differences were found between subjects with oral cancer and poor oral health (p<0.01), but no differences were found between occasional tooth washing and 1-2 washes/day (p=0.274).Kocaelli et al.  studied l health . The aceshes/day . Finallyet al. , 1.42 (95%CI = 0.91 – 2.24) and 1.7 (95%CI = 0.86 – 3.35), respectively, with I2 = 76% and Chy-square - Analysis according to smoking or alcohol habitsp=0.06) with no statistically significant differences. On the other hand, in ex-smoker patients an OR: 4.98  and in smokers an OR: 9.15 , both with statistically significant differences. The differences were not significant when the use of mouthwash was 1 time/day ; OR: 1.94 ; OR: 1.53  respectively), obtaining a positive dose-dependent trend  and OR: 1.25  respectively). Smokers with poor oral hygiene obtained an increased risk for oral, pharynx and larynx cancer compared to those smokers with good oral hygiene, with an OR: 3.60   .p=0.23) and OR: 1.20  respectively; however they were observed in smokers   .et al. . However, no significant differences were found between heavy smokers and moderate smokers . Oral hygiene was not assessed in the European case due to a limited sample. In the American sample, there were no significant differences in drinkers who presented good or bad oral hygiene , but they were significant in drinkers, with a higher risk for subjects with poor oral hygiene than those with good oral hygiene . In this case, there were no significant differences between the number of tooth washes per day and the consumption of alcohol in terms of the risk of oral, pharynx or larynx cancer . On the contrary, there seemed to be a non-statistically significant predilection in those subjects who used 1 or 2 mouthwashes, with a dose-dependent relationship. Gandini et al. , it is necessary to assess whether a high frequency of rinses may increase the risk of oral cancer. Several classic studies indicate that the use of this mouthwash significantly increases the risk of oral cancer . Guha etet al.  and Ahre (et al.  obtainedi et al. . Ahrens  (et al.  and Boff (et al.  observed (et al.  argued t (et al. ,29,33.In patients without other risk factors, the carcinogenic effect seems to be low and still arguable -32. On tTherefore, it seems that the evidence is limited to the carcinogenic effect of the mouthwash use in patients without other risk factors for oral, oropharynx or head and neck cancer. There might be a trend which indicates the presence of this effect but its existence is still not clear in a meaningful way, and if such an effect existed it would be low.However, although there were limited results in the included studies due to the heterogeneity between them and the subjects ,34, it iIn conclusion, alcohol-based mouthwash consumption significantly increases salivary acetaldehyde levels in the first few minutes. However, no evidence exists if long-term salivary acetaldehyde levels may increase with a high frequency of mouthwash use. There is still insufficient evidence of whether the use of alcohol-based mouthwash is an independent risk factor for oral or oropharynx cancer. Nonetheless, it does increase the risk when it occurs concomitantly with other risk factors such as smoking or alcohol.


In Europe the elderly population is projected to increase from 18.5% (93.9 million) in 2014 to 28.7% (149.1 million) by 2080. In the United States it is estimated that by 2030 more than 20% of the population will be aged 65 years or over. This specific population is at high risk of unrecognized or untreated psychiatric illnesses and suicide. It is well known that completed suicide rate increases with age in both men and women. Although elderly people attempt suicide less often than other age groups, they show a higher completion rate. Generally, the methods chosen by elderly are more lethal, the intent is more serious, they are more determined, and they show fewer warning signs than the younger population. A recent systematic review and meta-analysis of psychosocial intervention, following self-harm in adults, found that cognitive behavioral therapy was the most effective therapy in these patients. Unfortunately, there have been few reported trials of other potentially effective interventions. Because the scientific literature on psychosocial suicide prevention interventions in the elderly is still scant, we conducted a mini-review in order to take stock of the situation. Studies were identified through electronic searches of the Cochrane library, MEDLINE, Scopus and the Web of Science databases. PRISMA guidelines were followed and only seven articles met the inclusion criteria. No firm conclusions can be drawn about this topic because there is still very little data and studies use inconsistent outcome measures and designs. Nonetheless, the existing data suggests that psychosocial interventions are promising. According to the World Health Organisation’s (WHO) estimates, 800,000 people die from suicide every year . AlthougIn Europe the elderly population is projected to increase from 18.5% (93.9 million) in 2014 to 28.7% (149.1 million) of the population by 2080 [It is widely acknowledged that compared to other age groups, attempted suicide is less common in the elderly, whereas completed suicide is more common, probably due to the choice of more lethal means . Moreovead hoc structured interventions aimed at reducing their suicide risk. Age-sensitive interventions (including psychiatric treatment if necessary), focused on physical health perception and facilitating adjustment to change, may be helpful in reducing elderly suicide risk  with a focus on preventing suicidal thoughts and behaviors in elderly populations.• Design: randomized controlled trial (RCTs), quasi-experimental , observational, case-report.Exclusion criteria were:• Reviews and meta-analyses.• Papers not written in English.Four electronic databases  were searched from their inception up to 31st January 2018, with the search strings reported in Appendix Two reviewers (EG and MM) independently selected titles, abstracts and full-text publications using the inclusion and exclusion criteria specified above. Disagreements were resolved through discussion with a third reviewer (CG).We extracted the following information from all publications: country, design, characteristics of study participants, characteristics of the psychosocial interventions described, and a summary of the main study findings which focused on suicide. Ethical statements were not provided in the studies included.The search retrieved 144 articles; 127 articles remained after duplicates were removed. Twelve articles were excluded because they were not written in English, 23 were excluded based on the title (not relevant to the topic) and six were excluded due to the type of publication . A further 68 articles were excluded based on the abstract (not relevant) and one full text article was not available. Most of the articles which were excluded were not focused on the selected study population (elderly population), on the selected intervention  or on the intervention target (suicide prevention). Three eligible articles were identified through the database search and four from other sources, thus seven articles were included in this mini-review. The PRISMA flowchart is shown in Figure One of the selected articles  describep < 0.001). Moreover, a faster reduction in suicidal ideation rate was observed in the PROSPECT group (p = 0.01).In a later article, M = 76.9 years, SD = 9.0) and the control group of 70 individuals . The program consisted of scheduled calls that included well-being checks and emotional support, and weekly home counseling visits. Participants also had access to a 24 h telephone hotline. Suicide risk was evaluated by asking participants about their current and prior suicidal behavior , 42% of the intervention group had a lifetime history of suicidal thoughts and 14% had attempted suicide previously; in the control group the corresponding percentages were 30 and 7%. Participants who reported a history of suicidal thoughts were more likely to have a high level of depressive symptoms  and a high level of hopelessness . The 218 participants were contacted for another interview after 1 year. The results showed that after the intervention, the intervention group showed a reduction in hopelessness levels, which may indicate a reduction in suicide risk given that numerous studies have shown a link between hopelessness and suicidality.Another article  evaluateM age = 70.1 years, SD = 5.4) who were assessed for multiple late-life suicide risk factors using specific tests. Suicidal ideation was evaluated with the Geriatric Scale for Suicide Ideation (GSIS). Participants were offered a course of 16 weekly 50 to 60-min sessions of outpatient interpersonal psychotherapy, tailored to older adults at risk for suicide. Participants were helped to identify the factors that were contributing to their psychological pain and to alleviate feelings of desperation, which are common amongst depressed older patients, and opportunities to enhance social connections were identified. In the later phase of treatment, patients were encouraged to continue to develop interpersonal relationships and meaningful post-therapy pursuits. Participants, when they wished, were allowed to continue with therapy after the 16 scheduled sessions. A safety protocol was implemented to try to prevent potentially dangerous situations; this provided suggestions for family members or caregivers of the participants and 24/7 mobile phone access to the study therapist in case of emergency. The intervention produced reductions in suicide ideation (p = 0.003) and severity of depression symptoms (p = 0.001) whilst social adjustment, enjoyment of social and leisure activities increased (p = 0.001).M = 82.5, SD = 7.16) with unipolar, non-psychotic major depressive disorder, mild or moderate dementia and disability. Both psychosocial interventions were home-delivered and lasted 12 weeks. PATH is designed to reduce depression, depression-related symptoms and disability in elderly patients with depression and cognitive impairment, using a problem-solving approach, compensatory strategies, tools  and environmental adaptations. If the patient was unable to improve his or her emotional regulation with the help of the PATH tools, then the caregiver was asked to get involved. ST-CI is a non-specific therapeutic approach including empathetic listening, encouragement and understanding. It is based on Carl Rogers’ theory and differs from psychotherapies such as problem-solving therapy, interpersonal therapy, or cognitive behavioral therapy. Both the approaches were originally developed for patients with cognitive impairment. Participants’ suicidal ideation was assessed at baseline and every 4 weeks thereafter, using the suicide item (#16) of the Cornell Scale for Depression in Dementia (CSDD). After 12 weeks of treatment both the PATH and ST-CI groups showed similar reductions in suicidal ideation (p = 0.002).M = 81 years, SD = 9.5) or the Open Door group . The Open Door intervention is a brief, five-step, individualized psychosocial intervention designed to improve depression and its correlates. Sessions are delivered by a counselor who uses motivational interviewing to activate the individual’s wish to seek help. Both interventions lasted 8 weeks (three face-to-face visits during the first 6 weeks and one telephone meeting after 15 days) and suicidal ideation was evaluated using the Suicide Risk Assessment scale. Almost one third (26.7%) of all participants reported suicidal ideation at the baseline. No significant association was found between suicide risk and ethnicity, age, gender, or education. Unfortunately, suicide risk was not evaluated after the intervention.The final study  comparedSome of the psychosocial interventions investigated in the selected articles appear to be effective in reducing suicidal ideation in the elderly, namely the PROSPECT intervention, PATH, ST-CI and outpatient interpersonal psychotherapy tailored to older adults . One stuM = 76.9 years, SD = 9.0) than the others. Some of the interventions described were tailored specifically to older adults with dementia (Given the high risk of suicide in the elderly , the paudementia , whereasdementia . This heGiven that suicide risk is high in the elderly population and we live in an aging society, suicide prevention in the elderly is a topic that deserves more attention. It is notable that in the elderly suicide and the wish to die may be related to anxiety, social isolation, loneliness, pain, disability and institutionalization as well as to specific psychopathological conditions, such as depression, which can be treated psychopharmacologically . The forAlthough there have been several studies of psychosocial interventions in adults , researcWe found few studies, and the heterogeneity of samples and assessment methods made it difficult to compare the interventions described, but overall the results were promising. Articles reviewed suggested that it is important to assess suicide risk in older people. Once people at risk are identified, appropriate psychosocial interventions should be adopted. Furthermore, there is a need for studies which implement appropriate follow-up, including re-evaluation of suicide risk after intervention. Finally, as the two most important parameters in the field of psychosocial rehabilitation, efficacy, and cost-effectiveness should be taken into account in studies dealing with this topic.All authors contributed to the conception and design of the study, manuscript revision, read, and approved the submitted version. EG and MM reviewed the articles and wrote the first draft of the manuscript.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.


Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is expected to become the leading cause of end-stage liver disease worldwide over the next few decades. In fact, NAFLD encompasses different clinical scenarios, from the simple accumulation of fat (steatosis) to steatohepatitis (NASH), NASH-cirrhosis, and cirrhosis complications. In this context, it is fundamental to pursue strategies aimed at both preventing the disease and reducing the progression of liver fibrosis once liver damage is already initiated. As of today, no pharmacological treatment has been approved for NAFLD/NASH, and the only recommended treatment of proven efficacy are life-style modifications, including diet and physical exercise pointing at weight loss of 5%–7%. Different dietetic approaches have been proposed in this setting, and in this review, we will discuss the evidence regarding the efficacy of the Mediterranean Diet as a treatment for NAFLD. In particular, we will report the effects on liver-related outcomes. NAFLD is considered the hepatic manifestation of metabolic syndrome (MetS) and is defined as the accumulation of fat in the liver in patients who do not consume excessive amounts of alcohol . NAFLD encompasses different clinical scenarios, from the simple accumulation of fat in the liver (steatosis), to steatohepatitis (NASH), cirrhosis, and its complications .The burden of disease related to NAFLD is extremely high in the general population, and the global prevalence of liver steatosis is indeed around 25%, reaching a pike of 46% in the United States ,4. As a As of today, there are no approved drugs for the treatment of NAFLD, therefore no specific treatment can be recommended, even though the last NAFLD-European Association for the Study of the Liver guidelines suggested that vitamin E could be used as a potential treatment for non-cirrhotic NASH patients as it reportedly improves NASH histological features, although the long-term benefits of vitamin E administration are unknown and must be weighed against the potential occurrence of well-characterized side effects . In clinA variety of dietary patterns have been proposed for NAFLD-treatment but no pattern has adequately been evaluated in randomized controlled trials in large cohorts of patients. However, the Mediterranean diet (MD) may reasonably be an effective and easily reproducible diet pattern, as it is characterized by a balanced composition of macronutrients which have positive effects on NAFLD that can be found in foods from different areas in the world ,11,12. TIn the last decade, several studies have been conducted to assess the benefits of MD in NAFLD patients. In this review we will report the current evidence for the effects of MD in this setting, with particular attention to liver outcomes, since its beneficial effects on metabolic syndrome (MetS) have already been extensively described ,14,15,16The pathogenesis of NAFLD is multifactorial, being related to a complex interaction between environmental factors and genetic predisposition . InsulinThe MD is defined as “a plant-based diet characterized by a high ratio of mono-unsaturated fatty acids (MUFA) to saturated fatty acids (SFA) with a total fat accounting for 30%–40% of daily energy consumption” . The MD The MD is therefore rich in macronutrients that have been shown to have a beneficial effect on glucidic and lipidic metabolism and, consequently, on fatty liver disease . In partPUFAs, and in particular omega-3 fatty acids, exert a similar effect on NAFLD. More precisely, a diet rich in omega-3-fatty acids has been shown to be protective against fatty liver as it prevents hepatic fat accumulation and reduces hepatic steatosis ,38,39,40An additional benefit of the MD on fatty liver disease is related to its low content of refined sugars, fructose, and high content of complex carbohydrates and fibers. Epidemiologic reports have identified a directly proportional association between refined sugar, particularly high-fructose corn syrup, and the risk for NAFLD, even in the absence of additional risk factors ,46,47,48Unlike the Western diet, the MD is rich in whole grains, which have a high content of fibers. Whole grains and fibers may be beneficial in NAFLD patients for different reasons. The first is that they have less energy density and induce more satiety than refined carbohydrates. Secondly, they have prebiotic effects that modulate gut microbiota, which may play a role in the pathogenesis of NAFLD and its progression. Finally, they have well known protective effects against the risk for diabetes, dyslipidemia, cardio-vascular diseases, and all-cause mortality ,56. AnimA minimal amount of meat and processed meat intake is another characteristic of the MD. Meat contains cholesterol, saturated fatty acids (SFAs) which are relevant in NAFLD and some case-control and cross-sectional studies have shown the presence of a correlation between meat consumption and NAFLD ,60.p = 0.005) compared with not drinking. On the contrary, drinking ≥1.5 drinks per day showed a harmful effect  and the level of physical exercise significantly decreased hepatic steatosis, measured by Bright Liver Score (BLS) after 6 months in 90 non-diabetic obese patients (BMI 31.0 ± 5.2) . Interesp < 0.05), while alanine aminotransferase levels decreased from 48 U/L to 39 U/L (p < 0.05) [Additional evidence about the effect of a variant of the MD, i.e., a low-glycemic MD, on NAFLD severity, measured by means of ultrasonography was reported by an Italian randomized controlled trial including 98 men and women with moderate or severe steatosis . Low-gly < 0.05) .p = 0.036), and a greater improvement in cardiometabolic risk parameters (p < 0.05) than the low-fat diet, even after controlling for visceral adipose tissue changes. Importantly, after controlling for visceral adipose tissue loss, decreased hepatic fat content also remained independently associated with reductions in liver enzymes and glycated hemoglobin. These findings suggest that the beneficial effects of the MD/LC diet on specific cardiometabolic parameters may be mediated more by decreases in hepatic fat content than visceral adipose tissue loss.Interestingly, a recent randomized controlled trial addressed the question whether a reduction in hepatic fat content (HFC) has prognostic significance beyond the loss of visceral adipose tissue . In thisAdditional evidence about the effects of the MD on fatty liver disease in the mid- and long-term (12 months) will be shown in the near future by the results of the MEDINA study, a randomized controlled trial including 94 patients with NAFLD and insulin-resistance who have been randomized into two groups: MD or low-fat diet . This trp = 0.009) and liver stiffness (p = 0.004) as compared to the control group  whereas the MD group improved only liver stiffness compared with the control group (p < 0.001). No differences were noticed regarding the study’s primary and secondary outcomes  between the MD and ML groups, except that after controlling for baseline values and the proportion of weight loss-patients, the ML group tended to have a higher likelihood of halving their ALT levels compared with the MD group, though not significantly so . This evidence suggests that a lifestyle-guided intervention may be the optimal treatment strategy for NAFLD [As the reduction in liver enzymes is concerned, more evidence comes from a recent metanalysis including twenty randomized controlled trials including an overall 1073 NAFLD patients which showed that, compared to standard care—i.e., general advice for healthy diet and lifestyle—a more scheduled exercise and dietetic program improved aminotransferases, hepatic fat, and NAFLD activity score, irrespectively of weight change . Regardior NAFLD .p = 0.005), and less severe steatosis at histology (p = 0.08) among patients with NAFLD [p = 0.02) [p = 0.01) and correlated with NAFLD activity score >5 and to grade 2 fibrosis [To the best of our knowledge, the effects of the MD on NASH have been investigated only by two studies ,92. Kontth NAFLD . Moreove = 0.02) . Similarfibrosis .p = 0.0001) [The only study that has described the effects on liver stiffness so far is a prospective study by Abenavoli et al. aiming at the comparison between the effects of the MD with or without an antioxidant complex supplement in overweight patients suffering from NAFLD . The stu 0.0001) .EASL/EASD/EASO NAFLD guidelines recommend diet and physical activity as the best treatment for steatosis. However, a specific training program is not described. Studies investigating the effects of exercise on NAFLD have been conducted with similar results suggesting that both aerobic and resistance training reduce hepatic steatosis ,93,94,95NAFLD is going to become a major global health concern, and thus there is an increasing need to raise the awareness about the prevention and treatment of this disease, which nowadays seems to be very low .Although weight loss can be an effective treatment, for most patients it is a difficult goal to achieve and maintain. MD has recently been suggested as the diet of choice for NAFLD treatment but the evidence behind this recommendation is very low as most of the studies that have addressed this issue included few patients, differed in the inclusion/exclusion criteria, in the methods by which steatosis was measured, and in the measurement of outcomes.In order to have approved regimens for the treatment of NASH/NAFLD, therefore, more studies with large cohorts of patients, with consistent clinical endpoints as well as inclusion criteria and methods, are needed. Currently, the resolution of NASH and/or reduction of fibrosis stage are the accepted endpoints by the regulatory authorities since NASH progression and fibrosis stage have prognostic implications. In this context, although histologic NASH has been associated with advanced fibrosis, it is not an independent predictor of long-term mortality. In contrast, there are significant data to suggest that the fibrosis stage is the only robust and independent predictor of liver-related mortality, and it is auspicated that in the future, adequately powered studies will disclose whether the MD may truly represent a viable therapeutic means able to obtain these relevant goals ,100.


Several efforts aimed at discriminating between different degrees of on-road risky attitudes have been devoted to the identification of personality profiles among young drivers. However, the results are often inconsistent because of the limits of self-report measures. To overcome these limits, we tried to identify different profiles based on our study participants’ driving performances in a virtual environment and to look for psychological predictors of inclusion in one of three profiles. One-hundred and fourteen inexperienced adolescents were involved in this study, which included two experimental sessions. During the first, before riding along five virtual courses on a moped simulator, participants’ sensation seeking, locus of control, aggressiveness and beliefs about their peers’ on-road behaviors were measured by means of self-report tools. During the second session, the participants drove the simulator along six courses that were different from those faced in the first session. A cluster analysis was run on a wide number of indexes extracted from the participants’ performances to detect different riding profiles. Three profiles emerged , with specific riding patterns. The profiles also differed in terms of riding safety, assessed by means of the scores automatically given by the simulator to the participants’ performances. Reporting an external locus of control, underestimating peers’ on-road risky behaviors and showing less concern for fate among the possible causes of crashes are predictors that increase the risk of being included in the Imprudent profile. Low levels of dangerous thrill seeking predict inclusion in the Prudent profile, whereas high rates of self-reported anger play a role in discriminating the Insecure riders from the other profiles. The study indicates that it is possible to identify riding profiles with different degrees of on-road safety among inexperienced adolescents by means of simulated road environments. Moreover, inclusion in these profiles is predicted by different patterns of personality variables and beliefs. Further research is needed to verify the validity of these conclusions in real road conditions. Road crashes were the major cause of death in adolescents worldwide in 2015, especially in males, whose mortality rates are consistently higher than those of females , 2017. Ii.e., the prediction of an imminent hazard) can discriminate between novice and experienced drivers. During three different experiments, participants watched video clips showing risky or safe on-road scenes, spotting for hazards  and the need of teenage drivers to show off for their peer passengers. These behaviors are part of what i.e., peers driving other vehicles on the road), whose conduct is observed by adolescents, also have a role in influencing teenagers’ driving behavior , contributing to the increased crash rate.For instance, about 11,000 adolescents in the United States participated in a survey on their beliefs about factors that affect driving safety . More thAmong personality traits, sensation seeking (SS) is consistently linked to driving behavior. SS is usually defined as the tendency to seek novel, varied, exciting and intense sensations . In a syi.e., the tendency to act in a verbally and physically aggressive way and to experience anger and frustration) correspond to higher frequency of speeding behaviors among teenagers . The author concluded that, given the heterogeneity of the profiles’ characteristics and of their relations with self-reported risky driving behaviors and attitudes, young drivers cannot be treated as a homogenous group.The first approach adopted was to assess the relations between self-reported driving behaviors and drivers’ profiles that were identified through self-assessment personality measures. A survey of 6,000 Norwegian drivers, between 18 and 23 years old, was carried out by e.g., SS, anger, anxiety, and LC) and self-reported driving violations, errors, lapses and amount of accident involvement. Three clusters emerged: risky drivers , worried drivers (high levels of anxiety and hostility) and careful drivers . The participants in the first group reported the highest crash rate and the riskiest driving attitudes while perceiving themselves as less prone to accidents. Careful drivers showed a reverse profile, reporting the lowest rates of errors, violations, lapses and crashes. Finally, worried drivers were classified as a medium-risk profile, because they reported better attitudes than risky drivers but also a comparable number of lapses.In Italy, These two studies proved that young drivers of different cultures can be grouped in clusters with specific personality patterns and that the personality profiles show different degrees of risky driving behaviors and attitudes as measured by self-report questionnaires. Moreover, the results by e.g., hostility, assertiveness, SS, competitive speed and driving aggression). The most at risk cluster was characterized by, among others, high levels of hostility and of SS and by risky driving attitudes, such as high levels of competitive speed. Furthermore, participants in this cluster also reported high rates of risky driving behaviors but, at the same time, low crash rates. Then, the authors randomly selected a subsample of participants to test, through a driving simulator, whether the personality profiles differed in their behaviors during five courses with different features . The results showed that the more at-risk cluster was also more prone to the negative effects of workload, had difficulties in facing the hazardous scenes, and was less cautious in terms of driving speed in the emergency situation. Overall, these results show that it is possible to identify different profiles among adolescent drivers and that the profiles differ in terms of personality patterns and attitudes toward risky driving. These differences were confirmed when the driving behavior was assessed by means of a simulator: the risky drivers had the least safe performance and showed a lack of hazard anticipation.safe performance), B , C (near miss), and D (accident). The first measure analyzed was the number of accidents (D score). In addition, the authors developed a safe driving index based on scores A, B, and C. The at-risk cluster showed the highest rate of self-reported risky driving behaviors  and had the worst performance on the simulator, with the highest number of accidents and the lowest safe driving index score.The main contribution of the study by e.g., social desirability and overconfidence), preventing one from drawing predictions of real behaviors; (2) the use of these measures limits the inclusion of inexperienced drivers in the sample, resulting in the inability to discriminate between the role of driving experience and of personality traits in determining driving behaviors; and (3) the identification of profiles on the basis of personality traits led to inconsistent results, probably due to cultural peculiarities and to the instability of some personality traits during the lifespan .The approach examined in the previous paragraph , albeit extremely useful, has three main limits: (1) self-report measures of driving attitudes and behaviors can be influenced by a number of biases  used to identify specific profiles. In the first study  reported lower rates of on-road errors and lapses, but they also reported a higher rate of on-road risky behaviors. In the second study , even without proper driving or riding experience.For the second aim, we measured adolescents’ self-reported SS, LC, aggressiveness and beliefs, considering them as predictors of inclusion in the profiles. Beliefs were assessed through the 3DI questionnaire . The oriOne hundred and fourteen adolescents  enrolled in high schools of Padua, Italy, took part in the study. All of them had no on-road driving or riding experience, but they all used bicycles . All of the participants had correct or correct-to-normal vision. They were not paid for their participation. Written informed consent was obtained by all the participants and, for the participants under the age of 18, also by their parents. The project has been approved by the Ethical Committee for the Psychological Research of the University of Padova.The HRT is a riding simulator that includes a Pentium 4 PC with a Windows XP operating system and an LCD monitor (1024 × 768 resolution) placed on a base connected to a chassis equipped with moped-like controls that allow a person to ride along virtual courses. A speaker is placed on each side of the monitor through which instructions are given on the path to follow, in addition to reproducing the acoustic effect of the moped engine and the traffic.i.e., reconstructions of the most frequent hazardous on-road situations, based on the safe performance), B , C (near miss), and D (crash).The simulator provides a wide range of virtual courses, five on secondary roads and six on main roads. Each course includes seven or eight hazardous scenes : females are predominant in the Prudent cluster (30 F vs. 17 M), whereas males are predominant in the Imprudent cluster (6 F vs. 15 M).As depicted in Figure ous work  was labeF = 7.43, p < 0.001, ηp2 = 0.17. Univariate results indicate that significant differences are present in the percentages of each score, with F = 16.64, p < 0.001, and ηp2 = 0.23 for A score; F = 9.99, p < 0.001, and ηp2 = 0.15 for B score; F = 6.58, p < 0.01, and ηp2 = 0.11 for C score; and F = 17.74, p < 0.001, and ηp2 = 0.24 for D score.In order to better understand the differences among the identified riding profiles in terms of risky behaviors, a MANOVA was run on the percentages of A, B, C, and D scores of the second session  with the profiles as the between independent variable. At the multivariate level, the results show that the three profiles are significantly different with Wilks’ λ = 0.69, p < 0.001) and Insecure riders . Imprudent riders showed also the highest percentages of C and D scores: C scores were 9.5% in Imprudent participants vs. 4.9% in Prudent (p < 0.001) and 6.2% in Insecure ones (p < 0.05); D scores were 5.6% in Imprudent riders vs. 0.8% in Prudent (p < 0.001) and 2.4% in Insecure riders (p < 0.001).As depicted in Figure p < 0.01) but higher than Imprudent riders , and higher D percentages than Prudent riders  but lower than Imprudent participants . Finally, they did not differ from Prudent riders in terms of C scores and from Imprudent riders in terms of B scores.On the other hand, Insecure riders obtained lower percentages in A scores than Prudent riders .Overall, we can conclude that participants in the Imprudent cluster showed a less safe riding performance, with high percentages of scenes with crashes (D), near misses (C), and almost safe behaviors (B), reporting at the same time the lowest frequency of totally safe scenes (A). Prudent riders showed the opposite pattern, but they did not differ from Insecure riders in terms of near misses (C). Finally, participants in the Insecure cluster reported similar B percentages to those of the Imprudent cluster, testifying that Insecure riders’ performances, although overall better than those of Imprudent riders, included a significant amount of not totally safe scenes , thus allowing to rule out that the effects just described are due to differences in learning or driving skills already present before the test procedure (second session).As said, an identical MANOVA on the A, B, C, D scores obtained during the first session was carried out. Here, the factor The last step of the statistical analysis consisted in a multinomial logistic regression (stepwise backward method) on the cluster solution as the dependent variable and the scores on all the questionnaires’ scales as predictors. The aim of the regression was to identify patterns of personality traits and beliefs that can predict inclusion in the riding profiles.χ2(18) = 44.99, p < 0.001, explaining 33% of the variance (Cox and Snell’s Pseudo R2 = 0.33) with a classification accuracy of 60.5%. Seven predictors reached significance in the final model  and on the T-LOC Fate scale (p < 0.05 compared with Prudent riders and p < 0.01 compared with Insecure riders) but by higher scores at the CBA BG (p < 0.01 with respect to Prudent participants and p < 0.05 with respect to Insecure participants). Moreover, higher scores on the Dangerous TS and N–B Verbal Aggression scales play a significant role (p < 0.05) in discriminating between Imprudent and Prudent profiles.The regression coefficients reported at the top of Table p < 0.05). Moreover, reporting high scores on the Dangerous thrill-seeking scale (p < 0.05) but, at the same time, low scores on the Impulsive thrill-seeking scale (p < 0.05) increased the risk of being included in the Insecure profile, with respect to the Prudent profile.When the Insecure profile is used as the reference category .Following the procedure developed by The profiles showed different riding patterns. The Imprudent riders exhibited the most unsafe pattern, with high speed and acceleration levels, high frequency of speeding behavior, and high rates of accidents and instability. The Prudent profile showed the opposite tendency, whereas the Insecure riders had intermediate characteristics. Moreover, a significant difference in terms of sex has emerged between the profiles. The Prudent profile is mostly composed of females, whereas the Imprudent profile is mostly composed of males. A number of studies  and locus of control seem to play key roles in the predictions of participants’ riding profiles, with high levels of SS and an external locus of control being associated with an increase in the risk of an imprudent behavior . It is wLow levels of impulsivity and high levels of anger increased the risk of showing an insecure riding style among adolescents in our sample. Being less impulsive, although frequently associated with cautious behavior , might ai.e., anger, depression, and anxiety) and aggressive driving, which in turn led to more on-road violations, near misses and crashes. In our sample, anger has proved to be predictive of the inclusion in the Insecure profile. At the same time, Insecure riders showed more reckless behaviors than Prudent riders, as attested by the lower frequency of safe scenes (A scores) and the higher frequency of both almost safe scenes (B scores) and crashes (D scores). These results are in line with the conclusions by Concerning the role of anger, Finally, underestimating peers’ on-road risky behaviors increased the risk of showing imprudent behavior on the HRT, with significantly higher percentages of crashes and near misses. Indeed, a correct estimation of others’ potentially hazardous behavior is crucial to preventing crashes and it represents the basis of the development of hazard perception and defensive driving strategies.i.e., with at least 1 year of on-road experience) would offer the possibility to study the role of experience relative to that of personality traits.The principal limitation of the present study is related to the generalizability of the results to real on-road behaviors. Indeed, although it is true that the identification of profiles based on participants’ performances in a simulated environment rather than on self-report measures represents progress in the assessment methods of driving behaviors, there is still controversial evidence on the ecological validity of the simulators . Thus, ae.g., attention and decision making) are also thought to influence on-road behaviors  to the development of ad hoc training protocols that may provide a crucial contribution to preventing crashes.The present data indicate, first of all, that detecting different moped-riding profiles on the basis of a deep monitoring of the performance on a simulator is possible also among adolescents with no on-road experience. Second, the present study provides evidence that the identified profiles are not only dissimilar in terms of driving behaviors, but that they are also predicted by different personality patterns. These results represent the first step toward the development of an assessment method able to allow the early detection of risk-prone on-road profiles and of their predictors, along with potential protective factors. The practical implications of this new approach could range from the use of more complex virtual environments to identify driving profiles in specific populations with peculiar characteristics (This study was carried out in accordance with the recommendations of guidelines for psychological research of the AIP – Associazione Italiana Psicologia with written informed consent from all subjects. All subjects, and the parents of the subjects aged less than 18 years old, gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Ethical Committee for the Psychological Research of the University of Padua.EG conducted data collection, statistical analysis, and manuscript writing. MT supervised data collection and contributed to statistical analysis and manuscript writing. All authors contributed to research planning, results discussion, and revision of the paper.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.


Sarcopenia is a geriatric syndrome that leads to a loss of functionality and mortality.2 (kg/m2). We stratified patients by gender and age  and according to the interval between DXAs . The statistical analysis was performed using SPSS version 19. We assessed the prevalence of sarcopenia in HIV-infected patients attended in our HIV Unit who had at least two DXA scans from 2000 to 2016 . Sarcopenia was determinate according to appendicular skeletal muscle mass index (ASM) calculated as the ratio between skeletal muscle mass index (SMI) by DXA and height Median (IQR) age was 52  years, and 76% were male. The median (IQR) time with HIV infection was 8  years. The prevalence of sarcopenia was 25.7% , more prevalent in those aged >50 years (27.8%). Stratifying by gender, 43% of women aged >50 years presented sarcopenia compared with 8.8% of men. The frequency of sarcopenia increased from 37.6% to 49.4% when interval between DXA was 7-10 years (n=109), significantly higher in women than in men (p=0.016). In addition to the traditional risk factors, time with HIV infection was associated with sarcopenia . The prevalence and progression of sarcopenia in HIV-infected patients were high, mainly among women. Further studies are necessary to assess the best approaches to prevent this condition and its consequences. The enormous advances in antiretroviral treatment in the last two decades have made infection by human immunodeficiency virus (HIV) in developed countries to be considered a chronic disease. However, as a consequence of the improvement in survival, the prevalence of comorbidities is increasing, as shown by data from large observational cohorts of HIV-infected patients –3. In ad sarx, or flesh, and penia, loss) could contribute to an increased risk of falls and fractures (directly or increasing the frailty) , in patients with osteopenia , and in patients with osteoporosis .Multiple regression analysis adjusted for age and gender revealed associations between sarcopenia and other clinical and epidemiological variables included in the analysis , such asIn our study, sarcopenia affected one-fifth of the population and significantly increased over time, being more prevalent in women older than 50 years. Longer duration of HIV infection was associated with a greater risk of sarcopenia.Based on DXA scans, we found a high prevalence of sarcopenia in HIV-infected individuals (25%). This finding is similar to rates reported in longitudinal and other cross-sectional studies in HIV-infected persons after adjusting for age, gender, and BMI , 21. et al. [Ferreira Da Silva et al.  evaluate et al. [ et al. [Similarly, Wasserman et al.  reported et al. , 21 Yara[ et al.  found siThe small sample size of the previous studies, however, makes it difficult to stratify patients by gender and age. Our large sample, on the other hand, enabled us to assess differences between men and women of different ages and identify a higher prevalence among women, mainly those older than 50 years.The prevalence of sarcopenia clearly varies according to which diagnostic criteria are applied to different study samples.As expected, progression of sarcopenia was more pronounced in patients with an interval of ≥7 years between DXAs. Women aged ≥50 years presented more severe sarcopenia. Although data on progression are comparable to findings for other HIV-infected cohorts , 21–23, Our results confirm that the traditional risk factors for sarcopenia in HIV-infected population are the same as in the general population. Older age, female gender, and low BMI and low cholesterol were associated with low muscle mass . In addiThe retrospective design of our study was not possible to determine the impact of some risk factors  on the development of sarcopenia, due to the lack of necessary information on the medical report. Prospective studies are necessary (which included a non-HIV-infected control group) to compare the prevalence of sarcopenia between HIV-infected subjects and non-HIV population.Although we were able to draw robust conclusions especially in postmenopausal women owing mainly to the huge number of DXA scans , the wide age range (with 507 patients aged ≥50 years), and the high rate of women included (a quarter of the population).Therefore, given the prevalence and progression of sarcopenia over time and sarcopenia-associated consequences such as fragility, disability, and mortality , 21–23, In summary, this exploratory analysis shows a high prevalence of sarcopenia among HIV-infected persons, particularly women, and a positive association between sarcopenia and time with HIV infection. Future research should determine the impact of sarcopenia on morbidity, physical function, and quality of life in HIV-infected individuals and develop approaches to prevent the condition.


Limiting the analysis to 124 cases (41.9%) with available serum creatinine measurement, higher serum creatinine (dichotomised at the median: 0.67 mg/dL) was correlated with risk of PE (multivariate OR 17.277 (CI: 5.125–58.238)) and preterm delivery (multivariate OR 2.545 (CI: 1.100–5.892). Conclusions: Within the limits of a retrospective analysis, this study suggests that the risk of PE after ED is modulated by comorbidity. While the cause effect relationship is difficult to ascertain, the relationship between serum creatinine and outcomes suggests that more attention is needed to baseline kidney function and comorbidity.Background and objectives: Preeclampsia (PE) is a risk factor for kidney diseases; egg-donation (ED) increasingly used for overcoming fertility reduction, is a risk factor for PE. CKD is also a risk factor for PE. However, kidney function is not routinely assessed in ED pregnancies. Objective of the study is seeking to assess the importance of kidney function and maternal comorbidity in ED pregnancies. Design, setting, participants and measurements. Design: retrospective observational study from clinical charts. Setting: Sant’Anna Hospital, Turin, Italy (over 7000 deliveries per year). Selection: cases: 296 singleton pregnancies from ED (gestation > 24 weeks), who delivered January 2008–February 2019. Controls were selected from the TOrino Cagliari Observational Study (1407 low-risk singleton pregnancies 2009–2016). Measurements: Standard descriptive analysis. Logistic multiple regression analysis tested: PE; pregnancy-induced hypertension; preterm delivery; small for gestational age; explicatory variables: age; BMI; parity; comorbidity . Delivery over time was analyzed according to Kaplan Meier; ROC (Relative Operating Characteristic) curves were tested for PE and pre-term delivery, employing serum creatinine and e-GFR as continuous variables. The analysis was performed with SPSS v.14.0 and MedCalc v.18. Results: In keeping with ED indications, maternal age was high (44 years). Comorbidity was common: at least one potential comorbid factor was found in about 40% of the cases . No difference in age, parity and BMI is observed in ED women with and without comorbidity. Patients with baseline renal disease or “other” comorbidity had a higher risk of developing PE or preterm delivery after ED. PE was recorded in 23% vs. 9%, OR: 2.513 (CI 1.066–5.923;  As egg donation has increasingly come to be used as an assisted fertilization technique, its main role has progressively shifted from making pregnancy possible in patients with primary or early ovarian failure, or with severe genetic diseases, to extending the age of pregnancy beyond the physiological limit of fertility ,2,3.Notwithstanding the indications, egg donation is associated with a higher risk of virtually all adverse pregnancy outcomes, including caesarean section, preterm delivery, small for gestational age babies and the hypertensive disorders of pregnancy ,6,7,8,9.The risks of adverse pregnancy-related outcomes are at least in part linked to the procedure used. As a general rule, the more complex the procedure, the higher the risk; in vitro fertilisation is the most complex procedure, and the one with the highest risk ,14. FurtEven if the increase in comorbid conditions that goes along with maternal age is often mentioned as a possible cause for increased adverse pregnancy outcomes in egg-donor pregnancies, in which maternal age is usually higher, to date no study has focused on different comorbidity and, in this context, the “missing piece” is an analysis of kidney function, which is closely associated with pregnancy outcomes ,25,26,27It was in this context that we undertook the present retrospective analysis. Our aim is to assess the prevalence and the role of the main comorbid conditions, with particular attention to the presence of autoimmune and kidney diseases, and to try to understand how they affect the main pregnancy outcomes in singleton pregnancies from heterologous egg donation. Furthermore, the relationship between kidney function data was explored in patients who had at least one available creatinine test during pregnancy or at delivery. The study was performed at Ospedale Sant’Anna, a tertiary-care hospital, that is part of the Città della Salute e della Scienza in Torino, Italy; the low-risk controls were obtained from the archives of the Torino Cagliari Observational Study (TOCOS), dedicated to women with CKD, described elsewhere ,24. With an average of over 7000 deliveries per year, Sant’Anna Hospital is one of the largest European tertiary care obstetric facilities. Egg donation has only been available in Italy since 2014–2015 and even now, many restrictions apply to its use, in particular in high maternal age. Therefore, until 2015 patients who decided to have egg-donation pregnancies travelled outside the country, mainly to Spain, where these procedures are legal. As a consequence, pre-conception data are usually not available.The selection of the cases of pregnancy in women undergoing egg-donation included all patients who delivered at the Sant’Anna Hospital between January 2008 and February 2019.Pregnancies from egg-donation were identified in two main sources: the first was the hospital’s discharge database in which medical history, birth data and discharge letters are recorded. The search was carried out using the Italian keywords related to “egg-donation” in various combinations . Secondly, we searched the computerised records of pregnant women referred to the Prenatal Screening Center at the Sant’ Anna Hospital, where information on type of conception is mandatorily recorded . Low-risk pregnancies were selected from the TOCOS archives . In From the available databases, we selected singleton pregnancies with a duration of more than 24 weeks, with complete data at delivery . Abortions and therapeutic interruptions of pregnancy were excluded from the study.age, ethnicity, parity, baseline BMI; hypertension ; diabetes ;diagnosis of PE; diagnosis of HELLP syndrome; gestational week of delivery, type of delivery; baby’s weight at birth, centile;need for maternal intensive care unit, need for neonatal intensive care unit, perinatal death, maternal death;The following data regarding egg donation pregnancies were recorded: Whenever available, the following information was also included: previous PE, previous miscarriages, any other maternal disease; previous assisted fertilization; family history of CKD, cardiovascular disorders or preeclampsia.Serum creatinine was recorded whenever available in the clinical charts or in the hospital laboratory records before and during hospitalization. Jaffé Method was employed up to 2017, when it was substituted by the enzymatic method. Descriptive analysis was conducted as appropriate. The Shapiro Test was used to verify the normality distribution of the data. Median and min-max or range was used for non-parametric data, mean, and standard deviation for normal distribution. Statistical significance was assessed using ANOVA for parametric data and Kruskal-Wallis for non-parametric data, in compliance with standard indications for continuous variables. Dichotomous data are presented as risks, rates and proportions; in this case, the significance of the differences was analysed using the Chi-Square Test.t-test for normally distributed variables and the Wilcoxon Signed Rank Test for variables that were not normally distributed.The significance of differences between groups was assessed using the Logistic multiple regression analysis was performed for the covariates that emerged as significant in the descriptive analysis or were considered clinically relevant on the basis of the current understanding of the literature. Different outcomes were tested: preterm delivery ; small for gestational age baby ; preeclampsia (PE); pregnancy-induced hypertension (PIH); for this latter, only cases that were normotensive before pregnancy were considered. For the present study, we selected the outcomes of preterm delivery (<37 weeks), SGA < 10 centile and PE.The outcomes were tested in the whole population of egg-donation pregnancies and in the subset of cases in which at least one serum creatinine assessment was available. 2); parity (primiparous versus multiparous); presence of comorbidity . The following dichotomized covariates were tested: age (dichotomized at the median); BMI ; comparison between curves was made using the Log-Rank Test. ROC curves were tested for the outcomes’ pre-term delivery and preeclampsia, employing serum creatinine and e-GFR as continuous variables.The analysis was performed with SPSS software v.14.0  and MedCalc v.18 .This is an observational retrospective study, encompassing an analysis of the clinical charts of women who delivered after egg donation in a single Italian center in the years 2017–2018; the aim of the study was to detect predisposing factors. All patients evaluated in the present study signed, at time of hospitalization, a standard consent form, authorizing anonymous data management and publication. The study was notified to the hospital’s ethics committee. As expected, pregnancy-related adverse outcomes have a significantly higher incidence in the cohort of patients fertilized through egg donation, compared with low-risk pregnancies. The differences remain highly significant when only “no- risk” patients are considered. It is important to emphasize that the preeclampsia rate is of 11.1% after egg donation as compared 1.7% in low risk controls, and that they have 3.7% vs. 0.5% of early preterm babies  while, quite surprisingly, SGA rate differs only when specific comorbidities are considered. Further, it is of note that women who underwent egg donation have a significantly higher incidence of LGA babies (12.5% vs. 7.6% in controls).No difference in age, parity and BMI is observed in women with and without comorbid conditions who had been fertilized through egg donation. Conversely, a trend towards an increase in adverse pregnancy-related events is observed in patients with comorbidity who had received egg donation  and the difference reaches statistical significance for gestational hypertension, centiles and incidence of small for gestational age babies, which is roughly double in “at risk” mothers.The most commonly reported comorbid condition found was thyroid disease. Chronic kidney disease was present in 11 patients (3.7%). The diagnoses were kidney malformations (3); glomerular diseases (2); lupus nephropathy (3); kidney stones (2); diabetic nephropathy (1). One patient, previously on dialysis for lupus nephropathy, was a kidney graft recipient at the time of egg donation. She was the only one who was followed up in a nephrology-obstetric outpatient facility.Other comorbid conditions included: chronic hypertension (10 cases without CKD); cardiopathy (4); previous neoplasia treated by chemotherapy (5); fragile X or trisomy X syndromes (3); MTHFR homozygous mutation (5); other causes (5).The different “risk factors” do not appear to have the same weight. Thyroid diseases and other autoimmune diseases, do not appear to affect the risk of developing preeclampsia and of having a small for gestational age baby, or preterm delivery, as happens with kidney diseases and other comorbid condition . The incThe prevalence of small for gestational age babies was apparently not affected by the presence of comorbidity , but was twice as frequent after egg donation than in the control population . More inTo further analyse the relationship between kidney function and maternal-foetal outcomes, we analysed the kidney function data available during pregnancy. Due the particular characteristics of the study population , creatinine assessment, which is not a part of routine assessments in pregnancy, was available in only 42% of the cases, generally only at delivery. In this context, creatinine was more frequently assessed in complicated pregnancies, mainly in the context of preeclampsia and preterm delivery . This isIn the context of a “negative selection” of patients with egg-donor pregnancies, the patients with higher creatinine or lower glomerular filtration rates were not different from those with lower creatinine (or higher e-GFR) in terms of age, presence of all comorbidities, parity and BMI. A higher creatinine level was significantly associated with preeclampsia, gestational hypertension and pre-term delivery; conversely, the incidence of small for gestational age babies was not different across eGFR groups .ROC curves support the significant relationship between serum creatinine and e-GFR, analysed as continuous variables, preterm delivery and preeclampsia. The area under the curve is approximately 70% in both cases . The Youden index for the relationship between e-GFR and preterm delivery or pre-eclampsia is at ≤96 mL/min, and is at >0.64 mg/dL for preterm, and >0.63 mg/dL for the relationship between pre-eclampsia and serum creatinine. Interestingly, both indexes were in proximity of median values, respectively 0.67 mg/dL for serum creatinine and 103 mL/min for e-GFR .The multivariate analysis, shown in In the cohort in which serum creatinine assessment was available, the importance of this covariate is higher than that of comorbidity, and statistical significance is once more reached for preeclampsia and preterm delivery (OR 17.27 for preeclampsia) .In both cohorts , none of the covariates was significantly associated with early preterm delivery, defined as <34 or <32 gestational weeks.The presence of a higher serum creatinine or a lower eGFR is likewise significantly correlated with timing of delivery .Egg donation is increasingly being used as a fertilization procedure. It has proved to be effective in “extreme” cases of infertility or early ovarian failure, but involves a higher risk for adverse pregnancy outcomes, including pre-term delivery, preeclampsia and related disorders and giving birth to a child that is small for gestational age ,15,16,17While several studies have addressed obstetric and procedure-related risk factors, as well as at maternal age, the role of immunological diversity and the role of baseline maternal comorbidity have not yet been fully addressed. Various maternal conditions are considered as potentially affecting maternal-foetal outcomes in spontaneous pregnancies; however, less is known about their effect on pregnancies obtained by assisted fertilization techniques. Seeking to determine whether the “high risk” procedure of egg donation offsets the effect of baseline comorbidity, we undertook the present retrospective analysis, testing the effect of different classes of comorbidity on the outcomes of pregnancies after egg donation. Furthermore, within the limits later discussed in detail, we tried to explore the relationship of kidney function in this context, taking also into account the relationship between preeclampsia and long-term kidney health ,30,31,32As expected in a relatively old cohort of pregnant women, comorbidity was relatively common. 3.7% of the women were affected by a chronic kidney disease, which was however recognized as a high risk condition in only one case (a kidney transplant recipient); 6.4% had a history of an autoimmune disorder other than lupus and not a cause of kidney disease ; thyroid diseases, once more in metabolic balance, were frequently reported (18.9%), probably also because of the attention paid to these conditions in women with reduced fertility, while other relevant comorbidities, including baseline hypertension and diabetes or previous neoplasia, were reported in 10.8% of the pregnancies .The different comorbidities do not appear to play the same role: a history of thyroid disorders and of immunologic diseases was not associated with an increase in adverse pregnancy outcomes. Conversely, kidney diseases and other relevant comorbidities were associated with approximately twice as many preterm deliveries and cases of preeclampsia, while the increase in small for gestational age babies did not reach statistical significance in univariate and multivariate analysis . The presence of pre-conception comorbidity significantly affects the kinetics of delivery, as was shown using the Kaplan Meier curves .Given the importance of the kidney function in determining pregnancy outcomes, we further tried to analyze the subset of patients with available kidney functional data ,23,24,26Within the limits of a negative selection of cases, preeclampsia and pre-term delivery were significantly associated with higher creatinine levels, and consequently lower e-GFR levels. Interestingly, the association is present with a cut-point that is still in the normal serum creatinine range, defined using Youden’s index . The close association between pregnancy outcomes and kidney function has to be viewed with caution. First of all the selection is probably biased, and a higher number of cases with suboptimal kidney function may be present in the subset of cases with available data; the low number of data did not allow correlating severity of preeclampsia or early delivery with creatinine level. However, the relationship between complications and higher creatinine level suggests, in keeping with the data in the literature, that adding more non-complicated pregnancies would strengthen the results. Furthermore, available kidney functional data were mainly measured shortly before delivery, and, in this context, it is not possible to conclude that there is a cause effect relationship between relative kidney function reduction and complications. However, the association is close enough to suggest that kidney function should be monitored from preconception counseling throughout pregnancy in all women undergoing egg donation. This study has the strong point of novelty, being the first one addressed at establishing the role of preconception comorbidity, in a population of women with pregnancies obtained via heterologous egg donation. However, it suffers from relevant methodological limitations: the assessment of comorbidity was retrospective and based upon clinical charts, and it is possible that the attention to classic risk factors for infertility (such as thyroid or immunologic diseases) was higher in comparison with other conditions. This is also suggested by the fact that only one of the patients with a clinical history of chronic kidney disease had been identified and referred to the multidisciplinary follow-up facility. In this regard, the experience discussed in this study supports the need for an in-depth analysis of comorbidity in women undergoing egg donation, and hypothesizes that timely referral to specialized care could reduce the more than two-fold increase in preeclampsia and preterm delivery we observed. From a research standpoint, our data make it possible to define a prospective data set that should be gathered for future analyses. Within these limits, and in the wait for a prospective study, we feel that our analysis is worth being shared, as it draws attention to two crucial elements, baseline comorbidity and kidney function, whose influence is not offset by the effect of the complex fertilization procedure, and which should be acknowledged and systematically controlled as potential targets for reducing the incidence of adverse maternal-fetal outcomes in pregnancies from heterologous egg donation. Risks associated with pregnancy after egg donation is significantly influenced by baseline comorbidity. Furthermore, within the limit of incomplete data and of a negative selection of the cases with available data, pregnancy outcomes are associated with higher creatinine levels, even within the normal serum-creatinine range. While further studies are needed to determine the cause and effect relationship of this association, the association is close enough to suggest that kidney function should be monitored from preconception counseling, throughout pregnancy in all women, and in particular, in high risk situations, including women undergoing egg donation.


The prognosis of nasopharyngeal carcinoma (NPC) is poor with disease progression. Cadmium exposure is a risk factor for NPC. We aimed to investigate the effect of cadmium exposure, by measuring cadmium level, and clinicopathologic factors on NPC disease progression and prognosis. A total of 134 NPC cases were analyzed and venous blood samples were collected. Blood cadmium level was analyzed by graphite furnace atomic absorption spectrophotometry. Clinical data were collected at baseline for patients and tumor characteristics from medical records. Progression-free survival (PFS) was analyzed during follow-up. The effect of cadmium exposure and clinical factors on PFS was analyzed by the Kaplan–Meier method and Cox regression models. Blood cadmium level was associated with history of disease and smoking history and pack-years. On Kaplan–Meier analysis, a high blood cadmium level, male sex, smoking history and increasing pack-years, as well as advanced clinical stage were all associated with short PFS. On multivariate analysis, blood cadmium level was an independent risk factor and predictor of NPC prognosis and disease progression. Cadmium exposure and related clinical factors can affect the prognosis of NPC, which merits further study to clarify. Nasopharyngeal carcinoma (NPC) occurs in epithelial cells of the nasopharynx and belongs to head and neck cancers. Although NPC has similar tissue cells and blood systems as epithelial neoplasms, the two cancers differ in the head and neck region. The incidence of NPC is approximately 87,000 patients/year worldwide, and approximately 50,000 die from NPC annually . As compThe etiology of NPC is multifactorial and may be interactive. Possible risk factors include eating salted fish, smoking tobacco, drinking alcohol, exposure to fumes, etc. ,8,9. HowMany previous studies found that environmental exposure and occupational exposure to metals are associated with a variety of human cancers. Specifically, decreased selenium (Se) and zinc (Zn) levels may be related to cervical intraepithelial neoplasia and invasive cancer ; cadmiumCd, as a toxic metal, has not been specifically studied and may be involved in the development of NPC . Cd mainAlthough research on the pathogenesis of Cd in the body is relatively scarce, because of its long-term accumulation, Cd level is likely highly correlated with the prognosis of a tumor such as NPC and its progression. Many factors affect disease progression of NPC, and there may be an interaction between various factors. Disease progression refers to a 20% increase in the sum of the longest diameters of all target lesions and is not considered with increase in size of just one lesion. In addition to the expansion of local lesions, the other type of disease progression is transfer to another part. These two situations can be found mainly on imaging. Actually, clinical deterioration belongs to disease progression and is characterized by tumor spread and metastasis, disease recurrence, nosebleed, and lymph node transfer in the head and neck. The potential factors affecting the survival and prognosis of NPC can generally be divided into internal and external factors. The status of tumor cells themselves such as the nature of tumor cells and surrounding stroma may also be an important factor for clinical progression . MoreovePrevious studies have found that Cd level is possibly associated with the development of NPC ,36,37. IIn December 2014, from our medical records, we selected patients with a diagnosis of NPC from 1 August 2002 to 18 February 2014 at the Cancer Hospital in Shantou city. We included patients who were (1) receiving similar treatment (cisplatin and paclitaxel chemotherapy), (2) had no occupational exposure to Cd, and (3) had histopathologically confirmed NPC. The incidence of NPC is as high as 30/100,000 people in southern China, especially in Guangdong province , so mostRelevant general, pathological and clinical data were obtained from medical records following the procedures and guidelines of the Cancer Hospital in Shantou city. General information included age, sex, smoking, alcohol drinking, residence, occupation, etc. Relevant general information was obtained from medical records and by face-to-face and telephone interview. For the cumulative smoking dose, we divided patients into four groups by pack-years of smoking: no smoking, <30, 30 to 40, and ≥40 pack-years. Clinical data included age of diagnosis, family history of cancer, and history of disease . Pathological information mainly included tumor–node–metastasis  classification; Epstein–Barr virus antibody levels (early antigen (EA), viral capsid antigen antibody (VCA)); clinical stage; and pathological type.T, N and M classification were classified according to the TNM system of the International Union for Cancer Control and the American Joint Committee on Cancer. T classification is divided into four groups by site of tumor spread: T1 (limited to the nasopharynx), T2 , T3 (spread to bony structures), and T4 (spread to the brain or brain nerve). N classification is divided into four groups by the diameter of lymph nodes metastasized: N0 (no lymph node metastasis), N1 (largest diameter ≤3 cm), N2 (3–6 cm), and N3 (>6 cm). M classification is divided into two groups by whether the tumor has distant metastasis: M0 (no distant metastasis) and M1 (distant metastasis).All patients were interviewed after diagnosis and treatment at the cancer hospital in Shantou city. We collected patient information from medical records. To conduct a follow-up, we set the baseline time of NPC diagnosis from 1 August 2002 to 18 February 2014 and the endpoint as 31 December 2014. Disease progression was defined as the disease recurrence, metastasis or death. Survival time was defined as the cancer-free period from the start of diagnosis and treatment at the hospital to the onset of disease progression. If no disease progression was observed at the endpoint, these data were censored. During the follow-up period, the survival time was defined as full data if the patient died or disease progression occurred. Survival time was a significant indicator for evaluating disease progression.3 for over 24 h and rinsed three times with deionized water.Blood samples were used to analyze the risk of Cd exposure in patients. Blood Cd levels were measured by a standardized method also used in other publications . A volumt test. Data with non-normal distribution are represented by median (interquartile range (IQR)) and were analyzed by the Mann–Whitney U test and Kruskal–Wallis H test. Categorical variables were analyzed by the chi-square test. The data for blood Cd level were divided into two groups by median concentration (3.84 mg/L), named high level and low level, respectively. Survival time was defined as the time between the diagnosis of NPC and the discovery of progressive NPC or death. Kaplan–Meier log-rank tests were used to analyze survival time by various factors, and median survival time was also estimated by survival analysis. Progression-free survival (PFS) was analyzed by the variables age at diagnosis; family history of cancer; history of disease; T, M and N classification; clinical stage; EA and VCA positivity; pathological type; and blood Cd level by Cox proportional-hazard regression models, estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Spearman rank correlation analysis was also used to evaluate the relationships between investigated factors and blood Cd level with NPC. All tests were two-sided and p < 0.05 was considered statistically significant.Data were analyzed by using SPSS 23.0 . Data with normal distribution are represented by the mean ± SD and were analyzed by an independent-sample p = 0.018; p < 0.001, We included 134 patients with NPC . The median progression-free survival (PFS) for all patients was 2 months and 49 patients showed NPC progression: eight (16.3%) had a family history of cancers, 35 (71.4%) had a smoking history, and eight (16.3%) had a drinking history . The prop = 0.017), smoking history (p = 0.014), clinical stage (p = 0.016), and smoking pack-years (p = 0.003) (p = 0.004) (p = 0.025). Additionally, probability of high Cd level was associated with advanced disease stage but not significantly.Blood Cd level was related to the history of disease (= 0.003) . For fur= 0.004) . Probabip < 0.05), smoking pack-years , and smoking history  (p < 0.05).Blood Cd level was positively correlated with clinical stage  . We founp < 0.05; p = 0.039) and with than without a smoking history (p = 0.004). With increasing smoking pack-years and clinical stage, PFS decreased . Moreover, high blood Cd level was strongly associated with short PFS (p < 0.001). Nevertheless, short PFS was not associated with age at diagnosis, family history of cancer, alcohol drinking, pathological type, type of Epstein–Barr virus antibody , or T, N, M classification  of NPC patients ,47. Howep < 0.001) [p < 0.001) [Many studies have found Cd level as a risk factor for NPC ,36,37, b< 0.001) . AnotherWith the industrial production process, Cd  exists in water, soil, food and air . Cd was Here, we found that high Cd level was related to short PFS. Moreover, multivariate analysis concluded Cd as an independent prognostic factor for NPC progression after adjustment for other factors, including sex, residence, family history of cancer, history of disease, alcohol drinking, smoking pack-years, clinical stage, and blood Cd level. Previous studies have found that Cd level isa risk factor for NPC development and is also associated with the prognosis of NPC .There are many sources of metal exposure, and ingestion and inhalation are two major ways for metals to enter the body. Cd toxicity is well known and has a long half-life of approximately 20 years in an organism, so the concentration in body fluids must be monitored . Kidney p < 0.05) [Because of Cd exposure and accumulation in the body, the respiratory function and metabolism of the body are changed. With exposure to different chemical poisons, the involved genes have different detoxification mechanisms, such as the enzyme cytochrome P450 (CYP2E1). The activity of CYP2E1 increased in mucosal cells induces the formation of free radicals and leads to cell injury. Additionally, it may interfere with gene regulation and cell differentiation. Because of different repair mechanisms of DNA, abnormal gene expression that encodes cell growth promotes the occurrence of tumors ,61. Norm < 0.05) ,37, so Cp = 0.01). Smoking history was associated with short PFS on Kaplan–Meier but not multivariate analysis. Blood Cd level may mask the true effects of smoking. Further studies are needed to clarify whether smoking affects the prognosis of NPC.Apart from occupational and environmental exposures, lifestyle habits such as smoking are a major factor in Cd intake. Many studies have shown that tobacco smoke exposure increases Cd level in the body ,64, and We found that Cd, as a novel risk factor, affected the prognosis of NPC, which indicates the danger of behaviors and environmental metal exposure to the human body to some extent. Intervening in Cd exposure may better guide patients to better prognosis and clinical practice. However, our study contains some limitations, such as the confounding effect of clinical stage on prognosis, and other factors that may have contributed to biased results. Firstly, this was not a case-control study, but a survival analysis of factors affecting the prognosis of NPC cases. We included NPC cases and observed the occurrence of endpoint events during follow-up, so the proportion of outcomes and non-outcomes could not be designed in advance. Due to the limited sample size, the results may be slightly biased. Further intensive studies based on well-designed methods and larger sample size are needed to examine the association. Secondly, although we did not collect accurate information about the dose of chemotherapy using cisplatin and paclitaxel on NPC patients, the effect of chemotherapy on the findings was less likely. Since all the patients we included received similar chemotherapy, this is most likely to have resulted in the attenuation of risk estimates toward the null between two groups. Hence, the results of the study were unaffected and reliable. Certainly, the effect of platinum (Pt) used for chemotherapies on the prognosis of NPC patients also needsto be explored in future studies. Thirdly, to better reflect the effects of long-term and chronic exposure to metals, the sample tested should be urine; blood Cd is rapidly cleared by the kidneys, so it is often used as a biomarker of recent exposure . HoweverIn the present study, we assessed the effects of various factors on the prognosis and progression of NPC by measuring blood Cd level and clinicopathologic information. Cd level was an independent prognostic risk factor for NPC on multifactorial Cox regression analysis. Furthermore, high blood Cd level, male sex, smoking history and increasing pack-years as well as clinical stage were risk factors for short PFS with NPC. Subsequent studies are needed to clarify the effect of Cd exposure and other clinical factors on the prognosis and the progression of NPC.