Dental implants have become a mainstream treatment approach in daily practice, and because of their high survival rates over time, they have become the preferred treatment option for prosthetic rehabilitation in many situations. Despite the relatively high predictability of implant therapy and high costs to patients, patient perceptions of success and patient‐reported outcome measures have become increasingly significant in implant dentistry. Increasing numbers of publications deal with oral health‐related quality of life and/or patient‐reported outcome measures. The aim of this paper was to provide an overview of the available evidence on oral health‐related quality of life of fully and partially dentate patients rehabilitated with fixed and removable implant‐supported dental prostheses. A comprehensive electronic search was performed on publications in English up to 2021. A selection of standardized questionnaires and scales used for the evaluation of oral health‐related quality of life were analyzed and explained. The analysis encompassed three aspects: a functional evaluation of oral health‐related quality of life, an esthetic assessment of oral health‐related quality of life, and a cost‐related evaluation of oral health‐related quality of life for rehabilitation with dental implants. The data demonstrated that the preoperative expectations of patients markedly affected the outcomes perceived by the patients. As expected, reconstructions supported by implants substantially improved the stability of conventional dentures and allowed improved function and patient satisfaction. However, from a patient's perspective, oral health‐related quality of life was not significantly greater for dental implants compared with conventional tooth‐supported prostheses. The connection of the implants to the prostheses with locators or balls indicated high oral health‐related quality of life. The data also suggest that patient expectation is not a good predictor of treatment outcome. In terms of esthetic outcomes, the data clearly indicate that patients’ perceptions and clinicians' assessments differed, with those of clinicians yielding higher standards. There were no significant differences found between the esthetic oral health‐related quality of life ratings for soft tissue‐level implants compared with those for bone‐level implants. Comparison of all‐ceramic and metal‐ceramic restorations showed no significant differences in patients’ perceptions in terms of esthetic outcomes. Depending on the choice of outcome measure and financial marginal value, supporting a conventional removable partial denture with implants is cost‐effective when the patient is willing to invest more to achieve a higher oral health‐related quality of life. In conclusion, the oral health‐related quality of life of patients rehabilitated with implant‐supported dental prostheses did not show overall superiority over conventional prosthetics. Clinicians' and patients' evaluations, especially of esthetic outcomes, are, in the majority of cases, incongruent. Nevertheless, patient‐reported outcomes are important in the evaluation of function, esthetics, and the cost‐effectiveness of treatment with implant‐supported dental prostheses, and should be taken into consideration in daily practice. However, it is well known that biologic complications can arise with dental implant placement, and infections may develop that require a complex, protracted, and costly treatment of peri‐implant infections. Again, the patient is usually unaware of the risks associated with implant placement in terms of biologic complications.In this context, patients’ perceptions and psychological parameters are becoming more and more significant in evaluating treatment outcomes in implant dentistry.The aim of this narrative review was to summarize the current evidence on oral health‐related quality of life of fully and partially dentate patients rehabilitated with fixed and removable implant‐supported dental prostheses. Special emphasis was given to oral function, esthetic outcomes, and cost‐related aspects.22.1A comprehensive electronic search of the MEDLINE–PubMed database was performed for articles published in English up to 2021, applying the following free text terms: "PROMS" or "Oral health related quality of life" or "patient related outcome measures" or "patient satisfaction" or "esthetics" or "function" or "cost‐effectiveness" or "patient happiness" and "dental implants" or "implant dentistry". Moreover, the reference lists from the retrieved publications were screened to identify any additional relevant studies.2.2Oral health‐related quality of life is an established and relevant instrument with which to describe patient satisfaction. It was developed with a psychometric and social survey background and encompasses multiple dimensions of life, ranging from impairment  to social function, and to more global constructs such as “opportunity.” These dimensions have been linked to conceptual models, in which the effects of impairment on disability or reduced opportunity are mediated by intervening with personal and environmental factors.2.2.1The visual analog scale is defined as the distance on a horizontal line between two anchoring points representing the minimum and the maximum perception. The anchoring points are usually 10 cm apart, and the scale on the line is in millimeters or other units. In order to quantify a parameter on a visual analog scale, the evaluator will present a mark on the line. Thus, the distance from the mark to the anchoring point may be calculated.2.2.2The Likert scale is named after its inventor.2.2.3In the last 3 decades, a variety of standardized questionnaires have been proposed and propagated. The questionnaires usually comprise different areas.Prior to the conference on oral health‐related quality of life in North Carolina,The methods for the judgment of the esthetics by clinicians are depicted in Table 3The evaluation of oral health‐related quality of life of patients rehabilitated with dental implants can be summarized in three domains: the aspect of function, esthetics, and cost‐effectiveness. Furthermore, the functional aspect was subdivided into fully edentulous, partially edentulous patients, and the topic of implant‐supported vs tooth‐supported fixed dental prostheses. An overview of the results is summarized in Table 3.1The functional aspect of oral health‐related quality of life is not only important in the field of dentistry. Oral health‐related quality of life also affects the overall well‐being of the individual. In other words, oral health‐related quality of life correlates to general health‐related quality of life.3.1.1The majority of studies dealing with implant placement and oral health‐related quality of life has been performed in edentulous patients. Edentulism may be associated with functional impairment, which includes chewing ability, bite force, swallowing mechanism, differences in salivary flow, phonetics, and oral sensory function in general. Moreover, cleansability, as well as social behavior, are included. Ill‐fitting and unstable prostheses are a particular source of distress and reduced self‐esteem. Therefore, implant placement in edentulous patients severely impacts on their functional well‐being.Fonteyne et alThe question arises as to whether bone atrophy has an impact on the oral health‐related quality of life of patients treated with implant‐retained overdentures, foremost in the mandibular region. A 3‐year prospective study compared patients treated with implant‐retained mandibular overdentures with and without atrophic mandibles and, interestingly, did not reveal any statistical significant differences.With rehabilitations using implants, there is always a risk of peri‐implant diseases. An interesting cross‐sectional study, including 109 geriatric patients, revealed a statistically significant correlation between total oral health impact profile‐14 score, plaque index, and gingival index. These results suggest that peri‐implant health also affects patient satisfaction.In conclusion, there is increasing evidence that the use of dental implants to support either fixed or removable dental prostheses in fully edentulous patients significantly improves overall patient satisfaction when focusing on functional ability, especially in the lower jaw.3.1.2Replacing missing single teeth with dental implants has become a routine procedure for the rehabilitation of partially edentulous patients, although the lack of a periodontal ligament may have an impact on chewing sensation. The number of missing teeth is reflected in the oral health‐related quality of lifeKurosaki et alAccording to a questionnaire‐based survey, only 15.3% of patients receiving single implants considered masticatory function as their major concern. A total of 8.6% were most worried about food impaction and another 4.5% about pronunciation, occlusion, and swallowing.A systematic review with a meta‐analysis, including different questionnaires such as oral health impact profile‐49, oral health impact profile‐14, geriatric oral health assessment index, oral impacts on daily performances, and ad hoc satisfaction, indicated that not only the number of teeth lost, but also the location and distribution of missing teeth, affect the reduction in oral health‐related quality of life. Furthermore, the extent and severity of impairment appears to be context‐dependent .An evaluation of implants and their contralateral teeth clinically, alongside patient satisfaction by oral health impact profile‐14, confirmed that patients with implants were highly satisfied with their oral health‐related quality of life. The majority (72.8%) felt that they were never limited in function. Moreover, they indicated satisfaction with their dietary consumption (69.5%). Nearly half of the patients (48.9%) had encountered phonetic problems pretherapy and had become more self‐confident through implant treatment.Comparing the oral health‐related quality of life pre‐ and post‐implant placement revealed that, prior to surgery, patients reported functional problems, specifically eating (78%), but also speaking and smiling, which when considered together were a cause of general embarrassment (53%).3.1.3A recent review suggested that in partially dentate patients there was insufficient evidence that implant‐supported fixed dental prostheses yielded better oral health‐related quality of life scores than tooth‐supported fixed dental prostheses.To date there is limited evidence for partially dentate patients that implant‐supported fixed dental prostheses are superior in terms of patient perception than conventional fixed dental prostheses.3.2Loss of teeth, particularly in the anterior region, is associated with esthetic impairment and reductions in oral health‐related quality of life. In fact, a prospective study with 238 participants investigated patients with loss of anterior teeth and their satisfaction before implantation and following crown delivery. The results showed that oral health‐related quality of life, assessed with the oral health impact profile‐14 questionnaire, increased significantly after crown insertion,80 and the implant crown esthetic index.For many years, the evaluation of esthetic outcomes of care was obscure and not standardized in the dental literature. However, in 2005, two esthetic assessment methods were proposed and validated, namely, the pink esthetic scoreHence, it has to be realized that esthetic scores are dependent on the professional experience of the examiners, irrespective of the esthetic index system utilized.An important aspect to be mentioned is that professionals were more critical than patients when subjective patient‐evaluation was used.A further study on subjective and objective evaluations of esthetic outcomes in implant dentistry involved 30 patients treated with dental implants. Preoperative and postoperative images were graded using a visual analog scale. At the same time the images were shown to 10 independent clinicians using the same visual analog scale. The same outcome was reported and agreement between patients' and clinicians' evaluations was poor.A systematic review summarizing the existing evidence on esthetic oral health‐related quality of life of implant‐ and tooth‐supported fixed dental prostheses yielded no significant differences between the ratings for soft tissue‐level implants compared with those for bone‐level implants. The review encompassed 16 publications with a total of 19 relevant study cohorts, covering 816 implant‐supported reconstructions to be analyzed by patients. Despite the high heterogeneity among studies, the authors concluded that the esthetics of implant‐supported fixed dental prostheses are more highly rated by patients than by professionals.All‐ceramic and metal‐ceramic restorations were compared in a prospective study. A total of 59 patients with tooth agenesis were treated and followed up for 3 years. Finally, a total of 98 implant‐supported single unit crowns were evaluated. Materials used for crowns were either all‐ceramic or metal‐ceramic. Zirconia, titanium, and gold alloys were used for abutments, which retained these crowns. Patient‐reported and professionally reported esthetic outcomes were assessed with the oral health impact profile‐49 questionnaire and the Copenhagen index score, respectively.It is important to understand that esthetic outcomes should be evaluated separately for partially and fully edentulous patients. It is clear that patients in need of a single unit crown in the frontal region of the maxilla may have higher expectations than fully edentulous patients in need of implant‐supported overdentures. Obviously, patient priorities will be driven by individual differences in their perceived need. In addition, the patient is confronted with proportionally higher costs for a single crown compared with those for an implant‐supported overdenture. It is, therefore, important to understand patient satisfaction scores in conjunction with cost‐effectiveness, which is analyzed in the following section.3.3Introducing oral implants as a treatment for partially edentulous patients to improve their quality of oral health was usually accompanied by an increased cost compared with traditional removable prosthetic treatment.Despite the increasing levels of evidence in this field of dental research, adjunctive costs‐ related analyses should be encouraged, focusing particularly on the costs related to biologic and technical complications.4There is evidence that implant‐supported reconstructions have substantially improved the retention and stability of conventional dentures and, hence, enable better chewing and speaking ability of the patient.The connection of implants to prostheses with either locators or balls indicated high oral health‐related quality of life.Patient expectation is not a good predictor of treatment outcome.There is no convincing evidence that oral health‐related quality of life is improved by implant therapy compared with conventional bridge work.In general, there is poor agreement between patients' perceptions and clinicians' objective assessments of esthetic outcomes.There are no significant differences found between the esthetic oral health‐related quality of life ratings for soft tissue‐level implants compared to those for bone‐level implants.Comparison of all‐ceramic and metal‐ceramic restorations showed no significant differences in patients' perceptions in terms of esthetic outcomes.Depending on the choice of outcome measure and financial marginal value, supporting a conventional removable partial denture with implants is cost‐effective when the patient is willing to pay more for achieving a higher level of oral health‐related quality of life.Oral health‐related quality of life has become an important parameter for the assessment of treatment outcomes following implant therapy. However, there is no consensus on the definitions and standardization of this evaluation tool. The discrepancies in the terms, questionnaires, and scales presented in recent decades render a comparison of data challenging. Consequently, further studies with standardized questionnaires are necessary in the future. Nevertheless, the current evidence on function, esthetics, and cost‐effectiveness indicates that:55.1The following clinical case illustrates how the replacement of the missing tooth 46 with an implant‐supported single unit crown increased the patient’s quality of life Figures , 10, 11.generalized periodontitis: stage III, grade Bbruxismtrauma from occlusionendo‐periodontal lesion with root damageA 58‐year‐old female, systemically healthy patient was referred for treatment of advanced periodontal disease. Following the initial clinical and radiographic examination, the following diagnoses were made:Tooth 46 had to be extracted before steps 1 and 2 of periodontal therapyAfter prosthetic restoration, the patient was asked to compete the oral health impact profile‐14 questionnaire (Table According to Slade & Spencer,5.2The following clinical case illustrates how the replacement of the missing tooth 46 with an implant‐supported single unit crown increased the patient's quality of life Figures , 19, 20.generalized periodontitis: stage III, grade Bendo‐periodontal lesion without root damagecariesA 41‐year‐old male, systemically healthy patient was referred for treatment of advanced periodontal disease. Following initial clinical and radiographic examination, the following diagnoses were made:Tooth 46 had to be extracted before steps 1 and 2 of periodontal therapyAccording to Slade & Spencer,


Severe neuropsychiatric outcomes have been reported in individuals exposed to isotretinoin, but the evidence is inconclusive and complicated by several methodological limitations.To establish and quantify the association between isotretinoin use for acne and 1‐year incident neuropsychiatric adverse outcomes.A propensity score‐matched cohort study of electronic medical records between the years 2013 and 2019 with patients followed up for 1 year after their index dispensed prescription was conducted. The database included over 12 million patients aged 12–27 years. We analysed data for individuals with acne in this age range with a dispensed prescription for isotretinoin or a control prescription. Outcomes included diagnoses of any incident sleep or mental health disorder, or nonfatal self‐harm within 1 year of the index prescription.We included 30 866 patients prescribed isotretinoin for their acne, 44 748 prescribed oral antibiotics, 108 367 prescribed topical anti‐acne agents and 78 666 patients with acne but without an anti‐acne prescription. After propensity score matching for baseline confounders, the odds ratio (OR) for any incident neuropsychiatric outcomes in patients with acne exposed to isotretinoin was 0·80 [95% confidence interval (CI) 0·74–0·87] compared with those on oral antibiotics; 0·94 (95% CI 0·87–1·02) compared with those using topical anti‐acne medicines; and 1·06 (95% CI 0·97–1·16) compared with those without a prescription for anti‐acne medicines. Patients exposed to isotretinoin experienced significantly more incident physical symptoms than patients in any of the three comparison cohorts.Isotretinoin was not independently associated with excess adverse neuropsychiatric outcomes at the population level. When monitoring potential adverse outcomes during isotretinoin treatment, clinicians should also consider the high mental health burden associated with treatment‐resistant acne and the potential contribution of physical side‐effects of prescribed medication on mental health. What is already known about this topic?Severe neuropsychiatric outcomes have been reported in individuals exposed to isotretinoin, but the evidence is inconclusive and complicated by several methodological limitations.The neuropsychiatric risks potentially associated with isotretinoin treatment are an ongoing concern to clinicians and individuals with treatment‐resistant acne.Current isotretinoin prescribing guidelines recommend close monitoring for adverse mental health outcomes during isotretinoin treatment.What does this study add?After controlling for various potential sources of bias, isotretinoin was associated with a reduced incidence of adverse psychiatric outcomes  compared with oral antibiotics.Isotretinoin appeared to reduce the excess psychiatric risk associated with treatment‐resistant moderate‐to‐severe acne.In monitoring potential adverse outcomes during isotretinoin treatment, clinicians should also consider the high mental health burden associated with treatment‐resistant acne and the potential contribution of physical side‐effects of the prescribed medication on mental health.In this propensity score matched cohort study of electronic medical records, we found that after controlling for various potential sources of bias, isotretinoin was associated with a reduced incidence of adverse psychiatric outcomes  when compared to oral antibiotics. Isotretinoin thus appeared to reduce the excess psychiatric risk associated with treatment‐resistant moderate‐to‐severe acne.Linked Comment: J. Ravencroft and L. Eichenfield. Br J Dermatol 2022; 187:8–9.Plain language summary available online Acne vulgaris (acne) is a highly prevalent long‐term inflammatory skin condition with symptom onset typically in adolescence, with the highest prevalence between the ages of 14 and 19 years.There are several methodological limitations in the current evidence about the association between isotretinoin and severe neuropsychiatric adverse outcomes.We used the TriNetX  proprietary patient repository and analytics platform to identify patients with acne. The TriNetX Analytics Network provided access to pseudonymized aggregate‐level information on electronic healthcare records  from 56 healthcare organizations mainly in the USA . As this study used only de‐identified patient records and did not involve the collection, use or transmittal of individually identifiable data, this study was exempted from institutional review board approval. Data for this study were accessed via the TriNetX platform and analysed in August 2021 by using the TriNetX built‐in query builder. All data processing was conducted using the TriNetX built‐in proprietary algorithms. All diagnoses were identified using the International Classification of Diseases, tenth revision, clinical modification (ICD10‐CM) codes, and dispensed prescription medicines were identified using the RxNorm codes (n = 12 371 366) aged 12–27 years between the years 2013 and 2019. Patients were eligible if they were aged 12–27 years at index prescription, had diagnosed acne, did not have diagnosed neoplasms, and were alive for the subsequent 12 months after the index prescription. We focused on this age group because in the USA, isotretinoin is indicated in patients aged 12 or older and because 88% (30 866/35 100) of the eligible patients with acne treated with isotretinoin were within this age range. Excluding patients with acne aged over 27 years also limits the prevalence of adult‐onset acne and various comorbidities that could confound the observed association in older patients.The TriNetX Analytics Network included over 12 million patients  cohort of patients who did not have dispensed prescriptions for isotretinoin. Second, 108 367 patients were included in the topical anti‐acne cohort of patients who did not have dispensed prescriptions for isotretinoin or for the selected oral antibiotics (erythromycins or tetracyclines). Third, 78 666 patients were included in the acne control cohort of patients who did not have dispensed prescriptions for isotretinoin, any topical anti‐acne agents or for the selected oral antibiotics. For isotretinoin, oral antibiotics and topical anti‐acne agents, we used the first dispensed prescription in the data as the index prescription; whereas for the third control cohort we used the first healthcare visit because of acne as the index event.Propensity score matching was used to improve comparability between the isotretinoin‐exposed and control (isotretinoin‐unexposed) cohorts in relation to the type of acne, comorbidities and history of mental health problems, that is, to control for confounders that could bias the comparisons. For propensity score matching, we used the TriNetX built‐in algorithm, which was based on 1: 1 nearest neighbour matching with a caliper of 0.1 SDs. We included covariates occurring any time before the index prescription or event, and the same set of covariates were used to match isotretinoin‐exposed cohort and the three unexposed control cohorts.Cohorts were balanced at baseline for the following covariates: age at index prescription or event; sex; ethnicity/race; mental and behavioural disorders because of psychoactive substance use; schizophrenia, schizotypal, delusional and other non‐mood psychotic disorders; mood (affective) disorders; anxiety, dissociative, stress‐related, somatoform and other nonpsychotic mental disorders; sleep disorders not because of a substance or known physiological condition; disorders of adult personality and behaviour; behavioural and emotional disorders with onset usually occurring in childhood and adolescence; sleep disorders; vasomotor and allergic rhinitis; asthma; dermatitis and eczema; acne vulgaris; acne conglobata; other acne; unspecified acne; suicidal ideations; suicide attempt; intentional self‐harm; and dispensed prescriptions for sedatives and hypnotics; antidepressants; antipsychotics; and glucocorticoids. Patients in the isotretinoin cohort were successfully matched with patients in the oral antibiotics cohort , in the topical anti‐acne agents cohort  and in the acne control cohort without dispensed prescriptions for the selected acne medications .Primary outcome measures were 12‐month incident main categories of neuropsychiatric diagnoses, including psychotic disorders; mood disorders; anxiety, dissociative, stress‐related, somatoform and other nonpsychotic mental disorders; adult personality and behaviour disorders; behavioural and emotional disorders with onset usually occurring in childhood and adolescence; sleep disorders; and nonfatal self‐harm, which also included events of undetermined intent. We also included an incident outcome for any of the above neuropsychiatric conditions.Secondary outcomes were used to triangulate the primary outcomes and were used as proxies for clinically important neuropsychiatric outcomes receiving treatment. These secondary outcomes were 12‐month incident dispensed prescriptions for psychotropic medicines, including sedatives and hypnotics; antidepressants; and antipsychotics.Additionally, we included various physical symptoms of common side‐effects associated with isotretinoin treatment: headache, pain, eye conditions, conditions of mouth and lips, nausea and vomiting, malaise and fatigue. This is not an exhaustive list of all known side‐effects, but these reflect some of the most common physical side‐effects of isotretinoin. We also included an outcome for potential mental health side‐effects not fulfilling diagnostic criteria for any of the primary diagnoses, that is, symptoms and signs involving emotional state. This diagnostic group includes codes for symptoms such as nervousness, restlessness and agitation, unhappiness, demoralization and apathy, irritability and anger, hostility, violent behaviour, state of emotional shock and stress, low self‐esteem, worries, excessive crying, anhedonia, homicidal and suicidal ideations, emotional lability and impulsiveness. Furthermore, 12‐month inpatient and emergency visits were included as proxy outcomes for general health status during follow‐up.We also examined the association between acne symptom severity and adverse neuropsychiatric outcomes independently of isotretinoin, that is, we included comparisons between the three control cohorts. In these models, we compared patients with dispensed oral antibiotics (erythromycins or tetracyclines) who were not exposed to isotretinoin and patients with dispensed topical anti‐acne agents who were not exposed to isotretinoin or oral antibiotics (erythromycins or tetracyclines). We also compared patients with dispensed topical anti‐acne agents who were not exposed to isotretinoin or oral antibiotics (erythromycins or tetracyclines) and patients who did not have dispensed prescriptions for any of the selected acne medications.We included only incident outcomes for the primary and secondary outcomes. That is, in each model, we included only patients who did not have a recorded history of the given outcome in their EHR. We used a 14‐day washout period after the index prescription for measuring outcomes to reduce bias from conditions already present at the time of the index prescription. The EHR data included information on whether the patient had died while in hospital but did not include information on the cause of death. Those who died as inpatients were excluded from the main analyses. As a result of the lack of cause of death information we were unable to establish whether these deaths could be attributable to isotretinoin treatment. The number of inpatient deaths during the 12‐month follow‐up period are reported in Before propensity score matching, the distributions of baseline patient characteristics differed across the isotretinoin cohort and the three control cohorts , whereasWithout controlling for acne severity by using information on the different types of treatment, acne diagnosis was associated with an increased odds of 1‐year incident adverse neuropsychiatric outcomes , when compared with the sex‐, age‐ and race‐matched general patient population without an acne diagnosis .After matching for all included covariates, patients with dispensed prescriptions for any topical anti‐acne agents had an increased odds for incident adverse neuropsychiatric outcomes , compared with patients with an acne diagnosis but who did not have dispensed prescriptions for any of the selected acne medication . SimilarNo clear difference in inpatient mortality between patients with acne exposed to isotretinoin and patients with acne prescribed oral antibiotics was found during the 12‐month follow‐up period . The staThe OR for any incident neuropsychiatric outcomes in patients exposed to isotretinoin was 1·06 (95% CI 0·97–1·16) compared with patients with an acne diagnosis but who did not have dispensed prescriptions for any of the selected acne medication Table ; and 0·8Compared with patients with acne who did not have dispensed prescriptions for any of the selected acne medications, patients in the isotretinoin cohort had increased odds for incident mood disorders, anxiety disorders and sleep disorders Table . The strCompared with patients with acne using topical anti‐acne agents, patients in the isotretinoin cohort had increased odds for incident prescriptions for antidepressants  and for symptoms involving emotional state , but all other ORs were statistically nonsignificant, and most were close to a null association , and this applied to all neuropsychiatric outcomes except for psychotic disorders and symptoms involving emotional state with statistically nonsignificant ORs Table . The decPatients in the isotretinoin cohort experienced significantly more incident physical symptoms compared with any of the three comparison cohorts. The highest OR  for incident physical symptoms was observed when comparing patients in the isotretinoin‐exposed cohort with those without any of the selected acne medications Table .We examined the association between isotretinoin and incident adverse neuropsychiatric outcomes over a year in 30 866 individuals aged 12–27 years at index prescription. We observed a consistent association between increasing acne severity as indicated by anti‐acne treatment options and incidence of adverse neuropsychiatric outcomes, but the findings showed that isotretinoin exposure did not add to the risk of neuropsychiatric adverse outcomes over and above what was associated with oral antibiotics. Instead, we observed that isotretinoin was associated with reduced incidence of anxiety, depression, sleep problems, nonfatal self‐harm, and prescriptions for psychotropic medicines, when compared with patients with acne who were propensity score matched and prescribed oral antibiotics. Isotretinoin treatment, therefore, appeared to mitigate the excess neuropsychiatric risk associated with recalcitrant moderate‐to‐severe acne.Our results add to the evidence that has suggested improvement in symptoms of anxietyDespite concerns over isotretinoin‐induced idiosyncratic adverse effects,We observed that patients treated with isotretinoin significantly more often experienced incident physical symptoms than patients with acne receiving other types of treatment or no treatment with acne prescription medicines. An increased graded association by the severity of acne was observed for these physical symptoms. Acne‐related psychosocial stress in general or pre‐existing subclinical mental health problems together with an initial acne flare‐up or other isotretinoin‐induced physical side‐effects may trigger clinically relevant mental health symptoms in patients already vulnerable because of their severe acne, particularly among patients with limited coping and emotional resilience.As we used retrospective EHR data, we did not have control over treatment allocation. Our results thus represent real‐world treatment decisions. We did not have information on the duration of treatment or adherence, which may have confounded the observed associations. Among patients in a real‐world setting, there might be a considerable delay in seeking care for neuropsychiatric symptoms, particularly if symptoms are mild initially, which may obscure the correct sequence of events. We aimed to control for this by using a 14‐day washout period after index prescription for measuring incident outcomes to reduce potential bias from conditions that were already present at the time of index prescription. By propensity score matching, we aimed to control for confounding by indication and potential differences in baseline health status. However, it is possible that some residual confounding by indication remained in the models by unmeasured risk factors not captured by the EHR data.We were able to include a large number of patients from various healthcare organizations, but these organizations cannot be considered as representative of all healthcare organizations, and therefore differences in factors such as patient characteristics, data quality and isotretinoin prescription preferences across organizations may have affected the results. Also, if patients received treatment from healthcare organizations not participating in the TriNetX Network, before or after index prescription, this may have introduced bias because of misclassification in exposure status or loss to follow‐up for the outcomes. Furthermore, some of the isotretinoin‐induced physical or neurological side‐effects may have been misclassified, such as depression, because of unspecific or overlapping symptoms, such as fatigue, general malaise, emotional lability, and anhedonia.We observed that patients prescribed with isotretinoin had a slightly higher incidence of symptoms and signs involving emotional state, which is a diagnostically heterogeneous and nonspecific group of mental health symptoms. Misclassification bias may be more likely among patients treated with isotretinoin because of enhanced awareness of potential isotretinoin‐induced side‐effects. This type of misclassification would have led to overestimating the association between isotretinoin and adverse neuropsychiatric outcomes. Patients prescribed with isotretinoin are regularly monitored for abnormal blood test results, meaning that these patients are regularly in contact with healthcare organizations. This may have further overestimated the incidence of neuropsychiatric outcomes among patients prescribed with isotretinoin. As we used EHRs to identify adverse neuropsychiatric outcomes, we only identified patients receiving treatment for these conditions. This will have underestimated the number of individuals experiencing these outcomes with less severe symptoms.We did not have information on mortality, except for inpatient deaths. Further research with similarly improved design is thus needed to establish the association between isotretinoin and cause‐specific mortality. A major strength of our data was the relatively large number of patients initially prescribed isotretinoin, which improved the precision of our effect estimates. Furthermore, we were able to establish the associations for relatively rare outcomes, such as psychotic disorders, sleep disorders, personality disorders, behavioural disorders, and nonfatal self‐harm.In conclusion, when indirectly controlling for severity of acne, we found that isotretinoin was not independently associated with adverse neuropsychiatric outcomes at the population level. Patients with acne with prescriptions for oral antibiotics, but without prescriptions for isotretinoin, had the highest incidence of adverse neuropsychiatric outcomes over the 1‐year follow‐up period. These patients also had an increased odds for nonfatal self‐harm compared with those with less severe acne. This finding further highlights the need for timely and effective acne management.Tapio Paljarvi: Conceptualization ; formal analysis (lead); investigation ; methodology ; validation ; writing – original draft (lead); writing – review and editing . Tess McPherson: Conceptualization ; methodology ; supervision ; writing – review and editing . Sierra Luciano: Data curation (lead); formal analysis (supporting); investigation ; methodology (supporting); software (lead); validation ; writing – review and editing . Kimmo Herttua: Conceptualization ; methodology ; writing – review and editing . Seena Fazel: Conceptualization ; investigation ; resources (lead); supervision (lead); writing – review and editing .Appendix S1 Additional methods.Table S1 Medical codes used in defining the cohorts, in propensity score matching and in defining the outcomes.Table S2 Baseline characteristics of patients with acne in the isotretinoin and in the acne control  cohorts before and after matching.Table S3 Baseline characteristics of patients with acne in the isotretinoin and in the topical anti‐acne agents cohorts before and after matching.Table S4 Baseline characteristics of patients with acne in the isotretinoin and in the oral antibiotics cohorts before and after matching.Table S5 Overall inpatient mortality among patients with acne exposed to isotretinoin compared with patient with dispensed prescriptions for oral antibiotics for acne who were not exposed to isotretinoin during follow‐up by time after the index prescription.Table S6 One‐year incidence of neuropsychiatric outcomes among patients with acne compared with patients who were not diagnosed with acne.Table S7 One‐year incidence of neuropsychiatric outcomes among patients with acne with dispensed prescriptions for topical anti‐acne agents who were not exposed to isotretinoin or oral antibiotics for acne compared with patients with acne who were not exposed to isotretinoin, oral antibiotics for acne or topical anti‐acne agents during follow‐up.Table S8 One‐year incidence of neuropsychiatric outcomes among patients with acne with dispensed prescriptions for oral antibiotics for acne who were not exposed to isotretinoin compared with patients with acne with dispensed prescriptions for topical anti‐acne agents who were not exposed to isotretinoin or oral antibiotics for acne during follow‐up.Click here for additional data file.Video S1 Author video.Click here for additional data file.


On examination, his abdomen was flat with mild tenderness. Hypoxia was not noted. Blood examination revealed elevated D‐dimer . An enhanced CT of the trunk showed multiple thromboembolisms with large infarctions in the liver, spleen and lung  with no additional therapy except for rituximab plus chemotherapy against posttransplant lymphoproliferative disorder, which had been diagnosed after the event.A 57‐year‐old man was admitted to our hospital with vomiting. He had undergone liver transplantation for nonalcoholic steatohepatitis 2 years earlier. Four months after transplantation, he suffered from immune thrombocytopenia and was treated with prednisolone and eltrombopag, which led to a recovery of his platelet counts toward normal (from 23 to 121 × 10Takeda Science Foundation.Yutaka Shimazu declares that there is no conflict of interest.All procedures performed in this study involving the patient were in accordance with the ethical standards of our institutional and national research committee, and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from the patient.


Biological specimens in natural history collections constitute a massive repository of genetic information. Many specimens have been collected in areas in which they no longer exist or in areas where present‐day collecting is not possible. There are also specimens in collections representing populations or species that have gone extinct. Furthermore, species or populations may have been sampled throughout an extensive time period, which is particularly valuable for studies of genetic change through time. With the advent of high‐throughput sequencing, natural history museum resources have become accessible for genomic research. Consequently, these unique resources are increasingly being used across many fields of natural history. In this paper, we summarize our experiences of resequencing hundreds of genomes from historical avian museum specimens. We publish the protocols we have used and discuss the entire workflow from sampling and laboratory procedures, to the bioinformatic processing of historical specimen data. Their work pioneered the fields of museum and ancient genetics by opening the doors to using natural history collections and subfossils for genetic analyses. In the same year, Houde and Braun , the per‐base‐pair cost of short‐read sequencing decreasing and we envisage that it may soon be cheaper to resequence entire avian genomes rather than including an additional genome reduction step. The workflow that we present and discuss includes all steps from sampling and laboratory procedures, to how we handle degradation patterns present in DNA from museum samples to minimize adverse effects on downstream analyses  are somewhat similar to those of ancient samples . However, DNA from the latter is often more fragmented, occurs in lower concentrations and has lower proportions of endogenous DNA. Thus, in the literature, it is common to distinguish between historical and ancient DNA, but confusion remains as to the interchangeable terms used for various sources of old fragmented DNA. Here we follow the definition used in several other publications . As concentrations of hDNA may vary considerably between samples, we work separately with samples known or suspected to be particularly degraded. Although these precautions reduce the risk of contamination considerably, post‐inspection of the reads should always be conducted (see below).2.2The degradation of DNA in a specimen starts immediately after the individual is euthanized  both map poorly against the reference genome , while for sequences obtained from leg tissue (that presumably has dried faster) libraries for the same individuals map very well (97% mapping success for both samples). Another observation is that recently collected samples of birds (mainly from the 1980s or later) sometimes completely fail during genome library preparation. We speculate that such specimens have been treated differently from those collected earlier . For very old alcohol specimens  we also have a close‐to‐zero success rate, probably due to hydrolytic damage of DNA when the alcohol concentration has become too low. To conclude, our experience is that dry footpads from avian study skin samples represent an overall good source for DNA sequencing, but that other body parts such as tissue from the legs might occasionally work better, particularly for larger birds with fleshy footpads.Since the publication of Mundy et al. , footpad2.3−1) that are high enough to avoid the need for running additional index‐PCR cycles to an extent that clonality becomes an issue (for most samples we run 7–12 cycles). We have chosen to use the QIAamp DNA Micro Kit (Qiagen), as these spin columns are optimized for eluting small quantities of DNA in low elution volumes and the manufacturer's manual is followed with a few modifications , compared to 127 bp from libraries cleaned with beads . For five samples prepared using both cleaning methods, we obtained an average read length of 87 bp with spin columns and 130 bp with beads. Although we use the proportion of beads (1.8×) that should retain the same distribution of DNA fragments, we seemingly lose ~50% of the read‐length when using spin columns (even though MinElute spin columns should retain fragments between 70 bp and 4 kb). Despite apparent advantages of beads over spin columns, they are less efficient in removing free adapters in poor samples. Thus, we occasionally get high adapter peaks after the final cleaning of the indexed libraries Figure . As adapAs ligated fragments are randomly amplified in the index‐PCR step, a higher number of PCR cycles will increase the clonality . To circumvent this problem, we reduce the number of cycles as much as possible  and run multiple independent PCRs  per sample. To control for index hopping (when an index sequence for one sample is incorrectly assigned to a different sample in a pool), we also use dual indexing where both the P5 and the P7 adapters are indexed with unique barcodes , initial investments are needed so that sufficient samples can be multiplexed in a single sequencing run to make this cost‐efficient. Other Illumina platforms may be more suitable for smaller projects; for example, if one is aiming for a few genomes at relatively low coverage or only the mitochondrial genomes . As a rule of thumb, we pool 24 individuals  when we aim for 7–8× coverage (or 12 samples when aiming for ~15× coverage) when sequencing on one lane of the S4 flow cell on the Illumina NovaSeq platform. With current prices, the sequencing cost for a 7–8× coverage genome from a footpad sample is then around 180 EUR.3DNA damage in historical specimens can be characterized as fragmentation and deamination patterns towards the ends of the DNA fragments. Bioinformatic workflows that process sequencing libraries from historical samples should be specifically tailored to characterize the extent of damage and take the resulting biases into account during downstream analyses. Nonetheless, it is important to note that hDNA samples differ substantially from aDNA samples, and that appropriate pipelines therefore also vary. For example, the ratio of endogenous DNA recovered from avian footpads regularly exceeds 90% and the mean of the size distribution of DNA fragments ranges from 100 to 120 bp. The bioinformatic approach that we commonly follow is therefore more similar to pipelines suited for fresh tissue samples, but we have incorporated a number of adjustments in our workflow to account for fragmentation and deamination. Finally, the importance of sequencing coverage should not be underestimated, particularly for historical specimens for which accurate variant calling can be difficult due to the additional “noise” in hDNA . Bioinformatic workflows can only optimize results given the data available and the accuracy of downstream inferences therefore scales with the quality of the data produced.3.1nf‐polish; https://github.com/MozesBlom/nf‐polish). nf‐polish processes each sequencing library separately, rather than by individual, and we only merge libraries once they have been mapped to a reference. Prior to any library modification, nf‐polish quantifies the degree of (adapter) contamination and sequencing quality using fastqc  to remove PCR duplicates. Deduplication can be done by comparing each read in a library to each other  or by comparing the start coordinates of read‐pairs following mapping . However, for hDNA, coordinate‐based deduplication probably leads to a high proportion of false positives since only the start position of each read(−pair) is used to identify duplicates. Paired‐end reads have two starting coordinates (the first position in the 5′ direction of both the forward and reverse read) but cleaned hDNA libraries have a high proportion of merged reads (leading to an effectively single‐end data set with a single starting coordinate at the 5′ position). With duplicates largely removed, nf‐polish then trims away frequently used Illumina sequencing adapters . The final cleaning step includes the removal of low‐complexity reads (>50% of one nucleotide type) since these often stem from highly repetitive regions, are difficult to reconstruct and are prone to mapping error. Following each processing step, nf‐polish calculates processing statistics with seqkit  or heteroplasmy may result in some heterozygous sites, these should generally be rare and highly localized in any mitogenome. DNA damage may also lead to heterozygous calls but can be controlled for due to the relatively higher sequencing coverage of mitogenomes compared to nuclear loci.mitobim version 1.3; Hahn et al., In our workflow, we either map resequence data directly to a close mitogenome reference (if available) or use an iterative baiting and mapping approach for pseudo‐de novo assembly  and the suitability of the downstream analyses evaluated. For example, while phylogenetic or systematic inferences may be less affected by variant call uncertainty, demographic analyses that model changes in allele frequencies may be substantially changed. Here we briefly outline three different pathways for variant calling that are not necessarily mutually exclusive. We frequently employ multiple approaches to assess the robustness of our eventual findings.3.3.1gatk , variant calling can be performed for each individual using variant call software such as 3.3.2freebayes and gatk allow a neutral model of allele diffusion to be used to improve genotyping based on a population prior. In other words, the probability of a given genotype is determined depending on the frequency of the same allele(s) in the rest of the population. Moreover, the resulting variant call set can then also be filtered by individual and population simultaneously. For example, a questionable variant call can be excluded if a certain individual is the only individual with that specific allele or when a site has more than two alleles. Similarly, a consistent multifold increase in coverage for a given locus across many individuals may be a signature of a paralogous gene or repetitive region and would be worthwhile to exclude from downstream analyses.When multiple samples are sequenced per population, variant callers such as 3.3.3angsd  studies where coverage per individual may be low. 4With the increasing ease and cost efficiency of integrating high‐throughput sequencing, natural history museum resources are now accessible for genomic research. In this guide, we present a workflow for integrating museum specimens at a large scale and demonstrate how intrinsic properties of hDNA, such as damage patterns and increased risk of contamination, can be dealt with in the laboratory and bioinformatically for an optimal output. The purpose of this guide is to facilitate genomic research on natural history collections, as these collections hold an enormous potential to address biological questions.M.I. and M.P.K.B. conceived the study. All authors contributed to build the data set. M.I., F.T. and K.A.J. performed bioinformatics and made the Figures. M.I. and M.P.K.B. led the writing, and all authors contributed to the discussion of the results and the writing of the manuscript.The authors declare no conflicts of interest.Benefits from this research accrue from the sharing of our laboratory protocols and experience to conduct genome sequencing from avian hDNA samples. Data and results from all our studies that this paper are built on are available on public databases as described above.Figure S1Click here for additional data file.AppendixClick here for additional data file.


To assess the influence of COVID‐19‐imposed life changes on presentation and outcomes of patients with obstructing urinary stones complicated by infection.n = 66) and 1 year since its onset  were enrolled. Demographics, clinical presentation, laboratory panel, stone characteristics and outcomes were compared between groups. Univariate and multivariate logistic regression models were performed for analysis.All patients presenting with obstructing urinary stones and infection 1 year before the pandemic . The admission rate to intensive care units was double that of the pre‐pandemic period, whereas time between diagnosis and treatment was similar. The univariate analysis revealed higher rates of severe sepsis , systemic inflammatory response syndrome (SIRS) ≥ 2  and risk, injury, failure, loss of kidney function and end‐stage kidney (RIFLE) criteria ≥ 1  in the pandemic period group. The multivariate analyses revealed the COVID‐19 period as being the sole variable associated with severe sepsis , SIRS ≥ 2  and RIFLE ≥ 1 .The COVID‐19 period was characterised by younger patients, female predominance, higher temperature at presentation and more bilateral obstructing stones (The pandemic period was characterised by a worse clinical state at presentation of patients with obstructing urinary stones complicated by infection, probably reflecting delay in arrival to emergency services. The lockdowns that were imposed to control disease spread also contributed to difficulties in providing medical care. Public anxiety from exposure to the COVID‐19 virus was also contributory to delays in diagnosis and treatment for various non‐COVID‐19‐related emergencies.Stone disease, although benign in nature, can have detrimental effects on quality of life by causing pain and leading to disability. It may affect kidney function and carry a substantial risk of infective complications. The kinds of infections related to obstructing urinary stones represent a potentially life‐threatening medical emergency requiring urgent antibiotic treatment and kidney drainage. Delay in treatment and diagnosis has proved to be related to increased risk of mortality and morbidity.Previous studies that had evaluated the pandemic's impact on stone disease showed that there were significantly fewer patients seeking medical aid.2n = 66 patients) and during the COVID‐19 crisis . A computerised database was extended to include demographics, clinical characteristics at presentation , basic laboratory panel , stone characteristics  and subsequent clinical outcomes.The study was approved by the institutional review board (No. 0072‐21). It comprised all 111 patients presenting to the emergency room (ER) with obstructing ureteral stones and signs of urinary tract infection between 1 March 2019 and 28 February 2021. Their medical files were retrospectively retrieved for analysis. Two comparison groups were created according to timeframes: before COVID‐19  and at least one of the following signs of infection: fever (≥38°C) within 24 h prior the presentation and urine microscopy with ≥500 white blood cells (WBCs) per field and/or positive nitrites. All patients presenting during the pandemic period were assessed by rapid polymerase chain reaction (PCR) tests for COVID‐19 at presentation, during hospitalisation and at release from the hospital. Once the diagnosis of a urinary infection was established, the patients underwent kidney drainage by retrograde ureteral stent insertion or, in case of failure of that procedure, by percutaneous nephrostomy.2.1Outcomes were analysed by infection severity, admission to the intensive care unit (ICU) and overall hospital stay. Severity of infection was measured by the systemic inflammatory reaction syndrome (SIRS) criteria (negative ≤1 vs. positive ≥2), by severe sepsis as defined by organ dysfunction, hypotension or hypoperfusion and by the presence of bacteremia and/or bacteriuria.2.2U test. Categorical variables were reported as frequencies and compared with Fisher's exact and chi‐squared tests. Univariate and multivariate logistic analyses were performed to investigate the correlation between study outcomes and timeframe groups. All statistical analyses were two‐sided, and significance was defined as p < 0.05. SPSS software  was used for all statistical analyses.Descriptive statistics were used to assess patient characteristics. Continuous variables were reported as median and interquartile range (IQR) and compared between groups by means of the Mann–Whitney 3p = 0.02), female predominance , higher temperature at presentation  and more bilateral obstructing stones . In addition, there was a trend towards increased pain and heart rate, however, not statistically significant (p = 0.08 for both). No differences were found in baseline kidney function as measured by the calculated estimated glomerular filtration rate (eGFR), WBC counts, CRP values and stone characteristics. The time that had elapsed from presentation to NCCT and kidney drainage did not differ significantly between the study groups . Retrograde drainage by an internal stent was performed in 110 patients, and it failed in one patient who then underwent percutaneous nephrostomy.The study patients' baseline characteristics are summarised in Table p = 0.01), SIRS ≥ 2  and RIFLE ≥ 1 . There was a significant association between eGFR and severe sepsis, as well as age and RIFLE ≥ 1. The multivariate analyses revealed that the COVID‐19 era remained the sole clinical variable associated with severe sepsis , SIRS ≥ 2  and RIFLE ≥ 1  . The average hospital stay was 7 days for both groups (p = 0.9). None of the patients in the pandemic era group was COVID‐19‐positive at presentation nor had become positive during hospitalisation.The rates of bacteremia, bacteriuria and septic shock were similar for both study groups. The ICU admission rate during the pandemic was double that of the previous period; however, this trend did not reach a level of statistical significance  and an expanded number of beds needed for rehabilitation programmes.One U.S. study reported that 40.9% of adults having avoided medical care during the pandemic because of concerns about exposure to COVID‐19, including 12.0% who avoided urgent or emergency care and 31.5% who avoided routine care.In urology, we witnessed efforts to adapt to the rapidly changing medical reality with the creation of guidelines for addressing clinical urologic scenarios and processes of clinical prioritisation. Goldman and HaberDuring the pandemic, patients with stone events reported delay in seeking medical aid and in arriving to the ER. Those with obstructing pyelonephritis may have had higher complications rates and SIRS levels, and such delays were translated into higher rates of morbidity and mortality.We believe that our comparative study that followed a year‐long influence of pandemic on characteristics and outcome of patients presenting with stone obstruction complicated by infection provides additional and important insights to the sparse literature on these issues. Although we did not directly address the issue of delay in presentation, our patients who presented to the ER during the pandemic had a more severe clinical and biochemical grade of infection, suggesting that they had refrained from seeking treatment. The multivariate analysis revealed the COVID‐19 period as the single factor determining an around threefold greater severity of sepsis, SIRS and RIFLE in comparison with the period before the pandemic. On the other hand, the treatment was provided in a timely manner and with successful outcome, attesting to good institutional organisation despite the COVID‐19 impact on our healthcare system. Although the difference in our ICU admission rates did not reach a level of significance despite the twice higher rate during the pandemic (22% vs. 11%), it should be kept in mind that the greater burden on the ICUs probably determined a stricter triage of patients, resulting in the deferring of some of them to other medical facilities. Unlike our experience, however, other groups providing proper therapy timelines reported inferior clinical outcome, again suggesting a negative impact of patient delay in presentation.We are aware that our study has some limitations. First, it represents the experience of a single tertiary referral medical centre in a highly developed urban region with sufficient resources to cope with regular emergencies as well as the extra burden caused by COVID‐19‐infected patients. It is possible that the outcomes would have been different in lesser endowed circumstances. However, our experience showed that shifting resources to ensure medical care for pandemic needs and still provide urgent interventions should begin with reducing elective procedures.5The first year of the COVID‐19 pandemic was characterised by patient delay in seeking emergency care for infections related to obstructive urinary stones as well as by worse clinical states at presentation. Although well‐coordinated and optimised resources were able to maintain the capabilities to accommodate these cases with good results, the public will need to be convinced that treatment for other emergencies can be delivered safely without increased risk of COVID‐19 exposure.No competing financial interests exist.Haim Herzberg was responsible for the design, data acquisition and drafting. Ziv Savin did the statistical assessment. Rinat Lasmanovich performed the data acquisition. Ron Marom did the data acquisition and computerization of data. Reuben Ben‐David performed the data acquisition and completion of ethical requirements. Roy Mano did the scientific supervision. Ofer Yossepowitch was responsible for the scientific and ethical supervision. Mario Sofer did the overall supervision and final editing.


Elephas maximus), greater one‐horned rhino (Rhinoceros unicornis), tiger (Panthera tigirs), and leopard (Panthera pardus) mortality, as well as human mortality caused by these species. Over the 21‐year period, we recorded 1139 cases of wildlife mortality and 887 cases of human mortality. Leopard mortality was the highest, followed by that of greater one‐horned rhinos, tigers, and Asian elephants. Overall, the rate of wildlife mortality has been increasing over the years. Asian elephants were found to be more responsible for crop damage than greater one‐horned rhinos, while leopards were found to be more responsible for livestock depredation than tigers. The generalized linear model indicated that the mortality of wildlife in the districts is best predicted by the additive effect of human mortality, the proportion of agricultural land, and the literacy rate of the districts. Retaliatory wildlife mortality was the most challenging issue for wildlife conservation, especially for the large mammals. Findings from this study are important for mitigation of human–wildlife conflicts, controlling retaliatory killing, and conserving these threatened large mammals.Wildlife conservation in human‐dominated landscapes faces increased challenges due to rising conflicts between humans and wildlife. We investigated the human and wildlife loss rates due to human–wildlife conflict between 2000 and 2020 in Nepal. We concentrated on Asian elephant ( Elephas maximus), greater one‐horned rhino(Rhinoceros unicornis),tiger (Panthera tigris), and leopard, (Panthera pardus) loss and human loss by those species. Overall, the rate of loss of wildlife and human was increasing over the years. Loss of wildlife was found to be the best predicted by additive effect of human loss, proportion of agricultural land, and literacy rate of the district.We investigated the human and wildlife loss rate between 2000 and 2020 in Nepal. We focused on Asian elephant ( Human settlements near wildlife habitats have resulted in a decrease in wildlife habitat size. Such encroachment of natural habitat and lack of conservation knowledge in the community  (hereafter elephants), greater one‐horned rhinos (Rhinoceros unicornis) (hereafter rhinos), tigers (Panthera tigris) and leopards (Panthera pardus), are more involved in conflicts with people, including property damage and human casualties . A total of 192 species of mammals are found in Nepal Thapa, , encompa2.2r| < .7.We applied generalized linear models (GLM) with a Gaussian distribution to understand the influence of independent variables on wildlife mortality in 77 districts of Nepal  from the best‐fit model were used to generate the probability of wildlife mortality over two decades. The Inverse Distance Weighing (IDW) function in ArcGIS was used to generate the heatmap , to perform model selection. We selected the most parsimonious models based on a delta AIC < 2 and extracted the model averaged results to calculate parameter estimates using the MuMIn package   between wildlife and human mortality over the period of 21 years. We recorded 517 (SD ± 188.7) events of crop damage by the elephant, followed by the rhinos with 280 events (SD ± 39) yearly. Similarly, leopards contributed the highest livestock depredation  followed by tigers   HWC‐related large mammal losses and 887  human losses between 2000 and 2020 in Nepal  to predict wildlife mortality was the model with the additive effect of three variables . The average of seven best fit‐models (with delta AICc < 2)  play an important part in wildlife mortality.The incidence of casualties is particularly common in human‐dominated areas due to shared use of resources . These higher conflicts between humans and leopards could be primarily associated with lower prey availability in the forest  have the highest likelihood of loss for these large mammals. The fact that these habitats are home to all four large mammals may be one of the major factors contributing to the higher likelihood of wildlife mortality in this area. The higher percentage of agricultural lands in these districts and the greater number of human casualties could be considered additional factors. While several mid‐hill districts  had a higher likelihood of mortality, the majority of the mid‐hills showed a medium probability of wildlife mortality. The loss of wildlife in the mid‐hills is mostly represented by the events of leopard loss. Our study supported the findings of previous studies as high human–leopard conflict is frequently reported from the mid‐hill areas ; data curation ; formal analysis (lead); methodology (lead); visualization (lead); writing – original draft (lead); writing – review and editing (lead). Shivish Bhandari: Data curation ; formal analysis ; writing – review and editing . Binaya Adhikari: Data curation ; formal analysis ; writing – review and editing . Ripu M. Kunwar: Supervision ; writing – review and editing . Hari P. Sharma: Supervision ; writing – review and editing . Achyut Aryal: Supervision ; writing – review and editing . Weihong Ji: Supervision (lead); writing – review and editing .None declared.


On‐line hemodiafiltration (OL‐HDF) is currently the most advanced form of blood purification modality leading convective‐based therapies in end‐stage kidney disease patients. By adding a high convective component to the diffusive clearance achieved with highly permeable dialyzers, OL‐HDF reinforces removal of small MWt compounds and enlarges the spectrum of uremic compounds cleared up to middle and large MWt compounds. The biological and clinical benefits of convective‐based therapy are currently also being explored in a revisited hybrid modality, combining an increased internal filtration process with a more open membrane. Regular use of ultrapure dialysis fluid required by convective‐based therapies improves the bio‐incompatibility of the extracorporeal circuit so reducing inflammatory responses. On‐line production of substitution fluid, relying on a cold sterilization by ultrafiltration, has several advantages: First, it is a safe and established process; and second, it provides an unlimited amount of substitution fluid at the same cost as regular ultrapure dialysis fluid. As such, OL‐HDF is adaptable to all substitution modalities , thus allowing the dialytic convective dose to be adjusted to the individual patient needs. The development of OL‐HDF opens new pathways such as task automation simplifying care workflow. All these features make OL‐HDF the most versatile dialysis modality that can be now integrated in various treatment schedules according to session time and frequency  or location . This series of monographs provide an updated in‐depth assessment of OL‐HDF compared to conventional high flux hemodialysis. In this comprehensive review, most fields of interest for clinicians have been addressed by renown international experts providing an OL‐HDF State of the Art in a practical and objective manner. In brief, they include the Medical Rationale for OL‐HDF, Basic Physics, Technical Prerequisite, Clinical Implementation and Monitoring, Clinical indications, Clinical and Biological Effects in Adults and Children, and Patient Outcomes and Value‐Based Healthcare Perspective.Current state‐of‐the‐art technology and increasing numbers of patients treated worldwide confirm the absolute safety of OL‐HDF, the ease of implementation in multiple clinical settings, the superior efficacy of OL‐HDF compared to high flux HD in removing a larger molecular weight spectrum of uremic compounds and reducing the inflammatory state and vascular injury, and the immediate clinical benefits in terms of reducing intradialytic morbidity. In the long term, OL‐HDF has value‐based health care sustainable perspectives as indicated by its current acceptance by many different health care systems and has been reported to improve patient outcomes provided an adequate dialytic convective dose is delivered.2Two large randomized controlled trials (CONVINCE and H4RT) of more than 2800 patients are currently ongoing in Europe.In addition, several clinical studies are exploring the potential benefits of the combination of increased internal filtration with a more open dialyzer membrane, supporting the growing interest for convective‐based therapies in the renal community.3OL‐HDF remains a tool that has already brought advances in blood purification and already offers a paradigm shift in renal replacement therapy for patients with end‐stage kidney failure. However, as we have learned, renal replacement therapy for patients with chronic kidney disease has been a long journey that started some 60 years ago with improvements over time in its various components  supported by new clinical and biological findings. This continuous journey will not stop with OL‐HDF.Further developments are expected, coming either from more personalized treatment schedules , or from dialyzers offering additional clearance of uremic toxins, in particular modifications to remove protein‐bound uremic toxins (adsorption and displacement), or from new dialysis machine functionality  or from integration of dialysis machines into a web‐based network system facilitating remote monitoring, control, and providing support for clinical decision‐making.Success in renal replacement therapy is not a destination but rather a journey in which OL‐HDF represents a major step forward designed to improve patient perceptions and outcomes.No conflict of interests.


What is the topic of this review?Overview of the coagulation abnormalities, including elevated D‐dimers widely reported with COVID‐19, often labelled as COVID coagulopathy.What advances does it highlight?The review highlights the changes in bronchoalveolar haemostasis due to apoptosis of alveolar cells, which contributes to acute lung injury and acute respiratory distress syndrome; the pathophysiological mechanisms, including endothelial dysfunction and damage responsible for thrombosis of pulmonary microcirculation and potential contribution to the hypoxaemia of COVID‐19 acute lung injury; and changes in coagulation proteins responsible for the hypercoagulability and increased risk of thrombosis in other venous and arterial beds. The rationale for anticoagulation and fibrinolytic therapies is detailed, and potential confounders that might have led to less than expected improvement in the various randomised controlled trials are considered.Coronavirus disease 19 (COVID‐19) causes acute lung injury with diffuse alveolar damage, alveolar–capillary barrier disruption, thrombin generation and alveolar fibrin deposition. Clinically, hypoxaemia is associated with preserved lung compliance early in the disease, suggesting the lack of excessive fluid accumulation typical of other lung injuries. Notably, autopsy studies demonstrate infection of the endothelium with extensive capillary thrombosis distinct from the embolic thrombi in pulmonary arteries. The inflammatory thrombosis in pulmonary vasculature secondary to endothelial infection and dysfunction appears to contribute to hypoxaemia. This is associated with elevated D‐dimers and acquired hypercoagulability with an increased risk of deep vein thrombosis. Hypercoagulability is secondary to elevated plasma tissue factor levels, von Willebrand factor, fibrinogen, reduced ADAMTS‐13 with platelet activation and inhibition of fibrinolysis. Multi‐platform randomised controlled studies of systemic therapeutic anticoagulation with unfractionated and low molecular mass heparins demonstrated a survival benefit over standard care with full‐dose anticoagulation in patients with non‐severe disease who require supplemental oxygen, but not in severe disease requiring ventilatory support. Late intervention and the heterogeneous nature of enrolled patients can potentially explain the apparent lack of benefit in severe disease. Improvement in oxygenation has been demonstrated with intravenous fibrinolytics in small studies. Inhaled anticoagulants, thrombolytic agents and non‐specific proteolytic drugs in clinical trials for decreasing alveolar fibrin deposition might benefit early disease. Essentially, COVID‐19 is a multi‐system disorder with pulmonary vascular inflammatory thrombosis that requires an interdisciplinary approach to combination therapies addressing both inflammation and intravascular thrombosis or alveolar fibrin deposits to improve outcomes. Around a fifth of unvaccinated patients developed a severe disease, of whom a quarter progressed to critical illnesses  issues. The abnormalities of routine coagulation tests commonly seen include a prolonged prothrombin time, shortened or prolonged activated partial thromboplastin time (aPTT) or abnormal thrombin time. These changes can be associated with the abnormalities of D‐dimers, a marker of cross‐linked fibrin and clot turnover, and fibrinogen, an acute‐phase protein.2.2Acute lung injury or ARDS is characterised by extravascular fibrin deposition localised to the alveolar compartment following alveolar cell damage and disruption of the alveolar–capillary barrier. This fibrin deposition is essential for restoring the alveolar–capillary barrier and subsequent repair Idell, . It is pFibrin deposition is facilitated by in situ thrombin generation due to local overexpression of tissue factor on the injured cell surfaces and procoagulants in the leaked plasma. Elevated circulating extracellular vesicle tissue factor levels observed in COVID‐19 correlate with mortality and probably originate from damaged pulmonary tissue. Of note, in vitro studies of SARS‐CoV demonstrated an upregulation of mRNA for all three subunits of fibrinogen secondary to an expression of one of the SARS‐CoV proteins , with the latter demonstrating a more significant number of thrombi in post‐capillary venules of <1 mm (12 ± 14 vs. 35 ± 16). In pulmonary arteries of 1–2 mm, thrombi were variably present in around half of the patients in both groups with no difference in the density.Blood coagulation abnormalities in the form of significantly elevated D‐dimer were noted early in the clinical characterisation of COVID‐19 and have been associated with higher mortality , with thrombosis detected in 39.2% and pulmonary embolism (PE) in 22.1% , protein C and protein S  due to a combination of pulmonary vascular inflammatory thrombosis and systemic hypercoagulability. However, the exact prevalence and contribution to mortality are uncertain. One meta‐analysis reports a pooled frequency of PE in COVID‐19 in the emergency department, general wards and intensive care at 17.9%, 23.9% and 48.6%, respectively, and D‐dimer cut‐off levels used to identify patients vary from 2‐ to 10‐fold higher than the upper limit of normal , anticoagulants like unfractionated heparin (UFH) and non‐specific proteolytic drugs.Accumulated data from clinical and animal models suggest that both intravenous and inhaled thrombolytic drugs in acute lung injury are associated with increased oxygenation and improved mortality rates due to improved fibrin clearance from the alveolar space (Hofstra et al., Following an initial case report demonstrating the success of nebulised rtPA in ARDS (Gram et al., Drugs that are undergoing clinical trials include inhaled anticoagulants and non‐specific proteolytic drugs. The anticoagulant of choice for inhalation has been UFH. The clinical trials currently recruiting vary in their dosing regimen and duration of treatment and often include patients on mechanical ventilation. UFH is an indirect anticoagulant dependent on AT for total activity. The AT in alveoli appears to originate from the plasma exudate. UFH can affect the clot structure in the absence of AT (Yeromonahos et al., 3.2In COVID‐19, endothelial dysfunction due to proximity to the alveolar inflammation triggers pulmonary capillary vessel thrombosis, which may help localise the infection. Primary infection of endothelial cells accentuates this, and increasing severity results in the progression of the thrombosis from the microcirculation to the small vessels and subsegmental pulmonary arteries. Management of vascular thrombi is well‐established, and interventions like fibrinolytics either clear pulmonary vascular thrombi directly or indirectly with anticoagulants and antiplatelet agents. The archetype of inflammation‐induced thrombosis is Behçet's syndrome, where the role of anticoagulation in addition to immunomodulation is still the subject of debate (Ahn et al., 3.3Following the initial publication of potential survival benefits with prophylactic low molecular mass heparin (Tang et al., Multi‐platform randomised controlled studies of systemic therapeutic anticoagulation with unfractionated and low molecular mass heparins in COVID‐19 demonstrated a survival benefit with full‐dose anticoagulation in patients with non‐severe disease requiring supplemental oxygen compared to standard of care (Lawler et al., However, there are several challenges in interpreting this evidence, and some have been reviewed (Connors et al., Nevertheless, the concern is the assumption that adjuvant therapy, in this instance anticoagulation, might increase survival. The development of thrombosis in the pulmonary vasculature and deep veins is a complication of the underlying disease process. Interventions for the complication without addressing the underlying disease are unlikely to yield the desired results in patients with severe disease. Therefore, the lack of apparent efficacy cannot be ascribed solely to lack of effect. Indeed, it may indicate that combination therapies targeting inflammation and thrombosis might be needed.A reduction in hypercoagulability through prophylactic anticoagulation can decrease the risk of deep vein thrombosis and embolisation. There is also an active discussion about the use of D‐dimers for stratification of patients for prophylactic/therapeutic anticoagulation. Certain investigators have suggested anticoagulants in every patient with elevated D‐dimers, and others have recommended a restriction to patients with multiple comorbidities and at high risk of developing severe disease or patients hospitalised with the infection. It is important to recall that D‐dimers represent thrombus turnover and, therefore, coagulation activation but are not hypercoagulability markers. The underlying question that is yet to be answered unequivocally is the magnitude of the impact of antithrombotic treatment on survival and incidence of symptomatic thrombotic events.3.4Since the first demonstration of improvement in oxygenation following intravenous rtPA in ARDS associated with trauma (Hardaway, 4Coagulation is one of the host defence mechanisms to control infection and inflammation. There is now convincing evidence that hypoxaemia following SARS‐CoV‐2 infection is due to alveolar and endothelial damage with extensive capillary thrombi. Further, patients can also develop deep vein thrombosis with embolisation secondary to hypercoagulability and immobility. Elevated D‐dimers can serve as prognostic markers and identify patients who might benefit from imaging studies to exclude pulmonary vascular thrombosis. The detection of pulmonary vascular thrombi might require a higher D‐dimer threshold for imaging than conventional VTE.Whilst anti‐viral interventions and immunomodulatory agents have demonstrated clinical benefit, clinical trials of anticoagulation and fibrinolytic agents have been more challenging to conduct and interpret. Some of the challenges are related to the fact that infection has determined trial entry rather than the presence of thrombosis. However, a role for antithrombotic therapies is emerging in patients requiring oxygen support. In patients with severe disease, future trials will need to consider anticoagulants and antiplatelets as additional therapies to anti‐viral and immunomodulation strategies. As thrombotic events represent disease severity, the timing of initiation of antithrombotic intervention in relation to the duration and severity of illness is likely to influence outcomes. Intravenous fibrinolytic agents have also demonstrated a rapid improvement in oxygenation, but the lack of sustained improvement necessitates a review of the treatment regimen. Critically, the bleeding risk must be proportionate to the outcomes desired. The management of COVID‐19 is likely to benefit from stratification by both severity and duration of illness, and severe disease is likely to require multiple treatment modalities.No competing interests were declared.No funding was received for this work.


With the rapid increase in the average age of society, the number of people with dementia has increased in Japan. Thus, the need to prevent dementia is greater, and prevention programs have been implemented throughout Japan. This study aims to evaluate both the short‐term and the long‐term effects of a dementia prevention program on physical and cognitive function in community‐dwelling elderly.Cognitive and physical assessments were carried out at baseline for a sample including 57 elderly participants. The participants underwent an intensive training program lasting for 2 h per week for 10 days. After the last period of training, the assessment performed was reapplied. The outcome measures used to establish effectiveness were a Mini‐Mental State Examination, Five Cognitive Tests, a Cognitive Function Instrument, a Timed Up & Go Test, a grip strength evaluation, a Geriatric Depression Scale, an EQ‐5D and a Physical Activity Scale for the Elderly. Participants were then divided randomly into two groups: a booster group and a non‐booster group. The booster group received booster training every 3 months after the intensive training period, whereas the non‐booster group did not. Both groups were monitored every 6 months for approximately two and a half years after baseline assessment.The Mini‐Mental State Examination, the subtests of the Five Cognitive Tests  and the Timed Up & Go Test revealed a significant improvement after intensive training. For most of the outcome measures, the booster training showed no additional significant improvements.In this study, intensive training had a short‐term positive effect. Although the effect of the booster training was not clear, the functions of the elderly participants were found to be maintained during a follow‐up assessment. The study findings recommend conducting intensive training for the community‐dwelling elderly without follow‐up training. Japan is experiencing both an ageing population and a decline in birth rate that is unparalleled in the rest of the world. It is estimated that the elderly (< 65) made up 27.7% of the population in 2017.Alzheimer's disease (AD), which is the most common cause of dementia, is an incurable and progressive neurodegenerative disorder. At present, AD cannot be treated completely, although several medications such as acetylcholinesterase inhibitors can slow the disease's progression. In addition to pharmacotherapy, nonpharmacologic therapy is a potential pathway for treating dementia.Multiple potential risk factors, such as depression, cardiovascular and cerebrovascular disease, diabetes, cognitive function, physical function, self‐rated health and lifestyle characteristics, are reported to be associated with the incidence of dementia.Although efforts to prevent dementia have grown popular over time, there are no proven modalities for preventing dementia.In this study, we conducted intensive interventions for all participants and divided them into a booster training group (BTG) and a non‐booster training group (NonBTG). Then, we compared the cognitive and physical function changes between the two groups. Many previous intervention studies on dementia prevention compared the cognitive function changes between an intervention group and a non‐intervention group, but they did not compare the changes after conducting a common intensive DPP in all participants. The main aim of this study is to clarify the following two points: (i) short‐term effects of intensive training (once a week for 10 sessions); and (ii) longitudinal effects of regular booster training (once every 3 months) following intensive training and conducted over a 2‐year period.The sample population comprised community‐dwelling elderly aged at least 70 years who were flagged as being at high risk for mild cognitive impairment (MCI)/dementia because of unfavourable answers on the cognitive domain of the ‘Kihon Checklist’ in 2015 and consequently participated in a dementia prevention education program organised by Kobe City in 2016. The Kihon Checklist, which has been developed by the Japanese Ministry of Health, Labour and Welfare, is a simple 25‐item questionnaire used to identify frail citizens, and includes three items (Q18–20) on subjective cognitive function (the cognitive domain).The baseline assessment of cognitive and physical function for 57 elderly participants included the following elements: an MMSE, Five Cognitive Tests (Five Cog), a Cognitive Function Instrument (CFI), a Timed Up & Go Test (TUG), a grip strength evaluation, a Geriatric Depression Scale (GDS), an EQ‐5D, and a Physical Activity Scale for the Elderly (PASE). The intensive training program was conducted for 2 h per week for 10 days. After the last intensive training, the assessment performed at baseline was reapplied. Participants were then divided randomly into two groups: a BTG and a NonBTG. The BTG received booster training once every 3 months after the intensive training period, whereas the NonBTG did not. We monitored both groups every 6 months during follow‐up assessment. We conducted four follow‐ups (FU‐1–FU‐4) over approximately two and a half years.DPP training sessions were held in a group for 2 h at a time. We conducted the DPP once a week for 10 sessions during the intensive training period, and once every 3 months as booster training for the BTG following the intensive training. The DPP comprised physical exercise , cognitive training, dual task training, nutrition education by a dietitian and lectures on dementia. Aerobic exercise was performed for approximately 15 min in a standing or sitting position with music, and strength training was repeated with either a light or moderate load depending on the participant's physical function in consideration of their health risks. Cognitive training included the tasks such as working memory, calculation (the four basic arithmetic operations), spotting the difference between two similar pictures and reading aloud. As dual task training, exercise and cognitive tasks were performed simultaneously, such as calculation while walking. The lectures explained the factors related to the incidence of dementia and recommended physical and cognitively engaging activities, communication with neighbours, a well‐balanced diet and a moderate amount of sleep in daily life. The contents of the DPP were chosen from seemingly effective interventions for reducing cognitive decline in previous studies.We performed the baseline assessment in November 2017.U‐test was used to compare the results of the assessments of the BTG and NonBTG participants at post‐intensive training (PIT). To investigate the effects of the intensive training, the respective outcome measures evaluated at baseline and PIT were compared using the Wilcoxon signed rank test.The Mann–Whitney P < 0.05. Statistical analysis was carried out by JMP®15 .We used a linear mixed‐effects model to analyse the effects of the booster training. Dependent variables were the scores of outcome measures for each assessment period (‘time’). Independent variables were ‘group’ (BTG or NonBTG) (a fixed factor) and a within‐subjects factor (a variable factor). We transformed the scores of outcome measures using the Box Cox transformation. For the outcome measures for which we observed a significant interaction using a liner mixed‐effects model, we conducted a pairwise comparison in each case using Bonferroni's correction. The significance threshold was set at The MMSEThe Five CogThe CFIThe TUGThe GDSEQ‐5D7)The PASE,We measured grip strength of the dominant hand of the participant in kilograms by using a Smedley‐type handheld dynamometer .The primary outcome measure for establishing effectiveness was the change of cognitive function using the MMSE score. Secondary outcome measures included the changes in Five Cog, CFI, TUG, grip strength, GDS, EQ‐5D and PASE. Details of the outcome measures are as follows.Our study protocol was approved by the ethics review committee of Kobe Gakuin University and the WHO ethics committee (ERC.0002899). The study was carried out in accordance with the provisions of the Declaration of Helsinki and Japan's ‘Ethical Guidelines for Medical and Health Research Involving Human Subjects.’P = 0.39) and measurement results  who underwent 10 sessions of intensive training. The mean (SD) age of the participants was 76.4 (2.7) years, and the mean years of education were 12.0 (2.3) years. We excluded from the project subjects who missed the intensive training three or more times. Forty‐nine participants received PIT assessment. We randomly assigned 25 participants to the BTG and 24 to the NonBTG. Sixteen participants dropped out during the follow‐up period, and the eventual number of participants at the FU‐4 assessment was 16  in the BTG and 17  in the NonBTG. The chief causes of the dropouts were personal matters and hospitalisation due to poor physical conditions  and the subtests of the Five Cog (attention (P < 0.0001), memory (P < 0.0001), language (P = 0.035) and reasoning (P = 0.025)) showed significant improvement after intensive training. The TUG test time for evaluating physical performance also improved significantly (P < 0.0001). We did not find any improvement in CFI, grip strength, GDS, EQ‐5D and PASE  showedP = 0.006) and the TUG (P < 0.0001)  Table , the paiIn this study, we observed positive effects on cognitive function in the MMSE and the Five Cog assessments , although the CFI did not show any significant changes. MMSE showed a statistically significant improvement, but the score changed only by 1 point, showing no great clinical impact. There were 10 sessions of intensive training, carried out weekly, and the period between baseline and PIT assessment was only approximately 3 months. The result of the intensive training was the short‐term effect of the DPP.The training sessions mainly combined physical exercise and cognitive training; many other studies have shown the effects of each of these. A systematic reviewConversely, the results of cognitive training studies have indicated that training for executive functions  increases the efficiency of the prefrontal network, which provides support for brain functioning in the face of cognitive decline. Physical activity preserves neuronal structural integrity and brain volume, whereas cognitive activity strengthens the functioning and plasticity of neural circuits.Intensive training increased the scores for cognitive and physical functioning, but booster training had no significant effects on the psychosomatic functioning of the subjects in terms of changes both within and between the groups. The purpose of the 3‐monthly booster training was not so much as the direct effect of the training program itself but more to raise the participants' awareness of dementia prevention by training regularly. Raising awareness may lead to behaviour modification that promotes the health of the elderly in daily life. Exercises in daily life, particularly walking outside, can be a chance to communicate with one's neighbours. It has been reported that cognitive function tends to be reduced in people with few social networks, and a decrease in participation in social activity increases the risk of developing dementia.During the follow‐up period after the intensive training, neither group displayed a significant improvement at each evaluation. In a prospective observational study for the cognitively intact elderly (≦ 70), the MMSE scores of 16.9% of the participants fell by three points or more during the follow‐up period (average period of 2.7 years).This study was an exploratory study with a limited sample size, and the participants included cognitive‐healthy elderly individuals, excluding those with MCI. Therefore, the DPP effect on the incidence of dementia has not been clarified in this study. Although the booster training was performed on a 3‐monthly basis, the question of whether the municipality can bear the cost of such training should be considered, and it is possible that the effect may differ if the frequency is changed. Further research is required to develop a realistic and effective DPP.The intensive DPP might be useful for improving or maintaining the cognitive and physical functions of cognitive‐healthy elderly individuals. Although the effect of the booster training could not be verified, the physical and cognitive functions of the elderly participants were maintained for approximately two and a half years. These findings support conducting intensive training without follow‐up training, as this might have some effect in preventing dementia in the community‐dwelling elderly.