A single dose of preventive antibiotics is known to be sufficient to reduce the rate of infection-related complications in percutaneous nephrolithotomy (PCNL). However, some studies reported that the extended dose showed lower complications for high-risk groups. Therefore, we performed a systematic review and meta-analysis comparing single- and extended-dose antibiotic prophylaxis for PCNL.Relevant studies that compared single- and extended-dose antibiotic prophylactic therapies were identified. Articles were selected from PubMed, EMBASE, KoreaMed, and Google Scholar up to September 2021. Fever and systemic inflammatory response syndrome (SIRS) were compared by meta-analysis. A subgroup analysis was performed according to the degree of risk to the patient.2 = 64%]. Extended dose showed lower rate of SIRS compared to single dose ; in the subgroup analysis, extended dose also showed lower rates of SIRS compared to single dose in high-risk patients .A total of 10 articles were included in this study. There were no significant differences between single dose and extended dose in the rate of fever [p = 0.93, OR = 0.96, 95% confidence interval (CI) 0.44–2.13, IThe results of our meta-analysis showed that single-dose antibiotic prophylaxis can be effective for PCNL, but extended-dose antibiotics can be required in high-risk patients to reduce post-PCNL infection-related complications. Percutaneous nephrolithotomy (PCNL) has been the standard treatment for large renal stones since the first case reports by Fernstorm and Johnson in 1976 . To reduHowever, some studies have reported that an extended dose of prophylactic antibiotics showed lower rates of infection for high-risk groups vulnerable to post-PCNL complications compared to a single dose , 5. MoreIn its 2014 global monitoring report on antibiotic resistance, the World Health Organization (WHO) noted that the increased resistance of major bacteria to cephalosporins and fluoroquinolones was a serious health problem worldwide . ConsideThe inclusion criteria of this study were as follows: (a) patients with renal stones who underwent PCNL, (b) comparison of single- and extended-dose antibiotic prophylaxis for PCNL, and (c) outcome measures including fever and systematic inflammatory response syndrome (SIRS). A published study was excluded if it was not available in full text. This report was prepared in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement  7]. Thi. Thi7]. A systematic review was conducted to identify relevant, comparative articles that described the prophylactic use of single and extended doses of antibiotics for PCNL in PubMed, EMBASE, KoreaMed, and Google Scholar up to September 2021.Search strategies were established to include medical subject headings keywords, such as “kidney calculi,” “urolithiasis,” “percutaneous nephrolithotomy,” “PCNL,” “antibiotic prophylaxis,” and combinations of these search terms .Two researchers screened the titles and abstracts of articles that were independently identified by the search strategy to exclude irrelevant studies. They also assessed the full text of the articles for relevance. The most relevant articles were extracted from each study, and information such as author, year of publication, country, study design, patient characteristics , and treatments were recorded, as well as outcome variables such as “fever” and “SIRS”.We used the Cochrane Risk of Bias (ROB) tool for randomized control trial (RCT) and the methodological index for non-randomized studies (MINORS) for non-randomized trials.Quality of evidence was graded independently by our researchers (HDJ & DHK) using the Scottish Intercollegiate Guidelines Network (SIGN) methodology checklist. The SIGN checklist was used to assess the quality of various types of research, including systematic reviews and meta-analyses, randomized controlled trials (RCTs), cohort studies, case-control studies, diagnostic studies, and economic studies. All disagreements regarding the quality assessment results were resolved after discussion with a third reviewer (JYL).2 statistic was used to quantify heterogeneity [2 was less than 50%, we applied the fixed-effects model; otherwise, the random-effects model was used. The Higgins I2 statistic was calculated as follows:The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and reported. The chi-square test with p-values less than 0.05 was used to evaluate statistical heterogeneity, and the Iogeneity . If the A subgroup analysis was performed in three patient groups according to the degree of risk to the patient. If the patient had hydronephrosis or a stone size greater than or equal to 2 cm, the patient was classified as "high risk"; a patient was categorized as "low risk" in the absence of hydronephrosis or with a stone size less than 2 cm. Patients were considered "not specified" if the risk could not be determined. This systematic review is registered in PROSPERO, CRD 42022297928.A total of 831 studies were identified for potential inclusion in the meta-analysis. After a full-text review, 10 articles were identified as relevant for this study and selected for inclusion in the meta-analysis  4, 5, 99–16.The characteristics of the 10 included studies are shown in 2 = 64%). Random-effects models were used to compare the complication rates of fever between the use of single- and extended-dose antibiotics (2 = 53%), but the subgroup ("high risk" and "not specified") analysis revealed that there were few heterogeneities . Therefore, fixed-effects models were used to compare the complication rates between the use of single- and extended-dose antibiotics   . Risk cl2 = 53%). The results of subgroup analysis revealed lower rates of SIRS in high-risk patients who were administered extended dose of antibiotics compared to those administered single dose , but there were no significant differences between patients in the studies that did not specify the patient group   .et al. published a systematic review and meta-analysis on the use of antibiotic prophylaxis for PCNL [2 = 30%). On the other hand, the use of an extended dose of postoperative antibiotics was not superior to a single dose administered prior to anesthesia in terms of the sepsis rate . These authors concluded that extended-dose preoperative prophylactic antibiotics lowered the risk of postoperative sepsis and fever. However, in their study, the reason for the lower sepsis rate in patients administered extended dose of preoperative antibiotics may result from the fact that four of the five studies used in their meta-analysis were conducted in high-risk patients.Recently, Yu for PCNL . They anet al. conducted an RCT on the use of 2 days or 7 days of preoperative antibiotics for PCNL in patients at moderate to high risk of infection [et al. also reported that the use of extended-dose preoperative antibiotics offered no advantage in low-risk patients (negative preoperative urine cultures and no urinary drain) [There are no recommendations for the use of antibiotic prophylaxis for PCNL in high-risk patients in either the EAU Guidelines on Urolithiasis and Urological Infections or the AUA guidelines , 3. Recenfection . These ay drain) . In thei2 = 36%), but not in non-specified patients .We analyzed the effectiveness of preventive antibiotics for PCNL by distinguishing high-risk patients in a subgroup analysis. The use of an extended dose of antibiotics resulted in lower rates of SIRS compared to a single dose in high-risk patients  that could impact the outcomes. Since antibiotic resistance varies by country and region, it is not possible to analyze the effects of the same antibiotics for PCNL. The use of antibiotics is recommended according to local antimicrobial susceptibility information, clinical settings, and a patient’s risk factors for antibiotic resistance . TherefoA single dose of antibiotics administered prophylactically for PCNL can be effective and sufficient; however, in patients at high risk for post-PCNL infections, the use of extended dose of antibiotics may be required. Therefore, future prospective randomized trials with large sample sizes should be performed on this matter.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


APOE rs429358 and rs7412 polymorphisms) factors to study the progression of subjective cognitive impairment while observing patients for one year. Cognitive training was used as a protective factor. (2) Methods: Two groups of subjects over the age of 65 participated in the study: group with subjective cognitive decline receiving cognitive training and individuals who did not complain of cognitive decline without receiving cognitive training (comparison group). On the first visit, the concentration of antibodies to COVID-19 and APOE genotype was measured. At the first and last point (1 year later) the Mini-Mental State Examination scale and the Hospital Anxiety and Depression Scale were performed. (3) Results: COVID-19 infection did not affect cognitive function. A significant role of cognitive training in improving cognitive functions was revealed. Older adults with APOE-ε4 genotype showed no positive effect of cognitive training. (4) Conclusions: Future research should focus on cognitive dysfunction after COVID-19 in long-term follow-up. Attention to the factors discussed in our article, but not limited to them, are useful for a personalized approach to maintaining the cognitive health of older adults.(1) Background: Older people suffer from cognitive decline; several risk factors contribute to greater cognitive decline. We used acquired (COVID-19 infection) and non-modifiable (presence of  The aging of the population in developed countries around the world is currently taking place. Older people often suffer from cognitive decline: difficulties with memory, learning and later inability to care for themselves. Cognitive impairments seen in aging range from minor cognitive impairment to dementia .There are several risk factors for developing more severe cognitive impairment, age, gender, education and biological risk factors.In some cases, the degree of cognitive impairment in aging is classified as mild cognitive impairment (MCI). The term MCI represents a concept that reflect prodromal states of dementias of various underlying etiology . This co(APOE) gene remains the strongest genetic factor affecting the risk of AD after numerous large-scale genomic association studies and genomic association meta-analysis [APOE ε4 allele is found in 20–25% of AD patients, increasing the risk of the disease three-fold in heterozygous carriers and 15-fold in homozygous carriers [APOE ε4 allele is also associated with more severe tau pathology with higher Aβ plaque burden on PET studies and postmortem samples [APOE ε2 allele, on the contrary, is a significant protective factor [The main idea in identifying these intermediate stages of neuro-progression to dementia was the need for a timely identification of underlying disorder when a risk factor correction or pathogenetic intervention could be applied to prevent negative scenarios . Anotheranalysis . The APOcarriers . The APO samples . The APOe factor .APOEε4 allele increases the risk of MCI symptoms rapidly worsening into dementia [APOE ε4 and MCI led to more severe pathological symptoms [There are studies supporting evidence that the presence of dementia . Interacsymptoms .In our study we consider COVID-19 infection as an acquired risk factor.The possible cognitive effects of coronavirus disease are explained by the capacity of the virus to penetrate the blood–brain barrier, interacting with endotheliocytes, nerve cells and glia and causing neuroinflammatory reactions ,12. OverCoronavirus infection impairs neuroimmune axis function, which may be involved in cognitive impairment in mental illness and increases levels of IL-1β and IL-6 in the brain, both of which tend to suppress synaptic plasticity, affecting learning and memory .The most frequently disclosed psychiatric symptoms in coronavirus are low mood, mood swings, hopelessness, heightened anxiety, sleep/wake cycle dysregulation and neurocognitive disturbances including brain fog, difficulties with memory, concentration and executive function . It is aAPOE gene polymorphism can affect susceptibility to SARS-CoV-2 infection, COVID-19 severity and mortality [APOE ε4 allele was a risk factor for severe COVID-19 and post-COVID mental fatigue [ε2 allele against SARS-CoV-2 infection was shown [APOE ε4 carriers, suggesting that some of these effects may be mediated by increased cerebrovascular damage [In turn, as has been shown, the ortality ,22,23. T fatigue ,23, wherr damage .APOE genotype [It is assumed that the long-term cognitive and neurological effects of COVID-19 infection may also depend on the clinical course of the disease and the genotype ,25, but genotype . ProspecOne of the main strategies to intervene against acquired risk factors and reduce the progression of MCI into dementia is cognitive training, involving training memory, attention and other mental functions. Conducting various neurocognitive rehabilitation programs has a positive effect on the cognitive functions of patients with MCI. A study by Peng et al. showed significant cognitive improvement 6 months after starting training compared to the control group . SeveralAccording to the new paradigm of positive gerontology, the emphasis is not on dis-ease as an obligatory link to aging, but on the ability to use mental resources in the third and fourth age. The development of modern approaches to rehabilitation of cognitive deficits uses predictive models with multimodal markers, which is important for medical professionals for diagnosis and identification of therapeutic and rehabilitation targets, as well as for non-medical specialists who work with the problem of cognitive competence decline at the stage of late ontogenesis. Genetic and environmental factors are being studied both in connection with the development of neurodegenerative and cerebrovascular diseases and in connection with the re-organization of cognitive resources. The coronavirus pandemic is a new and serious factor in cognitive decline, the role of which requires a long study.APOE genotype as factors contributing to cognitive decline in older adults with a follow-up period of 1 year. An additional aim of our work was to investigate the assumption of a positive effect on cognitive function of the rehabilitation program in the presence of other risk factors.The aim of our study was to investigate association between COVID-19 infection and The study included individuals observed at the N.A. Alekseev Clinical Hospital No.1 from September 2020 to February 2022. The first point of observation was the end of 2020 (15 September 2020 for the first subject and the first follow-up took place on 7 October 2021).People who came to the “Memory Clinic” of Mental-health Clinic No. 1, named after N.A. Alekseev of the Moscow Healthcare Department, with subjective cognitive decline. These subjects received cognitive training. The study included individuals with complaints of forgetfulness, lack of attention and concentration , episodic difficulties in finding their way home, feeling if hard to articulate their thoughts, decreased professional and social productivity, impaired motor skills  and experiencing problems in everyday life .People who came to outpatient clinic No 121 (Moscow) to receive COVID-19 vaccination. This group of subjects did not complain of cognitive decline. No cognitive training was conducted with this group (comparison group).Two groups of subjects over the age of 65 participated in the study:APOE genotype was measured. At that observation point, there were no COVID-19 vaccinated individuals among the subjects. At the first and last follow-up point, cognitive tests were performed using the Mini-Mental State Examination (MMSE) scale [On the first visit, the concentration of antibodies to COVID-19 and E) scale  and clinE) scale . The perSubjects were excluded due to any of the following: dementia, psychiatric illness, positive family histories (first-degree relatives) of psychiatric illness; substance abuse; severe somatic diseases.As part of the federal project “The Older Generation” and the regional program “Active Longevity”, in 2016 Moscow organized a network of “Memory Clinics”, consisting of clinical and rehabilitation units for day care patients. An interdisciplinary team approach involving psychiatrists, psychologists, medical and social workers was used to implement a comprehensive medical and rehabilitation program.Fast recovery of individuals with cognitive decline after the medical and rehabilitation program and restoration of all components of the higher mental functions is shown; an adaptation of the program taking into account conditions of coronavirus pandemic did not demand increased duration, nor cardinal change in the form of training. The duration of the rehabilitation cycle is 6 weeks, 96 h of sessions, with a clear principle of progressive complication and repeated practice of structured tasks to improve certain cognitive functions. Rehabilitation was conducted in a group format. Groups of 8–9 persons were formed taking into account age and cognitive similarity. The first module of cognitive training, “psycho-education”, lasts 1 week, then during 2–6 weeks cognitive-therapeutic sessions include neurocognitive training twice a day for 60 min and classes of “adaptive physical training”  or sparing (70–85 points)) and psychotherapy. Neurocognitive training is aimed at restoration of visual-spatial gnosis, speech, mnestic, kinesthetic, tactile and somatognostic processes, attention, goal setting, control and the activation of energetic processes of the organism . Psychotε2/ε3/ε4 alleles of the APOE gene were determined by real-time PCR based on genotyping for the rs429358 and rs7412 markers as described previously [Genomic DNA samples were obtained from peripheral blood lymphocytes using an automated DNA extraction system  according to the manufacturer’s recommendations. The IgG antibodies to SARS-CoV-2 in subjects’ serum were determined using SARS-CoV-2-IgG-IFA-BEST and SARS-CoV-2-IgM-IFA-BEST test systems , providing positivity rate as a semi-quantitative measurement result.Study population was characterized by means of descriptive statistics providing means and standard deviations (S.D.) for continuous variables and absolute and relative frequencies for categorical variables. Between-group comparisons were performed using One-way ANOVA for continuous variables and Pearson Chi-square test for categorical variables.APOE-ε4 polymorphism on pre-post changes in total MMSE score.Full-factorial repeated-measures ANOVA model was used to assess effects of group, ant-COVID-19 IgG status and APOE polymorphism and COVID-19 affected changes in cognitive scale total score from background to endpoint across groups, we first built a regression model with dependent variable of MMSE total score changes, with group as fixed factor and age and baseline MMSE score as a covariate. As the second step, we separately added to this model a number of ε2 and ε4 alleles of the APOE as factors and IgG against SARS-CoV-2 as a covariate and evaluated gain in R2. To assess how Since depression may cause cognitive dysfunction and COVID-19 is associated with subsequent depression, we used ANCOVA to check ho background depression score on HADS scale as the covariant affected 1-year MMSE changes between groups and used Pearson correlation and one-way ANOVA to check if COVID-19 antibodies  influenced the HADS depression score.Graphical scheme of research and testing of statistical hypotheses is shown in Complete data were obtained from 125 people who applied for the cognitive training program and 34 in the comparison group. General characteristics of the studied population are shown in APOE polymorphisms and presence status and quantitative IgG content for COVID-19. Participants in the groups differed in their COVID-19 antibody content. APOE genotype.APOE-ε4 genotype and time × group × anti-COVID-19 IgG status and four-way time × APOE-ε4 genotype × anti-COVID-19 IgG status × group interaction are presented in Repeated-measures ANOVA  revealedp < 0.001) and arithmetically but not statistically significant deterioration in the comparison group  to 26.5 , p = 0.312). Status of anti-COVID-19 IgG  there was no improvement of MMSE total score during follow up period.Independently of anti-COVID-19 IgG status, and despite that there was no significant effect of observed C,D. In aThe ANCOVA showed no statistically significant effect of the initial HADS depression score on changes in the MMSE total score .p = 0.622) and did not differ between participants with positive and negative test for anti-COVID-19 IgG .Initial HADS depression score was not associated with IgG antibodies to COVID-19 , indicating that group factor significantly influenced 1-year MMSE total score changes after adjustment in age and background MMSE scores.The results of linear regression of MMSE changes with group as the fixed factor and age and background MMSE scores as covariates were significant , whereas adding of ε2 allele or anti-SARS-CoV-2 IgG count did not affect initial model results significantly.APOE rs429358 and rs7412 polymorphisms) factors. We also evaluated the effect of the cognitive training program on MMSE scores, taking these factors into account.We conducted a long-term study of cognitive function changes in older adults over 1 year under the influence of acquired (COVID-19 infection) and non-modifiable , MCI subjects who developed dementia, had lower scores on tests of long-term visual memory and semantic fluency. MCI subjects who developed dementia were more likely to have at least one copy of the 4 allele .APOE genotype, as this is well known from the literature. We based our analysis on age-appropriate cognitive changes in subjects and the available polymorphism. In our opinion, no strong correlations with the two polymorphisms have been shown, because an individual can be diagnosed with AD over the course of a lifetime and the study of associations is performed precisely on the diagnosis without regard to age. In addition, our subjects received cognitive training, which helped to reduce the progression of cognitive impairment and influenced score changes more than genotype. This suggests that, even though the APOE genotype is associated with dementia, with adequate treatment and cognitive training, the onset of severe cognitive effects can be delayed, improving quality of life. Thus, a subject’s genotype can be used to identify individual risk, in order to prescribe preventive cognitive training even before the onset of disease symptoms. In this case, the progression of MCI and the transition to dementia can be delayed almost as much as in people without the “bad” polymorphism.It is important to note that in our study we did not aim to test correlations between cognitive decline and the APOE genotype. In contrast, the general regression model revealed a significant contribution of this polymorphism. At first glance, these results appear conflicting, but these contradictions are eliminated if we understand the meaning of the results obtained. The small number of mutant allele carriers limits the statistical power of the study when we compare several groups. In contrast, regression analysis treats all participants as a single group, which increases the statistical power of the estimates. Our initial regression model estimated the variability of changes in MMSE total score and accounted for group, age and controlled for background MMSE total score. This model explains 25% of the variability in MMSE score changes. Adding APOE genotype variable into this initial model adds an additional 3% to the explanatory ability of the model. Thus, we found that APOE-ε4 polymorphism represents a significant and independent contributor to the 1-year change of total MMSE score in the older subjects.Based on repeated measures ANOVA, we did not find a significant effect of the The limitations of our study were that we did not assess the coronavirus infection in mid- and late 2021, while subsequent infection could also have affected cognitive function. However, it should be noted that the comparison group was recruited from those who presented to the outpatient clinic for vaccination; accordingly, most of the study subjects were vaccinated after one point of follow-up. It was already difficult to distinguish between the presence of antibodies due to the disease and due to vaccination at that time.Cognitive training is a positive factor in reducing cognitive impairment.COVID-19 infection had no effect on cognitive function during the 1-year follow-up in older adults.APOE-ε4 genotype showed no positive effect of cognitive training.Older adults with The main findings of our study were:Cognitive training is a protective factor against cognitive decline that retains its importance in COVID-19 survivors. Future directions should focus on a more thorough analysis of cognitive dysfunction after COVID-19 in different groups of psychiatric subjects.The findings are important for predictive models within the positive gerontology paradigm. Similar models contribute to the development of modern methods of specialized prevention of cognitive decline. Attention to the factors discussed in our article, but not limited to them, are useful for a personalized approach to maintaining the cognitive health of older adults.


The aims were to investigate the associations between specific mental and somatic disorders and subsequent all-cause and cause-specific mortality  in young refugees and non-refugee migrants compared with Swedish-born individuals of similar age.In this register-based prospective cohort study, all 1 003 760 individuals , 16–25 years old, residing in Sweden on 31 December 2004 were included. These individuals were followed regarding the outcome of all-cause and cause-specific mortality  between 2005 and 2016. The study population was also stratified according to any use of specialised healthcare for mental or somatic diagnoses before baseline (2000–2004). Cox regression models yielding crude and multivariate Hazard Ratios  with 95% Confidence Intervals (CI) were used to investigate the afore-mentioned associations.A lower proportion of both refugees (12%) and non-refugee migrants (10%) had college/university education compared with the Swedish-born individuals (17%). The proportion of unemployed (>180 days) among refugees (2.3%) and non-refugees (2.9%) was higher than the Swedish born (1.4%). Refugees and non-refugee migrants had about a 20% lower risk of all-cause mortality and external causes of mortality compared with Swedish-born individuals. An even greater reduction in suicide risk  was found. When restricted to those with a mental or somatic disorder, a lower risk of both general and specific mortality was also found among both refugees and non-refugee migrants compared with Swedish-born individuals. Refugees had, however, equal point estimates of all-cause mortality associated with substance misuse disorder and neoplasms as their Swedish-born peers with these disorders.With few exceptions, young migrants with specific mental and somatic disorders have a mortality advantage compared with their Swedish-born peers with the same disorders. Further research on protective factors is warranted. Longitudinal population-based design and use of national registers with high completeness and validity.Lack of data from primary healthcare may have led to differential underestimation of the mental and somatic disorders among migrant groups than Swedish-born host population.Generalisability is limited to countries with similar healthcare and social welfare systems, and populations with similar ethnic composition compared with Sweden.The results cannot be generalised to individuals living in refugee camps or immigration detention centres.During the past few years, there has been a substantial increase in global migration. In 2017, there were 258 million migrants worldwide, including 25.4 million refugees.6–12Despite the large numbers of young refugees worldwide and their higher morbidity risk, there is a scarcity of studies focussing on the most prominent health outcomes, that is, mortality, in this group. Mortality is a relatively rare event among young persons in general and death are mainly attributable to external causes including suicide, injuries, accidents and poisoning.Besides these higher prevalence rates of mental disorders, the occurrence of some somatic disorders (any non-psychiatric disorder), including, for example, infectious diseases as well as diseases of the respiratory system and the nervous system, appears to be prevalent in refugees.Studies report differences in the prevalence of both mental and somatic disorders as well as multimorbidity between subgroups of migrants.This study aims to address the afore-mentioned gaps in the literature by investigating if the risk of all-cause and cause-specific mortality differs in young refugees and non-refugee migrants compared with individuals in the host population of the same age. A further aim was to investigate if the potential differences in all-cause and cause-specific mortality vary by a prior diagnosis of specific mental and somatic disorders.A cohort study was conducted where the study population was defined as all individuals aged 16–25 years, residing in Sweden on 31 December 2004, that is, born between 1979 and 1988 (n=1 081 412). Only those with complete information on their reason for settlement in Sweden were included (n=1 048 762) because determining refugee versus non-refugee migrant status depends on the availability of this information. Individuals with incomplete information regarding this variable are primarily EU citizens who do not register their (and their families’) right of residence with the Swedish Tax Agency. For the non-refugee migrants, we excluded those who did not come from the same countries as the refugees (n=9008) to investigate if traumatic experience as a refugee had affected mortality outcomes given that the postmigration conditions and the cultural background can be considered similar between refugees and non-refugee migrants from the same countries. A further 35 994 individuals were excluded because they did not reside in Sweden during the period 2000–2004, that is, the period during which mental and somatic disorders were measured. The final study population comprised of 1 003 760 young individuals aged 16–25 years, including 40 305 refugees and 31 687 non-refugee migrants with residence permit . Individuals in the study population were then followed from 2005 to 2016 regarding the outcome measures (please see the section Outcome measures) by linking several nationwide registers.As this study builds on administrative registers, patients were not involved in the conduct of this study.We used the unique (deidentified) Swedish personal identity number to link information from several population-based registers. The researchers had full access to these databases. The Longitudinal Integration Database for Health Insurance and Labour Market Studies contains data on sociodemographic and labour market factors. The Longitudinal Database for Integration Studies holds migration-related information, including reasons for settlement . The National Patient Register (NPR) includes information on inpatient healthcare since 1987, and for specialised out-patient care since 2001. Diagnoses in NPR are coded according to the International Classification of Diseases, version 10 (ICD-10). The Cause of Death Register comprises information on causes and date of deaths of Swedish residents since 1952 (and including deaths registered abroad since 2012).Mental disorders were defined as having a main diagnosis from specialised healthcare , as recorded in the NPR between 2000 and 2004, of the following disorders: substance misuse disorders (ICD-10: F10–19), schizophrenia/non-affective psychotic disorders (F20–29), depressive disorders (ICD-10: F32–34), anxiety disorders (ICD-10: F40–42), stress-related disorders (F43) and behavioural disorders .Main diagnoses in specialised healthcare (2000–2004) for somatic disorders were divided into dichotomised variables of following groups of diagnoses, recorded according to the ICD-10: (1) infectious and parasitic diseases (ICD-10: A00–B99), (2) neoplasm (ICD-10: C00–D48), (3) diseases of the circulatory system (ICD-10: I00–I99), (4) diseases of the respiratory system (ICD-10: J00–J99), (5) diseases of the digestive system (ICD-10: K00–K93), (6) musculoskeletal diseases (ICD-10: M00–M99), (7) diseases of the nervous system (ICD-10: G00–G99) and (8) other somatic disorders .The outcome measures were defined as both all-cause and cause-specific mortality. More specifically, we studied external causes  as one outcome, and within this group, suicide  was examined separately.The covariates included in the analyses were (1) sociodemographic factors: sex, age, educational level, type of living area and family situation ;(2) work-related factors: unemployment ; sickness absence  and disability pension, all measured during 2004. Missing values in any covariates were treated as a separate category in the adjusted analyses. Categorisations of covariates are shown in Statistical analyses were conducted using SAS, V.9.4. Crude and multivariate analyses were performed using Cox regression models of time to diagnosis-specific and all-cause mortality during the follow-up. The proportional hazard assumption was verified graphically using log-minus-log plots  over the different categories for each of the covariates and exposure variables. We assessed person-years at risk by totalling the years that the individuals were living in Sweden during the follow-up period. Calendar day was used as the underlying timescale and age at study entry was adjusted for in the multivariate-adjusted models. The entry date was defined as 1 January 2005, and the exit date as the date of the first outcome, date of emigration or the end of follow-up on 31 December 2016. All individuals who emigrate are expected to notify the Swedish Tax Agency and this information is updated in all administrative registers. However, as it is possible that not everyone reports the emigration status, we additionally identified all individuals who did not have any information in the population register for two consecutive years and considered that they have emigrated during the former year (if they had not died before that) to compensate for the under-reporting. First, risk estimates for refugees and non-refugee migrants were compared with those for Swedish born regarding subsequent all-cause mortality and cause-specific mortality. The association of mental and somatic disorders and subsequent all-cause mortality with refugee status was then assessed. Here, analyses were performed for any mental or somatic disorders and then we conducted separate analyses for each diagnostic group (only specific disorders where number of cases exceeded 10 either in refugees or non-refugee migrants are shown in tables). We examined the associations between migrant status and each outcome in one crude and one adjusted regression model. Model 2 was adjusted for age, sex, education, family situation, type of living area, unemployment, sickness absence and disability pension, and finally morbidity . Due to lack of data on time-dependent variables, we measured these covariates only at baseline. All covariates known to be associated with both the exposure and the outcome that do not fall in the causal pathway and for which data were available were included in the multivariate adjusted models. The directed acyclic graphs of unadjusted and adjusted models  was found comparable to both Swedish-born (51%) and non-refugee migrants 49%, . There wBoth refugees and non-refugee migrants had about a 20% lower risk of all-cause mortality and mortality due to external causes, while the risk of suicide was around 50% lower among non-refugee migrants and nearly 40% lower among refugees compared with Swedish-born individuals . No diffCompared with Swedish-born youth without any mental disorder, Swedish-born individuals with mental disorders had higher risk of all-cause mortality  as well as for death by suicide  and external causes . These estimates were lower in both non-refugee migrants  and refugees  in the multivariate analyses. Similar patterns were found for specific mental and somatic disorders, with the exception of substance misuse disorder and neoplasms, where refugees and Swedish-born individuals had similar risk estimates.The lower mortality risk in young migrants compared with the host population is in line with previous studies including all age groups.Several models have been put forward to explain the mortality advantage among migrants.While estimates for all-cause mortality and mortality due to external causes were comparable, we found the suicide risk in the young migrants to be particularly low. This finding is in contrast to previous reports on an increased suicide risk in young asylum-seeking minors,Our study examined the associations between mental and somatic disorders and subsequent all-cause and cause-specific mortality in young refugees and non-refugee migrants. Studies investigating these associations in the general population—without a focus on migrants—have shown that individuals with mental disorders have a considerable higher risk for death due to external causes and suicide.24 35Two exceptions to this pattern occurred, however. Estimates for all-cause mortality were equally high for young refugees and Swedish born with substance use disorders and cancer.These differences in patterns might be related to the high medical severity of these two disorders and the fact that culturally influenced resilience factors such as favourable health behaviour and strong social ties might be less relevant in protecting against preterm mortality related to these disorders.This study has several strengths, including the longitudinal population-based design and use of national registers with high completeness and validity. The large cohort size allowed for detailed analyses of different types of mental and somatic disorders, the ability to adjust for important confounders and a rare outcome. Nevertheless, there are limitations. As information on primary healthcare was not available, we used data from specialised healthcare, which captures only the more severe forms of morbidity. Due to different barriers to access healthcare that are specific to immigrants,The risk of all-cause mortality as well as specific mortality due to suicide and death due to external causes is lower among young refugees and non-refugee migrants compared with Swedish-born individuals. The lower rate of mortality of refugees can also be seen among those with specific mental and somatic disorders. With few exceptions, young migrants with specific mental and somatic disorders have a mortality advantage compared with their Swedish-born peers with the same disorders. Further research on protective factors is warranted.


The adjusted models showed that the COVID-19 period had a significant relationship with a higher rate of ACA (odds ratio (OR) = 1.87; 95% confidence interval (CI): 1.23–2.52; p = 0.008) and longer length of hospital stays . (4) Conclusions: The fear of COVID-19 may prohibit patients from seeking medical help, worsening their clinical outcomes. The surgical community should take action to provide scientific information to relive mental stress.(1) Background: The coronavirus disease 2019 (COVID-19) pandemic had overwhelming impacts on medical services. During its initial surge, Taiwan was unique in maintaining its medical services without imposing travel restrictions, which provided an ideal environment in which to test if the fear of becoming infected with COVID-19 interfered with health-seeking behavior (HSB). We tested this hypothesis among adults with acute complicated appendicitis (ACA). (2) Methods: Adults with acute appendicitis were enrolled between 1 January and 30 June 2020 (COVID-19 period). The first two quarters of the preceding 3 years were defined as a historical control group. Outcome measures included the rate of ACA and the number of hospital stays. (3) Results: The COVID-19 era included 145 patients with acute appendicitis. Compared to the historical control (320 patients), the COVID-19 era was significantly associated with a higher length of symptom duration until presentation to the emergency room within >48 h (17.2% vs. 9.1%,  Health-seeking behavior is described as “steps taken by a patient who perceives a need for help when he or she tries to solve a medical disease” . In otheThe new variant of severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), first broke out in China in December 2019 and rapidly spread worldwide . As of 3Acute appendicitis is not only one of the most common causes of acute abdominal diseases in adults , but alsTaiwan is very close to the coast of China and was predicted to be likely to experience a high number of cases in 2020 due to the many flights that occur between the countries. However, Taiwan surprisingly controlled its sporadic outbreaks of COVID-19 well by implementing several public health responses  and did The rest of this paper is organized as follows. A retrospective study was conducted to review the records of adult patients with acute appendicitis (≥20 years) in one academic center during the COVID-19 epidemic period from January to June 2020. Next, patients with acute appendicitis from the same months, January to June, in 2017, 2018, and 2019 were considered as the control group. The same interval every year was analyzed because a previous study demonstrated that the incidence of acute appendicitis was associated with seasonal variation . The excThe data analyzed included clinical demographics such as age, gender, body mass index (BMI), residence in Taipei/New Taipei City, body temperature measured at the emergency room (ER), white blood-cell count (WBC), and the time interval from symptom onset to ER arrival. The weighted Charlson comorbidity index (CCI) score was used to account for the comorbidity burden ,17. FurtFurthermore, the trend of the total number of surgeries (elective and emergent operations) during the study periods was analyzed to reflect the overall impact of COVID-19 on surgical patients seeking medical services. p < 0.05.Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 26.0 software . Continuous variables  were presented as medians with interquartile ranges (IQRs), and categorical variables  were expressed as numbers (percentages). Categorical variables were compared using the Chi-square test or Fisher’s exact test (the numbers were <5). Continuous variables between groups were compared using the Mann–Whitney U test. The binary logistic regression model was used on associated variables to determine the odds of ACA occurrence. Furthermore, a linear regression model was created to predict the length of hospital stays. Statistical significance was assumed at p = 0.019) and a significantly higher rate of symptom duration until presentation to the ER within >48 h  in comparison with the non-ACA group. No differences were observed in the median age, gender, BMI, or CCI score category between adults with ACA and non-ACA.During the 26-week COVID-19 study period, 145 patients with acute appendicitis were treated in our institute . No patiTo determine the impact of the COVID-19 pandemic on the severity of appendicitis, 9/L, p = 0.010) and rate of symptom duration until presentation to the ER within >48 h  were significantly higher during the COVID-19 period compared to the control period. Overall, a higher incidence of ACA  and a longer median length of hospital stays  were observed during the COVID-19 period.For comparisons during the COVID-19 period, a control cohort comprising 320 patients was identified over 18 months between 2017 and 2019 . No diffp = 0.008) and symptom duration until presentation to the ER within >48 h  were significantly associated with ACA development. Further, the adjusted linear regression model was used to predict the length of hospital stays (p < 0.001) and the COVID-19 period  were significantly associated with a longer length of hospital stays.To validate the association between the COVID-19 period and ACA onset, one binary multivariate model was developed to predict ACA occurrence , showingal stays , demonstp = 0.180), respectively, whereas the mean numbers of emergent operations in the control period and the COVID-19 period were 4576 and 4601 (p = 0.650), respectively. Although both were not statistically significant, the COVID-19 pandemic caused a more significantly decreased number of elective operations compared to emergent operations. This implies that the COVID-19 pandemic not only changed the behavior-seeking surgical services of patients without emergent needs but also worsened the surgical outcomes of patients with emergent needs. On the other hand, the trend of the total number of surgeries during the study periods is shown in The COVID-19 pandemic was the most concerning health problem in 2020 because it caused not only health disorders but also extensive restrictions on people’s daily lives worldwide. During our study period, Taiwan avoided the worst effects of the pandemic due to its implementation of a broad public health infrastructure and domains of effective screening, isolation/quarantine, and facial mask use . AlthougIn our study, symptom duration from ER presentation to >48 h after was found to be significantly associated with ACA, which was similar to the results of a previous report . ProlongIn addition to the impact of clinical and socioeconomic determinants on outcomes, poor health-seeking behavior has been proven to increase morbidity and mortality . PatientAlthough healthcare systems, disparities of medical supplies, and socioeconomic status are the main barriers to medical services ,28, the Based on our experiences, surgical need declined during the COVID-19 pandemic even if the outbreak was not severe in Taiwan. We allocated the members of surgical teams to other departments in order to prevent infection and enable better care for patients with COVID-19. During the study period, more than 24,000 man-hours of labor were provided by our surgical teams. With this help, the workload of the departments in charge of care relating to COVID-19 was partially relieved. This study had some limitations. The study design was retrospective and it was conducted in one universal healthcare system, which alleviated part of the barrier of access to healthcare services. Second, the period from 1 January to 30 June 2020 was selected because the spread of COVID-19 was more severe during this period. The use of different study periods might lead to different results. Third, the referral policy was associated with delayed medical visits but was consistent during the study period in Taiwan. Some studies addressed the fact that general practitioners preferred to offer medical treatment for patients with acute appendicitis without referring them to the ER . Based oBased on our findings, the COVID-19 era had a significant relationship with a delayed presentation to the ER and led to an increased rate of acute complicated appendicitis in a community with normally functioning medical services and no travel restrictions. Medical professionals play a key role in delivering accurate information and knowledge, helping to eliminate panic, and encouraging patients to pursue medical attention promptly. With the recommendations made in this study, the collateral impact of this communicable disease may be partially alleviated. However, if the COVID-19 outbreak continues, medical services will be further negatively affected. Under these circumstances, healthcare systems should adopt other policies and rationally allocate medical resources in order to effectively maintain medical services.


Cancer is an important cause of morbidity and mortality worldwide, irrespective of the level of human development. Globally, it was estimated that there were 19.3 million new cases of cancer and almost 10 million deaths from cancer in 2020. The importance of prevention, early detection as well as effective cancer therapies cannot be over-emphasized. One of the important strategies in cancer therapy is targeted drug delivery to the specific tumor sites. Nanogels are among the several drug delivery systems (DDS) being explored as potential candidates for targeted drug delivery in cancer therapy. Nanogels, which are new generation, versatile DDS with the possession of dual characteristics of hydrogels and nanoparticles have shown great potential as targeted DDS in cancer therapy. Nanogels are hydrogels with a three-dimensional (3D) tunable porous structure and a particle size in the nanometre range, from 20 to 200 nm. They have been visualized as ideal DDS with enormous drug loading capacity, and high stability. Nanogels can be modified to achieve active targeting and enhance drug accumulation in disease sites. They can be designed to be stimulus-responsive, and react to internal or external stimuli such as pH, temperature, light, redox, thus resulting in the controlled release of loaded drug. This prevents drug accumulation in non-target tissues and minimizes the side effects of the drug. Drugs with severe adverse effects, short circulation half-life, and easy degradability by enzymes, such as anti-cancer drugs, and proteins, are suitable for delivery by chemically cross-linked or physically assembled nanogel systems. This systematic review summarizes the evolution of nanogels for targeted drug delivery for cancer therapy over the last decade. On-going clinical trials and recent applications of nanogels as targeted DDS for cancer therapy will be discussed in detail. The review will be concluded with discussions on safety and regulatory considerations as well as future research prospects of nanogel-targeted drug delivery for cancer therapy. Cancer is a major threat to humanity and is described as a generic term for large group of diseases that can affect any part of the body . The speThe objective of extraordinary research after the detection of malignancy is to find out quality method in the treatment of cancer using novel approaches. Over 60% treatment trials all going currently worldwide are centered on cancer . The choUse of chemotherapeutic is the important weapon of cancer and one of the most used cancer treatments that offers the best hope for cancer . ChemothChemotherapeutic agents can be categorized based on their chemical structures, mechanism of action and composition. Based on this category, some chemotherapeutic agents can fall into more than one group due to varied mode of action. The oncologists predict how effective a chemotherapeutic agent is by proper study on the mode of action including its side effects. Drug studies in combination chemotherapies help to decide the time, order and dosage of each drug administered in the therapy .Many cancers like lymphoma, leukemia, sarcoma, myeloma and Hodgkin’s disease are treated with alkylating agents . The mecAnthracyclines work by targeting DNA replication enzymes affecting cells in all cell cycle phases. They are also antibiotics. Various anticancer agents fall in the scope of this class of treatments. Exceeding a critical limit can permanently damage the heart and this is a big limitation of drugs under this group . ExampleAntimetabolites by incorporation, stop the growth of DNA and RNA as they are analogs for the units of DNA and RNA. This group of anticancer drugs affect the S phase of the cell in particularly and is used for the treatment of ovarian cancers, leukemia, intestinal tract and other forms of cancer . ExampleThese are antibiotics antitumor agents that do not belong to anthracycline. Examples include actinomycin D, mitomycin C, bleomycin. This class of anticancer drugs can damage the heart at high dosage . They caThese anticancer drugs cause the unwinding of DNA and so stop DNA replication. Most cancers like lung, leukemia, ovarian, gastrointestinal and others are treated with these drugs. Examples of topoisomerase I inhibitors are topotecan and irinotecan (CPT-II) and examples of topoisomerase II are etoposide (VP-16) and teniposide and mitoxantrone .These are plant alkaloids and are naturally derived products in nature. They function by inhibition of protein necessary for cell division especially in the mitotic phase of the cell cycle and subsequently damaging other phases too . These d®)  .Hormonal anticancer treatment is effective to treat cancer and is devoid of cytotoxicity which is associated with chemotherapy. Field of molecular biology advancement in recent years clarified the role of hormone therapy in cell growth and in regulation of malignant cells. About 40% of tumors in women and 25% in men are known to have hormonal basis. Hormone-like drug which are steroid are used in the treatment of cancers like lymphoma, multiple myeloma and leukemia. These steroids are also used as anti-emetic drugs to relief nausea and vomiting, they also mitigate hypersensitivity to the treatment in chemotherapy . ExampleCancer immunotherapy is made up of several vital steps and has been rapidly developed as a promising strategy for cancer treatment. The so–called cancer–immunity cycle include release of cancer antigens, presentation of cancer antigens by antigen-presenting cells (APCs), priming and activation of T cells, infiltration and trafficking of T cells to tumors and finally recognition and cytotoxic T cell killing of tumor cells. Current approaches to cancer immunotherapy mainly therapeutic antibodies, adoptive cell therapy, cancer vaccines might be the potential therapeutic target with various methods .Radiation therapy is a distinguished field of specialization in medicine with branches such as radiation oncology . This thAngiogenesis inhibitors are chemicals that can cut off blood supply to the tumor cells as nutrition to the tumor cells is provided by blood vessels. Examples of this agent are interferon, bevacizumab, thalidomide and cediranib, these drugs can be administered sometimes in combination with chemotherapeutic drugs to increase therapeutic outcome .Although all the available cancer therapies described in In recent years, nanogels have been proposed as potential drug delivery systems to overcome limitations of available conventional cancer therapies. The properties of nanogels and their applications as targeted drug delivery systems for cancer therapy will be discussed in According to 131I and camptothecin into a hybrid nanogel showed a high drug loading pH-controlled drug release profile capacity of 16.72 wt% with excellent biocompatibility and low hemolysis. This formulation enhanced drug accumulation at the tumor site, improved cell uptake and prolonged circulation in the blood. 3O4 nanoparticles were conjugated with Cy 5.5-labelled lactoferrin which served as bi-functional contrast agent for both MRI and intraoperative optical imaging for glioma  which was “incorporated into dendritic polyglycerol (dPG) cross-linked poly (N-isopropylacrylamide-co-N-isopropylmethacrylamide) nanogels (p (NIPAm-co-NIPMAm)) by semi-interpenetration to form the PPY/Co-dPG nanogels.”Physically cross-linked nanogels are supramolecular particles consisting of polymer molecules formed through non-covalent interactions . Physicac (CC).” The nanogels were efficacious against cancer cells with minimal toxicity to non-cancerous cells.Chemically cross-linked nanogels consist of polymers formed through covalent chemical interactions . The staN-isopropylacrylamide-co-acrylic acid) as shell to ensure optimal drug concentrations at tumour sites and cancer cell imaging. The nanogels were designed to shrink in respond to pH stimulus to enable increase in UV-vis absorption intensity for cancer cell imaging. The physicochemical properties of the inner core and outer shell enabled the nanogel penetrate into intracellular spaces for potential targeted and optimal anti-cancer drug delivery.Hybrid nanogels are defined as “composites of nanogel particles dispersed in organic or inorganic matrices” . ComposiNanogels are formulated with a varied range of materials. In drug delivery, the materials used in nanogel formulations are selected based on their safety profile, compatibility with the active pharmaceutical ingredients and their potential application. These materials can also affect the characteristics and stability of the finished nanogel formulation .N, N-dimethylamino) ethyl methacrylate). Nanogels are formulated with natural, or synthetic polymers or a combination of natural and synthetic polymers . NaturalBiomimetic nanogels have their surfaces coated with cellular membranes and other biological cellular components to mimic them. This enables them to evade elimination by the reticuloendothelial system and makes it possible for biomimetic nanogels to pass through physiological barriers for targeted drug delivery. They have been proven to exhibit high specificity and potency in cancer therapy . They arNanogels can be classified as stimuli-responsive nanogels based on their mechanism of drug release. Nanogels can be formulation to respond to different physical and environmental stimuli when ingested into the body. This feature of nanogels makes is possible for controlled and targeted drug delivery. Nanogels could be designed to release drugs only under certain physical or physiological conditions. These conditions may include specific temperatures, pH, magnetic fields, ultra-violet light, reduction reaction, oxidation-reaction, hypoxia conditions, among others . Stimulu+ T cells and natural killer (NK) cells for immunotherapy when compared to the free drug controls.Degradable stimuli-responsive nanogels are designed by cross-linking bonds that can disintegrate within the nanogel framework. When exposed to specific stimuli, the nanogel frame degrades through different mechanisms for targeted drug delivery. Nanogels have been used to successfully enhance the solubility of poorly soluble drugs, thereby improving their bioavailability. Nanogels have been reported to be effective in improving absorption of drugs with high molecular weights. Tacrolimus, is an immune-suppressive drug with high molecular weight. The nano-particulate dimension of nanogels provides them with unlimited prospects for targeted drug delivery. Targeting the delivery of drugs reduce drug losses within physiological spaces and enhances optimal drug concentration at targeted sites. In addition, targeted drug delivery reduces adverse drug reactions which may lead to poor adherence to medications. The vast range of materials used in nanogel formulations and their nano-sizes of nanogels produce versatile products which can be modified for controlled drug delivery. Nanogels have also provided opportunities for exploring new dosage forms of existing drugs. Artemether is currently available in oral and injectable dosage forms. Nanogels have also been reported to be efficient in the administration of proteins for therapeutic purposes. Ge10) nanogel, which rapidly converted Gemcitabine to its active derivative.When compared with other nanoparticles, nanogels have been useful in reducing the activation time of pro-drugs. Gemcitabine requires activation to be efficacious in cancer therapy. Nanogels have also been reported to be efficient in drug combination therapies. This feature is particularly important in reducing pill burdens, improving treatment outcomes of different disease conditions. Emerging formulation technologies have led to advancement in simultaneous combination of chemotherapy and other anti-cancer therapies through nanogels. Drug resistance in cancer therapy is a major limitation to efficient drug delivery to cancer cells and improved clinical outcomes. As discussed in Lung cancer is one of the most diagnosed type of cancer. Tobacco smoking has been reported to be the major causative factor for the high incidence of lung cancer globally . LiteratCisplatin , is an efficacious anti-cancer drug . CisplatGinsenoside Compound K (CK) is a secondary ginsenoside bio-transformed from major ginsenosides and serves as a potential anti-cancer compound . HoweverBreast cancer is the most diagnosed type of cancer in women. Certain physiological conditions have been reported to increase susceptibility to breast cancer . A few nHypoxia is one of the hallmarks of cancer micro-environments. It also reduces the efficacy of chemotherapeutic agents. Developing hypoxia-responsive nanogels is an innovative strategy to turn an apparent disadvantage into an advantage. The nanogels are designed to respond only to hypoxia in cancer micro-environments aiding the efficacy of targeted drug delivery . A few aThe nanogel released 75% of the RNase under hypoxic conditions within the cancer micro-environment. The tumor suppression rate (TSR%) of the free RNase was 0% while that of the RNase nanogel was 68.7%. They were able to achieve a higher TSR% of 91.7% for the RNase nanogel by incorporating vascular disrupting agents into the nanogel. This confirms that a significant increase in TSR% can be achieved when unstable anti-cancer drugs with poor membrane penetration are formulated as hypoxia-responsive nanogels.in vivo.” Analysis of the evaluation revealed there was over 6-fold higher cellular uptake of the protein from the dual-targeted nanogels when compared with the mono-targeted nanogels. The results concluded that dual-targeted protein therapy an efficacious therapy for breast cancer metastasis.epidermis and dermis” -loaded gelatin nanogels (GN) were formulated as inner cores while the outer cores consisted of platelets membranes (PTM). Since the outer core comprised of a natural membrane, the entire complex PTM/GN/IRN effectively evaded clearance by the reticuloendothelial system. The platelet also possessed the ability to accumulate at tumor sites, hence, it ensured accumulation of the complex at the tumor sites. They were able to prove that nanogels had the potential of improving drug delivery to solid tumors like colorectal cancer.Biomimetic nanogels have been described in via a modified water-in-oil-in-water (W/O/W) emulsion technique. In both methods, the DOX/CUR feeding ratio 1:1 was used. The nanogels were pH and thermo-responsive. The results of the experiment showed that the nanogel exhibited more anti-tumor efficacy than the individual drug formulations. Hence, simultaneous delivery of the dual drugs through the pH and thermos-responsive nanogels could synergistically potentiate the anti-tumor effects on colon cancer.Dual stimuli-responsive nanogels have been described in Prostate cancer is the second most common cancer type in men globally. The morality rate is declining due to early diagnosis and treatment .Aptamers are short single-stranded DNA or RNA oligonucleotides that can selectively bind to small molecular ligands or protein targets with high affinity and specificity . AptamerBladder cancer is the 12th -most common type of cancer globally . NanogelCamptotheca acuminata (Nyssaceae) and exhibits anti-cancer activity (co-l-cystine) (PLL–P (LP-co-LC)) containing 10-Hydroxycamtothecin (HCPT). The nanogel formulation penetrated the bladder walls, and released optimal concentrations of HCPT into bladder cancer cells. The HCPT nanogel was also retained longer in the bladder walls and had fewer side effects when compared with free HCPT. This proves that nanogels formulations of anti-cancer drugs have the potential to improve penetration of drugs through the bladder wall and ensure optimal drug concentrations in bladder cancer therapy.There is sub-optimal absorption of drugs used in the treatment of bladder cancer due to the poor penetration of the drugs through the bladder wall. The small quantity of drugs which are able to penetrate the bladder walls are often excreted rapidly as urine . 10-Hydractivity . Guo et Cancer of the brain and central nervous system (Glioma) is the 17th most common cancer type. Although scientists are still in the process of understanding the mechanism of malignant glioma formation, it is believed to be linked to the immune system . NanogelTerifunomide is currently being investigated for its potential therapeutic efficacy against glioma . GadhaveSquamous cell carcinoma (SCC) is an epithelial malignancy that occurs in various organs and tissues covered with squamous epithelium. The majority of SCC cases are reported to occur in non-melanoma skin cancer, head and neck cancer, esophageal cancer, and non-small cell lung cancer . In the Ovarian cancer is frequently aggressive and is generally detected at a late stage. It is the eighth most common cause of cancer death in women worldwide .In vivo evaluation showed that the nanogel discs were successful in the peritoneal delivery of paclitaxel and rapamycin in ES-2-luc ovarian-cancer-bearing xenograft mice.N-vinylcaprolactam) (PVCL), and glycidyl methacrylate (GMA) to develop dendrimer-decorated PVCL-GMA nanogels (NGs) for ovarian cancer therapy. The unique features of the polymers enabled manifestations of dual thermal and pH-responsive behaviors, which enhanced targeted drug delivery with minimal adverse effects.in vitro assay with a CD44 blocking/neutralizing antibody revealed that “hyaluronan receptor was involved in the nanogel internalization process.”in vivo and is a promising therapy for ovarian cancer.3 tumor volume of OncoGel was injected right into 18 superficial solid tumors of 16 cancer patients with no option of curative therapy. OncoGel injections were generally well tolerated. Out of the 14 patients who were assessed for disease progression, six had stable disease and eight had progressing disease. The drug remained localized at the tumor site thereby minimizing systemic effects. In the phase II dose escalation study, eleven esophageal cancer patients who were in advanced state of the disease and eligible for palliative external-beam radiotherapy (RT) were enrolled. Using standard endoscopic method, OncoGel was administered into the primary tumors, and RT initiated afterwards. From the result of the study, a combination therapy of OncoGel and RT was well tolerated in patients with inoperable esophageal cancer. The release of paclitaxel from the formulation was sustained and systemic exposure was minimal. Improvement in symptoms, reduction in tumor size and negative esophageal biopsies were seen in these patients  based vaccine candidates are the most promising applications of nanogels in cancer therapy. Cancer vaccines based on CHP nanogels have been in clinical trials since the late 2 decades with promising results. The preparation of CHP nanogel has been discussed in + and CD4+ immune responses in five patients  or OK-432. OK-432 is a low-virulence NY-ESO-1 is a cancer-testis antigen with restricted expression in germ cells and placental cells but frequently occur in multiple tumors like melanoma and carcinoma of lung, esophageal, liver, and prostate. It is a highly immunogenic antigen. However, due to the limited stability of NY-ESO-1 in aqueous solution, clinical applications will require an effective delivery system. Cholesterol-bearing hydrophobized pullulan (CHP) nanogels have been used to encapsulate NY-ESO-1 (CHP-NY-ESO-1) antigen and the safety and effectiveness tested in clinical trials. In another clinical trial, biweekly vaccination with CHP-NY-ESO-1 induced antibody production in all the 9 patients  enrolled in the study. This finding is in agreement with previous clinical trial and confirms the efficacy of CHP-NY-ESO-1 in eliciting humoral immune response. An enhancement in the CD4 T cell and CD8 T cell response was also seen in seven out of the nine patients. Unlike the CHP-HER2 vaccination where a truncated protein was used, tumor regression and improvement in symptoms were observed in four patients  vaccinated with full length NY-ESO-1 antigen. There was stabilization of prostate-specific antigen (PSA) values in 3 out of the 4 prostate cancer patients during the course of vaccination. The findings of this study suggest that using whole protein in cancer vaccines could help prevent cancers from eluding the immune response .There was a follow-up study on the patient with stage IV malignant melanoma. Blisters appeared at the lesion sites on day 25. The skin sample revealed a significant number of apoptotic melanoma cells expressing NY-ESO-1. Due to the presence of multiple metastases, the patient died on day 48. Antibody production was observed after the second dose of the vaccine, and the titre value rose with subsequent vaccinations. There was induction of NY-ESO-1-specific CD4 and CD8 T cell responses in this patient. Like the CHP-NY-ESO-1 vaccination generated specific humoral and cellular immune responses against NY-ESO-1 in melanoma patients. Immune escape could be explained by the presence of regulatory T cells, immune regulatory macrophages, and cytokines at the local tumor sites in this patient .In additional phase I clinical study, 8 esophageal cancer patients, including 4 from the previous study and 4 newly enrolled patients, were evaluated. Patients were injected subcutaneously at biweekly intervals with CHP-NY-ESO-1. Antibody induction was observed in seven patients while CD4 and CD8 T-cell responses were observed in 7 and 6 patients respectively. No significant adverse events were observed. The induction of NY-ESO-1 immunity and some positive clinical responses were observed in esophageal cancer patients. Notwithstanding, the tumors grew even after vaccination .A clinical trial using a combination of CHP-NY-ESO-1 and CHP-HER2 was carried out after the CHP-NY-ESO-1 vaccination showed encouraging outcomes. The CHP-NY-ESO-1 and CHP-HER2 combination vaccines were given to eight esophageal cancer patients with the adjuvant OK-432. In the combination vaccine research, responses to NY-ESO-1 were comparable to those of the single vaccine while there was reduced antibody response to HER2 in the combination vaccinations. Antibodies to OK-432 were not boosted. The combination vaccine was well tolerated, with just minor side effects, indicating feasibility and safety of targeting both NY-ESO-1 and HER2 using one vaccine .The safety as well as the immune and clinical outcomes of patients who received 100 μg or 200 μg of NY-ESO-1 protein complexed with CHP were evaluated in a clinical trial. Twenty-five patients with advanced/metastatic esophageal cancer were vaccinated subcutaneously with either 100 μg or 200 μg of NY-ESO-1 protein encapsulated in CHP nanogel. Thirteen patients were administered 100 μg of the vaccine while twelve patients received 200 μg, and the median doses were 8 and 9.5 doses, respectively. There were no major side effects associated with the vaccination. In the group that received 100 μg of the antigen, 5 out of 10 patients that were seronegative before the treatment showed antibody response, while antibody titers were raised in 2 patients that were seropositive before the vaccination. All five pre-seronegative patients in the cohort that received 200 μg turned positive, and there was elevation of antibody titer in all seven pre-seropositive patients. There was no evidence of tumor shrinkage. The patients in the 200 μg cohort, even patients who had more cancer burden or were unresponsive to previous treatment measures, demonstrated better survival than patients in the 100 μg cohort. The safety and immunogenicity of CHP-NY-ESO-1 vaccine were confirmed with this clinical study. The immune responses more effectively and suggested better survival benefits .In a recent randomized phase II clinical trial of CHP-NY-ESO-1to determine the clinical efficacy of the vaccine, 54 NY-ESO-1-expressing esophageal squamous cell carcinoma (ESCC). Patients were enrolled. Fifteen doses of the vaccine were subcutaneously given at 2 or 4-week interval for a duration of 12 months. There were no differences between the treated group and the control group in terms of disease free survival and overall survival. The clinical trial revealed that CHP-NY-ESO-1 vaccine alone did not display clinical efficacy compared to the control .Propionibacterium acnes, which have shown promising result in mouse model -3 agonist and it was investigated for use as adjuvant with CHP-NY-ESO-1 vaccine. In a recent clinical trial, poly-ICLC was used together with CHP-NY-ESO-1 in patients diagnosed with recurrent or advanced esophageal cancer. A total of six vaccinations at a dose of 200/0.5 or 200/1.0 (μg/mg) of CHP-NY-ESO-1/poly-ICLC was carried out biweekly. The tumor response, as well as the safety and immune response, were studied. The injection site skin reaction was reported as the most prevalent adverse event (AE). There were no drug-related AEs of grade 3 or higher. The immune responses were not dose dependent; and with a median of 2.5 vaccinations, all patients developed antibody responses. Both the group that received CHP-NY-ESO-1 alone and the group that received the poly-ICLC combination showed humoral responses, however the antibody titers in the combination group were higher. There was no tumor response. Like the previous non-clinical study with anti-PD-1 antibody, CHP-NY-ESO-1/poly-ICLC/anti-PD-1 combination vaccine inhibited the growth of tumors expressing NY-ESO-1 antigen in a mouse model . In humaCHP-MAGE-A4 is a melanoma vaccine candidate that has the MAGE-A4 antigen encapsulated in cholesteryl pullulan nanoparticles. The MAGE-A4 protein is not found in normal tissues but expressed in many cancers, and it triggers both antibody production and cell mediated immune responses . In a phIn another CHP-MAGE-A4 vaccine trial, 9 patients were vaccinated biweekly up to 6 times to assess the safety of administering CHP-MAGE-A4 with and without OK 432 and to assess the specific humoral immune response. 100 μg CHP-MAGE-A4, 300 μg CHP-MAGE-A4, or 300 μg CHP-MAGE-A4 + 0.5 clinical units of OK-432 were given to each group of three patients. There were no serious side effects from the vaccines. Four out of nine individuals were found to have stable disease. Total immunoglobulin (Ig) G titers against MAGE A4 increased in 7 of 9 individuals. IgG4 and IgE were found in 4/7 of the patients following repeated vaccination. It was found that frequent immunizations activate a Th2 dominant state in cancer patients. The authors linked the unfavorable clinical outcomes such as disease progression and the emergence of a new relapse lesion to Th2 conversion. The detection of a time dependent IgG subclass and IgE antibody production during vaccination could be a valuable surrogate marker suggesting a possibly negative changes in the immunological microenvironment for a successful antitumor immune response in cancer patients according to the researchers .A clinical trial by +CD25 + Foxp3+regulatory T cells (Tregs). Low Treg ratios both before and after vaccination were associated with a good prognosis, and a low Treg/CD4 lymphocyte ratio 7-week after the initial vaccination was correlated with a better prognosis. It was concluded that the Treg ratio following vaccination could be useful for predicting patient prognosis (Still on the search for good immune response markers, a dose of 300 μg of CHP-MAGE-A4 vaccine and 0.5 Klinische Einheit of OK-432 was administered to sixteen patients to investigate the effectiveness of predicting immune response using the percentage of CD4rognosis .The safety, immunological responses, and clinical outcomes of patients who received the CHP-MAGE-A4 vaccine were investigated in a recent clinical study. Twenty-two patients who participated in the study had advanced or metastatic cancer and were given either 100 μg or 300 μg of CHP-MAGE-A4 subcutaneously with a median of seven doses . There win vitro and in vivo stability of the dosage form is extremely important to ensure the dosage form reaches the target site intact. Nanogels have proven to be a very stable dosage form that can provide the needed payload to cancerous tissues through the main delivery routes of medicines for cancer–the intravenous route. However, considering the versatility of nanogels, topical formulations will likely be useful in localized skin tumors as their permeability can be optimized through appropriate engineering. Biomimetic hydrogels are expected to play a very significant role in intracellular drug delivery as they are expected to be biocompatible, and would evade the reticuloendothelial system and morph nuclear phagocytic system leading to prolonged in vivo circulation time. It is therefore the onus upon drug delivery scientist to focus on these new classes of nanogels without neglecting the use of natural polymers, which have traditionally been recognized as safe, biocompatible and biodegradable. Another aspect of nanogels that would attract the attention of formulation scientists in the next decade is the use of polymer hybrids or molecular blends consisting of mixtures of synthetic and natural polymers. The synthetic polymers would provide more functionality, while natural polymers would positively influence the biocompatibility and biodegradability. Natural polymers also do not produce toxic degradation products unlike some synthetic polymers and would serve as a very desirable candidate for implant delivery system for anticancer drugs. Nanogels can be implanted into the tumor sites and drug release will occur as predicted by the engineering strategies applied during formulation. This method of delivery will reduce drug migration to unwanted sites and thereby drastically reduce off-target toxicities associated with systemic delivery of some anticancer drugs.Nanogels hold the promise for unlocking the door to efficient target drug delivery to cancer cells and tissues. Cancer chemotherapy involves the interplay of a lot of factors ranging from drug related factors to patient-related factors. In all, the Nanogel formulations of anti-cancer drugs have extended the horizon for what might be one of the most important revolutions in targeted cancer therapies. Preliminary research on the potential applications of nanogels in targeted cancer therapy has shown great promise for the future. However, there is a need to standardize processes with a good manufacturing practice guideline for nanogel formulations. It is also important to scale-up nanogels research for targeted cancer therapy to expand current knowledge of nanogels and confirm their safety profile.+ and CD8+ T-cell responses as well as humoral immunity. Although the production of antigen-specific T-cell responses following vaccination is encouraging, more research is needed to properly comprehend CHP’s true potential or effectiveness in cancer vaccination. Despite a large number of clinical trials, the clinical efficacy of nanogel in cancer vaccines has been found to be insufficient, and the intended clinical outcome of tumor regression has not been detected in a significant number of clinical trials. Understanding the precise immunological pathways of immune response generation is critical for improving the efficacy of nanogel based cancer vaccines. Identification of more immunological biomarkers that could allow for a more precise assessment of the clinical outcome to cancer vaccination will surely be advantageous in this context. The overall prospect of nanogels as target delivery system for anticancer drugs remains high and start-up pharma companies are expected to utilize the opportunity offered by nanogels to advance anticancer drugs translational research.The results of multiple clinical trials using CHP-based anticancer vaccines showed that the vaccines were safe after repeated subcutaneous injection and that they were effective in generating both antigen-specific CD4


We investigated if dominance affected upper limbs muscle function, and we calculated the level of agreement in asymmetry direction across various muscle-function metrics of two heterologous muscle groups. We recorded elbow flexors and extensors isometric strength of the dominant and non-dominant limb of 55 healthy adults. Participants performed a series of explosive contractions of maximal and submaximal amplitudes to record three metrics of muscle performance: maximal voluntary force (MVF), rate of force development (RFDpeak), and RFD-Scaling Factor (RFD-SF). At the population level, the MVF was the only muscle function that showed a difference between the dominant and non-dominant sides, being on average slightly (3–6%) higher on the non-dominant side. At the individual level, the direction agreement among heterologous muscles was poor for all metrics . When considering the homologous muscles, the direction agreement was moderate between MVF and RFDpeak (Kappa = 0.37) and low between MVF and RFD-SF (Kappa = 0.01). The asymmetries are muscle-specific and rarely favour the same side across different muscle-performance metrics. At the individual level, no one side is more performative than the other: each limb is favoured depending on muscle group and performance metric. The present findings can be used by practitioners that want to decrease the asymmetry levels as they should prescribe specific exercise training for each muscle.  According to the dynamic dominance models , the domHandgrip muscles are the only ones that present a clear trend  of 8–16% towards a stronger dominant than non-dominant side . The effThe fact that the dominant limb is not stronger or weaker than the non-dominant one at the population level does not imply that one side would be stronger than the contralateral one at the individual level. Regardless of dominance, the interlimb asymmetry varies depending on the test selected, and, thus, the level of asymmetry may strongly depend on tasks . NumerouMeasuring the MVF is the most straightforward assessment to detect interlimb strength asymmetry . Since RIn the present study, we focused on upper limbs (elbow flexors and extensors) because they play a critical role in everyday living and sports context in non-disabled, amputee, and wheelchair users. We firstly aimed to examine if dominance affected muscle function. Secondly, we investigated if muscle function asymmetries are muscle-specific or, conversely, if one side is overall more performative than the other independently of the muscle group. Thirdly, we aimed to investigate if, within each muscle group, asymmetry direction is consistent among various muscle performance metrics .To answer the first experimental question, we adopted a linear mixed-effects model analysis, while to answer the second and third experimental questions, we tested the agreement between asymmetry direction among heterologous muscle groups and various performance metrics. We hypothesized that: (1) the dominance did not affect muscle functions ; (2) the asymmetry direction agreement among heterologous muscles  was low; and (3) the asymmetry direction agreement among the metrics adopted  in homologous muscles was low. Finally, we tested the inter-day repeatability of the custom-made isometric dynamometer adopted in the present study as a secondary objective.A total of 55 young  physically active healthy individuals  were recruited for the study. Five of them were left-handed. Inclusion criteria were: being adults (≥18 years of age); and being physically active, i.e., participating in moderate-intensity physical activity at least 150 min/week or vigorous-intensity physical activity at least 75 min/week or an equivalent combination of both moderate and vigorous physical activity. Exclusion criteria were: any upper-limb complaints and general illness in the past six months; any clinical evidence of cardiovascular, neuromuscular, or neurological disorders; and participation in any sports that require extensive asymmetric involvement of the upper limbs . All the participants were informed about the testing procedure and provided their written informed consent before participation in the experiments. Participants were instructed to refrain from performing strenuous physical exercise and consuming caffeine 24 h before the experimental session and completed a socio-demographic questionnaire before the experimental sessions. The study was approved by the Ethical Committee  and performed in accordance with the Helsinki Declaration.A picture of the experimental setup is reported in All participants completed one experimental session during which the muscle-function assessment was performed for elbow flexion and extension of the dominant and non-dominant limb in randomized, counterbalanced order. The experimental protocol was re-administered to a sub-sample of 15 participants to check its test–retest reliability. The experimenters placed particular attention on avoiding torso and shoulder movement during contractions execution. In addition, participants were instructed to avoid trapezius activation during the elbow flexion and body leaning forward during elbow extension. The same investigators conducted all test sessions. A rest of 5 min was observed between testing each muscle group. For each muscle group and limb, the protocol comprised: (1) a warm-up consisting of 10 submaximal isometric contractions (at intensities from 20 to 80% of the perceived maximum force); (2) familiarisation to ballistic contractions (see later); (3) two maximal voluntary isometric contractions; and (4) RFD-SF protocol.Two 5 s maximal voluntary contractions, interspersed by 2 min of rest, were performed to measure MVF. A third maximal voluntary contraction was performed when the MVF difference between the two trials was higher than 5%. Participants received standardized verbal encouragements during the execution of maximal voluntary contractions.The RFD-SF protocol started 2 min after the last maximal voluntary contractions. The original RFD-SF protocol requires the performance of 125 ballistic isometric contractions across a full range of submaximal amplitudes . As a reSignal processing was conducted using a custom-written software in MATLAB R2020b . MVF and RFDpeak were calculated over the raw force signal. MVF was computed as the 0.5 s epoch with the highest value of the force signal. To obtain the RFDpeak, we averaged the three contractions showing the highest maximal RFD .To calculate the RFD-SF, the force signal was firstly pre-processed using an overlapping moving window of 0.1 s ,26,32. T2 was also quantified as it reveals the consistency and linearity of the linear regression. Outliers were detected and removed using the Cook distance methodology to improve the fit of the linear regression [The RFD-SF was calculated as the slope of the linear regression between peak force and peak RFD obtained in each contraction C. RFD-SFgression .Descriptive data of the dependent variables are presented as mean and standard deviation (SD). The bilateral asymmetry index was calculated for each parameter according to the following formula :(1)Dominsymmetric when the interlimb difference was less than SWC [asymmetric, favouring either the dominant or the non-dominant side. Then, Kappa coefficients were calculated to determine the levels of agreement for the direction of asymmetry among muscle groups and performance metrics at the individual level [We calculated the smallest worthwhile change , we performed multilevel mixed-effect linear regression analysis . The adoFor each muscle function metric , intraclass correlation coefficient (ICC), standard error of measurement (SEM), and coefficient of variation (COV) were calculated to assess the interday reliability . Accordip < 0.05.Statistical analysis was performed in R , the figures were produced using the package ggplot2  and MATLp < 0.001) both in extensors (p = 0.010) and flexors (p = 0.001) compared to the non-dominant side. The RFDpeak was similar on both sides , while the RFD-SF was higher in the non-dominant side compared to the dominant side in the elbow extensors (p = 0.016) but not in the elbow flexors (p = 0.409). Based on SWC analysis  was fair for the agreement between MVF and RFDpeak (Kappa = 0.37), slight for the agreement between RFDpeak and RFD-SF (Kappa = 0.14), and null when comparing MVF with RFD-SF (Kappa = 0.01).2 of the RFD-SF protocol was on average ≈0.96 for both elbow flexors and extensors.The two most commonly adopted muscle performance metrics, MVF (ICC = 0.93) and RFDpeak (ICC = 0.92), showed excellent reliability, while the RFD-SF showed lower but still acceptable reliability (ICC = 0.69). The coefficient of variation of all variables was <10% . The RWe measured three muscle-performance metrics  in two muscle groups of the upper limbs  of the dominant and non-dominant sides. The main findings were that (1) at the population level, the difference between the dominant and non-dominant side was trivial, when present, and it was favouring the non-dominant side; (2) the asymmetry direction agreement between heterologous muscle groups were relatively poor for all metrics ; and (3) the asymmetry direction agreement between muscle performance metrics (among homologous muscles) was moderate between MVF and RFDpeak (Kappa = 0.37) and low between MVF and RFD-SF . Overall, the present findings suggest that no one side is more performative than the other: the objectively better side depends on muscle group and performance metrics adopted.At the sample level , the MVF was the only metric that showed a clear trend favouring one side compared to the other one. Indeed, in our sample, the MVF was higher on the non-dominant compared to the dominant side . This isFor each performance metric, the bilateral asymmetry index at the individual level was muscle-specific. The low Kappa values  showed that the between-muscle agreement of asymmetry direction was poor for each metric. Kappa values close to 0 suggest that the direction agreement between the two heterologous muscles was due mainly to chance. Therefore, if one metric favoured the dominant limb in one muscle group , this does not necessarily occur for the heterologous muscle . As a consequence, it is possible to suggest that participants do not have an overall stronger or quicker side. They have a muscle-specific level of strength and quickness instead. This may be due to differences in morphological (muscle size and architecture)  and neurAsymmetries rarely favoured the same side when considering different performance metrics of homologous  muscles. Except for the agreement between MVF and RFDpeak (which was moderate), all other Kappa values were low ≤0.14). RFDpeak has been previously reported to be more sensitive to detect asymmetry than MVF . RFDpeak. The preThe task-specific nature of interlimb differences has been clearly demonstrated by previous studies by Bishop and colleagues ,10,49. HFrom a practical point of view, the present findings suggest that to determine strength asymmetries, practitioners should adopt that specific test for each relevant muscle group. Even more importantly, the current study may inform the practitioners when they try to treat strength asymmetries, i.e., when they prescribe physical training to diminish the asymmetry level of a person. The strength asymmetry should not be treated just by performing more exercise on one side (the weakest limb) compared to the other (the strongest limb). Each side may need more specific training for the physical characteristic where it is less proficient. For example, one side may need more maximal strength training while the contralateral side may need more explosive training.The novel findings of the present study do not come without limitations. First, we measured only two of the many muscle groups of the upper limb (elbow flexors and extensors). Therefore, our results may not translate to shoulder or wrist muscle groups. Second, we only adopted isometric contractions; thus, the asymmetry agreement among other contraction modalities remains unexplored. Third, we only included physically active individuals, therefore, our results do not necessarily transfer to sedentary people or highly trained athletes. Even more importantly, our results do not relate to people participating in highly asymmetric sports such as tennis, badminton, or fencing. Indeed, we expect that the asymmetry levels in asymmetric sports would be much broader than the those reported in the present study. Lastly, we could not compare left- vs. right-handed individuals because we only recruited five left-handed individuals; therefore, this comparison’s statistical power would be too low. However, investigating whether left-hand individuals would show different asymmetry agreements would be attractive.Future studies should address two main questions that remain open from the present study. First, the neuromuscular determinants of the asymmetry should be elucidated: it is unknown if MVF and RFD asymmetries were more related to central  or peripheral  characteristics. Second, as we determined the asymmetry only once for each subject, we do not know if those asymmetries fluctuate with time or if they remain stable over long periods.At the individual level, the asymmetries are muscle-specific and rarely favour the same limb across different muscle groups. When adopting various performance metrics, there is no one limb more performative than the other in general: each limb is favoured depending on muscle group and performance metric, independent of dominance.


Teaching point: HHV6 encephalitis is a specific complication to be considered in a patient with neurological symptoms after hematopoietic stem cell transplantation and typically shows symmetrical involvement of the limbic system. A 45-year-old man with myelodysplastic syndrome presented with confusion after allogeneic hematopoietic stem cell transplantation (HSCT). Magnetic resonance imaging (MRI) of the brain showed no abnormalities. Four days later he was admitted to the intensive care unit because of neurological deterioration. Electroencephalogram (EEG) showed epileptiform activity. The MRI examination was repeated and showed new bilateral symmetric T2 and FLAIR hyperintense signal in the limbic system  suggestive of acute limbic encephalitis . A lumbaHHV-6 is a neurotropic virus of the human herpes family and consists of two subtypes (type A and B). Around 90% of the population is seropositive for HHV-6 by the age of two. After primary infection, the virus remains latent in the body, and may reactivate in immunocompromised patients, especially after allogeneic HSCT. Reactivation of HHV-6 occurs in 30–70% of the patients and typically manifests two to four weeks after HSCT. Several complications may occur like graft-versus-host disease, bone marrow suppression or, as in our case, acute limbic encephalitis.HHV-6-associated limbic encephalitis has clinical similarities with herpes simplex encephalitis (HSE) and presents with neurological symptoms such as amnesia, convulsions, and coma. On imaging, both HHV-6 encephalitis and HSE show an increased T2 and FLAIR signal and increased diffusion restriction bilaterally in the limbic system: the hippocampi and, variably, the adjacent mesial temporal structures . Contrast enhancement is usually absent in HHV-6 but can be seen in HSE. The extent and distribution of signal abnormalities is most useful to differentiate the two entities: HSE generally affects both the mesial and lateral temporal lobe  in an asymmetrical manner, whereas HHV-6 encephalitis is characterized by symmetrical signal changes limited to the mesial temporal lobes. The final diagnosis is made by a positive PCR test for HHV-6 in cerebrospinal fluid.Differentiating HHV-6-associated encephalitis from HSE is important as HHV-6 is resistant to acyclovir which is the treatment of choice for HSE. HHV-6-associated encephalitis is treated with other antiviral medications like foscarnet or ganciclovir. HHV-6 responds significantly faster to treatment than HSE, with complete resolution of the abnormalities on MRI, in contrast to HSE that often shows irreversible damage .