Malaysia is predicted to become an ageing population by 2035. Malnutrition among the elderly is one of growing concern. This study aims to identify the prevalence of malnutrition and its associated factors among the elderly in Malaysia.  Data from the National Health and Morbidity Survey (NHMS) 2018 was analysed. This survey applied a multistage stratified cluster sampling design to ensure national representativeness. Malnutrition was identified using a validated Mini Nutrition Assessment-Short Form (MNA-SF). Variables on sociodemographic, health status, and dietary practices were also obtained. The complex sampling analysis was used to determine the prevalence and associated factors of at-risk or malnutrition among the elderly. −2 were found to be protective.  A total of 3,977 elderly completed the MNA-SF. The prevalence of malnutrition and at-risk of malnutrition was 7.3% and 23.5%, respectively. Complex sample multiple logistic regression found that the elderly who lived in a rural area, with no formal or primary level of education, had depression, Instrumental Activity of Daily Living (IADL) dependency, and low quality of life (QoL), were underweight, and had food insecurity and inadequate plain water intake were at a significant risk of malnutrition , while Chinese, Bumiputra Sarawak, and BMI more than 25 kgm Currently, three out of ten elderly in Malaysia were at-risk or malnutrition. The elderly in a rural area, low education level, depression, IADL dependency, low QoL, underweight, food insecurity, and inadequate plain water intake were at risk of malnutrition in Malaysia. The multiagency approach is needed to tackle the issue of malnutrition among the elderly by considering all predictors identified from this study. A longer life brings many opportunities. However, it probably brings some adverse impacts if we do not correctly manage their life, especially on their health care.  The WorlMalnutrition among the elderly is one of the most growing concerns on this demographic shift. During the change into older years, often nutrition priorities change towards meeting and minimizing increased nutrient needs with fewer energy requirements and also preventing lean muscle loss . MalnutrMalnutrition among the elderly is related to multifactorial causality . It starMalaysia is predicted to become an ageing population by 2035 . InteresThis study is part of a community-based nation-wide cross-sectional survey conducted to assess the health status of the elderly in Malaysia. This survey applied a multistage stratified random sampling design to ensure the selection of a nationally representative sample. Details of the methodology of this survey are explained in the published technical report .The sample size was calculated using a single proportion formula for estimation of prevalence with adjustments for the total number of target population, design effect, expected nonresponse rates of 30% and to the need of the analysis by stratification of urban and rural. Based on the estimated prevalence of malnutrition or at-risk of malnutrition among the elderly of 42.5% from a local study, a total of 3,977 elderly were enough for the analysis .All the elderly aged 60 years and above from the randomly selected living quarters were invited to join this study. Those who were blind or deaf, illiterate, or found as having probable dementia, scored ten or below using Identification and Intervention for Dementia in Elderly Africans (IDEA), were excluded. Research ethical approval was obtained from the Medical Research & Ethics Committee's (MREC), Ministry of Health Malaysia (KKM/NIHSEC/P18-49(6)) on 18 January 2018 before starting the data collection.Malnutrition status was assessed using a validated Malay version of the Mini Nutrition Assessment-Short Form (MNA-SF).  The MNA-Other information also being collected from eight modules is as follows: (1) sociodemographic characteristics; age, sex, marital status, highest education levels, individual monthly income, and living arrangement; (2) self-reported or current medical report assessment on noncommunicable diseases status which were diabetes, hypertension, and hyperlipidaemia; (3) functional limitations which include Activities of Daily Living (ADL) using 10-item Barthel's ADL to assess personal self-care in getting ready for the day  and InstListing activities to identify eligible respondents (elderly aged 60 years and above) from the selected living quarters was conducted before the data collection. The face-to-face interviews were carried out by trained research assistants using mobile devices with structured questionnaires in tablet application. The application has an in-built quality control to ensure valid responses, with real-time data entry to our server at the institute. Self-administered modules which were filled up by the elderly in scannable paper format were sealed into envelopes and mailed to our institute for data processing.p value of 0.05, and control for all possible confounding factors.Data were analysed using complex samples module using the IBM Statistical Package for the Social Sciences (SPSS) software for Windows, Version 26.0. The prevalence of malnutrition and risk of malnutrition were calculated using complex samples frequencies. For logistic regression analysis, the data of at-risk and malnutrition were combined into the same group named malnutrition. The associations between malnutrition and other variables were evaluated using complex sample logistic regression, with 95% confidence intervals, significance level at the A total of 3,977 respondents aged 60 years and above were successfully recruited and completed MNA-SF. The distribution was almost equal by sex, and the majority of them stayed in urban areas. The distribution of respondents by age group and ethnicity mirrored the Malaysian population characteristic, as shown in Overall, the prevalence of malnutrition and at-risk of malnutrition by MNA-SF among the elderly in Malaysia was 7.3% and 23.5%, respectively. The prevalence of malnutrition and at-risk of malnutrition was higher in rural areas, among the older age group, among Indian, bumiputra Sabah, and other ethnicities, among unmarried or separated or divorced elderly, among lower education, among unemployed, and among lower individual income as shown in −2 were found to be significantly associated with at-risk or malnutrition with the odds ratio less than one as shown in Complex sample multiple logistic regression among 3472 respondents found that the elderly who lived in rural areas, with no formal or primary level of education, had depression, IADL dependency, and low quality of life, were underweight, and had food insecurity and inadequate plain water intake were significantly associated with at-risk or malnutrition. Meanwhile, elderly Chinese, elderly Bumiputra Sarawak, and the elderly with BMI more than 25 kgmPrevalence of malnutrition and at-risk of malnutrition among the elderly in Malaysia was 7.3% and 23.5%, respectively. This finding was comparable with a neighbouring country data where a cross-sectional study of a population-based cohort in Singapore reported that the prevalence of malnutrition was 2.8%, and at risk of malnutrition was 27.6% . MeanwhiHowever, the prevalence reported in this national survey was lower compared to finding from several local smaller-scale studies. A study among Malay older adults in Felda Sungai Tengi, Selangor, in 2013 showed that 42.5% of the elderly were malnourished or at risk of malnutrition . AnotherThis study found that sociodemographic characteristics which are the rural residence and low education level were among the risk malnutrition among the elderly. Meanwhile, Chinese and Bumiputra Sarawak in ethnicity were found to be protective. A study conducted in Ethiopia found that the elderly in the rural area were about two times more likely to be malnourished . AnotherDepressed older people were two times more likely to be at-risk or malnourished. A study conducted among the Japanese older people in Kyoto found that depression was strongly associated with MNA-SF score ≤11 . SimilarOther than depression, the elderly with IADL dependency were also found to be associated with at-risk or malnutrition. A study conducted among elderly outpatients in the Netherlands reported that depression and being IADL dependency were independently associated with an increased odd of at-risk of malnutrition and malnutrition with an adjusted odds ratio of 2.6 and 2.8, respectively . A studyLow quality of life is also a predictor of at-risk or malnutrition among the elderly in Malaysia. A previous study suggested that the elderly with malnutrition were more likely to experience poor quality of life . Evidenc−2 were about six times more likely to be at risk of malnutrition or malnourished in this study. BMI is often used as a crude screening tool for nutritional status in a primary health care setting. A survey among the elderly in Australia identified that the elderly who were classified as at-risk or malnourished had a significantly lower mean weight and BMI than those classified as well-nourished [−2 were at risk or malnutrition. Meanwhile, our study also found similar findings; the elderly with BMI more than 25 kgm−2 were protective against at-risk or malnutrition. However, BMI may be regarded as a tool for rapid insight for nutritional screening but should not be used to replace exact nutritional evaluation since malnutrition or malnutrition risk may be present even in higher BMIs [The elderly with body mass index (BMI) below 18.5 kgmourished . The samher BMIs .Food insecurity was another predictor for at-risk or malnutrition among the elderly. The previous study of Turkish elderly people showed that those who were food insecurity were around two times more likely to be at-risk or malnutrition . Food inOur study also found that inadequate plain water intake among the elderly was a significant risk factor to at-risk or malnutrition. Evidence suggests that the elderly have a higher baseline for osmolality and thus a higher osmotic operating point for a sense of thirst with little or no change in sensitivity, and indicates dwindled thirst in response to hypovolemia and hypervolemia of baroreceptors. For this reason, the means of water intake might be decreased as age increased . DrinkinAlthough the factors to at-risk or malnutrition have been identified, this study only recruited the elderly residing in the community only. The elderly in the institutionalized facilities were not included in this study. A current local survey found a higher prevalence of malnutrition (13%) and at-risk of malnutrition (37%) among the elderly in a care home . The facIn conclusion, rural areas, low education level, depression, IADL dependency, low quality of life, underweight, food insecurity, and low plain water intake were significant risk factors for at-risk of malnutrition or malnutrition. A healthy ageing nation can be achieved provided early intervention is done as most of the factors identified are modifiable factors. Therefore, more effectively, multiagency collaboration can be executed to enhance the welfare of the elderly in Malaysia.


Hepatocellular adenoma (HCA) is a benign hepatocyte-derived epithelial tumor. HCA isassociated with oral contraceptive use among Caucasian populations. We report a case ofhepatocellular adenoma with a pedunculated protuberance and high protein induced by vitamin Kabsence or antagonist-II (PIVKA-II) levels, which made diagnosis challenging. The patient was a22-year-old woman. In a medical check-up, a high γ-GTP level was detected and a 115-mm solidmass was found in her lower abdomen via abdominal ultrasonography. A blood test showed a highPIVKA-II level. Abdominal CT showed a tumor in the lower abdomen. Contrast-enhanced CT showed ablood vessel thought to be the left hepatic artery connecting to the mass, and a blood vesselthought to be the left hepatic vein returning from the mass to the inferior vena cava. InEOB-MRI, uneven enhancement was observed after contrast imaging, but washout in the equilibriumphase was unclear. Parenchymal hepatocyte phases showed a pale, non-uniform, high signal. Thesefindings indicated that the tumor was derived from the left lobe of the liver and wassuggestive of HCC. Surgical resection was then performed. A pathological examination led to adiagnosis of HCA, corresponding to unclassified HCA. The WHO classification of tumors of thedigestive system based on an immunohistological examination includes HNF1α-inactivated HCA,β-catenin-activated HCA, inflammatory HCA, and unclassified HCA. In summary, our patient had alarge HCA with pedunculated protrusion into the extrahepatic pelvic cavity. This case waschallenging to diagnose because of abnormally high PIVKA-II levels, and it was resectedlaparoscopically. However, the incidence of HCA in Asian women is not as high as that in othercountries, and this is thought to be due to differences in oral contraceptive use rates amongcountries.2 In 2010, the World Health Organization (WHO) classification of tumors of thedigestive system was revised and included four genetic phenotypes as follows: hepatocyte nuclearfactor 1α (HNF1α)-inactivated HCA(H-HCA), β-catenin-activated HCA(b-HCA), inflammatoryHCA(I-HCA), and unclassified HCA(u-HCA), each of which has characteristic clinical imaging, andpathology findings.3 We report here a case of alarge HCA with pedunculated protrusion into the extrahepatic pelvic cavity. This case waschallenging to diagnose because of an abnormally high protein induced by vitamin K absence orantagonist-II (PIVKA-II) level. The tumor was resected laparoscopically.Hepatocellular adenoma (HCA) is a benign hypervascular tumor that is composed ofcells resembling normal hepatocytes.The patient was a 22-year-old woman. A high gamma‐glutamyl transpeptidase (γ-GTP)level was noted during a health check-up and she visited a local doctor 11 months later.Examination findings: Abdominal ultrasonography showed a solid massof 115 mm in diameter in the abdominal cavity. Although there were signs of pressure on thesurrounding organs, continuity with these organs could not be confirmed. However, a tumororiginating from the ovaries was suspected and she was referred to our hospital on the followingday for further tests.At her first visit, she had good appetite and there was no weight loss or notabledigestive symptoms. There was no noteworthy medical history and no history of oral contraceptiveuse. Her height was 163 cm, weight was 49 kg, body temperature was 36.2 C, andeyeballs and palpebral conjunctiva were normal. Blood pressure, pulse, and respiratory soundswere normal. No heart noise was heard and no edema on the face or limbs was present. Onabdominal palpation, a fist-sized elastic, slightly hard, smooth mass was found under theumbilical cord. General blood biochemical tests showed no increase in any parameter other thanthe γ-GTP level. Blood tumor marker tests showed a high PIVKA-II level .Abdominal ultrasonography showed a multiloculated mass with a size of126×72 mm in the right lower abdomen, a slightly hyperechoic interior withnon-uniform areas, and no obvious vasculature. Continuity with surrounding organs could not beconfirmed .Plain abdominal magnetic resonance imaging (MRI) showed a solid tumor in the rightupper abdomen. Apart from the uterus and ovaries, there were no other obvious abnormalities inthe pelvis. T1-weighted imaging showed a light high signal. T2-weighted imaging showed aniso-signal with a non-uniform high signal internally and diffusion-weighted imaging had a lowsignal . AlthougAbdominal contrast-enhanced computed tomography (CT) showed a mass of130×145×70 mm in the lower right abdomen, and this was depicted in the lowerpelvis from the time of simple MRI. The tumor was infused by an artery continuous with the lefthepatic artery, and a vein was seen returning to the inferior vena cava via the left hepaticvein . The norAbdominal contrast-enhanced MRI (EOB) showed an uneven enhancement effect aftercontrast. In the equilibrium phase, washout was not clear and the hepatocyte parenchymal phaseshowed a pale, non-uniform, high signal . HCC wasOn the basis of the above-mentioned results, because the tumor was located in theleft lobe of the liver, and because HCC could not be ruled out because of early staining aftercontrast and the high tumor marker level, surgery was performed 2 months after the firstexamination.Surgical findings: Port insertion with an umbilical longitudinalincision open method was performed. A 12-mmφ port in the left flank and a 5-mmφ port under thespinous process were inserted. A pedunculated tumor continuous with the left lobe of the liverwas confirmed.The neck connecting the tumor and the lateral liver area was approximately 4 cmwide, approximately 5 cm long, and approximately 5 mm thick at the largest part. Afterraising the neck with vascular tape, resection was performed using a laparoscopic linear staplertwice. A skin incision of approximately 10 cm in length was made in the upper pubic boneand the tumor was removed. The surgical duration was 2 hours and 35 minutes, and the amount ofbleeding was 30 g .Specimen findings: A nodular and distended tumor of150×130×95 mm with capsule formation, but no capsular invasion, was observed.Formation of partitions was observed inside the tumor. There was no infiltration into the serousmembrane, portal vein, hepatic vein, hepatic artery, or bile duct, and no lymph node metastasis-1 was negative, cell proliferation waslow, cytokeratin 19 was negative, and no bile duct components were present. The patient wasnegative for glypican-3 and no apparent signs of interstitial hepatic cell infiltration werefound. She was diagnosed with HCA .On the basis of the above-mentioned findings, among the four subtypes specified inthe latest 2010 WHO classification of HCA, H-HCA was ruled out because of the absence ofhistological features, diffuse steatosis, or a history of oral contraceptive use. I-HCA, whichis the most frequent subtype, was ruled out because the tumor was amyloid A-negative. b-HCA wasruled out because the tumor was β-catenin-negative. Therefore, she was diagnosed with u-HCA.Postoperative course: The postoperative course was good, and the patient wasdischarged on the 7th day after surgery. The PIVKA-II level became normal 1 month after surgeryand no recurrence was observed 4 years later.2 HCA may also be complicated by intrahepatic portal blood flow abnormalities,such as portal vein defects, obstruction, or portal vein shunt formation.4 The main reasons for discovery of HCA are pain,symptomatic hemorrhage, and liver dysfunction, and accidental detection in one third of thecases. In the present case, the background factors were relatively consistent with those of HCA,although there was no history of oral contraceptive use.HCA is a benign tumor derived from liver cells that occur in the normal liver andhas an occurrence rate of three to four per 100,000 people in the USA and Europe. A total of 85%of cases of HCA occur in young women aged 20–40 years, and 80% to 90% of female patients arereported to have used oral contraceptives. The percentage of women diagnosed with HCA in Asiancountries including Japan is approximately 50% to 60%, and this lower rate is thought to be dueto the difference in oral contraceptive use between countries. An association of HCA with otheranabolic hormones and glycogenosis has been reported.1FNH has no background factors found in HCA, such as use of oral contraceptives, alcoholconsumption, obesity, or glycogenosis. In FNH, central scarring and abnormal blood vessels arefeatures observed in images, and the hepatocellular phase of EOB-MRI shows a high signal of 90%or more.5 Histologically, glutaminesynthetase–positive cells are distributed in a map-like form. Because there is no possibility ofbleeding or canceration, if FNH can be diagnosed, there is no indication for surgical treatment.However, HCA is a neoplastic growth of hepatocytes with poor or almost no histopathology, and asa complication, intraperitoneal hemorrhage from this tumor can be fatal. Additionally, there arealso reports of HCA leading to cancer, although the frequency is low.7Distinguishing HCA from well-differentiated hepatocellular carcinoma and focalizednodular hyperplasia (FNH) may be challenging.5 In the present case, washout waspoor, and no high signal in a diffusion-weighted image was observed. However, the PIVKA-II levelwas high, and the possibility of preoperatively, well-differentiated hepatocellular carcinomacould not be ruled out. Preoperative diagnosis of HCA or well-differentiated hepatocellularcarcinoma is considered an indication for surgery.Upon differentiation from hepatocellular carcinoma in MRI using EOB, T1-weightedimaging of HCC shows that, as the degree of differentiation increases, a change from an unevenlow signal to a high signal is observed. In T2-weighted imaging, a moderately high signal isseen, and in diffusion-weighted imaging, a high signal is seen. In the equilibrium phase, a lowsignal is observed, and in the hepatocyte phase, a low signal is observed. In the case of HCA,there are various characteristics depending on the subtype, and no specific findings have beenreported.8In the present case, formation of central scars and fibrous septa, which ischaracteristic of FNH, was not observed in preoperative imaging or postoperative pathologicalfindings. Because there was also no ductular reaction or dilatation, our case was considerednegative for FNH. Immunostaining was negative for cytokeratin 19, which is present in thebiliary duct epithelium. Immunostaining also showed a low score for MIB-1, which is a monoclonalantibody recognizing Ki-67, a marker of proliferating cells in tumor tissue. Because the tumorwas also negative for the biomarker glypican-3, well-differentiated hepatocellular carcinoma wasexcluded, and the patient was finally diagnosed with HCA.9 Similar mechanisms for PIVKA-II production could occurin HCA. The possible consequences of hepatocellular dysfunction induced by neoplastic changes inHCA have been considered.10 Elevation ofPIVKA-II levels is common in cases with malignant transformation, but high values may be found,even if there is no malignant change. Furthermore, no correlation of PIVKA-II levels with theWHO classification or clear features have been found.Possible mechanisms for PIVKA-II production in HCC include qualitative orquantitative abnormality of prothrombin precursors, altered activity of gamma-glutamylcarboxylase, and abnormality in the vitamin K cycle or a lack of vitamin K.3 H-HCA shows absence of liver fatty acid binding protein in immunostaining, andaccounts for 35% to 40% of all HCAs. In H-HCA, most cases are women, and histologically, it ischaracterized by diffuse steatosis and may be single or multiple. Although β-catenin-activatedHCA is infrequent, accounting for 10% to 15% of cases, the risk of cancer is high compared withother subtypes, and it is clinically important. Additionally, there are also many reported casesof β-catenin-activated HCA in men. Immunohistologically, glutamine synthetase is diffuselypositive and β-catenin is positive in the nucleus; it often occurs singly. I-HCA is the mostcommon subtype, accounting for 45% to 60% of cases. Inflammation-related proteins are found inI-HCA  Histologically,focal or diffuse inflammation is seen in I-HCA, along with sinusoid dilatation, congestion,purpura, and bile duct hyperplasia. u-HCA has a frequency of 10% or less, has noimmunohistological features, and none of the above-mentioned features are applicable.2 Although u-HCAaccounts for approximately 10% of all HCA cases in Caucasian populations, its rate isapproximately 30% in Japan, which is notable.2As mentioned above, differences in oral contraceptive use among countries may be the cause ofthis different in rate.According to the 2010 revision of the WHO classification of tumors of the digestivesystem, HCA was classified into the following four subtypes.ex3HCA), CTNNB1 mutation of exons 7 and 8 HCA ,sonic hedgehog HCA (shHCA), and u-HCA. Of these, bex3HCA and shHCA are associatedwith malignant transformation and the risk of bleeding, respectively. Although no geneticanalysis was performed in the present case, Nault et al. reported that approximately 50% ofu-HCA cases per the WHO classification would be classified into a new subgroup. Of the cases ofu-HCA based on the WHO classification, those with hemorrhage were found to be classified asshHCA via genetic analysis, and the rest of the u-HCA cases were considered to have no risk ofbleeding or malignant transformation. In the future, the nature of u-HCA will hopefully beclarified on the basis of such genetic analysis results. Consequently, clearer guidelines indiagnosis and treatment selection may emerge, and further studies on HCA are expected.12In recent years, a new subgroup classification of HCA related to risk factors,clinical behavior, and histological features has been proposed (HCA molecular classification in2017). Based on the results of gene analysis, HCA is classified as H-HCA, I-HCA, CTNNB1 mutationof exon 3 HCA (bThere have been more than 150 reports of liver tumors with pedicled growth in thelast 50 years. However, there are many cases of hemangiomas and HCC, and fewer than 10 cases ofhepatocellular adenomas. The reported cases of liver tumors with pedicled growth were publishedbefore WHO classification, and details such as type are unknown. The present case is consideredto be a rare case that could be diagnosed as liver-derived by blood flow evaluation by CT.We report a case of a large pedunculated HCA in the extrahepatic pelvic cavity. Thiscase was challenging to diagnose because of an abnormally high PIVKA-II level and it wasresected laparoscopically.The authors declare no conflicts of interest associated with this manuscript.Written informed consent was obtained from the study participants, including consentto participate and to publish the findings.


This cross-sectional study assesses whether having limited English proficiency was associated with lower video use compared with telephone use, especially among patients without prior video visit experience, during the COVID-19 pandemic. In patients self-scheduling a primary care visit during the COVID-19 pandemic, we hypothesized that LEP would be associated with lower video use compared with telephone, especially among patients without prior video visit experience.Telemedicine expands health care access for patients facing barriers to in-person care,STROBE) reporting guideline.The retrospective cross-sectional study received institutional review board approval at Kaiser Permanente Northern California (KPNC) and waived informed consent because this was a data-only study with no participant contact. We followed the Strengthening the Reporting of Observational Studies in Epidemiology  and LEP, which was defined as needing an interpreter. An LEP × prior video visit interaction term was added to the multivariate regression to examine whether barriers to the initial video visit can potentially explain video visit use differences by LEP .2 tests were used to calculate P values for patient sociodemographics, technology access, and provider factors for interpreter need . Two-sided χter need . Two-sidAmong 955 352 primary care telemedicine visits  scheduled by 642 370 patients. There were 22 476 (2.4%) with EHR-documented interpreter need, 454 741 (47.6%) White patients, 216 788 (22.7%) Asian patients, and 196 483 (20.6%) Hispanic patients; 720 338 (74.5%) patients aged 18 to 64 years, 409 632 (42.4%) men, and 195 612 (20.2%) patients from low SES neighborhoods . PatientP < .001 for interaction). Simple effects tests and adjusted video visit frequencies showed that among patients without prior video visit experience, adults with LEP vs without LEP were less likely to use video visits . However, among patients with prior video visit experience, adults with LEP did not differ from adults without LEP in their likelihood of choosing video visits .The association between LEP and visit type differed by prior video visit experience (In this large, diverse sample of patients seeking primary care during the COVID-19 pandemic, one-third of patients with LEP scheduled a visit by video instead of telephone. Patients with LEP chose video less often than patients without LEP, even after adjusting for technology factors. However, among patients with video visit experience, no significant difference in video visit use by LEP was found, suggesting that once patients with LEP have video visit use experience, they are not different from patients without LEP in likelihood to reuse video visits. Although our analyses cannot determine causality, it is reasonable to hypothesize that helping adults with LEP overcome initial barriers to using video visits will result in more frequent future video visit use.Our reliance on EHR-documented interpreter need as a proxy for LEP is a key study limitation. Nonetheless, with the rapid expansion and likely persistence of video telemedicine for delivering primary care, additional research is needed to identify barriers to initial video telemedicine use among patients with LEP.


The association of dizziness with CYP2D6 activity markers was analyzed. The number of CYP2D6 substrates taken, a CYP2D6 saturation score , a CYP2D6 saturation/inhibition score , and composed CYP2D6 activity using a genotyped subsample (n = 740) calculating additive effects of genotype and CYP2D6 saturation by drug exposure were used as CYP2D6 activity markers. Effects were compared to other frequent nonvigilance-related CNS ADR symptoms (syncope and headache). Secondary analyses were conducted to control for other ADR symptoms frequently associated with dizziness . The majority of all patients  took at least one drug metabolized by CYP2D6. Around a third took a CNS drug . The chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01–1.23]. Presenting with drug-related dizziness was more likely with CYP2D6 saturation and saturation/inhibition (both OR 1.27 [1.00–1.60]). The composed CYP2D6 activity was positively associated with dizziness (p = 0.028), while poorer activity affected patients more often with dizziness as an ADR. In contrast, nonvigilance-related ADR symptoms such as syncope and nausea were not consistently significantly associated with CYP2D6 activity markers. This study shows an association between the number of CYP2D6 substrates, the predicted CYP2D6 activity, and the occurrence of dizziness as a CNS ADR symptom. As dizziness is a vigilance-related CNS symptom, patients with low CYP2D6 activity might be more vulnerable to drug-related dizziness. This study underlines the need for understanding individual drug metabolism activity and individual risks for ADRs.Cytochrome P450 (CYP) 2D6 is a polymorphic enzyme expressed in the central nervous system (CNS), important in drug metabolism and with a potentially constitutive role in CNS function such as vigilance. This study aimed to analyze variability in CYP2D6 activity linked to vigilance-related adverse drug reactions (ADRs) in the CNS. A dataset of N = 2939 ADR cases of the prospective multicenter observational trial in emergency departments (EDs)  was analyzed. Dizziness as the most frequent reported CNS ADR symptom (12.7% of patients,  Central nervous system (CNS) drugs are often substrates of the phase-I enzyme cytochrome P450 (CYP) 2D6. Due to pharmacogenetic polymorphisms in CYP2D6, drug clearances may individually vary, thereby affecting drug efficacy and safety . TranslaSince CYP2D6 is also expressed in the brain, pharmacogenetic variability might influence the CNS’s vulnerability to ADRs . CYP enzADRs and their consequences have a substantial impact on the health-care system. Around 6.5% of all unplanned emergency department (ED) admissions are likely to be caused by ADRs , often aThe aim of this study was to analyze the role of CYP2D6 activity predicted by drug exposure and, if available, by genotype on CNS ADRs presenting to the ED connected to vigilance.Data of the multicenter observational study “Adverse Drug Reactions in Emergency Departments”  were analyzed. The ADRED study collects cases of ADRs that led to unplanned presentations to four large EDs of tertiary care and academic teaching hospitals in Germany. Within those hospitals, the prevalence of ADRs was shown to be 6.5% among all ED admissions . FurtherAdults presenting with symptoms, which were seen in a possible, probable, or certain relation to a drug after standardized causality assessment by study personnel using the WHO–Uppsala Monitoring Centre system were enrolled (definition of an ADR) . The stuwww.uptodate.com), DrugBank (www.drugbank.com), or PharmGKB (www.pharmgkb.org). Discrepancies were discussed and a consensus was established. Respective lists can be found in the supplement  . In thisn = 372), syncope , headache , confusion , seizure , and paresthesia (1.3% n = 38). We determined dizziness as the most common CNS symptom with association to vigilance. Analyses on the second and third most frequent CNS symptoms syncope and headache were included as a control testing for nonvigilance-related CNS ADR symptoms. As patients presented in median with two symptoms . The iPLEX®PGx 74 Panel together with the VeriDose™ CYP2D6 CNV Panel  were used for pharmacogenetic analyses. The VeriDose™ CYP2D6 CNV Panel detected copy number variations (CNVs) for CYP2D6, even in the presence of nonfunctional hybrid alleles, including *36, *13, and *68. The iPLEX®PGx 74 Panel analyses 69 single nucleotide polymorphisms in 20 pharmacogenes. In addition to CYP2D6, we characterized other polymorphic CYP enzymes CYP2C9 and CYP2C19. The characterization of this cohort and the phenotyping methods are published elsewhere . We usedWithin this subsample genotyped for CYP2D6 activity, we analyzed the additive effects of the CYP2D6 genotype and drug exposure of CYP2D6 substrates. For calculation of additive effects of CYP2D6 saturation by drugs, we modified the phenotype score in the following way: a PM kept poor activity. All other phenotypes were classified into the next lower activity phenotype in the case of moderate CYP2D6 saturation by drug intake as described above. For example, a person classified originally as CYP2D6 NM based on the genotype got classified as intermediate activity when taking one or two CYP2D6 substrates and classified as poor activity when taking three or more CYP2D6 substrates concomitantly .Continuous parameters were presented as median with interquartile range (IQR) and categorical parameters in absolute numbers and respective percentages. Patient characteristics of those presenting either with dizziness or without were compared using chi-squared test for categorical and Mann–Whitney test for continuous variables. Associations of dizziness with CYP2D6 activity markers, number of CYP2D6 substrate intake, the CYP2D6 saturation score, the CYP2D6 saturation/inhibition score, and composed CYP2D6 activity were analyzed using unadjusted binary logistic regression analyses for CYP2D6 substrate intake and the Mantel–Haenszel test of trend for CYP2D6 saturation and CYP2D6 saturation/inhibition scores, as well as for composed CYP2D6 activity in the genotyped subgroup.Assuming a different effect in terms of a negative control in other frequent CNS symptoms of CYP2D6 activity on nonvigilance-related ADR symptoms, we repeated these analyses with syncope and headache. To control for effects of correlating dizziness, we excluded patients with dizziness in a sensitivity analysis.In addition, we tested associations of CYP2D6 activity markers  with symptoms frequently associated with dizziness to control for other symptoms that might influence the effect of dizziness. Hereby, we excluded patients with dizziness likewise.In the last step, we adjusted the effect of CYP2D6 activity markers  on the occurrence of dizziness using binary logistic regression analyses. To this end, we tested the absolute number of CYP2D6 substrates taken continuously. For the analyses of the CYP2D6 saturation and CYP2D6 saturation/inhibition scores, we summarized the scores (any CYP2D6) of saturation or saturation/inhibition  vs. no CYP2D6 saturation or saturation/inhibition by drug exposure. For analyses of composed CYP2D6 activity, we summarized low activity (intermediate and poor) vs. higher activity . We tested two models. The first model was adjusted for age and sex, and the second model for age, sex, and the total number of taken drugs irrespective of being a CYP2D6 substrate and thereby adjusting for polypharmacy. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) are shown.p-value < 0.05 was considered statistically significant. A p-value < 0.1 gets reported as a tendency toward significance. All statistical analyses were conducted using IBM® SPSS® Statistics .A n = 1895) took at least one drug metabolized by CYP2D6, with 54.5% (n = 1337) taking at least one major CYP2D6 substrate, 40.8% (n = 1199) taking at least one minor CYP2D6 substrate, and 10.8% (n = 316) taking at least one CYP2D6 inhibitor. Around a third of all patients took at least one drug with intended CNS efficacy . Intake frequencies of single CYP2D6 substrates and drugs with intended CNS efficacy are shown in .In total, N = 2939 patients were enrolled that presented to the ED due to an ADR. The majority of all patients , (es) citalopram , and mirtazapine , whereas most frequent CYP2D6 substrates were metoprolol , simvastatin , and bisoprolol .CNS drugs most frequently taken were pregabaline (n = 372) presented with drug-associated dizziness. Of the total cohort, 12.7% (There was a significant difference in CYP2D6 substrate intake in patients with dizziness compared to patients without dizziness. Presenting with dizziness was positively associated with stronger CYP2D6 saturation but not with stronger CYP2D6 saturation/inhibition. Phenotyping results for polymorphic CYP enzymes are pictured in n = 404), general physical health deterioration , nausea , syncope , and falls . Dizziness was significantly associated with nausea, syncope, and falls as concomitant ADR symptoms.Presenting with syncope was associated with dizziness whereas headache was not. Patients with dizziness had more additional ADR symptoms on ED admission. The five ADR symptoms seen most commonly together with dizziness were dyspnea . Using unadjusted regression analyses, the chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01–1.23] as shown in Patients that presented with or without dizziness took in median one CYP2D6 substrate , even though differing significantly , although a tendency toward significance was observed. Patients that presented with headache took significantly less CYP2D6 substrates than those presenting without headache .There was no statistically significant difference in the number of CYP2D6 substrate exposure in patients that presented with syncope or not  vs. without syncope: 1 , p = 0.143, OR 1.10 [0.94–1.30] and with headache: 0  vs. without: 1 , p < 0.001, OR 0.54 [0.42–0.70], respectively).These associations with CYP2D6 substrate exposure were likewise seen when excluding patients with dizziness  vs. without: 1 , n = 1044) took no CYP2D6 substrate (no CYP2D6 saturation), 54.4% (n = 1599) took one or two substrates (moderate CYP2D6 saturation), and 10.1% (n = 296) took three or more substrates of CYP2D6 (strong CYP2D6 saturation). In the total population, 35.5% of patients (n = 39) presented with dizziness, with moderate CYP2D6 saturation 13.6% (n = 218), and without CYP2D6 saturation 11.0% (n = 114). CYP2D6 saturation score was not significantly associated with dizziness, but a tendency toward significance could be seen (p = 0.098) and the chance to present with drug-related dizziness was higher with CYP2D6 saturation by drug exposure (1.27 [1.00–1.60]). However, 7.1% (n = 21) of patients with strong CYP2D6 saturation presented with syncope, 6.9% (n = 111) with moderate CYP2D6 saturation, and 4.9% (n = 51) without CYP2D6 saturation with a linear association . Again, patients presenting with headache had commonly no CYP2D6 saturation by drug exposure  compared with moderate CYP2D6 saturation  and with strong CYP2D6 saturation  .Of patients with strong CYP2D6 saturation, 13.2% (n = 15) strong CYP2D6 saturation, 5.7% (n = 79) moderate CYP2D6 saturation, and 3.9% (n = 36) no CYP2D6 saturation, p = 0.062]. However, the same effect was seen for headache with stronger CYP2D6 saturation showing less headache .When excluding patients with dizziness, there remained only a tendency toward significance for a linear association with syncope ). Syncope was associated linearly with CYP2D6 saturation/inhibition , while headache was again reversely associated with CYP2D6 saturation/inhibition .Of patients with strong CYP2D6 saturation/inhibition, 0.8% (p = 0.059), while the association for headache remained significant (p < 0.001).With exclusion of patients with dizziness, syncope was not any longer associated with CYP2D6 saturation/inhibition (n = 740), 6.6% (n = 49) were PM, 36.8% (n = 272) IM, 53.2% (n = 394) NM, and 3.4% (n = 25) UM as predicted by the genotype. Including additive effects of CYP2D6 saturation by drug exposure, 35.8% of patients (n = 265) were expected to show poor, 44.3% (n = 328) intermediate, 18.4% (n = 136) normal, and 1.5% (n = 11) ultrarapid activity of the CYP2D6 enzyme. No patient with composed predicted CYP2D6 ultrarapid activity presented with dizziness or syncope to the ED. Among the patients genotyped for CYP2D6 (n = 51) presented with dizziness, with intermediate CYP2D6 activity 15.5% (n = 51), and with normal CYP2D6 activity 12.5% (n = 17). Composed CYP2D6 activity was associated linearly with the occurrence of dizziness (p = 0.028) in the genotyped cohort. There was no linear association of composed CYP2D6 activity with syncope . On the other hand, there was a linear association with headache .Of patients with poor composed CYP2D6 activity, 19.2% (n = 11) poor CYP2D6 activity, 8.3% (n = 23) intermediate CYP2D6 activity, and 4.2% (n = 5) normal CYP2D6 activity, p = 0.761]. There was no significant linear association for headache with exclusion of patients with dizziness, even though a tendency toward significance could be seen .We found similar results for syncope when excluding patients with dizziness ) to the CYP2D6 saturation score (1.54 [1.16–2.05]), with comparable results for the CYP2D6 saturation/inhibition score (1.54 [1.16–2.04]) and to the composed CYP2D6 activity using additive effects of CYP2D6 substrate exposure and genotype (1.77 [0.98–3.17]) as CYP2D6 activity marker. However, while the OR increased, the confidence interval intersects with one showing that the genotyped cohort was slightly too small to reach statistical significance.This study shows, to the best of our knowledge, for the first time an association of dizziness, an ADR symptom related to CNS function, with CYP2D6 activity leading to ED admission. This is a striking finding as it might point to a constitutive role of the polymorphic CYP2D6 enzyme on basic brain function.Dizziness is a common clinical phenomenon that can be related to a wide variety of drugs  and was Phenomenologically, dizziness is connected to alertness, attention, and vigilance. Our results are in line with the aforementioned fMRI studies showing an association of the CYP2D6 genotype on brain function connected with alertness and attention. However, in fMRI studies, conflicting results on the direction of sustained attention with lower or higher CYP2D6 activity were seen . Our stuCYP2D6 might be an important enzyme for local serotonin and dopamine syntheses in the brain  and therDizziness occurred frequently with other ADR symptoms in our dataset. We documented all ADR-associated symptoms on ED arrival, and therefore, dizziness might not always have been the primary symptom leading to ED presentation. However, even if not the primary symptom, but part of a symptom complex, we could show an association that points to a higher vulnerability for drug-associated dizziness in case of lower CYP2D6 activity. Furthermore, we analyzed concomitant ADR symptoms. While only dizziness and not those concomitant symptoms were consistently associated with CYP2D6 activity markers, those sensitivity analyses might underline the importance of CYP2D6 activity on drug-related dizziness. However, some concomitant ADR symptoms are likely to occur in the context of dizziness and reduced vigilance. As an example, drug-related falls were associated with CYP2D6 substrate exposure and with CYP2D6 saturation. This could be seen in line with many drugs metabolized by CYP2D6 that are considered fall-risk increasing . This fiThe results of this study are at least partially generalizable. CYP2D6 is expected to metabolize up to 25% of commonly taken drugs . Thus, CStrength of this study is first of all the large sample size of prospectively enrolled, well-characterized ADR cases, including genotypes for a large subsample. Secondly, to the best of our knowledge, this is the first study to analyze the impact of CYP2D6 activity on ADRs considering CYP2D6 saturation by concomitant substrate exposure and, in a smaller subsample, the additive effects of substrate exposure and genotype. While the use of pharmacogenetics is expected to increase drug safety by optimizing the individual drug treatment , data onin vitro studies and the effect in vivo, in particular in multi-medicated, older adults, might differ. We were not able to check patients’ medication adherence, for example, by measuring concentrations of drugs in blood or plasma of patients. However, our study is in line with a signal detection approach in pharmacovigilance, where the suspected case of an ADR is already a signal documented in surveillance databases such as EudraVigilance or the WHO database.Our study has potential limitations. We did not differentiate between CYP2D6 major or minor substrates for calculation of CYP2D6 saturation. Likewise, we assumed additive effects of saturation and inhibition. Thus, we built these analyses on assumptions testing linearity of CYP2D6 saturation, saturation/inhibition, and composed activity. In addition, we did not characterize the possibility to pass the blood–brain barrier. On the other hand, these classifications are usually derived from Notably, the genotyped subsample might have diverging limitations. For genotyping, we needed testing and written informed consent which was not possible to obtain from all patients for logistic and ethical reasons. Therefore, ADRs resulting in death and loss of consciousness are missing in this subsample. However, as genotyping was probably easier in hospitalized patients with extended hospitalization time, this subsample represents a group of serious ADRs. The extrapolation of the phenotype from the genotype represents current knowledge on functional variants in a constantly developing field. Limitations of CYP2D6 phenotype extrapolation based on genotypes are discussed more in detail elsewhere . In addiIn conclusion, for the first time, this study shows an impact of CYP2D6 activity on the occurrence of the clinically relevant CNS ADR symptom dizziness. As this is shown for the first time, it would need replication in a different dataset. While evidence points to an important role of CYP2D6 activity on brain function, alertness, and serotonergic and dopaminergic pathways, this study may underline the clinical relevance of CYP2D6 activity affected by genotype and drug exposure on drug-associated dizziness. As dizziness is a frequent symptom in ADR-related ED admissions, this study is of importance to understand individualized ADR risks in older, multi-medicated patients.


No significant difference was observed regarding TATI, SATI, and VATI among patients with low or moderate and high risk of malnutrition. In contrast, the proportion of male patients embracing visceral adiposity was higher in high malnutrition risk group compared with that in low or moderate group . Moreover, this disparity was of borderline statistical significance in women . Assessing adipose tissue distribution might potentiate the estimation of malnutrition risk in cirrhotics. It is pivotal to recognize visceral adiposity and develop targeted therapeutic strategies.Mounting evidence has suggested the clinical significance of body composition abnormalities in the context of cirrhosis. Herein, we aimed to investigate the association between visceral adiposity and malnutrition risk in 176 hospitalized patients with cirrhosis. The adiposity parameters were obtained by computed tomography (CT) as follows: total adipose tissue index (TATI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), and visceral to subcutaneous adipose tissue area ratio (VSR). Malnutrition risk was screened using Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT). Visceral adiposity was determined given a higher VSR based on our previously established cutoffs. Multivariate analysis implicated that male gender (OR = 2.884, 95% CI: 1.360–6.115,  Malnutrition is prevalent in patients with cirrhosis, which contributes to the increased risk of morbidity and mortality . It is oEvaluation of body composition, including muscle and adipose tissue, gives rise to an objective assessment of the patients' metabolic and nutritional status. Muscles are responsible for mechanical activity, whereas adipose tissue is involved in energy regulation and metabolic action . We and n = 83; women, n = 93; median age, 63 years }. Details of the diagnosis of liver cirrhosis, retrieval of laboratory results, and cirrhosis-associated complications have been comprehensively described elsewhere  between 2019 and 2020, 12 with acute-on-chronic liver failure upon admission, 19 with concurrent cancers and 36 without CT scan during hospitalization were excluded from this work . Therefolsewhere , 18. Thi2/m2). Accordingly, several parameters were obtained as follows: total adipose tissue index (TATI), visceral adipose tissue index (VATI), and subcutaneous adipose tissue index (SATI). Visceral adiposity was evaluated by visceral to subcutaneous adipose tissue area ratio (VSR) . Details in relation to image analyses of distinct adipose tissues have been explicitly depicted in our previous publication (io (VSR) , 16.2/m2; women, 26.75 cm2/m2), and VATI  , SATI  and 95% confidence interval (CI) were calculated. All p-values were two-sided, and we regarded p < 0.05 as statistical significance. The statistical analyses were carried out using MedCalc 15.2.2  and Stata 14.0 .Data were presented as mean ± standard deviation (SD), median (IQR), simple frequencies, or percentages (%) as appropriate. Continuous data were compared using an independent Student's Then, these patients were divided into two groups in terms of malnutrition risk determined by RFH-NPT score. Among them, 79 (44.89%) patients were in the low- or moderate-risk group and 97 (55.11%) were in the high-risk group. There were significant differences in gender, CTP class, etiology, the presence of ascites, BMI, the presence of sarcopenia, visceral adiposity, albumin, creatinine, and PT-INR. Patients with high risk of malnutrition were dominant in men, more CTP class B/C, more alcoholism, more ascites, lower BMI, more sarcopenia, more visceral adiposity, lower albumin, higher creatinine, and PT-INR.p = 0.041), male gender (p = 0.005), alcoholism (p < 0.001), CTP class (p = 0.011), ascites (p < 0.001), BMI (p = 0.001), sarcopenia (p = 0.007), visceral adiposity (p < 0.001), and albumin (p = 0.008) were significantly associated with high risk of malnutrition. Taking into consideration that alcoholic liver disease that exhibits a large weight on original RFH-NPT score, we decided to construct two multivariate logistic regression model. In model 1, our results indicated that visceral adiposity exhibits borderline significance . In model 2 excluding etiology, we found that male gender , BMI , albumin , and visceral adiposity  were independent risk factors of malnutrition risk determined by RFH-NPT in hospitalized patients with cirrhosis.The univariate and multivariate analyses of malnutrition risk are shown in 2/m2, p = 0.355; women: 111.70 ± 54.65 vs. 98.19 ± 49.92 cm2/m2, p = 0.219), SATI , and VATI  in both genders among patients with low or moderate and high risk of malnutrition. In contrast, the proportion of male patients embracing visceral adiposity was higher in high risk of malnutrition group compared with that in low or moderate group . Moreover, this disparity was of borderline statistical significance in women .It has been suggested that CT quantification unravels significant variations regarding adipose tissue distribution pattern by gender , 20. SpeAs far as we can determine, this is the first work to explore the association between CT-defined abnormal adiposity and validated tool (RFH-NPT) for screening malnutrition risk in hospitalized patients with cirrhosis. Our results implicated that high VSR that corresponds to visceral adiposity is associated with higher risk of malnutrition independent of BMI. Furthermore, the distribution of adipose tissue might alter more profoundly in comparison with other adiposity parameters when stratified by malnutrition risk.Mounting evidence has proved that malnutrition serves as a predictor of morbidity and mortality in patients with cirrhosis . It is tIn our work, the hospitalized patients with cirrhosis and high risk of malnutrition were at lower levels of BMI and prone to embrace higher proportion of visceral adiposity. Although BMI has been a concern in most researches evaluating clinical implications or outcomes in cirrhosis, it seems an inaccurate measurement of body composition. The main drawbacks of BMI include its inability to discriminate between muscle and adipose tissue as along with confounding impact of fluid retention in cirrhosis , 27. In Intriguingly, several studies have revealed the association between abnormalities in skeletal muscle and malnutrition risk in a wide array of pathological entities. Borges and colleagues showed that the presence of sarcopenia might predict comorbidities in 29%, and nutritional risk in 49% hospitalized patients with cancer . Akazawavia portal vein, consequently resulting in oxidative stress, lipid peroxidation, and hepatocellular inflammation  and by the Science and Technology Program of Tianjin (Grant 19ZXDBSY00020 to KJ).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Weakly supervised video anomaly detection is a recent focus of computer vision research thanks to the availability of large-scale weakly supervised video datasets. However, most existing research works are limited to the frame-level classification with emphasis on finding the presence of specific objects or activities. In this article, a new neural network architecture is proposed to efficiently extract the prominent features for detecting whether a video contains anomalies. A video is treated as an integral input and the detection follows the procedure of video-label assignment. The extraction of spatial and temporal features is carried out by three-dimensional convolutions, and then their relationship is further modeled using an LSTM network. The concise structure of the proposed method enables high computational efficiency, and extensive experiments demonstrate its effectiveness. In the past few decades, video anomaly detection has increasingly become a research focus because of its wide application, such as in public safety and online video censorship. Along with the popularity of camera hardware, the number of videos acquired by smartphones and surveillance cameras has increased so drastically, that manual processing of these videos becomes unfeasible in many scenarios due to its low efficiency. Anomaly detection refers to the problem of finding irregular patterns that do not conform to the expectation . AnomaliIn practice, anomaly usually happens in a short time slot, while the principal part of the video can still be considered normal. A natural way to find out whether a video contains an anomaly is to follow the idea of multiple instance learning (MIL), where a video is considered normal only when there is no anomaly in all its segments. To comply with this requirement, it is necessary to identify both the activities and the context of a video. In the early works towards video anomaly detection, features such as object trajectory and spatiotemporal context were manually selected and calculated for classification ,3. ScenaBased on the way of human intervention and the information used for training, usual deep learning methods for video anomaly detection can be classified into supervised, unsupervised, and weakly supervised methods. Supervised deep learning methods rely on the clear identifications of normal and abnormal activities; successful training depends on sufficient samples with accurate frame-level annotations, so their applications are limited by the availability of large-scale datasets. Unsupervised methods, on the other hand, do not require labeled samples; instead, the training set is composed of only normal videos to understand how the normal scenarios should be. Subsequently, a video is considered abnormal if it is dissimilar to the normal ones in the training set; the robustness of a model, therefore, relies on how representative the training videos are, and how the difference between normal and abnormal videos is defined and measured. Insufficient training or unrepresentative training samples can lead to a high false-positive rate. Many powerful and effective deep learning methods have been proposed ; along wThough a deep learning method requires no manual feature engineering, defining an effective architecture and choosing a suitable framework are critical for its performance. The focus of video anomaly detection is to identify events, activities, and contexts presented in temporal-sequential frames; therefore, dynamic spatial–temporal features are required. In this article, a new framework is proposed to efficiently detect anomalies using weakly supervised video datasets. Three-dimensional (3D) convolutions with max-pooling are adopted to extract the prominent spatial–temporal information, and then the long short-term memory (LSTM) network  is used Many deep learning methods have been proposed for video anomaly detection. The main difference between these existing methods is the way of how to discern the anomalies from the normal scenarios. A video or a video frame is commonly handled as an outlier when an object or event presented in it is significantly different from the ones learned from the training set. Autoencoder is a commonly adopted technique for these methods; with sufficient samples, the trained autoencoder can generate small reconstruction errors for normal videos and large errors for abnormal ones. In , a fullySome of the methods used transfer learning technique and combined the extracted features with other classification methods to carry out the detection ,14,15,16Along with the availability of large-scale weakly classified datasets, weakly supervised methods are the recent focuses in video anomaly detection. For example, the methods proposed in ,20,21,22Most of the current weakly supervised models adopted the way of dividing a video into a predefined number of segments to identify the segments that contain anomalies, like the way for a strongly supervised dataset. However, such a division is not accurate in most cases because without knowing the exact spatial and temporal location of anomalies, the integrity of an event can be broken or inter-related events can be separated, which will confuse the classifier; meanwhile, handling multiple segments is time-consuming, and class imbalance may become a problem during the training given anomaly only happens in a small time slot.To solve the aforementioned problems, a more natural way was adopted to decide whether a video contains anomalies conforming to the idea of MIL: a video is treated as an integral input and is considered normal only when it contains no anomaly. Max-pooling operations are used to replace the division of a video and to capture the most prominent spatial-temporal features corresponding to possible anomalies. In such a way, a video is classified based on the unique score generated by the framework. Hence, detection of anomalies in a video becomes a binary classification with the final output score in the range of , where 0 (zero) means no anomaly detected, and 1 (one) means anomaly present. The architecture of the proposed framework is illustrated in As discussed in The extracted features are used as the input for the second block where they are convoluted by 8 filters of In the last block, the number of filters is doubled again to 16, with the size of The output after these three blocks is a combination of the abstract spatial and temporal features ready to be used for further processing. Only three blocks are used here because 3D convolution is computationally expensive, especially when the spatial or temporal receptive field is large; also, too many max-pooling layers may suppress the contextual information too much, leading to the loss of the important temporal relationship between video frames. Consequently, features obtained in this step can still be called “local” features, and their long-temporal changes and relationship need to be further modeled. Fortunately, the convolution operations keep the temporal sequences of the extracted features, so these discrete spatial-temporal features can be processed as a time sequence series. The LSTM network is an efficient architecture to suit this requirement. While the LSTM was initially developed to solve the vanishing gradient problem for training traditional RNNs, its insensitivity to gap length forms a big advantage over other sequence learning methods in many applications. A single memory unit in the LSTM architecture consists of a cell state and its three gates: an input gate, an output gate and a forget gate. Therefore, in the second part of the proposed framework, the features extracted in the first part are flattened according to their temporal sequence, and then the formed series is fed into the LSTM network for training. A total of 1024 units are used in the network to capture the memory features of each timestep along the timeline; therefore, along with the training of the LSTM network, the important spatial-temporal features for each time step are stored in the hidden state as a 1024-dimension vector. Given that videos are weakly classified, the state of the last cell of the LSTM network, which corresponds to the reminiscent information at the end of a video, may not contain any useful information for detecting anomalies that happened in the video  as the activation function:The final output of the proposed framework is a value ranging from 0 (zero) to 1 (one) to indicate whether the video contains anomalies; in the ideal case of binary classification, a score of 1 (one) means that a video contains anomalies, and a score of 0 (zero) means no anomaly in the video. Therefore, the following binary cross-entropy loss is used as the loss function: With the three-parts architecture and the loss function defined in Equation (8), the proposed framework can be trained by proper datasets and used for detection in new videos. The small kernel sizes of architecture facilitate the computation and implementation, which enables high efficiency with potential use for both offline and online detection.The proposed framework followed a sound procedure to extract the critical features for anomaly detection. To demonstrate its effectiveness and objectively compare with other state-of-the-art methods, experiments were carried out on two currently available weakly supervised datasets: UCF-Crime and XD-Violence datasets. The UCF-Crime dataset is a large-scale video dataset introduced in . It consXD-Violence is another large-scale video dataset proposed for violence detection . The datThe two aforementioned datasets were selected because both are large-scale and contain a considerable number of training samples, so the framework is less likely to have problems of undertrained or overfitting.The training of the proposed framework was straightforward and end-to-end. A video was treated as an integral input formed by sequential video frames and fed to the network. The aspect ratio of a video was assumed to be the traditional 4:3; so, for each video frame, the width and the height were rescaled to 160 and 120 pixels, respectively. All the color channels of the video frame were divided by 255 to normalize their values into the range Given the training videos were weakly labeled, the exact spatial and temporal locations of the activities or objects, which determine the video attribute, are unknown. Consequently, some data augmentation techniques, like cropping and translation are not applicable due to their possible modification of sensitive information of an event or object. Nevertheless, a safe way was adopted to extend the training samples by generating a new training sample by flipping horizontally all the video frames; such a mirrored change does not lose any critical information for detection, nor alternates any critical features of activities when the background and context have the same alternation. Such augmentation of data can benefit the training, because it emphasizes the detection of events and activities themselves, without adding any artificial interpolation information to the process. Following the procedure of LSTM, each video was fed into the framework as one integral input, so the batch number was set to 1 (one). The stochastic gradient descent (SGD) algorithm was used as the optimizer for both datasets with a learning rate of 0.0002. Hyper-parameters for each layer were fixed as introduced in The proposed framework had no restriction on the number of frames contained in the input video. Therefore, the input videos can have any time duration and number of frames. However, if the time duration of a video was too long, the combined sequential video frames become a burden to the CPU/GPU memory and could lead to an overflow, either in the training when updating the weights, or in the testing when calculating the final score. To handle this problem, the maximum number of frames contained in an input video was set to be 4000; if a video contains more than 4000 frames, it was split into clips with each one containing 4000 frames (the last and the second last clip can have overlaps to satisfy this requirement). For each epoch of the training phase, a clip was randomly selected for the oversized video and fed into the network. For testing, each of the split clips was processed separately, and the final score of the video was defined as the maximum of these scores:The proposed framework outputs a score ranging from 0 (zero) to 1 (one) that can be considered as the possibility of a video containing an anomaly. For such a binary classification, the area under the ROC curve (AUC) is a conventional index to show how accurate the classifier is. TPR), which is also called sensitivity, and the horizontal axis is the false positive rate (FPR). The calculations of TPR and FPR were defined as: TP, FP, TN and FN stand for the numbers of true positive, false positive, true negative, and false negative video samples in the testing set, respectively. AUC provides an aggregate index of performance across all possible thresholds for classification by measuring the area underneath the ROC curve from  to . The AUC shows how well the classification is without focusing on a specific threshold, indicating, therefore, the overall performance of a classifier. The receiver operating characteristic curve (ROC) is a graph showing the performance of a classifier at different thresholds; the vertical axis is the true positive rate  and (11). The main difference between a ROC curve and a PRC curve is that the number of true negative samples is not used in PRC, so PRC focuses more on the positive cases, and is more used when there is class imbalance. For the XD-Violence dataset, the average precision (AP) of the precision-recall curve (PRC) was more frequently used to show the performance of a classifier. In a PRC curve, As can be realized from the data in Meanwhile, the XD-Violence dataset focuses on anomalies with violent activities, while the UCF-Crime dataset covers much more types of anomalies, so the large inter-variance among these types could decrease the detection performance. Also, though the UCF-Crime dataset contains a decent total number of videos with anomalies, the videos of each sub-categorical anomaly remain to be few. Hence, the trained framework can fail to detect certain types of anomalies, and the intra-variance inside the same type of anomaly may further decrease its performance. In summary, larger datasets that cover more samples and types of anomalies are still in demand to further improve detection accuracy.Given that the training of the new framework shared the same configurations for the two datasets, it would be interesting to see whether the performance of detection can be further improved if the two training datasets are merged. The results of combined training are illustrated in An efficient new framework was proposed to perform video anomaly detection. 3D convolutions and the LSTM architecture were used to extract the spatial and temporal features of videos for detection. The proposed framework followed the natural way of detecting anomalies in a video and has no restriction nor special pre-processing requirements on the video. The framework does not have restrictions on the temporal duration of the input video. It has a concise structure and is easy to be implemented; the efficient structure enables the possibility of both offline and online detection. Experiments on two large-scale weakly supervised datasets have been carried out, and the results demonstrated its effectiveness over other state-of-the-art methods. An exhaustive search in the hyperparameter space of the model may benefit even further the performance of the proposed method. Our future work will explore this aspect and devote to the fusion among multiple-channel information for detection; for example, by combining the videos with the sounds from the built-in microphone like the work carried out in  with theA new framework that provides an effective way of detecting anomalies by combining three-dimensional convolutions and the LSTM network.The structure of the new framework has high computational efficiency, which enables its application to videos with different resolutions and for different tasks.Experiments carried out in this study not only demonstrated the effectiveness of the new framework, but also improved the benchmarks on two large-scale datasets.Video anomaly detection has been a focus due to the large demands from different applications. The current framework achieved a state-of-the-art performance with a straightforward and effective architecture, but still has unsatisfactory performance in detecting certain types of anomalies. Further improvement and advances in video anomaly detection methods, rely on the availability of more large-scale video datasets that include sufficient training samples and cover various types of anomalies. To summarize, the main contributions of this study are:


P = .13). Breastfeeding was the most commonly used strategy. Watching the video increased the chance of implementing analgesic strategies by 2.1 times (P = .19), while nurses suggesting the use of analgesia increased this chance by 5.5 times (P = .006). Although no statistical significance was found, the results suggest the clinical significance and feasibility of the “Be sweet to babies” video as a KT tool targeted at parents on neonatal pain management during nonurgent painful procedures. In addition, maternal involvement in pain care significantly increased when pain relief strategies were recommended by nurses, which suggests that nurses have a key role in facilitating parental participation.The “Be sweet to babies” video is a knowledge translation tool targeted at parents on the use of analgesic strategies during painful procedures performed in neonates. This study aimed to evaluate the effectiveness of the Portuguese version of this video on maternal involvement in neonatal pain management during the newborn screening blood test. Nonrandomized, pragmatic clinical trial. The study was conducted in a rooming‐in unit. All mothers received a pamphlet regarding neonatal pain management and were invited to participate in daily education sessions conducted by nurses, which included the video. The intervention group included mothers who voluntarily watched the video, while the control group was comprised of mothers who did not attend the education sessions or left the session before watching the video. Data were collected by interviews conducted by the research team. Descriptive and inferential analysis considered a confidence interval of 95%. A total of 73 mothers were included in the study. Analgesic strategies were used in 14 (40%) of the procedures in the intervention group and 9 (24%) in the control group, a clinically important difference of 16% points between groups, although no statistically significant difference was found ( It demonstrates the use and effectiveness of breastfeeding,The video has been evaluated by parents and HCP as useful, easy to understand, applicable in real scenarios, persuasive, and an ideal length.We hypothesized that mothers exposed to the Portuguese version of the video would be more participative in using analgesic strategies during nonurgent painful procedures performed in neonates. Therefore, this study aimed to evaluate the effectiveness of the Portuguese version of the "Be sweet to babies" video on maternal involvement in neonatal pain management during the NBS blood test.22.1This is a nonrandomized, nonblinded, pragmatic clinical trial conducted in the rooming‐in postnatal maternity ward of an affiliated hospital of the University of São Paulo, Brazil. This institution is a public teaching hospital and certified by the BFHIAt the time of this study, there were no educational activities targeted at parents concerning pain management during NBS and there was no guideline on procedural pain management in the unit. However, all nurses had already watched the “Be sweet to babies” video in a previous study.2.2Mothers admitted to the rooming‐in unit during the study period, over the age of 16 years old, able to give informed consent, able to understand, read and write in Brazilian Portuguese, and whose newborns, born at any gestational age, were able to be breastfed, positioned SSC, or receive the sweet‐tasting solution of 25% glucose were eligible. After enrollment, the following exclusion criteria were applied: failure to successfully collect blood for NBS on the first heel lance attempt; NBS collected through venipuncture instead of the standard procedures of heel lance for capillary blood sampling; NBS collected without mothers’ presence; and newborns transferred to another unit.2.3Data collection occurred during the month of July 2017, during 17 uninterrupted days. Upon admission, all women received a pamphlet with the same information as the “Be sweet to babies” video to ensure the opportunity to receive information about effective pain‐reduction strategies. All women were invited to participate in daily postnatal education sessions conducted by nurses, which addressed postpartum and newborn care, and included the “Be sweet to babies” video as the last topic addressed. Nurses did not provide further opportunities to explain or discuss the content of the video.The IG was comprised of mothers who voluntarily watched the video (intervention), while the CG was comprised of mothers who did not attend the education sessions or left the session before watching the video. All mothers in the CG were invited to watch the video after completing the research questionnaire. Participants were not blinded due to the impossibility of concealing the proposed intervention in the routine of the rooming‐unit.,After 48 hours of birth, newborns underwent NBS. Lastly, mothers were invited to answer a questionnaire administered by the research team. The questionnaire was developed based on prior studies.2.4, with the aim of 80 participants, a level of significance (α) of 5%,power of (1 − β) 90%; and absolute difference of 39% in the use of analgesic strategies between groups and a loss to follow‐up rate of 20%.Sample size was based on a previous pilot study2.5Data were stored in a Microsoft Excel for Windows® (version 2011) spreadsheet, and descriptive and inferential analysis were performed in SPSS version 17.0, considering a confidence interval (CI) of 95%. Pearson's chi‐square (two‐sided) and Fisher's exact test (two‐sided) were used to analyze categorical variables, and the Paired t test (two‐sided) was used to compare the means of the quantitative variables between groups. In addition, a logistic regression evaluated the association of the primary outcome with the following variables: visualization of the video, pamphlet reading, number of children, number of previous painful procedures, father's and other relative's presence during NBS, and nurses’ suggestion of analgesic strategies’ use.3.During the study period, 113 mothers with their newborns were admitted in the unit. From these, 79 were included in the study. After exclusions and losses to follow‐up, data analysis comprised 73 participants Figure Demographic characteristics of participating mothers were similar between groups except for the mean number of children, which was higher in the CG Table Newborns’ demographic and clinical characteristics were similar Table P = .30). Fathers or other relatives accompanied mothers during 14 (37%) NBS blood tests performed in the CG and 15 (43%) in the IG (P = .87).The pamphlet on neonatal pain management was read by 16 (42%) mothers in the CG and 18 (51%) in the IG (3.1P = .13), an absolute difference of 16% between groups. Breastfeeding was the most commonly used strategy in both groups. SSC and non‐nutritive sucking (NNS) were provided only in the IG. Watching the video doubled the chance of using any analgesic strategy, breastfeeding 1.5 times, SSC 4.6 times, and NNS 2.2 times Table There was no statistically significant difference between groups in terms of mothers’ involvement in neonatal pain management. Analgesic strategies were used in 9 (24%) of the procedures in the CG and 14 (40%) in the IG P = .1, an absoP = .13) reported they held their newborns during NBS. Only one participant in the IG (3%) and none in the CG reported observing the procedure while the newborn was lying down on a crib (P = .48). There was no significant difference between groups regarding nurses’ encouraging parents’ participation (P = .57). Nurses suggested breastfeeding during NBS in approximately half of the cases , although this suggestion was not heeded by all mothers. Three (9%) mothers from the IG and none in the CG reported advocating for the use of analgesic strategies (P = .10).For infants who did not receive any pain management strategies, most of their mothers , increasing 5.5 times the chance of implementing analgesic strategies during NBS. Watching the video increased the chance of implementing analgesic strategies by 2.1 times Table In an adjusted analysis, nurses suggesting the use of analgesia were the only significant association (P = .49), such as vaccinations and blood collection. Three (8%) mothers in the CG refused to watch the video after answering the questionnaire. No adverse events associated with the video or the use of analgesic strategies were reported or observed.After participating in this study, all mothers in the IG and the majority of mothers in the CG (36/95%) intend to use breastfeeding, SSC, or sweet‐tasting solutions in future painful procedures , the absolute difference of 16% could be considered as clinically important. Based on the study conducted by Shah, Ipp, Sam, Einarson & Taddio,P values since they do not provide information on the magnitude of an effect, with special attention to the health relevance of the findings.Although no statistically significant difference was found between groups regarding the use of analgesic strategies during the NBS (P = .01) and breastfeeding during vaccination was the most commonly used strategy. Conversely, sucrose was the second most commonly used strategy, while sweet‐tasting solutions were not used at all in our study, despite the availability of 25% glucose in the unit for painful procedures.To date, few studies have evaluated the effectiveness of instructional videos on the use of analgesic strategies during painful procedures. A Canadian randomized controlled trial (RCT)In two additional RCTs conducted in Canada, the effectiveness of videos in complex and active interventions  increased the use of any pain relief strategies during infant's vaccination by 10%, being recommended in combination with sucroseThe “Be sweet to babies” video recommends the use of breastfeeding, SSC, and sweet‐tasting solutions, which are effective, low cost, safe, and easy to apply interventions. Breastfeeding was expected to be the most commonly used analgesic strategy in both groups in our study, since it was conducted in a rooming‐in unit certified by the BFHI that aims to promote, protect, and support breastfeeding.,In regard to the positive impact of nurses encouraging parents in the use of analgesic strategies during NBS, our findings confirm that nurses have a key role in facilitating parental involvement in neonatal pain management, as well as evaluate their impact in clinical practices. Parents and HCP have been accessing the “Be sweet to babies” video on social media platforms in many languages across many countries, with positive results in terms of knowledge acquisition, acceptability, feasibility, and intention to use the strategies for future painful procedures.,Furthermore, parents increasingly search for health information on the internetAfter participating in this study, the majority of mothers reported the intention to use breastfeeding, SSC, or sweet‐tasting solutions in future painful procedures performed in their infants, such as vaccination and blood collection. It is worth highlighting that the analgesic effects of breastfeeding4.1To the authors’ knowledge, this is the first study that investigates the effectiveness of an educational video targeted at parents on the use of analgesic strategies in the Brazilian neonatal context. Its pragmatic design enabled the evaluation of this KT tool in a real scenario, and results are therefore likely to be generalizable to other rooming‐in units around the world. A pilot study was conducted in the same setting (n = 23) to assess the feasibility of the full‐scale trial, elucidating the need to investigate nurses’ suggestion of use of analgesic strategies during the NBS blood test. Furthermore, for ethical reasons, mothers from the CG received a pamphlet on neonatal pain management upon their admission in the unit and had an opportunity to watch the video after participating in the study.High‐quality evidence supports the effectiveness and safety of breastfeeding, SSC, and sweet‐tasting solutions in reducing pain scores during nonurgent minor painful procedures.The nonblindness of participants and nonrandomized design are study limitations; however, this was a pragmatic trial, conducted in an ethical responsible manner. The mean number of children may have influenced mothers' allocation into groups since 16 mothers, who did not participate in the postnatal educational sessions, reported that they had already gained enough knowledge and experience caring for their other children. Regarding mothers who participated in the educational sessions, knowledge acquisition may have been hindered due to the fact that the video was shown at the end of the sessions, following a large amount of information. In addition, the small sample size based on an absolute difference of 39% in the primary outcome between groups, which is higher than the average used in KT studies, may have resulted in the study being underpowered, influencing the statistical significance of the results. However, there were no other studies that investigated the effectiveness of instructional videos targeted at parents on neonatal pain management to guide the sample size estimation. The decision to estimate the sample size based on a pilot study also considered ethical aspects, feasibility, and resources available to conduct this research.5Although no statistical significance was found, the results suggest the clinical significance and feasibility of the “Be sweet to babies” video as a KT tool targeted at parents on neonatal pain management during nonurgent painful procedures. The video was simply inserted in a rooming‐in unit routine, increasing the prevalence of use of analgesic strategies by mothers during the NBS blood test. However, in our study, nurses suggesting the use of pain relief strategies had greater impact on mothers’ participation on neonatal pain management.The authors have no conflict of interest to declare.LC, MB, and DH have made substantial contributions to conception and design of the study. LC, MV, and MB have been involved in data analysis. LC has been involved in drafting the manuscript. All authors have been involved in critically reviewing and revising the manuscript for important intellectual content and have read and approved the final manuscript.


International Brazilian Journal of Urology. This past year has seen ongoing incredible challenges to our global healthcare community in caring for patients impacted by COVID-19 during this ongoing pandemic. In consequence, many parts of the world have had to postpone elective surgeries for at times extended periods and also this has placed an incredible constraint on available surgical resources in caring for our surgical patients. Despite that, I am proud to say that we have continued to see an unwavering commitment by urologists across the world in offering first class surgical care to patients and there is no better example of this as depicted in this year's selection of the best video submissions and publications within our journal which are selected on a host of factors including originality, quality of the video and narration, and potential impact on improving surgical outcomes for patients through its widespread adoption by colleagues. In this regard, I am proud to announce that the 1st Prize for best video of the year is given to Dr. Tobias-Machado et al. from São Paulo, Brazil in the video entitled “Robotic parastomal hernia repair” published in March-April 2021 (Robot-assisted simple prostatectomy: the evolution of a surgical technique” by Dr. Rodrigues et al. from São Paulo, Brazil and published in May-June 2021 (It is that special time of the year where we celebrate the extraordinary surgical achievements and commitment to innovation of our contributors to the video section of the une 2021 . In thisIn conclusion, I wanted to thank each and every one of you for supporting our journal through truly unprecedented challenging times which has tested all of us in terms of our resilience and ability to adapt. I very much send my very best wishes to all of you and your families to remain safe and in good spirits. Very much looking forward to seeing you all in person within the coming months and years.Warmest regards and best wishes,