In total, 118 interpreters participated in the training sessions. Respondent knowledge improved, with gains maintained at 6-months (p < 0.01). There were no changes in self-efficacy, and attitudes. Training did not change self-reported practice behaviour, but there was notable pre-existing variability in participants’ methods of managing unknown genetic words. Most respondents agreed that training was useful (93%) and relevant (79%) to their work. More respondents reported learning more from the case study activity (86%) than the group activity (58%). Health Interpreters found the training acceptable and demonstrated sustained improvement in knowledge of genetic concepts. Increased delivery of this training and associated research is needed to assess findings in a larger cohort and to measure the impact on patients.Health Interpreters enable effective communication between health practitioners and patients with limited knowledge of the predominant language. This study developed and evaluated a training session introducing Health Interpreters to genetics. The online training was delivered multiple times as a single 2-h session comprising lectures and activities. Participants completed questionnaires  to assess the impact of training on knowledge, attitude, self-efficacy, and self-reported practice behaviour. Questionnaires were analysed using descriptive statistics, Fisher’s Exact, or independent  Health Interpreters provide a vital service within health systems for patients with limited knowledge of the predominant local language. Their involvement in clinical care is associated with improved quality of healthcare . RelayinOver the last decade genomic testing in clinical care has been increasing . TraininPost-qualification training of non-genetic health professionals in genetic and genomic concepts is common for physicians, nurses, and allied health professionals . This apHere we describe an interactive training session aimed to introduce Health Interpreters to basic genetic and genomic concepts and their clinical application. This study’s objective was to evaluate the training sessions’ effectiveness in improving Health Interpreters’ knowledge, attitude, confidence, and practice behaviour using genetic and genomic terms in their professional practice.The training involved an interactive workshop-style session, delivered in English to a mixed language cohort of professionally qualified interpreters see  between A genetic counsellor (LFF) and a genomic research academic with tertiary teaching experience (MEV) designed the content and format of the training session. The training content was based on the experiences of genetic counsellors working with interpreters in clinical practise. Interpreter service providers were consulted regarding the training session structure and delivery. The 2-h training session was comprised of three lectures and two activities .Interpreter service providers, which Queensland Health contracts to provide interpreters for the public health service, advertised the training session using promotional materials provided by Queensland Genomics (the sponsors). These providers advertised the training sessions to their contractors through direct email, newsletters, and social media posts.via an invitation email with a webpage link to both the participant information sheet and the questionnaire. The email for the pre-training session questionnaire was sent to registered participants 1 week prior to the training session. The post-session questionnaire invitation was sent to participants immediately after completing the training sessions and was open for 1-week. The 6-months follow-up questionnaire invitation was sent to participants 6-months after the training session with the questionnaire open for responses for 1-week. Completing the surveys was voluntary and not a prerequisite for attending the training session or receiving professional development points.Training session participants were recruited to the evaluation study The training sessions were evaluated using online questionnaires: pre, post, and 6-months follow-up. The questionnaire applied the Theoretical Domains Framework  as the uEach of the three questionnaires administered the same core 31-items, with post- and 6-months follow-up having additional questions. The response options for the questions included; rating scale, 5-point Likert scale, multiple-choice, and open text boxes. The core questions contained: 8-items assessing demographic information; 3-items assessing self-efficacy of understanding and interpreting genetic terms; 3-items assessing attitude on the importance of genetic health services to themselves or their family and their professional practice; 7-items evaluating self-assessed practice behaviours when interpreting genetic terms in a clinical appointment; and 10-items assessing knowledge of genetic concepts.The knowledge questions were from a validated knowledge tool . In thisIn addition to the core questionnaire items, the post-questionnaire had an additional 10-items evaluating the participants’ training session experience . The 6-months follow-up questionnaire had an additional 5-items capturing the experience of interpreting genetic concepts in the 6-months since the training session  .n = 11) and all questionnaires were reviewed by content experts (n = 3). The follow-up questionnaire contained the same core questions as the pre- and post-questionnaires. Only the questions related to the training evaluation which were specific to the post-questionnaire were not included in the pilot test.Items, other than knowledge questions, were customised for this questionnaire. Before use, the follow-up questionnaire was pilot tested by Health Interpreters  participants that sought additional education (self-seeking behaviour) and 2) participants that had post-intervention appointments, and those that did not.Descriptive statistics were used to summarise data characteristics for the questionnaire responses. Association between demographic variables and questions related to the domains self-efficacy, attitude, and self-reported behaviour were compared using Fisher’s Exact test. Mean changes in knowledge between questionnaires were analysed with an independent p ≤ 0.05. Analyses were conducted in Stata (version 15.1)  with languages categorised based on the region of language origin. For example, Spanish originated in Europe, so it is classified as a European language. Variables related to past training and work experience were reduced to two categories, with “unsure” combined with “no”. Likert scale questions for self-efficacy, attitude, and self-reported behaviour were reduced to two categories. The categories that expressed overall ease, positive attitude, and agreement were combined (e.g. strongly agree and agree), as were those that expressed overall difficulty, negative attitude, and disagreement . Responses collected in open text fields for self-reported practice behaviour were thematically analysed by manual coding (MEV and PRM), using process previously described . Resultson 15.1) .via the self-determined code. Given the very low sample size of linked data (n = 6), paired analysis suited to longitudinal datasets was not possible due to a lack of power in the analysis. Unpaired statistical methods were used for the analysis of this data.There were 180 registered participants, with 118 participating in the training sessions. The pre-questionnaire was sent to 180 registered participants, 37 started answering the questionnaire (response rate 20.5%), but four were excluded as they were incomplete. There were 33 complete responses to the pre-questionnaire. Of the 118 participants who attended the sessions, 48 (response rate 40.7%) and 24 (response rate 20.3%) started the post and 6-months follow-up questionnaires, respectively. After excluding incomplete responses, 43 post responses and 22 6-months follow-up responses were included in the analysis. Of the respondents, six completed all three questionnaires as identified n = 118) interpreted 49 spoken languages, 26 of these languages were interpreted by one participant. No sign language interpreters attended. The majority of training session participants interpreted Asian languages (59.8%), with Mandarin (24%), Vietnamese (13%), Arabic (6%), and Korean (6%) being the most common. Interpreter languages (by region) were similar between training session participants and the questionnaire respondents  and remained consistent in the 6-months follow-up  (t-test p < 0.0001) and 6-months follow up questionaries   . Compare 0.0005) . While t 0.0005) .There was no change in self-reported behaviour after attending a training session. “Asking the clinician to rephrase or explain” was the most common action for “words not known by the interpreter” and “words that do not have an equivalent in LOTE”, for both multiple-choice  and openn = 13, 59.1%)  . Howevern = 4) identified having appointments with specialists in; genetics , allergies and immunology , breast and endocrine surgery , gynaecology , maternity and neonatal medicine , and paediatrics . No appointments were identified for general practice, or with specialists in cardiology, endocrinology, neurology, oncology, or nephrology. Most appointments where respondents interpreted genetic or genomic terms utilised telehealth or telephone communication. Due to COVID-19 restrictions on in-person appointments during the 6-months follow-up period, this may not represent the usual interpreter experience. Those respondents that had appointments after the training session where they used genetics terms considered it easier to understand genetic and genomic terms in English than those respondents that did not have appointments after the training session  (Those respondents that had client appointments in the 6-months follow-up period (= 0.088) .Respondents had high levels of overall agreement that the training session was clearly presented (93.0%) and informative (97.7%), with it being useful to their work (93.0%), with slightly fewer respondents considering it relevant to their work (79.1%) . RespondRespondents felt the training session could be improved by delivering the content at a slower pace or over multiple sessions. Respondents identified that providing information or slides for the presentations before the training session would assist with participant expectations and support participant learning of complex topics. Respondents also indicated that they would like more examples of different diseases and more details on clinical interactions with genomics .Health Interpreters are an essential part of the equitable provision of quality healthcare to people with limited English language skills . The useContinuing professional development of health professionals, including the use of short educational interventions, is a common mechanisms for upskilling health workers . The outGenomics is being implemented across health services with increasing frequency, creating more medical appointments where these complex concepts are discussed. To improve patient outcomes, training in genetic and genomic terminology for Health Interpreters has been identified as an unmet area of need . While tIn other studies assessing educational interventions in genetics training for healthcare workers, improved respondent knowledge is consistently observed despite variations in the mode of delivery and duration . This waThe questionnaire assessed self-efficacy and attitude to self/family and professional practice in the context of genetics and genomics. There was no change in either domain observed in this study. Self-efficacy is context-specific within individuals, with day-to-day circumstances influencing perception and confidence about professional practice . The neuAttitudes to the use of genetics in clinical settings by non-genetic health professionals are dependent on multiple factors including: their clinical specialty, clinical utility of testing in case management, and clinician’s consideration of the individual patient’s needs . The HeaThe presenters did note that participant questions during the training session often referenced their personal history and/or their family members’ histories rather than their professional practice or clients. This indicates that a number of participants found personal relevance in training by connecting genetic concepts and health services utility to their own family. Incorporating personal family elements may be a way of engaging participants in educational interventions in genetic and genomic concepts.As is experienced with medical language in general, the English terminology for genetics and genomic concept often do not have equivalent words in LOTE. It is part of an interpreters’ professional practise to manage how terms are delivered, for example through the selection of equivalent words or requesting clarification by the speaker. When the interpreter is unaware of an equivalent word, or it does not occur in the LOTE, asking the clinical client for clarification is the preferred method identified by participants in this study. This practice reflects the Australian training practices and the interpreters’ professional code of ethics . There wThere is a lack of professional development opportunities for Health Interpreters in Australia and so there was strong support for this training, with requests from Health Interpreters to increase the scope of training to include other medical specialties. To meet the demand for training, the delivery format may need to be adjusted as using live online sessions may not be practical. This mode restricts availability for some users due to the inflexible timing of sessions, has high resource requirements for delivery, and requiring participants to have a reliable internet connection and an interruption-free environment. Other studies of genetic education have demonstrated effective knowledge increase in non-genetic health professionals when using self-directed online training programs and on-demand recorded sessions tailored to the needs of the specific health profession . The impThe original design of this research was a linked longitudinal study. The main limitation was the insufficient amount of paired data for analysis, which necessitated unpaired methods for analysis. The analysis type weakens both the power and the longitudinal inference of the results. There were moderate responder rates for each individual survey but very low repeat responder rates. To maintain responder anonymity, we did not collect responder contact details. This meant we could not provide targeted reminders to those who did not complete follow-up surveys and could not provide professional development incentives for participating in the research. The researchers would consider methods for re-contacting participants to improve repeat response rates in the future. There is potential responder bias as only 18–32% of training participants completed each of the questionnaires. Based on the response rate and survey findings we would suggest that the evaluation method and domains explored be reassessed to determine if these metrics are suitable for the assessment training in the context of continuing professional development for Health Interpreters.Research has identified that improving Health Interpreters’ knowledge of genetic and genomics concepts would improve their client interactions during genetic counselling sessions . This st


The patients were also instructed against weight-bearing during hospitalization. The values of radiographic joint space width and Japanese Orthopaedic Association hip score for pain at hospital admission, discharge, and at the 6-month post-discharge checkup were evaluated. Although the hospitalization period and daily time spent performing the jiggling exercise varied in each case , the joint space width increased in all patients and there was an improvement in the hip pain scores in eight patients. The mean values of the minimum joint space width and hip pain scores at discharge were the highest compared to those at hospital admission and 6 months post-discharge. Our results suggest that intensive jiggling exercise for inpatients with advanced- and terminal-stage hip osteoarthritis leads to earlier improvement in joint space width and pain. Daily jiggling exercise for an adequate duration or in combination with non-weight-bearing practices may be a feasible conservative treatment for hip osteoarthritis.Jiggling exercise is a conservative treatment for hip osteoarthritis, which involves continuous shaking of the foot and leg in small oscillations while seated. Previous studies have shown beneficial effects of jiggling exercises for outpatients with advanced- and terminal-stage hip osteoarthritis when performed for longer than 1 year, including increases in joint space width and remission of symptoms. We aimed to use the data from our own treatment to evaluate the short-term impact of intensive jiggling exercises on inpatients with hip osteoarthritis to further examine the clinical utility of this exercise. This retrospective case series study included nine patients (57 ± 12 years) with nine hip joints with advanced- or terminal-stage hip osteoarthritis who performed continuous daily jiggling exercises, beginning from day of hospitalization to 6 months post-discharge. Jiggling exercise was performed seated, using the KENKO YUSURI Hip osteoarthritis (OA) is the most common joint disease and a leading cause of chronic pain, contributing to limited range of motion, walking, and activity. In 2017, approximately 2 million new patients were diagnosed with hip OA globally, bringing the number of individuals worldwide suffering from the condition to ~40 million [The widely recommended guidelines for the treatment of hip OA include non-pharmacological methods such as patient education and self-management, exercise therapy, weight loss in case of overweight or obese individuals, and walking aids as indicated, which are commonly applied as first-line treatment , 4. ThouJiggling exercise has been proposed as a new therapeutic exercise for hip OA , with reWe hypothesized that intensive jiggling exercises for inpatients with hip OA would result in earlier improvement in JSW and pain, which might serve as a disease-modifying non-invasive intervention for hip OA. The purpose of this study was to use the data from our own treatment to evaluate the short-term effectiveness of intensive jiggling exercises in relation to JSW and pain in inpatients with hip OA, to examine the clinical utility of this exercise.This study was a single-center retrospective case series. The protocol followed the tenets of the Declaration of Helsinki and was approved by the ethics committee of the Yanagawa Rehabilitation Hospital, Fukuoka, Japan (authorization number 2019–334). All study participants provided written informed consent. All the patients’ information was anonymized and de-identified prior to analysis.We retrospectively reviewed the records of all patients with hip OA who performed jiggling exercises at Yanagawa Rehabilitation Hospital  in inpatient settings between July 1st, 2017 and January 31st, 2019.The inclusion criteria were as follows: (1) diagnosis of advanced- and terminal-stage hip OA; (2) some pain related to the hip joint; (3) narrowing radiographic JSW of the hip joint; (4) patient’s desire to avoid surgery; and (5) continuous daily jiggling exercise performed from date of hospital admission to 6 months post-discharge. The exclusion criteria were as follows: (1) bilateral hip OA, (2) extreme decrease in acetabular head index (<50%), (3) history of neurological disease, (4) missing measurements, and (5) loss to follow-up.We assessed nine hip joints in nine patients. The cohort consisted of three male and six female patients, and their ages at the time of hospital admission ranged from 37 to 71 years  . Each pa®  was applied as this score is associated with roentgenographic changes in hip OA . This scThe intervention period (days) and jiggling exercise duration (hours) varied in each case. The period of hospitalization and daily jiggling exercise time ranged from 27 to 98 days and 2 to 6 hours, respectively . The daiThe records from one patient (patient A) illustrating the radiographic changes in the hip joint at hospital admission, discharge, and at the 6-month post-discharge checkup is presented in The results of the JOA hip pain scores are presented in This is the first study to examine short-term minimum JSW changes in inpatients with advanced- and terminal-stage hip OA after intensive jiggling exercise. Our results suggested that intensive jiggling exercises may facilitate early improvement in pain and radiographic JSW values.A previous study on jiggling exercise for outpatients with hip OA has reported that the JSW increased in 65 of 92 patients with post-Chiari pelvic osteotomy 70.7%) . The aut0.7% . Th® significantly reduces muscular stiffness of the gluteus maximus and biceps femoris muscles in patients with hip OA [The increased value of the JSW may have been caused by a decrease in muscle tension around the hip joint. A previous study has reported that 10 minutes of jiggling exercise using a KENKO YUSURIh hip OA . Thus, sh hip OA . It is ph hip OA . Due to The JOA hip pain score increased in eight patients (88.9%) at discharge (+10–40 points). Regarding the relationship between the minimum JSW and the hip pain, previous studies have reported that hip OA pain is associated with a minimum JSW of <2.0 mm  or <1.5 While all nine patients continued the jiggling exercise for up to 6 months post-discharge, the mean value of the minimum JSW at discharge was the highest. The daily jiggling exercise duration for nine patients ranged from 2 to 6 hours daily during hospitalization, and 1 hour daily post-discharge. Thus, it may be desirable to conduct jiggling exercises for at least 2 hours daily to increase the JSW. Each patient was expected to return to independent living following discharge; therefore, although they were instructed to perform jiggling exercises for preferably 2 hours daily, they were realistically expected to do so for at least 1 hour. The result was 1 hour of jiggling exercise performed daily by all patients following discharge. The fact that the patients accepted hospitalization for the jiggling exercise indicates that they were highly motivated to perform the exercise. This high level of motivation may have been influenced by the patient’s desire to improve the severity of their pain, which may have been difficult to maintain following discharge when the pain had improved or reduced. In addition, the combination of jiggling exercise and non-weight-bearing during hospitalization may have been effective as well. However, patient H, who had the longest hospital stay and daily duration of jiggling exercise, showed no change in minimum JSW at discharge. It is necessary to further examine the factors that lead to the improvement in the minimum JSW.This study has some limitations. First, although there were several potential patients at the beginning of this study, the number of patients decreased due to the stringent inclusion/exclusion criteria. It was, however, crucial to have a homogeneous group of patients with hip OA to precisely evaluate the short-term effectiveness of intensive jiggling exercise. Second, as the intervention period (days) and daily jiggling exercise duration (hours) varied in each case, a statistical analysis could not be performed. Third, detailed information on the combined effects of jiggling exercise and non-weight-bearing remains unclear. A randomized controlled trial is required to confirm the same. Fourth, the relationship between increased JSW and walking ability could not be examined. Future investigations on changes in walking and daily routine activities are also required.Our results suggested that intensive jiggling exercises for inpatients with advanced- and terminal-stage hip OA facilitated early improvement in radiographic JSW and pain. Daily jiggling exercise for a sufficient duration or a combination of this therapy and non-weight-bearing might be a feasible conservative treatment for hip OA.


Background: In 2020, during the COVID-19 pandemic, Italy implemented two national lockdowns aimed at reducing virus transmission. We assessed whether these lockdowns affected anti-seizure medication (ASM) use and epilepsy-related access to emergency departments (ED) in the general population. Methods: We performed a population-based study using the healthcare administrative database of Tuscany. We defined the weekly time series of prevalence and incidence of ASM, along with the incidence of epilepsy-related ED access from 1 January 2018 to 27 December 2020 in the general population. An interrupted time-series analysis was used to assess the effect of lockdowns on the observed outcomes. Results: Compared to pre-lockdown, we observed a relevant reduction of ASM incidence  and ED access , and a slight decrease of ASM prevalence . During the post-lockdown the ASM incidence reported higher values compared to pre-lockdown, whereas ASM prevalence and ED access remained lower. Results also indicate a lower impact of the second lockdown for both ASM prevalence  and incidence . Conclusion: The lockdowns implemented during the COVID-19 outbreaks significantly affected ASM use and epilepsy-related ED access. The potential consequences of these phenomenon are still unknown, although an increased incidence of epilepsy-related symptoms after the first lockdown has been observed. These findings emphasize the need of ensuring continuous care of epileptic patients in stressful conditions such as the COVID-19 pandemic. The coronavirus disease 2019 (COVID-19) pandemic has affected everyone around the world, not least through pressure on healthcare systems and delivery of care. The initial wave and consequent lockdowns led to the cancellation of routine investigations and elective interventions, and many health care providers had to move to alternative models of care delivery ,4. The nEpilepsy is one of the most common neurological conditions, impacting about 46 million people worldwide . This diSome studies have already analyzed the impact of the COVID-19 outbreak on patients with epilepsy. However, these studies were mainly questionnaire-based  or carriThis is an observational study based on the healthcare administrative database (HAD) of Tuscany. This source of data has already been used to conduct a study on ASM use . The HADEncrypted demographic information  from the demographic registry was linked, at patient level, with the outpatient pharmacy claims registry and the ED access database. The pharmacy claims registry includes data on dispensing date, number of packages, substance name, anatomical therapeutic chemical code (ATC) and defined daily dose (DDD). The ED database reports information related to date of access, date of discharge/hospitalization, one main and five secondary diagnoses codified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) . This stThe reference population was the general population of Tuscany, which accounted for approximately 3.7 million inhabitants. The population was stable through the study period, males accounted for 48%; 15% of the population was under 18-years and 32% was above 60-years. In the general population, we built the time series of weekly prevalence and incidence of ASM use and of weekly access to the ED for epilepsy and related disorders from 1 January 2018 to 27 December 2020 (study period).To evaluate the use of ASM in the general population we selected a dynamic cohort of subjects with at least one dispensing of ASM (ATC: N03A*) in the study period. The date of the first ASM dispensing was considered as the index date. We excluded patients with less than 1 year of database history prior to the index. For each patient, ASM dispensing was collected from the index date until the 27 December 2020 or death/emigration, whichever came first. We then computed treatment episodes of drug use for each subject. For this purpose, the duration of each dispensing was estimated by dividing the total amount of active substance contained in each dispensing by the relevant Defined Daily Dose (DDD) ,18. We cFinally, the weekly prevalence and incidence of ASM use were computed as the number of prevalent or incident users in the corresponding week, divided by the number of inhabitants living in the region as of 1 January of each corresponding calendar year as reference population .The times series of ED accesses for epilepsy and related diagnoses included all subjects who accessed an ED during the study period with the following main diagnoses: epilepsy (ICD9-CM: 345.x), myoclonus (333.2), convulsion febrile or afebrile spasm (780.3), and other abnormal involuntary movements (781.0). Similarly, we estimated the weekly ED access by dividing the number of cases occurred in a specified week during the study period with the number of inhabitants living in the region as of 1 January of each corresponding year as reference.To assess the effect of lockdown measures (LM) on study outcomes, the observation period was divided into segments: a pre-lockdown period from 1 January 2018 to 8 March 2020 (114 weeks), a first lockdown period from 9 March 2020 to 15 June 2020 (14 weeks), a post-lockdown period from 16 June 2020 to 15 November 2020 (22 weeks) and a second lockdown period from 16 November 2020 and 27 December 2020 (6 weeks).We then used an Interrupted Time Series (ITS) approach ,21 to esi), spline function) and a dummy holiday indicator  to account for time trend and seasonality. The coefficients: β0 represented the baseline level during the pre-lockdown period; β2, β4 and β6 estimated the level change during the first lockdown, the post-lockdown and the second lockdown, respectively; β3, β5 and β7 estimated the trends/slopes of the time series during the aforementioned periods [The model predictors were a non-linear function of the week  to assess potential variation in prevalence estimation during the studied period.In this study, both the data processing and data analysis were performed using the R studio software . In particular, the ITS analysis was conducted by using “tsMODEL”, “splines”, and “mgcv” R packages.As reported in The weekly incidence of ASM use reported significant variations during the study period. In detail, the ITS regression model depicted a significant reduction of ASM incidence after the first LM implementation (Incidence Ratio (IR): 0.65; 95%CI: 0.59–0.72) followed by a gradual increase from the 4th week of the first lockdown  B with a The analysis of weekly ED access for epilepsy and related disorders showed significant variation as already described for ASM use . In factIn this large population-based study, we observed during the first LM implementation a significant reduction in both incidences of ASM use and epilepsy-related ED access compared to pre-lockdown. On the contrary, for ASM prevalence, only a slight reduction was reported.Fear of contagion, along with the overload of the healthcare services associated with the hospital adaptation/reorganization for COVID-19 cases, might have limited non-COVID-19 patients’ access to healthcare services, including ED access for patients with epilepsy-related symptoms ,13,24.It is also possible to speculate that even the observed decrease of ASM incidence might be related to the corresponding decrease of epilepsy-related ED access, since lack of availability of trained clinicians and specialist services, as observed during the COVID-19 epidemic peaks, is likely to affect treatment initiation ,26. On tIn the post-lockdown, we observed an increase in ASM use and ED access. Nonetheless, ED access never returned to the values reported in the pre-lockdown period, whereas ASM use increased, with reported values higher than those registered during the pre-lockdown. These findings suggest an increased incidence of epilepsy-related symptoms in the general population following the first epidemic peak. Moreover, it is likely that during the post-lockdown, the management of patients with epilepsy was conducted outside the hospital setting not only for prevalent but also for incident cases.The increased incidence of ASM use in the post-lockdown may be the result of the stressful effects of the LM implementation experienced by susceptible individuals. Animal studies have in fact suggested that stressful events may trigger epilepsy onset and/or worsening. Thus far, two pathological mechanisms have been hypothesized: first, stress can increase glucocorticoid levels that influence serotonin, glutamate and GABA levels with consequent cortical hyperexcitability and seizure onset ,30,31,32Finally, study results indicate a significantly lower impact of the second LM in the observed outcomes. This different impact might be the effect of the stricter public health measures implemented during the first COVID-19 wave compared to the second one. This might have also contributed to the selection of more severe patients who accessed the ED during the post-lockdown and subsequent period, with consequent reduction of non-severe cases .This study has some limitations that should be acknowledged. First, in the study we did not include benzodiazepines, which are commonly prescribed for epilepsy management ,45. ThisOur findings emphasize the need to provide appropriate management of patients with epilepsy, particularly in potentially stressful conditions such as the COVID-19 pandemic. Patients with epilepsy are more prone to develop psychiatric and neurological comorbidities  compared with non-epileptic individuals . Therefo


Background: Hospital staffing shortages are again (mid-year 2021) becoming a significant problem as the number of positive COVID-19 cases continues to increase worldwide. Objective: To assess the costs of sending HCW into quarantine (Scenario 1) from the hospital’s and the taxpayer’s perspective versus the costs arising from implementing point-of-care COVID-19 antigen testing (POCT) for those staff members who, despite learning that they have been exposed to hospital patients later found to be infected with COVID-19, continue to report to work (Scenario 2). Methods: A mathematical model was built to calculate the costs of a sample-and-stay strategy for exposed healthcare workers (HCW) in Germany by utilizing a high-quality antigen fluorescent immunoassay (FIA), compared to the costs of quarantine. Direct costs and wage costs were evaluated from the hospital as well as from the taxpayer perspective assuming a SARS-CoV-2 infection prevalence of 10%. Results: Serial POCT testing of exposed HCW in Germany (Scenario 2) who do not go into quarantine but continue to work during a post-exposure period of 14 days at their working place raises costs of EUR 289  per HCW at the expense of the employing hospital while the extra-costs to the taxpayer per exposed HCW are limited to EUR 16 (±20%: EUR 13 to EUR 19). In contrast, sending HCW into quarantine (Scenario 1) would result in costs of EUR 111 (±20%: EUR 89 to EUR 133) per exposed HCW for the hospital but EUR 2235 (±20%: EUR 1744 to EUR 2727) per HCW at the expense of the taxpayer. Conclusions: Monitoring exposed HCW who continued working by sequential POCT may considerably reduce costs from the perspective of the taxpayer and help mitigate personnel shortages in hospitals during pandemic COVID-19 waves. The severe acute respiratory syndrome COVID-19, caused by coronavirus 2 (SARS-CoV-2), first appeared in December 2019 in Wuhan, China, with an accumulation of pneumonia and has since spread across the globe .The rapid escalation of the situation caused the World Health Organization to declare a pandemic on 11 March 2020 . Since tThe current reference test used to establish SARS-CoV-2 infection worldwide is the real-time reverse transcriptase polymerase chain reaction (RT-PCR). However, in Germany, currently 71.5% of all hospitals have eliminated their in-house laboratories . To ensuIn contrast, lateral flow assay (LFA) SARS-CoV-2 antigen tests, which are based on lateral flow technology that uses monoclonal antibodies, can be performed at point of care, i.e., in the hospital itself, provide results within 15–30 min and are inexpensive. Numerous SARS-CoV-2 POC antigen tests are currently available, whose use offers the potential for rapid identification of those individuals who are not only infected, but infectious and are therefore at greatest risk of spreading the infection . AlthougIn our model, we separately calculate the economic consequences of a sample-and-stay strategy, which uses periodic POCT at least once every 48 h together with the wearing of a FFP2 mask compared to the costs of sending these HCW into quarantine during a period of 14-days. We did not include the healthcare costs arising from symptomatically infected HCW requiring treatment; such costs have to be covered by the German Public Statutory insurance and thus lie beyond the perspective of the hospital as employer and that of the taxpayer. Also, additional costs arising through quarantine caused by food suppliers or other services could not be considered.With respect to exposed HCW, two scenarios are considered: In the first one, as usually performed in Germany, the HCW are sampled for a RT-PCR test immediately at the hospital in order not to overlook a very early infection during the gap of 1–2 days when the increasing viral load may still be below the antigen tests’ limit of detection. In case of a negative result, the HCW will then go home into quarantine for 14 days. If the HCW does not have symptoms, a final antigen test must be done after 14 days, the negative result of which ends the quarantine .In the second scenario, by way of derogation from the first one , exposedRelying on recently published figures, we assumed a sensitivity of 80% and a specificity of 98.9% for POC antigen-testing in symptomatically infected COVID-19 subjects . Due to The cost parameters used in our calculation are all derived from fixed or pre-weighted costs. Our calculation does not take into consideration outcomes from clinical trials or different size samples. Therefore, we always use mean costs. Confidence intervals are not provided, as their application to this non-probabilistic model would have been inappropriate. However, we performed a sensitivity analysis by varying all costs by ±20% of the base-case value according to international practice.The incubation period for COVID-19 has a median time of 5–6 days from exposure to onset of symptoms and is thought to extend to 14 days  thereaftPersons fully vaccinated against COVID-19 are exempt from quarantine measures after exposure to a confirmed COVID-19 case  as they Absence due to quarantine, which is usually ordered and checked by the locally responsible health department according to para 28 Section 1 of the German Law on Protection against Infection (IfSG), is fully reimbursed to the hospital employing the HCW by the responsible authority, i.e., by the taxpayer, upon request as long as the HCW does not develop disease—in which case the HCW are put on sick leave and the hospital has to absorb the costs of the sick leave days from that date. That means that during the 14-day period of quarantine, the taxpayer must bear the wage costs as long as no symptoms due to SARS-CoV-2 infections appear.® SARS Antigen FIA, the final result of which is available in 15 min  minus EUR 12.83 [Scenario 2]) per exposed HCW, whereas the net cost of the hospital rises to EUR 231.62.® SARS Antigen FIA, which can claim specificity of nearly 99%, come close to laboratory RT-PCR testing in their ability to very rapidly and reliably exclude the presence in a patient of transmissible COVID-19. In the meantime, asymptomatic staff testing by POC antigen tests has been a core component of some national infection control testing strategies, such as those in the UK, the US and Germany [Newer real-time POC tests, such as the Sofia Germany ,28,29. B Germany , it coulDue to the potentially increasing pressure on hospitals to develop strategies to mitigate healthcare personnel staffing shortages, the CDC —and in tThe infection prevalence in exposed HCW under the strict security standards now in place in German hospitals can generally be considered low, with concerns mostly centered around casual attitudes towards personal protection held by a minority in a given hospital ward. Hence one may assume limited exposure risk, under which a high negative predictive value of POCT in such contacts can be expected. We assumed a moderate test sensitivity of 80% for POC antigen-testing for the 80%-symptomatically infected COVID-19 subjects and a 58.1% sensitivity for the remaining 20% infected persons in our model. As symptomatic patients will always be retested with RT-PCR even if the POCT is negative, no infections of symptomatic patients remain unrecognized. Of note, the number of false-negative results in asymptomatically infected HCW infections during the 14-day incubation period is low (0.84 persons out of 100 HCW). Given the fact that wearing FFP2 masks reduces the risk of contagion by 67% , the risAs the working wages for contact persons of COVID-19 patients in Germany who must remain in quarantine for 14 days are paid by the taxpayer, a total of EUR 2235 would have been transferred to the hospital as employer per exposed HCW. In contrast, serial POCT testing at their workplace (every other day during the 14-day post-exposure period) of exposed HCW who don´t go into quarantine but who volunteer to continue coming to work under a regulatory derogation, results in extra costs at the expense of the employing hospital of only EUR 178 per HCW. Even reducing all costs of the taxpayer by 20% in sensitivity analysis and simultaneously increasing the hospital’s costs by the same percentage shall not change this discrepancy. Although it might seem counterintuitive for a hospital to not accept pay-off, the latter approach avoids a possibly threatening thinning out of the workforce, and thus can be considered a win-win situation.Our model has several limitations: A general limitation of our study that must be kept in mind when interpreting its results is that, as always, a single-center economic model cannot depict the true local SARS-CoV-2 infection prevalence among exposed HCW. Furthermore, we do not know how many HCW would in fact follow the offer to return to work due to missing data. Finally, the probabilities of becoming infected on different days during the quarantine period could only be derived as point estimators from McAloon´s log-normal distribution. Since that model cannot be varied, a more comprehensive sensitivity analysis demonstrating the robustness of our findings was not possible. Therefore, to validate our estimates, prospective cost studies are required.High-quality POC antigen tests, used for serial testing of healthcare workers exposed towards COVID-19 patients in their hospital, can lessen the burden of quarantine on hospital staff. They allow asymptomatic HCW to continue working (or to return to work earlier) on a voluntary basis, while wearing FFP2 masks and maintaining careful self-observation for signs of developing symptoms, and thus help to avoid unnecessary shortage of urgently needed employees. As such, POCT can also reduce costs from the taxpayer perspective and allow resources to be allocated for other precautions. Prospective clinical studies should be undertaken to further evaluate its economic advantages in the immediate future.


We investigate the emergence of electronic excitations from the inhomogeneous electronic structure at warm dense matter parameters based on first-principles calculations. The emerging modes are controlled by the imposed perturbation amplitude. They include satellite signals around the standard plasmon feature, transformation of plasmons to optical modes, and double-plasmon modes. These modes exhibit a pronounced dependence on the temperature. This makes them potentially invaluable for the diagnostics of plasma parameters in the warm dense matter regime. We demonstrate that these modes can be probed with present experimental techniques. Research on WDM has received increased attention due to its relevance for fusion energy experiments, novel materials discovery, and high-energy astrophysical phenomena. From a technological point of view, warm dense conditions occur in the heating process of inertial confinement fusion capsules6. In terms of materials science, understanding WDM propels the discovery of unexplored material properties such as novel chemistry8, non-equilibrium effects10, and phase transitions11. On a fundamental science level, probing warm dense conditions is essential for obtaining new insights on astrophysical objects, such as Earth’s core13, the interior of both solar planets16 and exoplanets18, the properties of brown and white dwarfs20, and neutron stars21.An emerging research area where electronic excitations—such as plasmonsa denotes mean interelectronic distance and 22. Additionally, WDM phenomena are transient in experiments—covering the range from femtoseconds to picoseconds. Studying WDM phenomena is therefore highly challenging23—common concepts from well-established fields of physics do not apply: the persistence of quantum effects and strong coupling renders plasma physics concepts inaccurate, while accurate approaches from condensed-matter physics are often infeasible due to the length, time, and temperature scales involved.One labels the state of matter as WDM when (1) the Fermi energy 29. The array of experimental techniques that probe excitations in WDM include X-Ray absorption spectroscopy30, emission spectroscopy32, X-Ray Thomson scattering33, resonant inelastic X-Ray scattering34, and the most recently developed ultrafast multi-cycle terahertz measurement technique35.The aforementioned applications and the intricate nature of WDM have triggered a growing number of cutting-edge experimental activities, often in large-scale research facilities37. For example, consider determining the electronic temperature in warm dense samples. In principle, the temperature can be obtained from the detailed balance of the dynamic structure factor38 that is probed in X-Ray Thomson scattering. In practice, however, the noise in the measured signals renders a purely experimental temperature determination inaccurate39.Due to its challenging nature, reliable diagnostics of WDM properties (such as temperature and density) can only be achieved by joint efforts of experimental campaigns with accurate, first-principles modeling techniques40, and a formally exact formulation of dielectric models is provided by the local field correction41. Their accurate parametrization is provided by quantum Monte-Carlo calculations of the uniform electron gas in its ground state43 and at finite temperature45. A notable example is the recently introduced effective static approximation47. Extensions of dielectric models to take into account electron-ion collisions are based on the Mermin approach (MA)50, but only in an approximate manner. An alternative simulation method for WDM diagnostics is Kohn-Sham density functional theory (KS-DFT)52 and its extension to the time domain53. Similar to dielectric models, the electron-electron correlation is approximated in practice, but electron-ion collisions are tackled more directly. These calculations have become the workhorse among modern simulation methods in materials55 and most recently also for WDM modeling58.Historically, WDM modeling has relied on dielectric models such as the random-phase approximation59 or KS-DFT calculations60. Despite the combined efforts of experiment and simulation, determining the electronic temperature is still subject to significant uncertainties61. Assuming a homogeneous WDM sample is justified when relaxation effects are considered. Their time scale is typically on the order of several picoseconds62. Moreover, this assumption underpins the uniform electron gas45 as a paradigm for modeling phenomena in WDM.In prior diagnostics efforts of WDM, a homogeneous electronic structure of the samples has commonly been assumed, particularly regarding the modeling aspects. Under this assumption, the electronic temperature of the induced WDM states has been determined from X-Ray Thomson scattering signals, for instance, in warm dense aluminum either by dielectric modelsinhomogeneous WDM, (2) illustrate the potential utility of these modes for the temperature diagnostics of WDM, and (3) numerically demonstrate the emergence of these modes in the inhomogeneous electronic structure imposed on warm dense aluminum.In this Report, we break away from the common assumption of a homogeneous electronic structure in WDM diagnostics. We (1) show the emergence of yet unexplored modes of electronic excitations in 66. For example, the dynamics of emerging electronic structures was recently shown in laser-driven WDM samples where inhomogeneities were imposed by a periodic grating structure65. Furthermore, spatially modulating electronic structures can also be triggered by free electron25, VUV67, and THz lasers66. Therefore, we discuss the temperature dependence of excitation signals in the inhomogeneous warm dense electron gas that can be utilized for WDM diagnostics.We show that features in the new modes are absent in the spectrum of homogeneous WDM states which is dominated by the well-known plasmon mode. The variety of features we observe depends on the degree of the density deviation from the homogeneous state. They include satellite signals around the standard plasmon feature, transformation of plasmons to optical modes, and double-plasmon modes. We demonstrate that both the realization of the required perturbation amplitudes and the observation of the proposed features are feasible using present and upcoming experimental facilitiesN is the total number of electrons and 69. In Eq.  in terms of the Hamiltonian73. Electronic excitations are identified by distinct features located at the maxima of the EELF74.We utilize the electron energy-loss function (EELF) to illustrate the emergence of electronic excitations in inhomogeneous WDM75. Likewise, the X-Ray Thomson scattering signal is proportional to the EELF via the dynamical structure factor36 obtained from the fluctuation-dissipation theorem76. The electronic excitations we predict are computed using first-principles calculations of the EELF based on the Hamiltonian in Eq.  measured in the experiment (purple data point). Secondly, our predicted features in inhomogeneous WDM (blue curve) can be resolved with the current experimental accuracy, i.e., the uncertainty in the experimentally measured plasmon energy (dashed purple) is sufficiently small. Importantly, this example is as an illustration and, in general, other  values of the wave numbers can be probed. We note that recently an energy resolution better than 85. This enables probing various new features in the electronic excitation spectrum discussed in this work.We demonstrate that the resolution achieved in present experiments is sufficient to measure the predicted electronic excitations that emerge in inhomogeneous WDM. To that end, in Fig. 85 is sufficient to resolve the emerging modes and features.We have demonstrated the emergence of novel electronic excitations in the inhomogeneous warm dense electron gas. From a physical perspective, the well-known plasmon is transformed into a more complicated mode with multiple peaks. Its details can be readily controlled via the imposed perturbation amplitude. Ultimately, an increasing degree of inhomogeneity results in both an optical mode and a double-plasmon feature. These physical effects are interesting in their own right, and the required perturbation amplitudes can be realized in experimental facilities. We also show that the energy resolution of present experimentsFrom a practical point of view, the presented EELF spectra of inhomogeneous WDM exhibit a substantially stronger dependence on the electronic temperature than the standard plasmon in homogeneous WDM. Furthermore, their directional dependence and richer structure provide additional constraints on theory and simulation. This can be used to solve the long-standing problem of temperature diagnostics in WDM, which is rather unconstrained at present.72 for details) can be realized at LCLS25, the European X-FEL28, and FLASH86. A particularly promising experimental setup capable of measuring dynamics following intense terahertz excitation of 66 , The time-dependent density functional theory (TDDFT) calculations were performed with the GPAW code81. The number of bands was set to 60 at In the case of isochorically heated Aluminum, we compute changes in the electronic structure due to both the imposed external perturbation and the electron-ion interaction. Here, the face-centered-cubic crystal structure with a lattice constant 90 for details) without any nodal restrictions. Furthermore, we employ the primitive factorization of the density matrix using 82.The QMC data shown in Fig. Supplementary Information.


This case reports on the successful maternal to fetal transfer of neutralizing antibodies after vaccination with BNT162b2 in a pregnant woman at 25 weeks of gestation. The levels of neutralizing antibodies were approximately 5-fold higher in the umbilical cord than in the maternal blood while the level of total antibodies showed only a 2-fold increase. This suggest that the antibodies that crossed the syncytiotrophoblast cell barrier have specific characteristics that correlate to functional neutralizing capacity. Although pregnant and lactating women have been excluded from clinical trials for several reasons including ethical concerns about fetal exposure, accumulating evidence has now revealed that these vaccines are safe and efficient for both the fetus and the woman. Vaccination against COVID-19 in pregnancy is vital to control disease burden and to decrease morbidity in the ante-, peri- and post-natal periods. Inclusion of pregnant women in research programs for the development of SARS-CoV-2 vaccines should be mandatory to provide this population with the equitable benefits of vaccine research. Before the vaccine rollout, multiple cohort studies documented that pregnant woman were more susceptible to severe COVID-19 compared to age-matched non-pregnant women ,3. This Both neonates and pregnant women are particularly susceptible to respiratory infections, including influenza and respiratory syncytial virus (RSV) ,20,21, aNeonates rely on the transfer of maternal immunoglobulin G (IgG) across the placenta for protection against pathogens, and vaccination aims to mimic the presence of pathogens to stimulate the maternal immune response. Data from the literature show that maternal to neonatal transfer of anti-SARS-CoV-2 antibodies is efficient although the maternal to fetal transfer ratio of IgG antibodies may differ depending on gestational age and the type of immunization, i.e., disease- or vaccine-induced ,31,32,33This case-report assessed the neutralizing capacity of umbilical cord blood compared to maternal blood in addition to conventional serological assay in a woman who received ta two-dose regimen of BNT162b2 during the antenatal period. To appreciate the magnitude of the antibody response of this dyad, a comparison with an age-matched cohort will also be done.A 28-year-old pregnant woman received her first dose of BNT162b2 mRNA COVID-19 vaccine  at 25 weeks of gestation. The second was administered at 30 weeks. No problem was reported during the antenatal period, and no severe adverse events were reported after the vaccination. The patient only complained headache and tiredness the day after the second dose, which resolved with the administration of paracetamol twice a day. The delivery was planned to be on the 4th of July but occurred 8 days earlier, on the 26th of June at the Centre Hospitalier Régional (CHR) of Huy , 90 days after the administration of the first vaccine dose. No delivery complications were reported, and all of the parameters of the newborn were normal. At 4 weeks, the newborn was still doing well. On the day of delivery, umbilical cord blood was collected as well as maternal blood to permit comparison of the level of SARS-CoV-2 neutralizing antibodies.To compare the results obtained with the umbilical cord and maternal blood samples, 13 non-pregnant women of a similar age  with no history of previous SARS-CoV-2 infection , were included. These vaccinated controls were recruited at the Clinique Saint-Luc Bouge  due to their participation in the CRO-VAX HCP study, a study which has already been described in detail elsewhere ,35,36. ABlood samples were collected in SST™ II advanced tubes  and were processed according to the manufacturer recommendations to obtain serum. Serum samples were then aliquoted and were stored at −20 °C until analysis. Antibodies against the SARS-CoV-2 nucleocapsid  and the receptor binding domain of the S1 subunit of the spike protein  were measured at each time point. Results above 0.8 U/mL (manufacturer’s cut-off) or 0.165 COI (cut-off index as found previously ) for antNeutralizing capacity was estimated by performing a surrogate virus neutralization test (sVNT) . The iFlThe total anti-RBD titers of the maternal and the umbilical cord blood were 1120 U/mL and 2349 U/mL compared to 1747 U/mL  in the control group at the identical time point, i.e., 90 days post-vaccination. The NAbs titers were 163 and 906 AU/mL for the maternal and the umbilical cord blood, respectively, compared to 427 AU/mL  for the control group at 90 days post-vaccination. The maternal to fetal transfer ratio was 2.10 for total anti-RBD antibodies and 5.56 for NAbs. A summary of the results is presented in Recent investigations suggested that maternal SARS-CoV-2 immunization, either induced by the disease or by the vaccination, may provide neonatal protection through the transplacental transfer of antibodies ,31,32,33Zdanowski et al. observed a slightly lower maternal to fetal ratio, i.e., 1.28 ± 0.80 . Mittal Interestingly, our case also confirms the presence of neutralizing antibodies in the umbilical cord blood . AnotherThe observations that we made in this case report following vaccination with BNT162b2 are not so surprising. For most pathogens, umbilical cord titers of IgG are higher than in maternal blood due to endosomal transport of IgG across the syncytiotrophoblast cell barrier from maternal to fetal circulation ,43,44. AInterestingly, in line with the above explanations, immunization transfer may also depend on whether it is acquired after vaccination or previous infection. Indeed, some cases were reported and described inefficient maternal to fetal transfer following COVID-19 disease during pregnancy ,49. ThisThis may influence the neutralizing capacity of the antibodies and may impact the transfer of immunity, especially during the third trimester ,47,50. NAlthough these data have been obtained in a small number of subjects, these are quite reassuring, and the present case demonstrates that the antibody subtypes that are transferred possess high neutralizing capacity.This case reports on the successful maternal to fetal transfer of neutralizing antibodies after vaccination with BNT162b2 in a pregnant woman at 25 weeks of gestation. The levels of neutralizing antibodies were approximately 5-fold higher in the umbilical cord than in the maternal blood, while the level of total antibodies showed only a 2-fold increase. This suggests that the antibodies that crossed the syncytiotrophoblast cell barrier have specific characteristics that correlate to functional neutralizing capacity. Although pregnant and lactating woman have been excluded from clinical trials for several reasons including ethical concerns about fetal exposure, accumulating evidence has now revealed that these vaccines are safe and efficient for both the fetus and the woman. Vaccination against COVID-19 in pregnancy is vital to control disease burden and to decrease morbidity in the ante-, peri- and post-natal periods. Inclusion of pregnant women in research programs for the development of SARS-CoV-2 vaccines should be mandatory to provide this population with the equitable benefits of vaccine research.


Colorectal cancer (CRC) treatment can be limited to surgical resection for low stages of the disease while subsequent chemotherapy is the preferred treatment for the higher-stage disease. This chemotherapy relies heavily on fluoropyrimidine: 5-fluorouracil (5-FU) and capecitabine, a role played for decades. Fluoropyrimidine-linked treatment can present important and even lethal toxic events at the cardiac level like acute coronary syndrome, arrhythmias, and death.The production of these toxic events depends on the capacity of a subject to metabolize the fluoropyrimidines adequately, and this depends on the activity of the enzyme dihydropyrimidine dehydrogenase (DPD). Any change that affects the quantity or quality of this enzyme will compromise its capacity to metabolize the fluoropyrimidines. The resultant abnormal enzyme activity exposes the patient to continuously high levels of the chemotherapeutic agent or its catabolites. Consequently, the patient becomes more susceptible to pyrimidine-linked toxic adverse events.Genetic testing of patients for potential decreased DPD activity before subjecting them to fluoropyrimidine-based chemotherapy will help identify subjects at greater risk of increased cardiotoxicities, the possibility of prompt intervention, should these appear, and a multidisciplinary strategy aimed at managing these cases. Potential cases of cardiotoxicity in CRC patients, candidates to fluoropyrimidine toxicities, can be anticipated by pretreatment screening of DPD activity. Pretreatment screening will reduce many hospitalizations with a consequent decrease in costs both to the patients and the healthcare system.This review article will examine the 5-FU linked cardiotoxicity, known correlated risk factors, clinical manifestations, management strategy, and the role of genetic testing in identifying high-risk patients. Patients with advanced colorectal cancer (CRC) need to undergo adjuvant or neoadjuvant chemotherapy with fluoropyrimidines like 5-fluorouracil (5-FU), a cytotoxic antineoplastic, and antimetabolite chemotherapeutic agents. Its oral equivalent, the prodrug capecitabine, serves the same purpose. Throughout the world, both drugs represent the principal chemotherapeutic agents used to treat many solid malignancies, gastrointestinal as well as breast cancer ,2. NotwiMultiple studies register fluoropyrimidine-linked cardiotoxicity with varying frequencies, from 1.5% to even 30% of patients treated with 5-FU ,4-6. CliDPYD) sequence caused by numerous single-nucleotide polymorphisms (SNPs) may lead to a partial or complete deficiency of DPD activity with significant severe fluoropyrimidine toxicity [Dihydropyrimidine dehydrogenase (DPD) catalyzes the breakdown of over 80% metabolism of 5-FU. An inadequate activity of DPD plays a significant role in augmented cardiotoxicity . Variatitoxicity ,8. ApproDPYD is a very polymorphic gene, and some variants such as c.1236G>A/ HapB3, c.1679T>G, c.1905+1G>A, and c.2846A>T, when deficient, produce insufficient enzyme activity with increased incidence of severe adverse drug reactions [DPYD variants makes it possible to reduce the risks of adverse drug reactions. This investigation notwithstanding, significant and even lethal fluoropyrimidine linked reactions could happen at any moment during the treatments, even in patients that present no DYPD defects connected to the numerous SNPs [This review presents a glimpse of a therapeutic approach to managing colorectal cancer with 5-FU as the critical therapeutic agent. It examines the factors responsible for potentially lethal cardiotoxicity. It emphasizes a multidisciplinary approach as a way forward to identify high-risk patients before exposure to fluoropyrimidine therapy to reduce adverse 5-FU related adverse reactions. An open question remains the eventuality of an effective screening method on all patient candidates to chemotherapeutic treatment with fluoropyrimidines like 5-FU and capecitabine. How beneficial will an efficient screening process of CRC patients be before subjecting them to chemotherapy with 5-FU compared to post-treatment hospitalization and management of patients due to complications arising from their chemotherapy regimens?Our review article examines the published studies on CRC with its diffusion and impact worldwide. We consider fluoropyrimidine, the principal drug used in treating metastatic CRC, and its cardiotoxicity. We analyze the metabolism of said chemotherapeutic, the main enzyme involved, and its role in the previously mentioned toxicity. Are alterations in fluoropyrimidine predictable? How are cases of cardiotoxicity managed? Can pretreatment screening reduce the adverse drug reactions observed and even reduce hospitalization? Our article confronts these concerns in the following sections.Colorectal cancerCRC is among the principal reasons people die of cancer worldwide, the second most common cause for cancer-linked death in North America and Europe ,9. WorldAbout 78% of cases of CRC occur in subjects aged 55 years or above. Based on the current trend, the SEER predicts an increase in the incidence of colon cancer of 90% in subjects aged 20-34 years by 2030 and an increase of rectal cancer of 124.2%. For subjects aged 35-49 years, the SEER predicts an increase in the incidence of 27.7% for colon cancer and an increase of 46% for rectal cancer [Arnold M et al. observed approximately 66% or more CRC cases in nations with elevated human development index and about 60% cases of deaths . These nMetastatic colorectal cancer treatmentThe treatment of CRC depends on the stage of the disease. Low-stage cancers need surgery alone. High-stage cancers (stage II & stage III) need adjuvant and neoadjuvant radiochemotherapy ,15. TablThere is a significant improvement in the outcome of cases of metastatic CRC (mCRC) observed in the past two decades, especially in the West, with an increase in survival rates as well as a decrease in cases of local recurrence. This progress results from the fact that more and more patients benefit from preventive measures, screening, and early diagnosis and receive excellent surgical treatment, good chemotherapy regimens, or other treatments that ensure ablation ,14,15. MFluoropyrimidines cardiotoxicity5-FU as well as capecitabine, its prodrug, are among the fluoropyrimidines, which are the antitumoral medications employed in the treatment of solid malignant neoplasia of the gastrointestinal system affecting practically any organ from the esophagus to the anus, neoplasia of the bladder, the head, neck, and the breast ,17,18. TA precise mechanism of how fluoropyrimidine provokes toxic effects at the cardiac level is not fully understood. What seems likely is that some products of the breakdown of 5-FU and capecitabine play essential roles ,21. VasoAll cases of angina in the setting of fluoropyrimidine therapy require the collection of a complete medical history with an evaluation of cardiovascular risk factors and thorough cardiopulmonary physical evaluation. Details noted of the therapy concern the types of drugs used, the means of administration, and the treatment schedule. Each of these could contribute to generating the cardiac adverse effects observed . ImmediaThe toxic events of fluoropyrimidine at the heart level usually occur at the beginning of treatment, as early as within the first 12 hours after drug administration. These effects are unpredictable and may happen at any moment of treatment and sometimes as late as 24 or 48 hours from the onset of therapy. Stopping the drug causes the symptoms to regress rapidly. Considering the highly lethal cardiotoxicity linked to 5-FU treatment, immediately suspending the therapy must be the first thing to do once symptoms present themselves. Following is the empirical management of these symptoms with standard drugs for acute coronary syndrome, as needed, like calcium channel blockers, beta-blockers, and nitrates. The next step is fundamental, for it requires clinical judgment. It consists of determining if the symptoms can be related to 5-FU. This is important because, on the one hand, further exposure to the drug could negatively affect morbidity and mortality. On the other, depriving the patient of life-saving treatment may jeopardize the patient’s possibility of cancer treatment. In making this clinical judgment, the direct relationship between the time elapsed from the administration of 5-FU to the appearance of the cardiac symptoms represents a good hint .If the clinician correlates the cardiotoxicity to 5-FU, a change of chemotherapeutic regimen is the most prudent option. The clinician assumes 5-FU related cardiotoxicity in patients with normal coronary vessels and extremely low-risk factors for coronary artery disease. If available, non-fluoropyrimidine regimens should be considered. The re-use of fluoropyrimidine after cardiotoxicity must entail a detailed discussion between the clinician and the patient on the potential risks and benefits of such a measure. In this case, a prophylactic measure with calcium channel blockers and nitrates associated with meticulous clinical observation could reduce the cardiotoxicity risks .Fluoropyrimidine metabolism and the role of pharmacogenetic testing5-FU is among the most frequently used chemotherapeutics to treat CRC since its first application in 1957 . It playMany enzymes participate in the biological breakdown of fluoropyrimidines and form various by-products. The critical step in this process depends on the enzyme DPD. It catalyzes the metabolism of more than 80% of the amount of fluoropyrimidine administered, forming 5-fluoro-5,6-dihydrouracil (5-FDHU). An impediment to the function of DPD results in reduced metabolism of 5-FU, which will result in an augmented risk of toxicity ,32-34.85-90% of 5-FU is quickly metabolized in the liver by DPD. Initially, 5,6 dihydrouracil results from this action, and then eventually, alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine (FBAL). About 90% plasmatic 5-FU is eliminated in the urine in less than 24 hours as FBAL. FBAL is ulteriorly metabolized to fluoroacetate and F-acetate ,35. F-ciDPYD and a consequent alteration of the various steps involved in translating the gene, which will affect the protein activity [DPYD have are known, some of which seem to be accompanied by reduced DPD activity, while a significant number are unclear roles [DPYD, which codifies for the enzyme, results in a complete or partial loss of functionality of the enzyme, influencing the adverse events observed in using fluoropyrimidines [DPYD gene. It is associated with significant and even mortal adverse drug reactions [DPYD mutated variants observed to have high chances of toxic adverse reactions linked to fluoropyrimidines are c.1679T>G and c.2846A>T [DPYD before starting fluoropyrimidine therapy and eventually adjusting the doses of the medication if these variants are present [The main reason a patient might present DPD deficiency seems to result from pathological modifications of the encoding gene activity ,34. Overar roles ,36. Chanimidines . The DPYeactions , especiaeactions . Other D.2846A>T . Some ceDPYD gene are not associated with altering the enzyme activity, using one method alone in assessing patients might prove insufficient; applying both genotyping and phenotype variations has been described in studies [Besides genotyping, another technique that can permit the identification of DPD deficiency is evaluating its action in the peripheral mononuclear cell (PBMC), which is the phenotypical expression of the enzyme . Because studies . The latLimitationsSince there was no restriction of publication of the included articles, we consulted a few older studies to synthesize the current review. We exclusively selected only studies that we could find published in the English language; hence, we cannot exclude the possibility of missing out on relevant articles published in other languages.DPYD before initiating therapy. This approach is not yet a common practice for CRC, which has a treatment (5-FU) that can have potentially lethal cardiac adverse effects. Considering the significant advances made in CRC management, like primary and secondary preventive measures, we believe further improvements require addressing the adverse events related to 5-FU linked chemotherapy more. Identifying patients who bear DPYD variants linked with increased cardiotoxicity and better management of their therapeutic regimes in a multidisciplinary fashion reduces these risks of adverse pyrimidine-related adverse reactions. These interventions lower the chances of hospitalizations and its costs and initiate better patient care for CRC, which is a significant cause of cancer-related deaths.CRC is a significant cause of death by cancer worldwide, the second most frequent. Surgery is fundamental but often insufficient to treat advanced stages of CRC. Adjuvant and neoadjuvant chemotherapy is necessary to treat higher stages of the disease. In this regard, 5-FU and its prodrug and oral equivalent, capecitabine, have significantly reduced mortality by improving prognosis in CRC patients. A small percentage of individuals present mutations of the gene that codifies pyrimidine dehydrogenase. These persons risk significant toxicity when exposed to pyrimidine-based chemotherapy. This possibility influences the continuation of the regime of therapy. It inevitably means prolonged hospital admission with necessary diagnostic workouts and treatment when cardiotoxicity occurs and increases healthcare costs. Some cancer centers consider pre-therapy testing to identify mutated variants of the


Objectives: This study aimed to identify key factors affecting Healthcare workers (HCWs) perceived stress and risk of contracting COVID-19 among themselves and their family members during the pandemic.Methods: A cross-sectional online questionnaire study was conducted between 19 March and April 5, 2020 in Hong Kong. HCWs from public hospitals and private dentists, and their family members participated.Results: A total of 747 HCWs and 245 family members participated. Higher perceived stress in HCWs was associated with more negative changes in family relationship (p = 0.025). The HCWs’ perceived stress, however, was positively associated with family cohesion (p = 0.033) and stress levels of family members (p < 0.001). The level of HCWs’ satisfaction toward the hospital policies in response to the COVID-19 outbreak was associated with lower levels of perceived stress and risk of themselves or their family members contracting COVID-19. HCWs’ previous frontline experience of SARS was significantly associated with less perceived risk of themselves or their family members contracting COVID-19.Conclusion: Hospital policies addressing HCWs’ needs, frontline experience of SARS, and family relationship influenced psychological wellbeing of HCWs during the COVID-19 outbreak. The coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already caused more than 34 million confirmed cases and over one million deaths worldwide as of early-October 2020 [Previous evidence already suggest that HCWs are susceptible to psychological distress, anxiety, post-traumatic stress disorder, sleep disturbances, and burnout during and after major infectious disease outbreaks –7. Risk This study aimed to examine the levels of HCWs’ perceived stress and risk of infection by COVID-19 while caring for patients during the pandemic and to identify how individual, family, and policy factors, and previous frontline experience during the SARS 2003 outbreak influenced these outcomes.This was a cross-sectional online questionnaire study of HCWs and their family members at the peak of the COVID-19 pandemic in Hong Kong. The inclusion criteria for participation in the study included HCWs working in the Hong Kong public healthcare system such as doctors, dentists, nurses, allied health professionals, pharmacists, and healthcare assistants; dentists working in the private sector; and both HCWs and their family members aged 18 years or above. We disseminated the online survey through the public hospital network and the web-link was published on several websites affiliated with key HCW associations in Hong Kong. After providing consent electronically, recruited subjects (HCWs and their family members) were invited to complete the questionnaire, which was available in both English  and ChinThe study questionnaires covered basic characteristics, mental health status, family relationships, and risk perception of HCWs and family members contracting COVID-19.We obtained detailed information from HCWs regarding the nature of their job, experience of managing suspected or confirmed COVID-19 cases and cohabitation status, as well as previous frontline experience of the SARS 2003 outbreak.Both HCWs and their family members were asked to rate their perceived stress level respectively using the 10-item Perceived Stress Scale (PSS-10), which is a widely used instrument for measuring psychological distress that has been validated in the Chinese population . The 10 Both HCWs and their family members were asked to rate separately their perceived family support using the Family APGAR  scale, which has been validated in the Chinese population . This scThe HCWs were asked “How bad do you feel if you were diagnosed with COVID-19” and to rate their perceived risk of infection by COVID-19 on a 5-point scale from “not bad at all” to “very bad.” This reflected how badly they would feel if they or their family members were diagnosed with COVID-19. A higher score indicated a higher perceived risk of infection.The HCWs were asked to rate their satisfaction toward hospital policies in response to the COVID-19 outbreak, which included the provision of PPE for those working in high-risk areas , PPE for those working in non-high-risk areas , special accommodation allowance for HCWs working in high-risk areas to stay at hotels to prevent transmitting COVID-19 to family members, and special salary increments for HCWs working in high-risk areas. The four items were rated on a 5-point scale between −2 and +2, and the total score represented the overall satisfaction. As most dentists in Hong Kong work in the private sector, their responses were excluded from this analysis.t-test, Chi-square test and Fisher’s exact test to compare the perceived stress and risk of being diagnosed with COVID-19 across different groups as appropriate. The relationships between the study variables were examined using bivariate correlations. A series of regression models were conducted to explore the factors associated with HCWs’ perceived levels of stress and risk of infection during the COVID-19 outbreak. Univariate regression analyses were first conducted to measure the crude independent effects of different factors including age, role in healthcare sector, perceived level of family cohesion and changes in family relationships during COVID-19 outbreak, satisfaction toward the overall and individual hospital special policies, and measures of HCWs, and perceived stress levels and family relationships of family members. Multiple regression models were performed to examine the adjusted associations while controlling for the impacts of sex, marital status, role in healthcare sector, age, and number of years of work experience. All statistical analyses were conducted using SPSS version 25.0 . All statistical tests were two-tailed and a p-value of less than 0.05 was considered statistically significant.We used Student’s Between 19 March and April 5, 2020, a total of 747 HCWs and 245 family members completed the online questionnaires. p < 0.05). The HCWs who worked in the healthcare sector and those on the frontline caring for SARS patients had significantly lower perceived risk of COVID-19 infection for themselves and their family members . However, HCWs working in high-risk areas and their decision to live separately from their families was not correlated with their perceived levels of stress and risk of COVID-19 infection.p < 0.001). Whereas, both HCWs’ perceived risk of COVID-19 infection for themselves and their family members were negatively correlated with their satisfaction with hospital policies . Age and years of work experience were also negatively correlated with their perceived risk of COVID-19 infection for themselves and their family members.Correlation analyses  demonstrp = 0.001). Higher perceived stress in HCWs was associated with more negative changes in family relationship (p = 0.025). The HCWs’ perceived stress level was also positively associated with their perceived family cohesion (p = 0.033), and stress levels of family members (p < 0.001). The HCWs’ satisfaction with overall and individual special hospital policies in response to the COVID-19 outbreak were negatively associated with their perceived levels of stress , and risk of contracting COVID-19 for themselves and their family members . HCWs with experience of working in healthcare sector or with frontline experience during SARS outbreak were found to have significantly lower perceived risk of COVID-19 infection for themselves and their family members .This study was conducted at the peak of the COVID-19 outbreak in Hong Kong . To the The SARS epidemic in Hong Kong is unique as not all regions of the world were severely affected by the SARS outbreak. Our study showed that the experience as frontline workers during the SARS outbreak was associated with a lower perceived risk of contracting COVID-19 for the HCWs and their family members after adjusting for sex, marital status, and role. Age and years of experience were not included in the adjusted model, as all HCWs who had experienced the SARS epidemic were senior staff. Such observation is possibly explained by the fact that SARS-CoV and SARS-CoV-2 shared similarities in terms of their genomic sequences and biology . This maThe mean stress scores in this study indicated a moderate level of stress among the HCWs and their family members in fighting COVID-19, which was similar to other parts of the world, including China, Singapore, North America, the Middle East and Europe –21. The Our study demonstrated that HCWs’ perceived level of stress was significantly associated with their job role. Doctors, nurses, and dentists who were frequently in contact with infected patients experienced higher levels of stress than other supporting staff. Standard precautions including barrier protection, such as masks, face-shields, and disposal gowns, are recommended to protect them from airborne infections, and was proven to be effective in Hong Kong where no HCWs were being infected with COVID-19 in their workplace –33. ThisRecent studies have now focused on intervention to alleviate the adverse psychological impact of the COVID-19 pandemic on HCWs. In the United States, a multidisciplinary peer support model known as “Battle Buddies” was developed for the management of psychological stress exposure in providers deployed to disasters . In ChinThis study had several limitations. First, this cross-sectional survey was carried out in Hong Kong during an outbreak period and did not measure the HCWs’ levels of stress and mental health status during the pre-outbreak period as comparison baseline levels. Second, the level of psychological distress in HCWs may change and hence this cross-sectional survey may not capture the fluctuations in stress levels over the highly dynamic course of the pandemic. Nevertheless, the study was conducted in the peak period of the COVID-19 outbreak  which waOur study highlighted the key factors at the individual, family, and policy level affecting HCWs’ perceived level of stress and risk of being infected by COVID-19 for themselves and their family members during a pandemic. These factors included the nature of their work, change in family relationship during the outbreak, hospital policies, and prior experience of the SARS outbreak. Provision of adequate PPE and special allowance to the HCWs show great promise in protecting the psychological wellbeing of HCWs in fighting a pandemic.


While sensitivity and specificity are important characteristics for any diagnostic test, the influence of prevalence is equally, if not more, important when such tests are used in community screening. We review the concepts of positive/negative predictive values (PPV/NPV) and how disease prevalence affects false positive/negative rates. In low-prevalence situations, the PPV decreases drastically. We demonstrate how using two tests in an orthogonal fashion can be especially beneficial in low-prevalence settings and greatly improve the PPV of the diagnostic test results. The need for robust screening policies is essential in the current pandemic. This has yet to be achieved: one study  of 936 cMany rapid SARS-CoV-2 tests  are now available to assist in the screening and management of COVID-19. Although rapid nucleic acid tests are available and desirable due to their greater analytical sensitivity, supply of these reagents may be rate limiting, and they are also more expensive than antigen testing . AlthougHowever, in addition to testing frequency, it is important to understand how prevalence influences the performance of these tests, especially in low-prevalence situations. In previous articles that explore diagnostic methods of COVID-19 testing ,15,16,17There are several articles ,19 that The classic monograph  providesApplying these values to the readily available calculator from the Food and Drug Administration (FDA) , using aThis means that in a population with a low disease prevalence, a positive result is confounded by a greater percentage of false positive cases. It is only when disease prevalence is at least 1.4%/3.1%/2.3% for the antigen/molecular/antibody POCTs that PPVs exceed 50%. This is especially important when testing the general population who are largely asymptomatic and when disease prevalence is low.In low-prevalence settings, the high false positive results can be reduced by using two tests in an orthogonal fashion. In this situation, a second test is used to confirm the positive results from the first test. Only when both tests are positive is the final result considered truly positive. Calculations can be easily made on the FDA calculator . In thisDisease prevalence must be considered when interpreting test results. In a low-disease prevalence population, using one POCT on its own will generate more false positive results than when used in a higher-prevalence situation. This is especially challenging as the disease prevalence of COVID-19 varies greatly between and within populations. One recent meta-analysis  showed tn = 4333) [n = 1000) with a SARS-CoV-2 antibody POCT (Instant-view IgG/IgM Antibody COVID-19 LFIA) and had a positive rate of 3.3%. After applying a second automated antibody test (Roche Elecsys Anti-SARS-CoV-2 RUO assay) in an orthogonal fashion, all initially positive tests were considered false positives.However, in populations with a low disease prevalence, using two POCTs in an orthogonal fashion markedly improves the PPV of the results. The performance of orthogonal testing algorithms has already been reported. In a community COVID-19 seroprevalence study ( = 4333) , second- = 4333)  tested aIn summary, we wish to re-emphasize that population prevalence must always be considered when planning to implement SARS-CoV-2 population screening. In low-prevalence settings, the false positive rate may be unacceptably high, with disastrous consequences such as loss of confidence in the screening program, or over-use of resources from misclassification of cases. If community screening is planned, the use of two tests in an orthogonal fashion for cases with a positive first test is an important means to improve the PPV of COVID-19 screening: only cases with a positive first test are evaluated with a second test, and only when both tests are positive is the patient considered to have tested positive. As the second test is only used in those with a positive first test, this would be more cost efficient than performing two tests for all subjects.