Evidence supports that gut‐modulating foods potentially can suppress bone loss in postmenopausal women. This study aims to investigate the effect of milk calcium‐enriched milk, yogurt, and yogurt‐inulin combination on the gut–bone association.Clostridiaceae members in Y‐Ca is associated with an increased spine BMD. Increases in Bifidobacterium pseudolongum, Turicibacter, Blautia, and Allobaculum and gut short‐chain fatty acids in Y‐I‐Ca are not reflected in bone parameters.A 6‐week intervention study is conducted in ovariectomized rats. Four pastes containing milk calcium‐fortified milk (M‐Ca), milk calcium‐fortified yogurt (Y‐Ca), inulin‐fortified Y‐Ca (Y‐I‐Ca), or an isoconcentration of calcium carbonate (Ca‐N), and a calcium‐deficient paste are provided. M‐Ca does not influence bone mineral density and content (BMD and BMC), femur mechanical strength, or femoral microstructure compared to Ca‐N, but Y‐Ca increases spine BMD. The serum metabolome reveals that Y‐Ca modulated glycine‐related pathways with reduced glycine, serine, and threonine. No additive effects of yogurt and inulin are found on bone parameters. Correlation analysis shows that increased lactobacilli and reduced Yogurt as calcium vehicle contributes to increased spine BMD concomitant with changes in the gut microbiome and glycine‐related pathways, while adding inulin to yogurt does not affect bone mineralization in ovariectomized rats. Clostridiaceae gut microbiota members, and simultaneous changes in glycine‐related metabolism. Neither milk nor addition of inulin to yogurt affect the measured bone mineralization, although inulin supplementation markedly modulates gut environment.This study investigates how milk, yogurt, and yogurt‐inulin combination influence bone mineralization in ovariectomized rats. Results indicate that a beneficial effect of yogurt on bone mineralization involves increased lactobacilli, reduced  Estrogen plays an important role in the inhibition of bone remodeling, which explains why women experience a rapid bone loss in the early stages of menopause (decline in estrogen de novo synthesis). Menopause has recently been reported to be accompanied by changes in the gut microbiome composition and function, and a potential relationship between gut microbiome and bone metabolism has therefore received attention. To investigate the role of gut microbiome in estrogen deficiency, Li et al. implemented a murine model and found that ovariectomy‐induced bone loss is lower in germ‐free mice than in conventional mice. Furthermore, ovariectomy‐induced bone loss in conventional mice could be attenuated by treatment with probiotics, including Lactobacillusrhamnosus GG and the commercial probiotic mixture VSL#3 . Hypotheses explaining how the modification of gut microbiome impacts bone metabolism involve a reduction in bacteria‐induced inflammatory response on osteoclast‐mediated bone resorption and effects on bacterial‐derived metabolites ) involved in the regulation of calcium absorption.Osteoporosis is a systemic skeletal disease characterized by a reduced bone mineral density (BMD) which exposes elderly to a high risk of fracture.1 Intr Besides being rich in calcium and milk proteins, fermented dairy products also contain starter cultures. Interestingly, in adults with low‐grade inflammation and high risk of osteoporosis, intake of yogurt increased the abundance of some species of Lactobacillus and Streptococcus that are commonly used starters in yogurts and simultaneously increased bone formation markers. Moreover, a double‐blinded randomized control study in postmenopausal women showed that intake of three different Lactobacillus strains over a period of 7 months reduced bone loss significantly. Changes in gut microbiota upon yogurt consumption also alter the gut metabolome, e.g., propanoate and butanoate production with potential to maintain systemic homeostasis, such as gut barrier function. However, whether certain gut‐derived metabolites are causal links between yogurt consumption and bone health remain unknown. Consequently, discovery of related causes are important for developing dietary strategies to promote bone health.Emerging evidence suggests that intake of fermented dairy such as yogurt is associated with an increased BMD and a reduced risk of fracture in postmenopausal women.11 Bes), may be added to yogurt as synergistically “bone‐friendly” nutrients as a result of their ability to stimulate growth and activity of certain gut microbes and hereby mutually lower colon pH and stimulate SCFAs production—both of which have been found to impact bone metabolism.Prebiotics , mTo investigate the effects of dairy matrixes  and addition of inulin to yogurt on bone mineralization, a 6‐week dietary intervention study was conducted in ovariectomized (OVX) rats to simulate the physiological condition of estrogen deficiency in postmenopausal women. In addition, to provide further evidence for the proposed gut–bone axis, the present study also elucidated the potential associations between bone mineralization and specific gut bacteria, as well as the gut and serum metabolomes.22.1During the intervention, all rats had a significant BW gain . Rats fed Y‐Ca had a higher spine BMD than the Ca‐N group (p < 0.05) and a higher spine BMC than the M‐Ca group and the Ca‐N group (p < 0.05). In addition, rats fed Y‐I‐Ca tended to have a slightly higher spine BMD than the Ca‐N group even not statistically significant (p = 0.096). To adjust for BW variations  (Table Q2 > 0.5), including Ca‐D versus Ca‐N, Y‐Ca versus Ca‐N, M‐Ca versus Ca‐N, and Y‐Ca versus Y‐I‐Ca  or inulin‐fortified diet (Y‐I‐Ca) were discriminated from rats fed other diets in all intestinal segments and feces Figure1. OPLSFigureThe concentrations of SCFAs  were quantified from the NMR data Figure2A–C. In  in cecal content, while there were no significant differences between groups in other intestinal segments and feces  was also quantified because it has been reported to be associated with bone metabolism in former studies20  were negatively correlated with spine BMD and/or total BMD Figure3A. Intr However, no significant effect of diet on serum TMAO was found  was also quantified as it has been associated with bone mineralization.20 HowQ2 < 0.5) of the complete serum NMR metabolite profiles could not discriminate between different diet groups.PCA  , rats fed Y‐I‐Ca had the lowest observed index compared with the other four diets  , as shown in FigureLactobacillus (Rho = 0.51), Streptococcus (Rho = 0.55), RF39 order (Rho = 0.40), and Enterococcaceae (Rho = 0.46), and negatively correlated with Clostridium (Rho = −0.61), Clostridiaceae family (Rho = −0.56), Caloramator (Rho = −0.58), and Peptostreptococcaceae family (Rho = −0.43)  in the spine compared to other bone sites  may contribute to a more rapid response during an intervention.In this study, OVX rats fed Y‐Ca and Y‐I‐Ca showed higher spine BMD in comparison to the Ca‐N group and the M‐Ca group, suggesting that ingestion of yogurt has the potential to prevent bone demineralization in postmenopausal women as also found in clinical studies.21 AddLactobacillus and Streptococcus  treatment could suppress bone loss in estrogen‐deficient mice. Studies indicated that the beneficial effects of Lactobacillus supplementation on bone mass may be associated with increased generation of SCFAs in the gut. However, the results here do not support this mechanism, indicating that other potential mechanisms related to Lactobacillus may play a crucial role in promoting bone mineralization in OVX rats. Li et al. found that lactobacilli could attenuate bone loss in OVX mice by preventing estrogen deficient‐induced increase in intestinal permeability.In our study, ingestion of calcium‐fortified yogurt significantly modulated the gut microbiome. A PLS model revealed a strong correlation between the fecal microbiome and spine BMD, and correlation analysis revealed that this could be ascribed to abundances of s Figure . These f3.2 indicating that blocking the activities of some bacteria might be an effective target for gut‐modulating foods to improve bone health. In the present study, the decreased Clostridiaceae family and its two specific genus  in the Y‐Ca group was negatively correlated with spine BMD, indicating that the beneficial effect of yogurt on spine BMD might be associated with inhibition of some bacteria from the Clostridiaceae family. A higher abundance of Clostridium has been observed in rats OVX rats after ovariectomy and in postmenopausal women with osteoporosis as compared to osteopenia (pre‐symptoms of osteoporosis), indicating that Clostridium may be associated with bone loss and osteoporosis risk in postmenopausal women. Hou et al. also observed a negative correlation between the relative abundance of the Clostridiaceae family and BMD in humans. However, limited evidence currently exists to confirm that the reduced levels or Clostridium, Caloramator, and the Clostridiaceae family can prevent estrogen deficiency‐induced bone loss.Both the use of antibiotics and germ‐free conditions have been found to increase BMD of mice,25 ind3.3 recently reported that the glycine, serine, and threonine metabolism was associated with BMD in a clinical cohort study, with a negative correlation between glycine and the lumbar spine BMD. In addition, Xu et al. found that a beneficial effect of lactoferrin on bone formation of rats also involved the glycine, serine, and threonine metabolism. A possible link between the glycine, serine, and threonine metabolism and bone metabolism involves collagen, the most abundant protein in the bone matrix, consisting of repeating units of Gly‐Pro‐X. A cross‐sectional study in discordant monozygotic twins showed that an increased intake of glycine resulted in increased BMD. However, how yogurt ingestion in the present study affected the glycine, serine, and threonine metabolism, apparently related to collagen metabolism in bone, remains unknown.In this study, lower concentrations of especially serum glycine, but also serum serine and threonine in the Y‐Ca group were associated with an increased spine/total BMD Figure , suggest29 rec3.4B. pseudolongum, Turicibacter, Blautia, and Allobaculum) in the present study, consistent with observations in previous studies. However, changes in the gut environment caused by the combination of inulin and milk calcium‐fortified yogurt had no additive effect on BMD compared to only milk calcium‐fortified yogurt supplementation in this study. Previous studies suggested that Turicibacter, Blautia, and Allobaculum were positively correlated with BMD in certain specific situations, but these links have not been confirmed by direct studies.Inulin significantly changed the gut metabolome and modulated the gut microbiome composition . Positive effects of gut‐derived SCFAs on bone mineralization may also be related with hormonal effects. Li et al. reported that nutritional supplement of butyrate synergistically increased the beneficial effect of intermittent parathyroid hormone (iPTH) on bone formation, but did not directly improve bone health of germ‐free mice without the treatment of iPTH.Microbial metabolites are potential mediators affecting bone metabolism and bone health.9 Inul3.5 Thus, it is plausible that the beneficial effect of yogurt on bone mineralization as compared with milk also can be ascribed to a higher bioavailability of calcium in the proximal part of the intestine where the majority of calcium absorption is taking place. A recent meta‐analysis found that a definitive conclusion on a beneficial effect of milk on bone health could not be drawn when diets were adjusted for calcium intake. Therefore, a positive correlation between milk intake and BMD in many epidemiological observational studies is likely associated with the rich calcium content in milk rather than milk as delivery matrix. A cross‐sectional study based on 4310 Irish older adults (>60 years) showed that yogurt consumption was positively correlated with BMD in three different regions  in women but not in men, while milk consumption was not significantly associated with changes in BMD and bone turnover markers. Our results provide further evidence to support that yogurt may be a more effective calcium vehicle than milk to attenuate bone loss in postmenopausal women.Calcium supplementation showed a pronounced effect on BMD and BMC, but while milk calcium‐fortified yogurt intake did promote bone mineralization, milk calcium‐fortified milk did not. In addition to modulating gut microbiome, our data also revealed that yogurt consumption was associated with a pH‐lowering effect in the proximal part of the intestine . The food paste for the five different groups were produced by mixing the dry ingredients ) with the corresponding wet component , as shown in Table  All rats were allowed ad libitum access to a standard diet  for 1 week to adapt to the new housing environment before aseptically ovariectomy was performed through the flank under anesthetization with 0.2 mL g−1 body weight (BW) with 25% Midazolam  and 25% Hypnorm . Subsequently, 44 recovered OVX rats were randomly allocated to 15 cages, three rats per cage (except for one cage that only accommodated two rats), and allowed ad libitum access to one of five experimental diets (three cages per group) for 6 weeks. The experimental diets were refreshed every 24 h, and BW of the rats was recorded once a week. After the 6‐week dietary intervention, all rats were anesthetized, and heart blood samples were collected before head decapitation. Finally, jejunal content (10 cm up the cecum), cecal content, colon content (8 cm down the cecum), and feces of all rats were collected and stored at −80 °C for 16S RNA sequencing or −20 °C for metabolome analysis. The rat bodies were stored at −20 °C for 1 month until the measurement of bone parameters.Fifty‐five 6‐week‐old female NTac:SD (Sprague‐Dawley (SD)) rats  were purchased and housed in 1354 G cages with high lids  and aspen bedding  with three or four rats per cage. Cages were enriched with a cardboard igloo, aspen biting sticks, and an aspen tunnel . Health monitoring was performed according to FELASA guidelines.47 AllThe rat study was authorized by the Animal Experiments Inspectorate in Denmark (License No. 2020‐15‐0201‐00434) and implemented at Department of Veterinary and Animal Sciences Copenhagen University in accordance with the Directive 2010/63/EU on protection of animals used for scientific purposes. to evaluate bone mineralization.DXA scanning was performed to measure the bone mineral density (BMD) and bone mineral content (BMC) of rats by scanning the whole body using a 1.8 μGy scanner . Total BMD and BMC as well as spine BMD and MBC were determined,48 to −1 was loaded at the midpoint of the femur to measure the power at fracture.Three‐point bending test was employed to evaluate the mechanical strength of femur bone in a TMC‐touch texture analyzer . The space between the two supporting points was 20 mm, and the femur was placed at the two points. Subsequently, the downward mid‐diaphysis with a speed of 1.0 mm minX‐ray micro‐computed tomography (µCT) was measured in an Xradia 620 Versa X‐ray microscope  to evaluate potential changes in the microstructure of the distal femoral metaphysis. The detailed method was provided in the supplementary file . The detailed methods for sample preparation  were provided in supplementary material . 1H NMR spectra were acquired using a Bruker Avance IVDr NMR spectrometer equipped with a 5 mm 1H‐optimized double resonance broad‐band probe operating at a frequency of 600.13 MHz . A one‐dimensional NOESY pulse sequence was adopted to acquire the 1H NMR spectra with specific parameters including measurement temperature: 300 K, relaxation delay: 4 s, spectral width: 7212 Hz, data points: 32k, and scans: 32. A line‐broadening factor of 0.3 Hz was employed to process free induction decays before Fourier transformation. All spectra were baseline and phase corrected before further analysis. Identification and quantification of metabolites from the obtained NMR spectra were implemented in Chenomx .Sample preparation for pH measurement and NMR spectroscopy was performed according to previously published methods.49 The with slight modifications. Briefly, DNA was extracted from 100 mg cecal content or feces using the Micro Bead beat AX kit . Amplicon sequencing was prepared from 1 ng µL−1 DNA with a two‐step PCR method targeting the 16S rRNA gene V3 hypervariable region (forward primer NXt_338_F and reverse primer NXt_518_R). The PCR products were purified with Agencourt AMPure XP Beads  and pooled in equimolar for NextSeq‐based  high throughput sequencing. For bioinformatics, raw datasets were merged and trimmed using ‐fastq_minovlen 100, ‐fastq_maxee 2.0, ‐fastq_truncal 4, ‐fastq_minlen 130. The UPARSE pipeline was employed to purge the dataset and construct de novo Operational Taxonomic Units (OTU), and then SINTAX was used to predict taxonomy. Alpha and beta diversity analyses were based on a contingency table rarefied to 23 000 (feces) and 14 000 (cecum content) reads per sample, and pairwise wilcoxon test and PERMANOVA were performed to determine statistically significant differences in diversity metrics. Responding taxonomic features were extracted through two‐group comparison using DESeq2 with a preset adjusted p‐value of 0.05. Data visualization were mainly performed in R3.6.2  by using a “ggplot2” package.Gut microbiome composition was analyzed according to the method described by He et al.49 witTo reveal the differences in the gut metabolome or gut microbiome between dietary groups, multivariate data analysis (MVDA) was performed in SIMCA 16  or R by using a package of “vegan.”52X‐variables and to correlate Y. The predictability (Q2) of PCA, OPLS‐DA, and PLS model were evaluated by 7‐fold cross‐validation that leaves out one observation and fits the model with the remaining six observations every round . To avoid overfitting, permutations plot was employed to assess the model rationality. Principle coordinate analysis (PCoA) was used to cluster the β‐diversity of bacteria based on the dissimilarity matrix generated by weighted‐UniFrac method.Prior to MVDA, baseline and phase‐corrected NMR spectra were processed with the following steps: alignment, removal of the outer spectral regions (<0.6 and >9.0 ppm) and the region containing the residual water signal (4.76–4.90 ppm), normalization (to sample weight), and binning using a bin width of 0.005 ppm. Pareto scaling was conducted to scale these binning variables before MVDA. Principal component analysis (PCA) was performed to obtain an overview of all NMR profiles. Furthermore, to revel differences between two treatment groups, orthogonal projections to latent structures discriminant analysis (OPLS‐DA) was employed. The S‐line plot of OPLS‐DA was used to elucidate specific differences between two groups. Partial least squares regression (PLS) was employed to build the relation between two sets of variables. Variable importance for the projection (VIP) and the coefficients between specific variables were used to illustrate the important variables to explain  For the correlations between gut microbiota and BMD/BMC, Spearman rank correlation was conducted. Pearson correlation analyses were conducted to examine the correlations between bone parameters and other parameters. If variables were not normally distributed (Shapiro‐Wilk test), variables were log‐transformed before Pearson correlation analysis. For bacterial data and correlation analysis, the false discovery rate (FDR) method was conducted to adjust p values. A p value of 0.05 was considered the significance threshold.All results were reported as mean ± standard deviation (SD). One‐way ANOVA followed by Tukey's post hoc was employed to compare the mean values between groups in Origin 2018 . If not normally distributed and homogeneous in the variances, data were analyzed by the Kruskal–Wallis test followed by paired multiple comparisons with Bonferroni correction. Correlation analysis was conducted in R by using a package of “Hmisc.”53 Forhttps://ivh.ku.dk/english/employees/?pure = en/persons/107126). All other authors declare no conflicts of interest.A. Andersen is employed by Arla Food Ingredients, and H.J. Andersen is employed by Arla Food amba. A.K. Hansen has collaborated with food and pharmaceutical enterprises (listed on H.C.B. formulated the idea, W.H., D.S.N., H.J.A., A.K.H., and H.C.B. designed the animal study, A.A. developed diets, L.S.Z. and A.K.H. performed OVX, L.S.Z. supervised the animal study, W.H., Z.X., N.K.W., R.T., L.S.Z., and H.C.B. performed the experiments and analyzed the results, W.H., Z.X., N.K.W., A.A., H.J.A., H.B., D.S.N., A.K.H., and H.C.B. discussed the results, W.H. wrote the manuscript draft and all authors commented on the manuscript.Supporting InformationClick here for additional data file.


Little is known about frailty in the ambulance setting, or its association with outcomes relevant to ambulance services. We sought to measure frailty in people aged ≥ 50 attended by an ambulance, and describe the relationship between frailty, odds of conveyance to hospital, and duration at scene.n = 112) measured patient frailty using the Clinical Frailty Scale (CFS). Additional information was extracted from ambulance care records. Weighted regression models examined associations between frailty, hospital conveyance, and duration at scene.An observational study between 01/01/2021-30/06/2021 in North East Ambulance Service, England. Participants were aged ≥ 50 attended by an ambulance, excluding patients requiring immediate treatment for a life-threatening condition or with Glasgow Coma Scale < 15. Paramedics . Frailty prevalence (CFS ≥ 5) was 58.7%. Median duration at scene was 47.0 min (interquartile range 34.0–67.0 min). Ambulances spent a median of 8.2 (95%CI:5.4–11.0) minutes longer with frail patients than non-frail patients. Frail patients were less likely to be conveyed to hospital than non-frail patients .Frailty is common among people aged ≥ 50 attended by an ambulance and an important influence on workload. Ambulance services need a good understanding of frailty to meet patient needs. As populations age, community support should be prioritised to deliver appropriate frailty care and reduce demands on ambulance services. National Health Service (NHS) ambulance services are at the heart of the urgent and emergency care system in the United Kingdom (UK) . In addiFrailty is a distinct health state associated with the ageing process. It has been described as one of the most problematic expressions of population ageing , presentIn urgent care settings, frailty assessment is advocated for use to enhance patient-centred care and clinical outcomes . HoweverThis study aimed to measure frailty in people aged ≥ 50 in an ambulance setting (the phase of care delivered by a paramedic), using the Clinical Frailty Scale (CFS) , and desA cross-sectional observational study conducted between January and June 2021, reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines . The stuEligible patients were aged ≥ 50 years and attended by a study paramedic in response to an emergency call. Patients who required immediate treatment for a life-threatening condition   were excAmbulance priority categories are assigned by means of a uniform approach in England and specify the urgency of a patient’s condition based on information gathered by call handlers during the initial emergency call . The GCSn = 112) undertook an online training package in how to use the CFS. They then used routinely collected data and clinical judgement to assess the frailty status of eligible patients for the day of contact and for two weeks prior to the day of contact   in both cases), although the weighted mean CFS score was higher on the day of attendance (mean CFS = 4.88 [95%CI:4.80–4.96]) than the baseline score (mean CFS = 4.61 [95%CI:4.53–4.69]) , 23.6% (n = 419) were estimated to have had a change in CFS score over the two-week period, of which nearly all  increased.All patients had CFS information for the current attendance, but a proportion  were missing a baseline frailty score (the estimated CFS score two weeks prior to contact). In patients with baseline frailty scores, the weighted The likelihood of a patient being assessed as frail increased with age, NEWS2 ≥ 5 and deprivation  resulted in conveyance to hospital, and weighted median duration at scene was 47.0 min (interquartile range 34.0–67.0 min).Duration on scene for frail patients was on average nine minutes longer than for non-frail patients , after adjusting for NEWS2, age, gender, area deprivation and rurality Table . Higher Frail patients were 25% less likely to be conveyed than non-frail patients  of 5.5 (95% CI: 3.3–9.1) of conveyance. Other covariates  were not associated with changes in the odds of conveyance.When paramedics assessed a patient’s CFS to have increased over the past two weeks, their odds of conveyance also increased  after adjusting age, gender, NEWS2, area deprivation and rurality Appendix .In this observational study of people aged ≥ 50 using an ambulance service, a large proportion of patients (58.7%) were frail (CFS ≥ 5). Frailty prevalence increased with advancing age and deprivation. Ambulance crews spent more time attending to people who were frail compared to people who were not. However, frail people were less likely to be conveyed to hospital.Frailty is not well described in older populations using the ambulance service, and to our knowledge there are no published studies reporting frailty in this setting. Published estimates of community frailty prevalence vary, reflecting heterogeneity in clinical settings, population characteristics and frailty measures.6 to 8% among adults aged ≥ 50 .CFS scores did not vary significantly over the course of the study Fig. . Large c


Chikungunya, a mosquito‐borne disease, is posing threat to neonatal population in Cambodia because of its challenging diagnosis and insufficient attention compared with Dengue. In what follows, we present a case of serologically‐confirmed congenital chikungunya in a newborn presenting early‐onset sepsis, and the mother was underdiagnosed with intrapartum flu‐like infection. In adults, CHIKV mostly causes two common clinical features including acute febrile arthralgia and maculopapular rash.Chikungunya virus (CHIKV) is an arthropod‐borne virus that shares the same vectors, namely In Cambodia, CHIKV was first identified in 1961. In 2011, 24 sporadic cases, in which the patients' ages range from 2 to 56 years, were reported across the country.In what follows, we report a rare case of serologically‐confirmed chikungunya infection in a 3‐day‐old neonate, born to a mother with intrapartum flu‐like syndrome. The girl was initially treated for early‐onset sepsis (EOS) and later suspected of mosquito‐borne congenital infection due to the new onset of eruptive fever and petechiae on Day 3 of life and progressive thrombocytopenia.22.1A female neonate was delivered at 38 + 6 weeks of gestation with a birth weight of 2250 g (below 3rd percentile) via vaginal delivery. The amniotic fluid was clear, and the Apgar scores were 8, 9, and 10 at 1, 5, and 10 min, respectively.9/L, platelets 223 × 109/L, and hemoglobin 115 g/L. Urine examination was normal, and hemoculture later was proven negative. Dengue serology was negative. Few hours after admission, the delivery was spontaneous and uneventful.The 23‐year‐old primigest mother had no pregnancy‐related complications. Prenatal care was done regularly at a private clinic with unremarkable serology in the first semester: Hepatitis B, HIV, and syphilis negative. She had flu‐like syndrome and an episode of fever (38.5°C) 2 days prior to admission. At arrival, she was afebrile and COVID‐19 rapid antigen test was negative. She was admitted for unspecified sepsis during labor and treated with ampicillin for 5 days. During her stay, the initial investigation demonstrated an isolated elevated C‐reactive protein (CRP) of 130 mg/L. Complete blood count (CBC) was normal, with leucocytes 4.4 × 102.29/L), with an absolute neutrophil count of 7.2 × 109/L, lymphocytes of 2.3 × 109/L (20%) and immature to total neutrophil ratio (I/T ratio) 0.01; hemoglobin and platelets were within the normal range  and increased CRP (43 mg/L). Syphilis tests were nonreactive. Hemoculture and gastric aspirate done at admission were negative. Brain ultrasound, done before Lumbar Puncture (LP), showed no bleeding signs. Heart ultrasound showed no defect. The second blood culture was drawn, and LP was done, with normal results: leucocytes 06/mm3, albumin 0.5 g/L, and glucose 0.79 g/L. Based upon local guidelines, the clinicians upgraded the antibiotics to second line: Meropenem and Amikacin.At Day 3 of life, the infant started to develop morbilliform rash with petechiae, predominantly found over the back Figure , and intAbout 48 h later, because of the persistently on–off fever and progressively decreasing platelets, we interviewed parents by phone during the restricted period amid COVID pandemic to get more detailed information before any further investigations. According to the mother about 2 days after delivery, she started developing rash, with low‐grade fever and persistent arthralgia. Given the information, we decided to rule out other mosquito‐borne congenital infections, in an early stage, by combined PCR, which later confirmed the diagnosis of congenital chikungunya . She was brought for a follow‐up on day 20, with good weight gain and normalized platelets. The girl will be follow up every 3 months until the age of 2 years, following our local follow‐up program for low birth weight.The treatment was supportive. Apyrexia was noted on day 6 of life. Antibiotics were discontinued 7 days after the negativation of the second blood culture. Platelets increased progressively to 112 × 103Mother‐to‐child transmission of Chikungunya was first described in La Réunion during the outbreak between 2005 and 2006, during which 19 out of 39 neonates from the mothers with intrapartum viremia were infected, corresponding to the transmission rate of 48.7%. Maternal infection was considered intrapartum when the symptoms appeared 2 days prior to the delivery and 2 days after.Most infected newborns are asymptomatic at birth, and symptoms appear mostly after 3 days of life.Although Chikungunya is a self‐limited viral disease in healthy adults, young children and the elderly with co‐existing conditions are considered high‐risk population.Chikungunya virus serology, specifically IgM, can be used for the diagnosis; however, it is challenging in neonates since the virus is detected from about 5 days (range 1–12 days) following the onset of symptoms.The treatment in the neonatal period relies on supportive care, consisting of close monitoring , antipyretics, and fluid management. Antivirals have no indication.In our case, the neonate was asymptomatic at birth with normal CBC and increased acute phase reactants. She developed intermittent fever, rash, and petechiae, with moderate thrombocytopenia on day 3 of life. Vertical mosquito‐borne infection was not initially considered due to the negativity of mother's dengue serology and the local burden of bacterial early‐onset sepsis. Syphilis tests were done due to the resurgence of congenital syphilis in our setting.There are few limitations to our case report. First, there are no MRI in our facility to fully evaluate the neurological involvement. However, brain ultrasound showed no lesions, and normal LP ruled out neurological involvement. Second, antibiotics were used even after the confirmatory diagnosis and stopped only after 7 days of the negativation of the second hemoculture. It was for safety coverage due to severe sepsis. Lastly, out of financial concern, only PCR was done in the neonate on Day 5. Serology might be nonreactive in such an early stage, and together, it costs a lot.4Chikungunya neonatal infection is rare, which makes the diagnosis quite challenging. A careful maternal history plays a leading role in suspecting the possible perinatal infection. In a dengue‐endemic country, congenital arboviral infections, basically CHIKV, should be suspected and ruled out in case of early‐onset sepsis not corresponding to conventional antibiotics in neonates born to the mothers from dengue‐endemic regions with flu‐like syndrome around delivery time.Sakviseth Bin: Conceptualization; investigation; methodology; validation; writing – original draft; writing – review and editing. Kimyi Phou: Investigation; writing – review and editing. Sethikar Im: Supervision; writing – review and editing.There was no funding support for the case report.None declared.No ethical approval is required.Written informed consent was obtained from the patient's parents and is available for review upon request.


Validated acute heart failure (AHF) clinical decision instruments (CDI) insufficiently identify low‐risk patients meriting consideration of outpatient treatment. While pilot data show that tricuspid annulus plane systolic excursion (TAPSE) is associated with adverse events, no AHF CDI currently incorporates point‐of‐care echocardiography (POCecho). We evaluated whether TAPSE adds incremental risk stratification value to an existing CDI.cont), ΔSensitivity (NRIevents), and ΔSpecificity (NRInonevents). Random forest assessed variable importance. To benchmark risk prediction to standard of care, ΔSensitivity and ΔSpecificity were evaluated at risk thresholds more conservative/lower than the actual outcome rate in discharged patients.Prospectively enrolled patients at two urban‐academic EDs had POCechos obtained before or <1 h after first intravenous diuresis, positive pressure ventilation, and/or nitroglycerin. STEMI and cardiogenic shock were excluded. AHF diagnosis was adjudicated by double‐blind expert review. TAPSE, with an a priori cutoff of ≥17 mm, was our primary measure. Secondary measures included eight additional right heart and six left heart POCecho parameters. STRATIFY is a validated CDI predicting 30‐day death/cardiopulmonary resuscitation, mechanical cardiac support, intubation, new/emergent dialysis, and acute myocardial infarction or coronary revascularization in ED AHF patients. Full (STRATIFY + POCecho variable) and reduced  logistic regression models were fit to calculate adjusted odds ratios (aOR), category‐free net reclassification index (NRIp = 0.009). Five right heart  and no left heart measures improved prediction (p < 0.05) adjusted for STRATIFY. Right heart measures also had higher variable importance. TAPSE ≥ 17 mm plus STRATIFY improved prediction versus STRATIFY alone , and specificity improved by 6%–32% (p < 0.05) at risk thresholds more conservative than the standard‐of‐care benchmark without missing any additional events.A total of 84/120 enrolled patients met inclusion and diagnostic adjudication criteria. Nineteen percent experiencing the primary outcome had higher STRATIFY scores compared to those event free (233 vs. 212, TAPSE increased detection of low‐risk AHF patients, after use of a validated CDI, at risk thresholds more conservative than standard of care. Acute heart failure (AHF) accounts for 1 million emergency department (ED) visits annuallyIn a previous pilot study we identified that tricuspid annulus plane systolic excursion (TAPSE) on EP‐performed point‐of‐care echocardiography (POCecho) is associated with short‐term adverse AHF events.The Right ventricular Echocardiography in ED AHF (REED‐AHF) study was a two‐center prospective cohortThe primary methods, protocol, design, and patient cohort of REED‐AHF have been described previously.REED‐AHF was a prospective multicenter cohort study at two urban EDs with 80,000–100,000 annual visits each. Detroit Receiving Hospital is an urban‐academic referral hospital and Level I trauma center; Sinai‐Grace Hospital is an urban‐community Level II trauma center. Both sites host 3‐year emergency medicine (EM) residencies.Patients were enrolled from September 2019 to February 2020 and November 2020 through March 2021. Enrollment was paused during the intervening 8 months per institutional policies regarding clinical research during the early phase of the COVID‐19 pandemic. Patients were screened 7 days per week by trained research staff and study personnel; however, enrollment was limited to times when a study sonographer was available.Full inclusion, exclusion, and diagnostic adjudication criteria have been described previously.The POCecho protocol, performed using a Vivid q ultrasound system, has been described previously.Demographic and clinical variables were collected prospectively at enrollment, throughout hospitalization, and through 90‐day follow‐up as previously described.STRATIFY was chosen as the primary clinical risk measure for a few reasons. First, as cited above, it is one of three CDIs endorsed by ACEP to be helpful in risk stratification.The primary clinical outcome was the 30‐day composite of serious adverse AHF events which STRATIFY was derivedOutcomes were adjudicated by telephone follow‐up, supplemented by multiple blinded abstractors reviewing electronic medical record data and health information exchange data for the state of Michigan as previously described.All statistical analyses were performed in the R language (R Studio 2021.09.1). Patient characteristics were stratified by those with versus without the primary outcome, and echocardiography parameters by outcome and ED disposition, to calculate descriptive statistics using the Wilcoxon rank‐sum test for continuous variables and Fisher's exact test for categorical variables (α = 0.05).Based on our pilot study which showed association between adverse events and TAPSE < 17mmAdditional right heart measures included fwRVLS, RV‐LV ratio, pulmonary artery systolic pressure (PASP) by tricuspid regurgitant jet velocity , RV fractional area change (FAC), pulmonary vascular resistance, and RVOT acceleration time. Left heart measures included left ventricular ejection fraction (LVEF), mitral E/A ratio, septal E', lateral E', E/E' ratio, and LV global longitudinal strain (LVGLS) by speckle tracking.Exploratory analyses were conducted with two goals. First, we explored the possibility that measures besides TAPSE may have incremental value in risk stratification, since few descriptions of any POCecho measure exist in ED‐based AHF risk stratification literature. Second, the other measures served as indirect comparators to TAPSE in evaluating our primary hypothesis. We approached comparison in two ways: (1) evaluating relative variable importance of all POCecho measures with STRATIFY in a random forest model and (2) modeling each POCecho variable in the same way as TAPSE in full (POCecho measure plus STRATIFY) and reduced (STRATIFY only) logistic regression models for measures of incremental improvement in prediction . Secondary POCecho measures were also analyzed as continuous variables and using a priori binary cutoffs corresponding to the American Society of Echocardiography guidelinesThe random forest model for assessing variable importance was run under the following specifications: (1) all 15 echo variables including TAPSE and the STRATIFY score were able to be incorporated into classification trees; (2) no more than two total variables  were allowed to be sampled in a single classification tree ; and (3) 10,000 trees were grown for prediction of the clinical primary outcome using the randomForest package in R, with importance (mean decrease in Gini) calculated and plotted. Random forest utilized in this way aids in selection of independent variables (features) in the context of high dimensionality by calculating the importance of each variable in predicting the outcome of interest, of which mean decrease in Gini is a common importance measure.cont). NRI measures the degree by which addition of a single variable to an existing prediction model improves the classification of that model, focused on the observations which are reclassified to a different prediction category by the added predictor, and specifically whether or not those reclassifications resulted in fewer or greater correct classifications overall .cont assesses classification across all risk thresholds, while the categorical NRI assesses reclassification at specific risk cutoffs.events) and nonevents (NRInonevents) by methods previously describednonevents = ΔSpecificity and NRIevents = ΔSensitivity—i.e., the improvement or worsening in sensitivity and specificity in the standard risk stratification  after adding a novel risk marker Reduced  and full (POCecho measure plus STRATIFY) logistic regression models were fitevents/ΔSensitivity and NRInonevents/ΔSpecificity) were calculated at thresholds that would ensure that the model's “miss rate” was more conservative than the standard‐of‐care miss rate. The rationale of this approach was that even if the exact value of an “acceptable miss rate” is debated, most EPs would likely agree that a model which misses fewer events than the standard of care is potentially useful, particularly if it can also increase identification of low risk  without adding missed events .There is no currently agreed upon “acceptable” miss rate for serious adverse events at which patients should be considered for outpatient treatment of AHF after ED treatment. To account for this, we benchmarked categorical risk prediction and reclassification to standard‐of‐care risk stratification. Model predicted risk thresholds  were chosen to be below the true/observed rate of the primary outcome among patients actually discharged from the ED by standard EP decision making. Thus, measures of categorical reclassification , PH, ED systolic blood pressure (SBP), pre‐ED adherence to guideline‐directed medical therapy, and sex were chosen a priori as patient‐level factors that could be associated with both TAPSE and outcomes while not being incorporated in STRATIFY. Several treatment‐level variables were chosen based on being possible therapeutic indications why a patient would not be a candidate for outpatient treatment , including total ED IV furosemide dose, ED NIPPV, ED IV nitroglycerin, and any new or increased oxygen requirement during the ED visit compared to baseline. Finally, EP disposition decisions of discharge versus admission and ICU versus another level of care were included to assess actual clinical decision‐making compared to the POCecho variables. EPs were blinded to all POCecho data during the study, including when selecting disposition.cont when added to STRATIFY by similar methods as described above for the echocardiography variables in sensitivity analyses. The hypothesis of these sensitivity analyses was that significant improvement in classification by any of these variables compared to STRATIFY alone would diminish the importance of any risk stratification benefit observed for a POCecho variable, since these clinical variables are more easily obtained through history and medical record review than a POCecho, are commonly found in current AHF risk stratification literature and ED‐based CDIs, and/or inherently reflect the standard‐of‐care in EP decision‐making.Each of the variables here was tested for NRI2 initiation, and +102 min (+47 to +177) after ED arrival. A CONSORT diagram with enrollment details has been previously published.n = 11), failure to obtain consent from the patient or a representative within 24 hours of the POCecho (n = 20), and expert‐adjudicated diagnoses of not‐AHF (n = 5), 84 patients remained for analysis.A total of 120 patients met initial inclusion criteria, with POCechos obtained at a median of −75 min (interquartile range [IQR] −131 to +13) before first IV loop diuretic, +33 min (+6 to +59) after initiation of PPV, −21 min (−49 to +23) before first IV/SL nitroglycerin, +33 min (−234 to +162) after first supplemental On = 50), 18% received NIPPV (n = 15), 3.6% (n = 3) were admitted to the ICU, 14% (n = 12) placed in outpatient observation, and 9.5% (n = 8) discharged from the ED.Description for selected clinical and POCecho measures are presented in Tables n = 16) had one or more serious adverse AHF events in the composite primary outcome at 30 days, including three (3.6%) deaths. Experiencing the primary outcome was associated with (Table Nineteen percent of patients n = 6 had onep = 0.011), TAPSE/PASP (p = 0.035), TAPSE/RVDD (p = 0.011), and fwRVLS (p = 0.034). There was no difference in TAPSE between admitted versus discharged patients , as did TAPSE/RVDD (+0.67 [+0.18 to +1.16]) and fwRVLS (+0.49 [+0.01 to +0.98]). Significant reclassification by NRIcont was not observed for other POCecho variables or any of the clinical variables of interest including past history of COPD, history of PH, new or increasing supplemental O2 requirement, ED IV loop diuretic dose, ED NIPPV or intubation, ED IV nitroglycerin, or disposition decisions of ICU or discharge home  and ΔSpecificity (NRInonevents) obtained when TAPSE at the a priori cutoff of ≥17 mm was added to STRATIFY. At every risk threshold less  than the 8.3% benchmark (standard‐of‐care event rate among discharged patients), TAPSE ≥ 17 mm significantly increased specificity without changing sensitivity. At the 8% cutoff, a peak 32% (95% CI 20%–44%) of event‐free patients at 30 days would have been appropriately reclassified from high risk  to low risk (by STRATIFY and TAPSE ≥ 17 mm). At an even more conservative 4% predicted risk cutoff, 15% (6%–24%) of patients incorrectly classified as high risk by STRATIFY alone would have been appropriately reclassified to low risk. Figure ED treatments and disposition decisions were similar between events and nonevents Table . Figure Figure Figure Four additional right heart variables were associated with the outcome after adjusting for STRATIFY: TAPSE/RVDD ratio (aOR 0.35 [0.13–0.94]), TAPSE/PASP ratio (0.38 [0.15–0.96]), RV‐FAC (0.41 [0.17–0.94]), and fwRVLS (0.31 [0.11–0.9]). RV‐LV ratio < 1 (but not as a continuous variable) was also associated with the primary outcome after adjustment (0.24 [0.06–0.78]). No left heart measures were associated with the primary outcome.cont, aOR, and the ability to identify low‐risk AHF patients  without increasing “missed” high‐risk patients . Second, TAPSE and other right‐heart measures showed greater importance .events] and ΔSpecificity [NRInonevents]) to risk thresholds more conservative than the actual outcome rates experienced by patients whom POCecho‐blinded EPs chose to discharge. This was done to acknowledge the status quo: conservative disposition practices resulting in admission for 80%–90% of patients and < 50% of patients receiving an intervention requiring hospital admission . At the outcome rates observed, we would have required more than eight times the number of patients enrolled to have enough events to prevent overfitting on logistic regression fitting an entirely new CDI with as many variablesThird, we had slightly less than 10 events per variable when considering both the STRATIFY score and a POCecho variable . Our sample size was slightly abridged due to the COVID‐19 pandemic as discussed, and prior research has shown that as low as five events per variable is usually sufficient to prevent overfitting.Fourth, we did not directly test learning curves for TAPSE in EP hands , although ICC to experts was high and feasibility of EP‐performed TAPSE for risk stratification has been demonstrated in prior studies of PE.Fifth, the study was not designed to compare POCecho variables head to head, and the abridged enrollment likely decreased this power even further. Given this, we cannot say that other echocardiography variables such as LVEF and mitral inflow parameters are of low utility, but rather only that we had low power to detect a difference among various echocardiography parameters. Nevertheless, other measures all had lower variable importance Figure  and aOR Sixth, our population is medically underserved, predominantly non‐White, coming from only two hospitals  and two institutions (Wayne State and Michigan State University College of Osteopathic Medicine). Generalizability to different populations is therefore uncertain.Tricuspid annulus plane systolic excursion (TAPSE) significantly improved risk stratification compared to the validated STRATIFY clinical decision instrument. Most critically, TAPSE appears to improve detection of low‐risk acute heart failure, even among patients misclassified as high risk. TAPSE, the TAPSE/PASP ratio, the TAPSE/RVDD ratio, and fwRVLS may all help increase the identification of low‐risk acute heart failure patients in the ED who could be considered for outpatient treatment rather than hospital admission. Our hypothesis‐generating results support a need to further define and evaluate point‐of‐care echocardiography's role in acute heart failure risk stratification. Future studies should investigate the incorporation of point‐of‐care echocardiography variables, and particularly right‐heart measures, into acute heart failure clinical decision instruments given their demonstrated potential here, the face validity for acute heart failure risk‐stratification, and the status of echocardiography as one of the few accessible clinical parameters not already used to risk‐stratify acute heart failure in the emergency department.Study concept and design: Nicholas E. Harrison, Robert Ehrman, Mark J. Favot, Phillip Levy, Aiden Abidov. Acquisition of the data: Nicholas E. Harrison, Laura Gowland, Jacob Lenning, Sarah Henry, Sushane Gupta, Robert Ehrman, Mark J. Favot. Analysis and Interpretation of the data: Nicholas E. Harrison, Jacob Lenning, Laura Gowland, Robert Ehrman, Mark J. Favot. Drafting of the manuscript: Nicholas E. Harrison. Critical revision of the manuscript for important intellectual content: all authors. Statistical expertise: Nicholas E. Harrison, Robert Ehrman. Acquisition of funding: Nicholas E. Harrison, Robert Ehrman, Mark J. Favot.Funded by the Blue Cross Blue Shield of Michigan Foundation (BCBSMF) Investigator‐Initiated Grant Program. This publication was made possible with support from Grant Numbers, KL2TR002530 , and UL1TR002529  from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award.JL, SH, SG, and LG report no conflicts of interest. NH's first institution, Wayne State University, has received grant money to conduct investigator‐initiated research conceived and written by NH from BCBSMF. NH and their second institution, Indiana University, have received grant money to conduct investigator‐initiated research conceived and written by NH from the Doris Duke Foundation and the National Institutes of Health (5KL2TR002530‐05). NH's second institution, Indiana University, has received grant money for industry‐initiated research from Abbott Laboratories and Roche Diagnostics. NH has received funding from Vave Health Inc. for consulting. RE has received grant money to conduct investigator‐initiated research from the National Institutes of Health conceived and written by Dr. Peter Pang at Indiana University (1R34HL136986‐01) and investigator‐initiated research conceived and written by NH from BCBSMF. RE has received funding from UltraSight for consulting. MF has received grant money to conduct investigator‐initiated research conceived and written by NH from BCBSMF. MF serves on the medical advisory board for Echonous Inc. and has received stock options from Echonous Inc. AA has received grant money to conduct investigator‐initiated research conceived and written by NH from BCBSMF. PL has received funding for consulting from Apex Innovations, AstraZeneca, BMS, Mespere, Novartis, Cardionomics, Baim Institute, Ortho Clinical Diagnostics, Roche Diagnostics, Siemens, Hospital Quality Foundation. PL and their institution have received investigator‐initiated research support from American Heart Association, Beckman Coulter, Agency for Healthcare Research and Quality (AHRQ), BCBSMF, Emergency Medicine Foundation, Edwards Lifesciences, CardioSounds, Michigan Department of Health and Human Services, Michigan Health Endowment Fund, Patient Centered Outcome Research Institute, and the National Institutes of Health NIH. PL is a member of the ACC's National Cardiovascular Data Registry Oversight Committee.Figure S1Figure S2Click here for additional data file.


Hip fractures are a common health problem among the elderly with an increasing incidence. They are associated with high mortality and morbidity. Optimal pain management remains challenging and inadequate pain control is known for negatively affecting outcomes. Loco-regional anaesthetics (LRA) have been proven to benefit pain management and to lower the risks of opioid use and -related side effects. We aimed to evaluate the use and efficacy of different LRA in elderly hip fracture patients.Single-center cohort study of elderly hip fracture patients, who were treated in central Switzerland. We compared patients who received LRA in the form of a femoral nerve block (FNB) or a continuous femoral nerve catheter (CFNC) with patients who did not receive LRA. Primary outcomes were pain—as measured in perioperative morphine use—hospital length of stay (HLOS), postoperative complications, postoperative falls and mortality.p = 0.007). Postoperative morphine use differed significantly and was lowest in patients with FNB and highest in patients without LRA (p < 0.001). The use of LRA was a significant predictor for postoperative morphine use for postoperative morphine use at the recovery room and for postoperative morphine use 48 h after surgery. No significant differences were found in postoperative complications, a significant difference was found in 1-year mortality.407 patients were included for analysis. Mean age was 85.2 (SD6.3). There was a significant difference in intraoperative morphine use between the groups (This article shows that LRA in the form of FNB and CFNC causes a significant decrease in postoperative opioid consumption. Differences between single-shot FNB or CFNC were minimal. There were no significant differences in clinical outcomes such as HLOS, delirium, 30-day and 90-day mortality and postoperative falls. We suggest that use of LRA should be incorporated in the perioperative treatment of elderly patients with a hip fracture. For future research, we recommend evaluating the number of postoperative complications and mortality.The online version contains supplementary material available at 10.1007/s00068-021-01674-4. Hip fractures in elderly patients are the most common type of fracture and a well-known public health problem . They arNonetheless, determining optimal pain management in this patient population, in which comorbidities and polypharmacy are common, remains challenging . Recent At a level-1 trauma center in Central Switzerland, a geriatric fracture centre (GFC) was recently implemented to optimize surgical treatment in elderly (hip) fracture patients. An important aspect of the GFC was to optimize anaesthesia. This study was based on a quality assessment and aimed to assess the quality and use of  anaesthesia in hip fracture patients treated in the Luzerner Kantonsspital (LUKS). Therefore, we evaluated perioperative pain control—as measured by the opioid use—in elderly hip fracture patients with LRA (in the form of FNB or CFNC) versus elderly hip fracture patients without LRA. The secondary aim was to evaluate the number of postoperative complications , postoperative 30-day and 90-day and 1-year mortality and to observe potential differences between the forms of anaesthesia . We hypothesized that use of LRA would lead to fewer opioid use.This article is written in accordance with the STROBE statement .A single-center observational cohort study based on quality assessment on the anaesthetic protocol of elderly hip fracture patients was conducted at the largest trauma center of Central Switzerland. This study was based on data that were collected for quality improvement purposes. Ethical approval for the quality improvement project was given by the responsible ethical commission/ Institutional Review Bord (IRB) . Since this was considered a quality assessment, the IRB waived the requirement for written informed consents.All patients, who were 70 years of age or older, presenting to the hospital with a proximal femur fracture, between 01.01.2015 and 07.30.2017 who received operative treatment were included for analysis. Fractures were classified using the Arbeitsgemeinschaft für Osteosynthesefragen (AO) fracture classification system.  PatientsThe primary outcome measure was the amount of pain—as measured by opioid use—of all patients. Secondary outcomes included 30-day-, 90-day-, and 1-year mortality and complications, such as HLOS, delirium (as measured by the CAM test), and the number of falls within 48 h after the placement of a block or the catheter. All patients were analysed within three moments in time, namely preoperatively, intraoperatively and postoperatively.Preoperative data consisted of:Age, gender and ASA score. Type of intervention was categorised into the three following groups: (i) patients who had not received any LRA (ii) patients who had received FNB and (iii) patients who had received CFNC.Opioid use at the emergency ward was noted and, in an attempt to make data on opioid use as uniform as possible, we used morphine equivalents, calculated using an equianalgesic calculator. Intraoperative data were categorised in two ways. First, we observed the whole study population in terms of surgery time, time to surgery, type of surgery received, and type of anaesthetic used . Hereafter, we divided the patients into the three previously named groups based on intervention. We then evaluated: type of LRA used , amount of LRA anaesthetic used (in ml), the number of patients that received a second gift of LRA . The time between admission of the intervention and the start of surgery, the time spent at the recovery room and opioid use .Postoperative data were:Opioid use during time spent in the recovery room, opioid use 48 h postoperatively, total HLOS, complications , cerebrovascular accident (CVA), wound infection, urinary tract infection, decubital ulcer and anaemia [all according to the World Health Organization [WHO] guidelines]) . In addiAs for the choice of intervention: preferably, in all patients administered to the emergency ward who required extra analgesia CFNC was the primary choice of LRA. However, if coagulation disorders were noted, FNB was given due to the fact that a single-shot FNB-induced less trauma  then a CFNC. If patients suffered from severe coagulation disorders, no LRA was giving due to high risk of bleeding. This was assessed by the anaesthesiologist on duty. If patients had a history of femoral-popliteal bypass or if they had an infection , no LRA was given as well.Patients received CFNC or FNB from a fully educated anaesthesiologist and anaesthesiologists in training under supervision. The fully educated anaesthesiologist also made the choice of type of LRA. According to protocol, ultrasounds were used for block placement. Further specifications on placement on block and catheter are found in the hospitals’ protocol. Descriptive statistics were used for analysing baseline-, peri-, and postoperative data. Means (M) and standard deviations (SD) were calculated for numeric, normally distributed data. Medians (Mdn) and interquartile ranges (Q1:Q3) were calculated for quantitative, skewed data. The Shapiro–Wilk test was used to test for normality. Missing data were excluded from analysis. For calculating the use of opioids, we used the aforementioned opioid equianalgesic calculator to covert opioid consumption to intravenous milligram morphine equivalent . SubgrouThe ANOVA test was used to test for mean differences in the use of anaesthetics preoperatively, intraoperatively and postoperatively up to 48 h. The alpha-level for statistical significance was set at 0.05. Analyses were carried out using SPSS Statistics version 25 .In total, 428 patients were admitted with a proximal femur fracture. Of those, 21 were excluded because they did not meet eligibility criteria. Figure p = 0.011). When comparing only LRA to no LRA, no significant difference in ASA score was found (p = 0.327).At presentation, 1 patient was scored ASA 1 (0.2%) and 276 (68.1%) patients received an ASA 3 score. A total of 176 (43.3%) of the 407 included patients received CFNC. 118 patients (29.1%) received FNB and 112 patients (27.6%) received no LRA. A significant difference in ASA score at baseline was found (n = 360) received general anaesthesia (Table Mean time to surgery was 23.3 h (SD 4.8) and mean surgery time was 118 min (SD 51.9). Type of surgery performed was hemiarthroplasty in 155 patients (38.3%) and in 164 patients cannulated screws were used (40.4%). Most patients . When comparing FNB to only CFNC, we found no significant differences in either preoperative opioid use (p = 0.146), intraoperative opioid use (p = 0.119), postoperative use at the recovery room (p = 0.225) and postoperative use after 48 h (p = 0.422).Mean opioid use  preoperatively in the FNB group was 3.5 mg  .In total, mean preoperative opioid use was 6.4 mg . Intraoperative opioid use was 28.8 mg  and opioid use at the recovery room and after 48 h was 1.9 mg  and 3.1 mg . Postoperative opioid use at the recovery room and intraoperative opioid use were significantly lower than the group that did not receive LRA (recovery room: p = 0.007). Postoperatively, opioid use at the recovery room was 3.3 mg  and opioid use 48 h after surgery was 3.3 mg . Postoperatively, patients used significantly more opioids at the recovery room and 48 h after surgery than the intervention groups . Median outcomes on opioid use are shown in supplement 1.Preoperative opioid use was 2.8 mg , intraoperative opioid use was 34.5 mg . The intraoperative opioid use was significantly higher than the intervention groups .Delirium: Observing the total of patients who experienced delirium, we found a non-significant difference between the groups (p = 0.354).Anaemia: In the CFNC group, 64 patients had anaemia (36.4%). No significant difference was found between the intervention groups (p = 0.126).Urinary tract infections: FNB patients had the highest percentage of urinary tract infections (7.6%), no significant differences were found between the intervention groups (p = 0.122).CVA: 1 patient from the no-LRA group had a CVA (0.9%). No significant difference between groups was found (p = 0.268).Myocardial infarction: MI was observed in three patients, two of which were in the no-LRA group. (p = 0.270).Decubital ulcer: In total, one patient out of the no-LRA group had a decubital ulcer. .Wound infection: 3 patients suffered from a wound infection, 2 of which were in the FNB group .Total number of patients with a complicated course:p = 0.430).In the FNB group, 50 patients (42.2%) had a complicated course, in the CFNC group 88 patients (50%) and in the no-LRA group 49 patients (43.8%). No significant differences were found when comparing the intervention groups (p = 0.590).When comparing HLOS between patients that received LRA and patients that did not receive any LRA, no significant difference was found. (Time from admission of LRA to surgery:p < 0.001).Regarding time from admission to surgery, we found that patients in the CFNC group had a significantly longer time than patients in the FNB group  vs .A difference was found concerning time spent at the recovery room. Patients who received CFNC spent most time at the recovery room, namely 5 h and 36 min (SD 4:33) and patients who received FNB spent the least amount of time at the recovery room (4:02 (SD 2:44)). Patient who received conventional therapy (no LRA) spent an average of 4:43 h at the recovery room (SD 4:11). Patients with CFNC spent significantly more time at the recovery room . In the CFNC group, 90-day mortality was highest . No significant differences were found in 30-day mortality (p = 0.409) and 90-day mortality (0.317). In the CFNC group, 1-year mortality was highest . There was a significant difference in 1-year mortality between the intervention groups (p = 0.013). When comparing patients who received any form of LRA (FNB or CFNC) to patients who did not receive LRA, no significant difference in 1-year mortality was found.In the no-LRA group, 30-day mortality was highest  and age.p = 0.026), with an R2 of 0.018. Patients’ predicted preoperative morphine use is equal to 0.842 + 2.472 (intervention) + 1.163 (ASA) -0.050 (age) + 0.506 (gender), where intervention is coded as 0 = no LRA 1 = FNB or CFNC, ASA is coded as 1 = ASA 1, 2 = ASA 2, 3 = ASA 3, 4 = ASA 4, gender is coded as 1 = female, 2 = male and age is coded in years. Patients’ preoperative morphine use increased with 1.163 per ASA classification and it decreased with 0.050 per year of age. Females used 0.506 times more morphine than man. Patients without LRA used 2.472 times less morphine than patients with LRA.A significant regression equation was found  = 2.800, p < 0.001), with an R2 of 0.164. Patients’ predicted intraoperative morphine use is equal to 51.328 − 4.919 (intervention) + 0.257 (ASA) + 0.106 (operation duration) -0.277 (age) -2.124 (gender), where intervention is coded as 0 = no LRA 1 = FNB or CFNC, ASA is coded as 1 = ASA 1, 2 = ASA 2, 3 = ASA 3, 4 = ASA 4, operation duration is coded in minutes, gender is coded as 1 = female, 2 = male and age is coded in years. Patients’ postoperative morphine use at the recovery room increased with 0.257 per ASA classification and increased with 0.106 per minute of surgery. It decreased with 0.277 per year of age and males used 2.124 times more morphine than man. Patients without LRA used 4.919 times more morphine than patients with LRA.At the recovery room: A significant regression equation was found  = 15.505, p < 0.001), with an R2 of 0.060. Patients’ predicted postoperative morphine use at the recovery room is equal to 8.139 -1.689 (intervention) + 0.489 (ASA) + 0.006 (operation duration) -0.063 (age) + 0.084 (gender), where intervention is coded as 0 = no LRA 1 = FNB or CFNC, ASA is coded as 1 = ASA 1, 2 = ASA 2, 3 = ASA 3, 4 = ASA 4, operation duration is coded in minutes, gender is coded as 1 = female, 2 = male and age is coded in years. Patients’ postoperative morphine use at the recovery room increased with 0.489 per ASA classification and increased with 0.006 per minute of surgery. It decreased with 0.063 per year of age and females used 0.084 times more morphine than man. Patients without LRA used 1.689 times more morphine than patients with LRA.At the recovery room: A significant regression equation was found  = 5.080, p < 0.001), with an R2 of 0.055. Patients’ predicted postoperative morphine use after 48 h is equal to 12.236 -2.076 (intervention) + 1.950 (ASA) + 0.010 (operation duration) − 0.132 (age), − 1.195 (gender) where intervention is coded as 0 = no LRA 1 = FNB or CFNC, ASA is coded as 1 = ASA 1, 2 = ASA 2, 3 = ASA 3, 4 = ASA 4, operation duration is coded in minutes, gender is coded as 1 = female, 2 = male and age is coded in years. Patients’ postoperative morphine use after 48 h increased with 1.950 per ASA classification and increased with 0.010 per minute of surgery. It decreased with 0.132 per year of age and males used 1.195 times more morphine. Patients without LRA used 2.076 times more morphine than patients with LRA.After 48 h: A significant regression equation was found  = 5.615, Hip fractures in elderly patients are a common health problem and optimal pain management is needed to prevent complications and opioid-related side effects and to optimize perioperative care. This study compared FNB and CFNC to no use of LRA. We found significantly lower opioid use intraoperatively, postoperatively at the recovery room and postoperatively after 48 h in patients who had received LRA. Moreover, the use of LRA was a significant predicter for postoperative opioid use, both at the recovery room and after 48 h.To our knowledge, this is the first and only study that compares both FNB and CFNC to no LRA and that also investigates (long-term) mortality. We found no significant differences between the two different types of LRA. Previous literature focused mostly on either CFNC or FNB. In earlier randomized controlled trials, a decrease in opioid use in patients with LRA has been reported. , 15, 16.Previous literature reports as a possible side-effect, FNB may cause a motor block, which leads to a higher risk of in-hospital falls . Hence, Remarkably, there was a high percentage of patients who received general anaesthesia, though usually spinal anaesthesia is preferred in hip fracture surgery. This was due to hospital guidelines and surgeon preferences. A Cochrane review found no significant differences between both techniques aside from a lower risk of deep venous thrombosis in patients without prophylactic anticoagulation therapy who received spinal anaesthesia . We alsoStrengths of this study include the fact that it includes both CFNC and a single-shot FNB concurrently. Furthermore, the observation period is relatively long, and we obtained data from pre-, intra-, and postoperative periods. In addition, this is one of the few studies that contained data on (long-term) postoperative mortality. Data collection was performed by three independent researchers, which makes it reliable. However, little data in the Electronical Medical Record (EMR) were available for outcomes such as falls, delirium and other complications which suggests data may have been incomplete. There are several other limitations to this study. First, it has a retrospective design which causes known and unknown sorts of bias. Second, the decision on type and use of LRA was not protocolized. Instead, it was mostly operator- and patient dependent. Patients with a local infection or with a severe coagulopathy were not deemed suitable to receive LRA. This may have posed a selection bias. Third, there was no uniformity in the dose of anaesthetic that was administered to the catheter or the block. Therefore, an omitted variable bias may have occurred. However, this is explained by the fact that the design of this study was a quality assessment of everyday clinical practice. Last, incorrect placement may have caused an overestimation in the reporting of pain.This retrospective cohort study shows that LRA in the form of FNB and CFNC causes a significant decrease in postoperative opioid consumption and that LRA is a significant predictor for postoperative opioid use. It also showed that differences in single-shot FNB or CFNC were minimal and non-significant. Nonetheless, there were no significant differences in clinical outcomes such as HLOS, complications, short-term mortality and postoperative falls. Therefore, we suggest that use of LRA should be incorporated in the perioperative treatment of elderly patients with a hip fracture: we recommend FNB for patients with minor coagulation disorders and CFNC for patients without any coagulation disorders and without a local infection. We do not recommend use of LRA in patients with severe coagulopathy or in patients who have a history of a femoral-popliteal bypass. For future research, we recommend to further investigate the 1-year mortality rates between LRA and no LRA and the difference between CFNC and FNB.Supplementary file1 (DOCX 7117 kb)Below is the link to the electronic supplementary material.


To the Editor,Given the available clinical evidence through the literature search when the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J‐SSCG2020) was creating, J‐SSCG2020et al.Recently, Lamontagne n = 3,534). Thereby, the desirable anticipated effect was thought to be “trivial.” The estimated values of the effects on mortality were as follows: long‐term mortality, namely more than 60 days, yielded a risk difference (RD) of 42 more per 1,000 , 28 or 30 days mortality yielded an RD of 34 fewer per 1,000 , in‐hospital mortality yielded an RD of 20 fewer per 1,000 . Of these three mortalities, long‐term mortality was chosen as the effect on mortality since we predetermined that the highest certainty of evidence was adopted. Subsequently, the estimated values of the other undesirable anticipated effects were as follows: the length of hospital stay yielded an MD of 0.24 days longer , and acute kidney injury yielded an RD of 6 more per 1,000 . Thereby, the undesirable anticipated effects were “moderate.” Thus, we presumed that administering vitamin C was inferior to the placebo or control. Judgment of values, acceptability, and feasibility were not changed, namely, “probably no important uncertainty or variability,” “probably yes,” and “probably yes,” respectively.In our updated meta‐analysis, the estimated value of the desirable anticipated effect was as follows: the length of ICU stay yielded a mean difference (MD) of 0.25 days shorter : 0.72 days shorter–0.22 days longer) .”Ethics approval and consent to participate: Not applicable.Consent for publication: Not applicable.Conflicts of Interest (COIs) and members' roles: All financial and non‐financial competing interests were declared in the J‐SSCG2020.Appendix S1. PRISMA flow diagram, risk of bias summary, forrest plot, funnel plot, and evidence to decision table.Click here for additional data file.


Patients with unresectable or metastatic differentiated thyroid carcinoma (DTC) are rare and require individualized therapy. This may require approaches not typically used in resectable disease. We report a patient treated with lenvatinib and external beam radiation therapy.An 87‐year‐old woman presented with cT4N1aM1 papillary thyroid carcinoma with tracheal invasion. She was not a candidate for surgery, radioactive‐iodine, or radiation, so a trial of lenvatinib was offered. Her tumor showed clinical, biochemical, and radiological response after 5 months of lenvatinib, and she subsequently received external beam radiation. She enjoys good quality of life without evidence of cancer progression off therapy 21 months post‐initiation of treatment.Lenvatinib may be effective in RAI‐naïve advanced DTC patients as a component of individualized multimodal therapy when conventional options are not feasible. She reported a six‐month history of increasing stridor, shortness of breath, and hemoptysis, which prompted investigation with a biopsy of her left thyroid and computed tomography (CT) of the neck and chest. Imaging showed a 4.2 cm left thyroid mass indenting and displacing the cervical trachea, an enlarged left supraclavicular node, a 4.0 cm right adrenal mass, and bilateral pulmonary nodules suspicious for metastases Figure . She wasFlexible nasopharyngoscopy visualized a sluggish left vocal cord. Thoracic surgery assessment with flexible bronchoscopy visualized extensive tumor invasion of the left anterior tracheal wall involving the cricoid cartilage, decreasing the tracheal diameter by approximately 50% Figure . It was The patient declined surgery due to her desire for voice preservation. She was not a candidate for RAI given her intact thyroid gland and nondebulked primary tumor. There was tepid enthusiasm for EBRT given the size of the treatment field. Lenvatinib was thus offered, with an understanding that it was being used under exceptional circumstances for a non‐approved indication, and the patient gave informed consent to proceed with therapy . In view of her age and health status, the starting dose was lenvatinib 14 mg p.o. daily with a plan to dose‐titrate based on tolerance.Initially the patient was monitored weekly, and lenvatinib was well‐tolerated with gradual disappearance of stridor and dyspnea. After 1 month, treatment was interrupted for 2 weeks due to diverticulitis, then restarted at the same 14 mg dose. CT scan after 3 months of treatment demonstrated decrease in size of the left thyroid mass (2.9 cm), pulmonary nodules, and right adrenal mass (3.9 cm), compared to 2 months prior to treatment initiation Figure . ThyroglAfter 5 months of lenvatinib, local therapy was discussed in anticipation of eventual treatment resistance. The patient remained reluctant to pursue voice‐sacrificing surgery, and there had been no changes in recommendation regarding RAI, as the remnant normal thyroid remained large. Thus, 1 week after stopping lenvatinib, she received EBRT 50 Gy in 20 fractions to the thyroid, bilateral neck, and superior mediastinal nodes. She experienced moderately severe fatigue and radiation pharyngitis, which resolved over several months. Following EBRT, thyroglobulin was 25.7 μg/L and TSH 0.01 mIU/L, and CT showed stability of the thyroid mass Figure . In this4The optimal therapeutic approach for the rare patient with unresectable and/or metastatic DTC is uncertain, may not be curative, and is usually individualized. Our patient was elderly, had metastatic and locally advanced disease threatening her airway, and refused surgery due to the need for laryngectomy. Given large unresectable tumor burden, RAI would have been ineffective and significantly delayed other potentially more effective therapies. This is because the expression of sodium iodide symporter necessary for RAI absorption is much more pronounced in normal thyroid tissue then in primary DTCs or metastases.A literature search for lenvatinib use in RAI‐naïve DTC identified six reports Table . In all Hugh Andrew Jinwook Kim: Conceptualization ; visualization ; writing – original draft ; writing – review and editing . Anthony Charles Nichols: Conceptualization ; writing – original draft ; writing – review and editing . Ramanamurthy Rachakonda: Conceptualization ; writing – original draft ; writing – review and editing . Richard Inculet: Conceptualization ; writing – original draft ; writing – review and editing . Jinka Sathya: Conceptualization ; writing – original draft ; writing – review and editing . Irina Rachinsky: Conceptualization ; writing – original draft ; writing – review and editing . Eric Winquist: Conceptualization ; supervision ; visualization ; writing – original draft ; writing – review and editing .Eric Winquist has served in a consulting/advisory role for Amgen, Bayer, Eisai, Ipsen, Merck, and Roche; and received research funding (institution) from Roche/Genenetech, Merck, Pfizer, Eisai and Ayala Pharmaceuticals. The other authors have no disclosures.Informed consent was obtained to use images and information from the patient whose case is published in this study.


After repair of degenerative mitral regurgitation (DMR), the focus is on functional mitral stenosis (FMS) when there is a decline of mitral hemodynamics. Yet, the clinical impacts and a standardized definition are still undecided. Since common mitral hemodynamic parameters are influenced by transmitral flow, the aim of this study is to seek the impact of flow adjusted transmitral pressure gradient (TMPG) by left ventricular stroke volume (LVSV) on the midterm outcomes.Three hundred one patients who had undergone isolated mitral valve repair for degenerative lesions with annuloplasty prosthesis between October 2012 and June 2019 were included. Postoperative adverse events occurred in 20 patients (6.6%). Flow adjusted TMPG was defined as TMPG/LVSV.p = .037, .005, and .035). Flow adjusted TMPG was significantly higher in the full ring group compared to the partial band group  and had a significantly negative correlation with the size of the annuloplasty prosthesis .Common mitral hemodynamic parameters were not associated with adverse events. By multivariable analysis, patients’ age, left ventricular ejection fraction (LVEF) and mean TMPG/LVSV were isolated as independent predictors (adjusted hazard ratio: 1.05, 0.95, and 1.16; Conventional mitral hemodynamic parameters were not associated with adverse cardiac events after repair for DMR. Adjustment by flow has a potential to advance pressure gradient to a more sensitive indicator of FMS associated with clinical outcomes. Long‐term success of surgical repair results from prevention of recurrent mitral regurgitation (MR). This has been attempted by focusing on restrictive annuloplasty for ischemic functional MR by reducing the mitral effective valve orifice area (EOA). At the same time, this may cause functional mitral stenosis (FMS) and elevation of the transmitral pressure gradient (TMPG). Mitral hemodynamic decline  relevant to the midterm outcomes after repair for DMR.22.1This study is a retrospective evaluation of mitral valve hemodynamic status measured by resting echocardiogram at several weeks after surgery. Three hundred six patients underwent isolated mitral valve repair for degenerative lesions with annuloplasty prosthesis at the Sakakibara Heart Institute of Okayama between October 2012 and June 2019. After excluding 5 patients with residual mitral regurgitation ≥ moderate, the remaining 301 patients were enrolled. Primary endpoints were defined as postoperative adverse events during follow‐up . This study was approved by the institutional ethics committee in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments . Consent for using patients’ data was obtained from all patients. It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research.2.2Surgical characteristics are presented in Table 2.3MV/VTILVOT), and peak flow velocity was measured based on standard guidelines.Standard transthoracic echocardiography was performed on all patients in the left lateral decubitus position by experienced sonographers before and after symptom‐limited exercise, using a commercially available ultrasound machine . Standard data, such as left ventricular ejection fraction (LVEF), end‐diastolic and systolic dimensions, and tricuspid regurgitation pressure gradient (TRPG) were obtained from the official echocardiographic report.2.4U‐test. Categorical variables are given as a count and percentage of patients and were compared using the χ2 test. When any expected frequency was less than 1, or 20% of expected frequencies were less than or equal to 5, Fisher's exact test was used. Risk factors for cardiac adverse events were evaluated by multivariable Cox proportional hazard regression after univariable analysis. Freedom from adverse events after surgery was compared by the Kaplan–Meier model and the log‐rank test. All data were analyzed using the Statistical Analysis Systems software JMP 12.0 (SAS Institute Inc.).Continuous data are presented as median and interquartile values (the first to the third quartile). Categorical variables are given as a count and percentage of patients. Continuous data were compared with a Mann–Whitney 33.12 (1.50–1.78). A partial band was used for 158 (52.5%) patients and a full ring for 143 (47.5%) patients. For the partial band group, CG future (Medtronic Inc.), Cosgrove (Edwards Lifesciences), Duran (Medtronic Inc.), and Tailor (Abbott Laboratories) bands were implanted in 23, 82, 20, and 33 patients, respectively. For the full ring group, 68 Carpentier‐Edwards Physio/Physio II (Edwards Lifesciences) and 75 Memo 3D (LivaNova) rings were implanted.Patient characteristics are presented in Table 3.22 (1.44–2.09), 1.04 cm2/m2 (0.89–1.30), 1.28 m/s (1.08–1.53), 6.6 mmHg (4.7–9.3), and 2.6 mmHg (2.0–3.4), respectively.Postoperative echocardiographic data was shown in Table 3.3Postoperative adverse events during follow‐up occurred in 20 patients (6.6%), and the adverse events included: 4 stroke, 4 readmission due to de novo arrhythmia, 6 readmission due to heart failure, and 6 reoperation for FMS. The overall 1‐year and 5‐year freedom from adverse events rate was 96.3% and 84.0%, respectively.p = .006), LVEF , left atrial dimension , TRPG , SPAP , and mean TMPG/LVSV  were detected as risk factors for adverse events. After multivariable analysis, patients’ age , LVEF  and mean TMPG/LVSV  were isolated as independent predictors of adverse events after repair for DMR. Univariable and multivariable Cox proportional hazard analysis data are shown in Table Univariable Cox proportional hazard analysis revealed no significant correlation in common mitral hemodynamic parameters . Patients’ age . The Kaplan‐Meier curve revealed a significant difference in the 5‐year freedom from adverse events rate . The Kaplan–Meier curve revealed a significant difference in 5‐year freedom from adverse events rate . The location of lesions was not correlated with flow adjusted TMPG (p = .40). Flow adjusted TMPG was significantly higher in the full ring group compared to the partial band group  and had a significantly negative correlation with the size of annuloplasty prosthesis . Flow adjusted TMPG was significantly greater in patients with a smaller full ring (≤30 mm), but equivalent in patients with larger annuloplasty prostheses  the percentage of adverse events after mitral repair for DMR was 6.6% (20/301 patients) and the overall 5‐year freedom from adverse events rate was 84.0%, (2) conventional mitral hemodynamic parameters were not associated with adverse events, (3) patients’ age, postoperative LVEF and mean TMPG/LVSV were identified as independent risk factors for adverse events, (4) risk stratification by mean TMPG and LVEF reflected the midterm outcomes, predictively, and (5) although a full ring and smaller size of annuloplasty were associated with elevation of flow adjusted TMPG, the type of annuloplasty prosthesis (band or ring) did not have an influence in patients with a larger size (≥32 mm).r = .25, p < .001). Although isolated mean and peak TMPG was not a predictor of cardiac adverse events, TMPG adjusted by flow (LVSV or LVEF) was identified as a significant predictor and may have a potential to be a more sensitive indicator of FMS associated with clinical outcomes. The cut‐off value of mean TMPG/LVSV was 0.041, therefore, mean TMPG should be controlled to less than LVSV × 0.041 to avoid flow adjusted FMS. As shown in Figure In previous studies, FMS, defined as elevation of TMPG, was associated with quality of life, atrial fibrillation, and left atrial remodeling after repair of DMR. Several studies reported that smaller prostheses may result in a higher mean TMPG, and may inhibit reverse remodeling of the left atrium, which caused a risk of late atrial fibrillation.Regarding the risks of FMS, smaller‐sized annuloplasty prostheses and complete rings reduce valve area and anterior leaflet motion, which may result in FMS.4.1There were several limitations. First, this study was a retrospective observational study in a single center. Therefore, there was a selection bias to decide the techniques of repair and products for mitral annuloplasty. Additionally, the influence of atrial fibrillation may not have been eliminated. Second, this cohort included physically small Asian patients, therefore, appropriate annuloplasty size selection may be different with a variant population. Finally, stress echocardiogram may be a better option for detailed evaluation. However, a stress echocardiogram cannot be performed routinely for all patients in all institutes. Therefore, we used resting echocardiographic parameters for simple and reproducible data.5TMPG is commonly emphasized to evaluate FMS. However, the definition and clinical impacts of FMS are still unclear. Adjustment by flow has a potential to advance a pressure gradient to a more sensitive indicator of FMS associated with clinical outcomes after repair of DMR. Although smaller complete rings may be useful to control regurgitation, they can cause a risk for FMS.The authors declare no conflict of interest.Conception or design of the work: Arudo Hiraoka and Akihiro Hayashida. Data collection: Arudo Hiraoka, Toshinori Totsugawa, and Misako Toki. Data analysis and interpretation: Arudo Hiraoka. Drafting the article: Arudo Hiraoka and Genta Chikazawa. Critical revision of the article: Akihiro Hayashida, Hidenori Yoshitaka, and Taichi Sakaguchi. Final approval of the version to be published: Arudo Hiraoka.