Case report: Echinococcus multilocularis infection in a dog showing gastrointestinal signs in Hokkaido, Japan.

Echinococcus multilocularis is a cestode that causes human alveolar echinococcosis, a lethal zoonotic disease distributed in the northern hemisphere. The life cycle of this parasite is maintained in nature by voles as intermediate hosts and foxes as definitive hosts in Hokkaido, Japan. Although dogs are also susceptible to the parasite, the infection has been considered typically asymptomatic. We report the detection of E. multilocularis eggs in the diarrheal feces of a dog with chronic gastrointestinal signs, which disappeared after anthelmintic treatment. The mitochondrial genome sequence constructed by sequencing of the overlapping PCRs using DNA from the eggs was identical to the most predominant haplotype previously reported in red foxes in Hokkaido. This case highlights that Echinococcus infection should be considered as a differential diagnosis for diarrheal dogs in the disease endemic areas. Further efforts are needed to accumulate parasite genotypes in domestic dogs as well as humans to assess the risk of human infection from dogs.

Effects of early enteral nutrition on persistent inflammation, immunosuppression, and catabolism syndrome in critically ill patients: A claims database study using a propensity score analysis.

BACKGROUND & AIMS: Early enteral nutrition (EEN) potentially improves immune-related outcomes via the maintenance of intestinal immunity; however, the effects of EEN on clinical outcomes, including infectious complications, are controversial. Therefore, we herein investigated whether EEN affected persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which represents the immunocompromised state after critical illness. METHODS: This retrospective cohort study utilized the administrative claims database of inpatients and laboratory findings. Patients admitted to and treated in the intensive care unit (ICU) for more than 3 consecutive days were included. The primary outcome, a composite of PICS or mortality on day 14 after admission, was compared between the EEN group, which received enteral nutrition (EN) on the first 3 days (day 0, 1, or 2), and the late enteral nutrition (LEN) group, which did not receive EN on the first 3 days, but then received EN on days 3 through 7, using a propensity score-matched analysis. Secondary outcomes included the composite outcome on day 28, in-hospital mortality, the Barthel index, and laboratory data. Patients who met at least two of the following conditions were diagnosed with PICS: CRP >2.0 mg/dL, albumin <3.0 g/dL, and a lymphocyte count <800/µL. RESULTS: A total of 7530 matched pairs were generated after propensity score matching. The primary outcome was significantly lower in the EEN group (risk difference -3.0%, 95% confidence interval (CI) -4.5 to -1.4%), whereas mortality did not significantly differ. The 28-day composite outcome was similar in the 2 groups (risk difference -1.5%, 95% CI -2.8% to -0.2%, no significant difference in mortality). There was no significant difference in in-hospital mortality between the EEN and LEN groups; however, the Barthel index at discharge was higher in the EEN group (the medians, 50 vs 45, P = 0.001). Laboratory data showed lower Albumin and CRP on day 14 in the EEN group, but no other significant differences. CONCLUSIONS: In patients admitted to the ICU, EEN was associated with a lower incidence of PICS on days 14 and 28, but was not associated with mortality. This positive association was not observed in sepsis, cardiac diseases, or gastrointestinal diseases.

The water imbalance of skeletal muscle and muscle weakness in patients with heart failure.

AIMS: A high extracellular water (ECW) to intracellular water (ICW) ratio of skeletal muscle as assessed by bioelectrical impedance analysis is reportedly associated with loss of muscle strength. However, the validity of this index for heart failure (HF), which is likely associated with changes in the water distribution, is unclear. METHODS AND RESULTS: This study involved 190 patients with HF. The total ECW and ICW of both upper and lower extremities were measured, and a high ECW/ICW ratio was defined as an ECW/ICW ratio higher than the median (≥0.636 for men, ≥0.652 for women). Low muscle strength was defined as reduced handgrip strength according to the criteria established by the Asian Working Group for Sarcopenia. Patients with a high ECW/ICW ratio had a lower handgrip strength (21.1 ± 8.1 kg vs. 27.6 ± 9.3 kg, P ≤ 0.05) and 6 min walk distance (329 ± 116 m vs. 440 ± 114 m) than those with a low ECW/ICW ratio. An increasing ECW and/or decreasing ICW was associated with a higher ECW/ICW ratio and a lower handgrip strength (P < 0.05). In the multivariate logistic regression analysis, a high ECW/ICW ratio and low skeletal muscle mass were independently associated with low muscle strength (P < 0.05). CONCLUSIONS: A high ECW/ICW ratio in limb muscles, that is, the water imbalance of increasing ECW and/or decreasing ICW, is useful in assessing muscle quality in patients with HF.

GeF-seq: A Simple Procedure for Base-Pair Resolution ChIP-seq.

Nucleotide sequences recognized and bound by DNA-binding proteins (DBPs) are critical to controlling and maintaining gene expression, replication, chromosome segregation, cell division, and nucleoid structure in bacterial cells. Therefore, determination of the binding sequences of DBPs is important not only to study DBP recognition mechanisms but also to understand the fundamentals of cell homeostasis. While ChIP-seq analysis appears to be an effective way to determine DBP binding sites on the genome, the resolution is sometimes not sufficient to identify the sites precisely. Here we introduce a simple and effective method named Genome Footprinting with high-throughput sequencing (GeF-seq) to determine binding sites of DBPs with single base-pair resolution. GeF-seq detects binding sites of DBPs as sharp peaks and thus makes it possible to identify the recognition sequence in each "binding peak" more easily and accurately compared to the common ChIP-seq.

Relationship between Very Early Enteral Nutrition and Persistent Inflammation, Immunosuppression, and Catabolism Syndrome in cardiovascular surgery patients: A propensity score-matched study.

BACKGROUND: Early enteral nutrition (EN) is recommended for patients with critical illness to maintain intestinal immunity. However, the optimal timing of the commencement of EN remains unclear, particularly after cardiovascular surgery. OBJECTIVE: We herein focused on Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) as a predisposing immunodeficiency, and investigated its association with very early EN (<24 hours) in patients who underwent cardiovascular surgery. DESIGN: In this retrospective study, we used an administrative claims database with laboratory examinations between 2008 and 2021 to identify adult patients admitted to the intensive care unit after cardiovascular surgery. Patients who received EN the day after surgery were assigned to the EN <24 h group, while those who received EN on day 2 or 3 were assigned to the control group. The primary outcome was a composite of the incidence of PICS and mortality on day 14 after surgery. We defined PICS as patients hospitalized for >14 days and meeting at least two of the following conditions: a lymphocyte count <800/µL, albumin <3.0 g/dL, and CRP >2.0 mg/dL. We compared the two groups using a propensity score analysis. RESULTS: Propensity score matching generated 2,082 pairs. The primary outcome was significantly lower in the EN <24 h group than in the control group on days 14 (risk difference [95% CI], -3.1% [-5.9%, -0.3%]) and 28 (risk difference [95% CI], -2.1% [-3.7%, -0.4%]). Mortality did not significantly differ between the two groups. The length of hospital stay was significantly shorter in the EN <24 h group: the difference (95% CI) was -2.2 (-3.7, -0.7) days. CONCLUSIONS: Among patients who underwent cardiovascular surgery, very early EN provided on the day after surgery was associated with a lower incidence of PICS and a shorter length of hospital stay than EN provided two or three days after surgery.

Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates.

Signal regulatory protein alpha (SIRPα) is an immune inhibitory receptor on myeloid cells including macrophages and dendritic cells, which binds to CD47, a ubiquitous self-associated molecule. SIRPα-CD47 interaction is exploited by cancer cells to suppress anti-tumor activity of myeloid cells, therefore emerging as a novel immune checkpoint for cancer immunotherapy. In blood cancer, several SIRPα-CD47 blockers have shown encouraging monotherapy activity. However, the anti-tumor activity of SIRPα-CD47 blockers in solid tumors seems limited, suggesting the need for combination therapies to fully exploit the myeloid immune checkpoint in solid tumors. Here we tested whether combination of SIRPα-CD47 blocker with antibody-drug conjugate bearing a topoisomerase I inhibitor DXd (DXd-ADC) would enhance anti-tumor activity in solid tumors. To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. DS-1103a inhibited SIRPα-CD47 interaction and enhanced antibody-dependent cellular phagocytosis of Dato-DXd and T-DXd against human cancer cells. In a whole cancer cell vaccination model, vaccination with DXd-treated cancer cells led to activation of tumor-specific T cells when combined with an anti-mouse SIRPα (anti-mSIRPα) Ab, implying the benefit of combining DXd-ADCs with anti-SIRPα Ab on anti-tumor immunity. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.

Effects of Energy Delivery Guided by Indirect Calorimetry in Critically Ill Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: The utility of using indirect calorimetry (IC) to estimate energy needs and methods for its application to this purpose remain unclear. This systematic review investigated whether using IC to estimate energy expenditure in critically ill patients is more meaningful for improving survival than other estimation methods. METHODS: Comprehensive searches were conducted in MEDLINE using PubMed, Cochrane Central Register of Controlled Trials, and Igaku-Chuo-Zasshi up to March 2023. RESULTS: Nine RCTs involving 1178 patients were included in the meta-analysis. The evidence obtained suggested that energy delivery by IC improved short-term mortality (risk ratio, 0.86; 95% confidence interval [CI], 0.70 to 1.06). However, the use of IC did not appear to affect the length of ICU stay (mean difference [MD], 0.86; 95% CI, -0.98 to 2.70) or the duration of mechanical ventilation (MD, 0.66; 95% CI, -0.39 to 1.72). Post hoc analyses using short-term mortality as the outcome found no significant difference by target calories in resting energy expenditure, whereas more frequent IC estimates were associated with lower short-term mortality and were more effective in mechanically ventilated patients. CONCLUSIONS: This updated meta-analysis revealed that the use of IC may improve short-term mortality in patients with critical illness and did not increase adverse events.

Acute muscle loss assessed using panoramic ultrasound in critically ill adults: a prospective observational study.

PURPOSE: Panoramic ultrasound is one of the recently introduced ultrasound evaluation techniques. We herein examined the relationship between the cross-sectional area of the rectus femoris muscle on panoramic ultrasound and its volume based on the gold standard computed tomography (CT) evaluation. METHODS: This was a single-center prospective observational study. A panoramic ultrasound assessment of the cross-sectional area of the rectus femoris muscle and a simple CT evaluation of its volume were performed on days 1 and 7 of hospitalization. Physical functions were assessed at discharge. RESULTS: Twenty patients were examined. The rate of change in the cross-sectional area of the rectus femoris muscle on panoramic ultrasound correlated with that in its volume on CT (correlation coefficient 0.59, p = 0.0061). In addition, a correlation was observed between the absolute value for the rectus femoris muscle cross-sectional area on panoramic ultrasound and physical functions at discharge. Rectus femoris muscle distances did not correlate with either. CONCLUSION: In the acute phase of critical illness, the cross-sectional area of the rectus femoris muscle on panoramic images correlated with its volume on CT and, thus, it is a valid method for assessing muscle mass.

Effects of mechanical insufflation-exsufflation on ventilator-free days in intensive care unit subjects with sputum retention; a randomized clinical trial.

BACKGROUND: Mechanical insufflation-exsufflation (MI-E) facilitates extubation. However, its potential to reduce the duration of ventilator use remains unclear. Therefore, the present study investigated whether the use of MI-E shortened the duration of mechanical ventilation in patients with high sputum retention. METHODS: A randomized open-label trial was conducted at a single intensive care unit (ICU) in Japan between November 2017 and June 2019. Ventilated subjects requiring suctioning at least once every hour due to sputum retention were randomly assigned to the MI-E group or conventional care group. The primary endpoint was the number of ventilator-free days on day 28. Secondary endpoints were ventilator days in surviving subjects, the length of ICU stay, and mortality and tracheostomy rates among survivors. RESULTS: Forty-eight subjects (81% males) with a median age of 72 years (interquartile range [IQR], 65-85 years) were enrolled. There were 27 subjects in the MI-E group and 21 in the control group. The median number of ventilator-free days was 21 (IQR, 13-24) and 18, respectively (IQR, 0-23) (P = .38). No significant differences were observed in the ICU length of stay (median, 10 days (IQR, 7-12) vs 12 days (IQR, 6-15); P = .31), mortality rate (19% vs 15%; odds ratio [OR], 1.36 [0.28-6.50]; P = .69), or tracheostomy rate among survivors (14% vs 28%; OR, 0.40 [0.08-1.91]; P = .25). CONCLUSION: In ventilated subjects in the ICU with high sputum retention, the use of MI-E did not significantly increase the number of ventilator-free days over that with conventional care.

Association of a Transitional Heart Failure Management Program With Readmission and End-of-Life Care in Rural Japan.

Background: Evidence on transitional care for heart failure (HF) in Japan is limited. Methods and Results: We implemented a transitional HF management program in rural Japan in 2019. This involved collaboration with general practitioners or nursing care facilities and included symptom monitoring by medical/nursing staff using a handbook; standardized discharge care planning and information sharing on self-care and advance care planning using a collaborative sheet; and sharing expertise on HF management via manuals. We compared the outcomes within 1 year of discharge among patients hospitalized with HF in the 2 years before program implementation (2017-2018; historical control, n=198), in the first 2 years after program implementation (2019-2020; Intervention Phase 1, n=205), and in the second 2 years, following program revision and regional dissemination (2021-2022; Intervention Phase 2, n=195). HF readmission rates gradually decreased over Phases 1 and 2 (P<0.05). This association was consistent regardless of physician expertise, follow-up institution, or the use of nursing care services (P>0.1 for interaction). Mortality rates remained unchanged, but significantly more patients received end-of-life care at home in Phase 2 than before (P<0.05). Conclusions: The implementation of a transitional care program was associated with decreased HF readmissions and increased end-of-life care at home for HF patients in rural Japan.

A de novo nonsense variant in the DMD gene associated with X-linked dystrophin-deficient muscular dystrophy in a cat.

BACKGROUND: X-linked dystrophin-deficient muscular dystrophy (MD) is a form of MD caused by variants in the DMD gene. It is a fatal disease characterized by progressive weakness and degeneration of skeletal muscles. HYPOTHESIS/OBJECTIVES: Identify deleterious genetic variants in DMD by whole-genome sequencing (WGS) using a next-generation sequencer. ANIMALS: One MD-affected cat, its parents, and 354 cats from a breeding colony. METHODS: We compared the WGS data of the affected cat with data available in the National Center for Biotechnology Information database and searched for candidate high-impact variants by in silico analyses. Next, we confirmed the candidate variants by Sanger sequencing using samples from the parents and cats from the breeding colony. We used 2 genome assemblies, the standard felCat9 (from an Abyssinian cat) and the novel AnAms1.0 (from an American Shorthair cat), to evaluate genome assembly differences. RESULTS: We found 2 novel high-impact variants: a 1-bp deletion in felCat9 and an identical nonsense variant in felCat9 and AnAms1.0. Whole genome and Sanger sequencing validation showed that the deletion in felCat9 was a false positive because of misassembly. Among the 357 cats, the nonsense variant was only found in the affected cat, which indicated it was a de novo variant. CONCLUSION AND CLINICAL IMPORTANCE: We identified a de novo variant in the affected cat and next-generation sequencing-based genotyping of the whole DMD gene was determined to be necessary for affected cats because the parents of the affected cat did not have the risk variant.

Intensive care unit follow-up clinic activities: a scoping review.

The importance of ongoing post-discharge follow-up to prevent functional impairment in patients discharged from intensive care units (ICUs) is being increasingly recognized. Therefore, we conducted a scoping review, which included existing ICU follow-up clinic methodologies using the CENTRAL, MEDLINE, and CINAHL databases from their inception to December 2022. Data were examined for country or region, outpatient name, location, opening days, lead profession, eligible patients, timing of the follow-up, and assessment tools. Twelve studies were included in our review. The results obtained revealed that the methods employed by ICU follow-up clinics varied among countries and regions. The names of outpatient follow-up clinics also varied; however, all were located within the facility. These clinics were mainly physician or nurse led; however, pharmacists, physical therapists, neuropsychologists, and social workers were also involved. Some clinics were limited to critically ill patients with sepsis or those requiring ventilation. Ten studies reported the first outpatient visit 1-3 months after discharge. All studies assessed physical function, cognitive function, mental health, and the health-related quality of life. This scoping review revealed that an optimal operating format for ICU follow-up clinics needs to be established according to the categories of critically ill patients.

Predictor of A4 amplitude using preprocedural electrocardiography in patients with leadless pacemakers.

BACKGROUND: Based on historical studies of leadless pacemakers (LPs), high atrioventricular synchrony (AVS) with mechanical sensing-based VDD pacing is largely influenced by A4 amplitude. A limited study investigated the predictors of A4 amplitude using clinical and echocardiographic parameters. OBJECTIVE: The purpose of this study was to investigate the predictors of A4 amplitude preoperatively to select patients who could benefit the most from AVS among patients with VDD LPs (Micra-AV, Medtronic). METHODS: Data from patients who received Micra-AV implantations from November 2021 to August 2023 at Tottori University Hospital were analyzed. Twelve-lead electrocardiography and transthoracic echocardiography were performed before the Micra-AV implantations. To assess the electrical indices associated with the A4 signal, electrocardiographic morphologic P-wave parameters were analyzed, including P-wave duration, P-wave amplitude, maximum deflection index (MDI), and P-wave dispersion. RESULTS: A total of 50 patients who underwent Micra-AV implantations (median age 84 years; 64% male) were included and divided into 2 groups based on the median value of A4 amplitude, the high-A4 group (A4 amplitude >2.5 m/s2; n = 26), and low-A4 group (A4 amplitude ≤2.5 m/s2; n = 24). There was a significant difference between the high-A4 and low-A4 groups with regard to left ventricular ejection fraction (P = .01), P-wave dispersion (P = .01), and MDI (P <.001). Multivariate logistic analysis revealed that lower MDI was an independent predictor of high A4-amplitude (odds ratio 0.78; 95% confidence interval 0.67-0.92; P = 0.003). CONCLUSION: Preoperative electrocardiographic evaluations of P-wave morphology may be useful for predicting A4 amplitude. MDI was the only independent A4 amplitude predictor that seemed promising for selecting Micra-AV patients.

Post-intensive care syndrome: Recent advances and future directions.

Post-intensive care syndrome comprises physical, cognitive, and mental impairments in patients treated in an intensive care unit (ICU). It occurs either during the ICU stay or following ICU discharge and is related to the patients' long-term prognosis. The same concept also applies to pediatric patients, and it can greatly affect the mental status of family members. In the 10 years since post-intensive care syndrome was first proposed, research has greatly expanded. Here, we summarize the recent evidence on post-intensive care syndrome regarding its pathophysiology, epidemiology, assessment, risk factors, prevention, and treatments. We highlight new topics, future directions, and strategies to overcome post-intensive care syndrome among people treated in an ICU. Clinical and basic research are still needed to elucidate the mechanistic insights and to discover therapeutic targets and new interventions for post-intensive care syndrome.

From bedside to recovery: exercise therapy for prevention of post-intensive care syndrome.

BACKGROUND: As advancements in critical care medicine continue to improve Intensive Care Unit (ICU) survival rates, clinical and research attention is urgently shifting toward improving the quality of survival. Post-Intensive Care Syndrome (PICS) is a complex constellation of physical, cognitive, and mental dysfunctions that severely impact patients' lives after hospital discharge. This review provides a comprehensive and multi-dimensional summary of the current evidence and practice of exercise therapy (ET) during and after an ICU admission to prevent and manage the various domains of PICS. The review aims to elucidate the evidence of the mechanisms and effects of ET in ICU rehabilitation and highlight that suboptimal clinical and functional outcomes of ICU patients is a growing public health concern that needs to be urgently addressed. MAIN BODY: This review commences with a brief overview of the current relationship between PICS and ET, describing the latest research on this topic. It subsequently summarises the use of ET in ICU, hospital wards, and post-hospital discharge, illuminating the problematic transition between these settings. The following chapters focus on the effects of ET on physical, cognitive, and mental function, detailing the multi-faceted biological and pathophysiological mechanisms of dysfunctions and the benefits of ET in all three domains. This is followed by a chapter focusing on co-interventions and how to maximise and enhance the effect of ET, outlining practical strategies for how to optimise the effectiveness of ET. The review next describes several emerging technologies that have been introduced/suggested to augment and support the provision of ET during and after ICU admission. Lastly, the review discusses future research directions. CONCLUSION: PICS is a growing global healthcare concern. This review aims to guide clinicians, researchers, policymakers, and healthcare providers in utilising ET as a therapeutic and preventive measure for patients during and after an ICU admission to address this problem. An improved understanding of the effectiveness of ET and the clinical and research gaps that needs to be urgently addressed will greatly assist clinicians in their efforts to rehabilitate ICU survivors, improving patients' quality of survival and helping them return to their normal lives after hospital discharge.

Relationship between critical care nutrition and post-intensive care syndrome in surviving ventilated patients with COVID-19: a multicenter prospective observational study.

The impact of nutrition therapy in the acute phase on post-intensive care syndrome (PICS) remains unclear. We conducted a multicenter prospective study on adult patients with COVID-19 who required mechanical ventilation for more than three days. The questionnaire was mailed after discharge. Physical PICS, defined as less than 90 points on the Barthel index (BI), was assigned as the primary outcome. We examined the types of nutrition therapy in the first week that affected PICS components. 269 eligible patients were evaluated 10 months after discharge. Supplemental parenteral nutrition (SPN) >400 kcal/day correlated with a lower occurrence of physical PICS (10% vs 21.92%, p = 0.042), whereas the amounts of energy and protein provided, early enteral nutrition, and a gradual increase in nutrition delivery did not, and none correlated with cognitive or mental PICS. A multivariable regression analysis revealed that SPN had an independent impact on physical PICS (odds ratio 0.33, 95% CI 0.12-0.92, p = 0.034), even after adjustments for age, sex, body mass index and severity. Protein provision ≥1.2 g/kg/day was associated with a lower occurrence of physical PICS (odds ratio 0.42, 95% CI 0.16-1.08, p = 0.071). In conclusion, SPN in the acute phase had a positive impact on physical PICS for ventilated patients with COVID-19.

Post-intensive care syndrome follow-up system after hospital discharge: a narrative review.

BACKGROUND: Post-intensive care syndrome (PICS) is the long-lasting impairment of physical functions, cognitive functions, and mental health after intensive care. Although a long-term follow-up is essential for the successful management of PICS, few reviews have summarized evidence for the efficacy and management of the PICS follow-up system. MAIN TEXT: The PICS follow-up system includes a PICS follow-up clinic, home visitations, telephone or mail follow-ups, and telemedicine. The first PICS follow-up clinic was established in the U.K. in 1993 and its use spread thereafter. There are currently no consistent findings on the efficacy of PICS follow-up clinics. Under recent evidence and recommendations, attendance at a PICS follow-up clinic needs to start within three months after hospital discharge. A multidisciplinary team approach is important for the treatment of PICS from various aspects of impairments, including the nutritional status. We classified face-to-face and telephone-based assessments for a PICS follow-up from recent recommendations. Recent findings on medications, rehabilitation, and nutrition for the treatment of PICS were summarized. CONCLUSIONS: This narrative review aimed to summarize the PICS follow-up system after hospital discharge and provide a comprehensive approach for the prevention and treatment of PICS.

Raludotatug Deruxtecan, a CDH6-Targeting Antibody-Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models.

Cadherin-6 (CDH6) is expressed in several cancer types, but no CDH6-targeted therapy is currently clinically available. Here, we generated raludotatug deruxtecan (R-DXd; DS-6000), a novel CDH6-targeting antibody-drug conjugate with a potent DNA topoisomerase I inhibitor, and evaluated its properties, pharmacologic activities, and safety profile. In vitro pharmacologic activities and the mechanisms of action of R-DXd were assessed in serous-type ovarian cancer and renal cell carcinoma cell lines. In vivo pharmacologic activities were evaluated with several human cancer cell lines and patient-derived xenograft mouse models. The safety profile in cynomolgus monkeys was also assessed. R-DXd exhibited CDH6 expression-dependent cell growth-inhibitory activity and induced tumor regression in xenograft models. In this process, R-DXd specifically bound to CDH6, was internalized into cancer cells, and then translocated to the lysosome. The DXd released from R-DXd induced the phosphorylation of Chk1, a DNA damage marker, and cleaved caspase-3, an apoptosis marker, in cancer cells. It was also confirmed that the DXd payload had a bystander effect, passing through the cell membrane and impacting surrounding cells. The safety profile of R-DXd was favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys. R-DXd demonstrated potent antitumor activity against CDH6-expressing tumors in mice and an acceptable safety profile in monkeys. These findings indicate the potential of R-DXd as a new treatment option for patients with CDH6-expressing serous-type ovarian cancer and renal cell carcinoma in a clinical setting.

Enteral nutrition practice in the prone position in patients with coronavirus disease 2019: An international one-day point prevalence analysis.

BACKGROUND & AIMS: Enteral nutrition (EN) in the prone position for severe respiratory failure is considered possible with care. However, the extent to which it is feasible, especially its association with the length of intensive care unit (ICU) stay, is unclear. Therefore, we investigated the relationship between the duration of prone position therapy and adequacy of EN delivery and explored factors associated with this relationship in an observational study of critically ill patients with coronavirus disease 2019 (COVID-19) who were actively treated in the prone position. METHODS: This study was a secondary analysis of a worldwide one-day prevalence study in the COVID-19 era. We investigated the care and nutritional therapy provided to critically ill patients with COVID-19 admitted to ICU, along with ICU-related information. We targeted patients who received only tube feeding and analyzed the relationship between the duration of prone position, length of ICU stays, and nutrition delivery via EN. In addition, a multivariate analysis was performed to examine factors affecting the achievement of EN delivery of 20 kcal/kg/day or more in patients who were placed in the prone position for at least 6 h. RESULTS: A total of 399 patients who received only EN, excluding parenteral nutrition and oral intake, were included, of whom 58 % received EN energy delivery of ≥20 kcal/kg/day; this rate increased with the length of ICU stay, regardless of the duration of prone position. In a multivariate analysis of 121 patients who were in the prone position for at least 6 h, the presence of dedicated dietitians in the ICU (OR = 6.91, 95 % CI = 1.98 to 24.1, p < 0.01) was associated with a higher energy delivery. Conversely, the use of muscle relaxants (OR = 0.32, 95 % CI = 0.11 to 0.98, p = 0.04) and presence of nutrition protocols (OR = 0.24, 95 % CI = 0.07 to 0.77, p = 0.02) was associated with a lower energy delivery. CONCLUSIONS: Patients with COVID-19 received adequate nutrition by EN even during prone position. Target EN delivery would be achieved with the introduction of prone position.