The type I CRISPR system has recently emerged as a promising tool, especially for large-scale genomic modification, but its application to generate model animals by editing zygotes had not been established. In this study, we demonstrate genome editing in zygotes using the type I-E CRISPR-Cas3 system, which efficiently generates deletions of several thousand base pairs at targeted loci in mice with 40%-70% editing efficiency without off-target mutations. To overcome the difficulties associated with detecting the variable deletions, we used a newly long-read sequencing-based multiplex genotyping approach. Demonstrating remarkable versatility, our Cas3-based technique was successfully extended to rats as well as mice, even by zygote electroporation methods. Knockin for SNP exchange and genomic replacement with a donor plasmid were also achieved in mice. This pioneering work with the type I CRISPR zygote editing system offers increased flexibility and broader applications in genetic engineering across different species.

Following the European Commission decision to develop a roadmap to phase out animal testing and the signing of the US Modernisation Act, there is additional pressure on regulators and the pharmaceutical industry to abandon animal experimentation in safety testing. Often, endeavours already made by governments, regulators, trade associations, and industry to replace, reduce and refine animal experimentation (3Rs) are unnoticed. Herein, we review such endeavours to promote wider application and acceptance of 3Rs. ICH guidelines have stated 3Rs objectives and have enjoyed many successes driven by global consensus. Initiatives driven by US and European regulators such as the removal of the Abnormal Toxicity Test are neutralised by reticent regional regulators. Stream-lined testing requirements have been proposed for new modalities, oncology, impurity management and animal pharmacokinetics/metabolism. Use of virtual controls, value of the second toxicity species, information sharing and expectations for life-threatening diseases, human specific or well-characterised targets are currently being scrutinised. Despite much effort, progress falls short of the ambitious intent of decisionmakers. From a clinical safety and litigation perspective pharmaceutical companies and regulators are reluctant to step away from current paradigms unless replacement approaches are validated and globally accepted. Such consensus has historically been best achieved through ICH initiatives.

UNASSIGNED: Revision hip and knee total joint arthroplasty (TJA) carries a high burden of postoperative complications, including surgical site infections (SSI), venous thromboembolism (VTE), reoperation, and readmission, which negatively affect postoperative outcomes and patient satisfaction. Socioeconomic area-level composite indices such as the area deprivation index (ADI) are increasingly important measures of social determinants of health (SDoH). This study aims to determine the potential association between ADI and SSI, VTE, reoperation, and readmission occurrence 90 days following revision TJA.
UNASSIGNED: 1047 consecutive revision TJA patients were retrospectively reviewed. Complications, including SSI, VTE, reoperation, and readmission, were combined into one dependent variable. ADI rankings were extracted using residential zip codes and categorized into quartiles. Univariate and multivariate logistic regressions were performed to analyze the association of ADI as an independent factor for complication following revision TJA.
UNASSIGNED: Depression (p = 0.034) and high ASA score (p < 0.001) were associated with higher odds of a combined complication postoperatively on univariate logistic regression. ADI was not associated with the occurrence of any of the complications recorded following surgery (p = 0.092). ASA remained an independent risk factor for developing postoperative complications on multivariate analysis.
UNASSIGNED: An ASA score of 3 or higher was significantly associated with higher odds of developing postoperative complications. Our findings suggest that ADI alone may not be a sufficient tool for predicting postoperative outcomes following revision TJA, and other area-level indices should be further investigated as potential markers of social determinants of health.

BACKGROUND: Chief Executive Officer\'s (CEO) are integral leaders of health care organisation. Over the last two decades in United States (US) hospitals, it has been noted that CEO turnover rates are increasing, and it was reported that the CEO turnover rates have augmented from 14% in 2008 to 18% in 2017 in the private sector. In Australia, it was discovered that during two years, 41 executives had 18 distinct positions. It has been highlighted that the increasing CEO turnover is a major issue for Australian and international health care organisations. Some of the negative consequences of CEO turnover include organisational instability, high financial costs, loss of human capital and adverse effects on staff morale and patient care.
OBJECTIVE: Our scoping review aimed to map and summarise the evidence associated with CEO turnovers in both health and non-health setting, and answer the following questions: 1. What are the reasons for CEO departure?, 2. What are the strategies to minimise CEO turnover?
RESULTS: A protocol explaining the objectives, inclusion criteria and methods for this scoping review were specified in advance and published. This scoping review included 17 studies (13 health and 4 non-health setting) published over a 31-year period that investigated and described the increasing CEO turnover rates. All 17 studies identified causes of CEO turnover along with certain studies identifying facilitators of CEO retention. We classified CEO\'s departure reasons into three major themes: organizational, performance, and personal. Organisational factors include CEO departures due to issues within the organisation, performance factors include issues with CEO\'s work and personal factors captures personal reasons for CEO\'s leaving their job.
CONCLUSIONS: CEOs are under immense pressure to deliver good results and drive growth while satisfying the interests of internal and external stakeholders. There are various reasons for CEO\'s departure however the most common factor identified is organisational.

BACKGROUND: Besides return to work (RTW) and return to sports (RTS), patients also prefer to return to daily activities (RTA) such as walking, sleeping, grocery shopping, and domestic work following total knee arthroplasty (TKA). However, evidence on the timelines and probability of patients\' RTA is sparse.
OBJECTIVE: To assess the percentage of patients able to RTA, RTW, and RTS after TKA, as well as the timeframe and influencing factors of this return.
METHODS: A retrospective cohort study with prospectively collected data was conducted at a medium-sized Dutch orthopedic hospital. Assessments of RTA, RTW, and RTS were performed at 3 mo and/or 6 mo following TKA. Investigated factors encompassed patient characteristics, surgical characteristics, and preoperative patient-reported outcomes.
RESULTS: TKA patients [n = 2063; 66 years old (interquartile range [IQR]: 7 years); 47% male; 28 kg/m2 (IQR: 4 kg/m2)] showed RTA ranging from 28% for kneeling to 94% for grocery shopping, with 20 d (IQR: 27 d) spent for putting on shoes to 74 d (IQR: 57 d) for kneeling. RTW rates varied from 62% for medium-impact work to 87% for low-impact work, taking 33 d (IQR: 29 d) to 78 d (IQR: 55 d). RTS ranged from 48% for medium-impact sports to 90% for low-impact sports, occurring within 43 d (IQR: 24 d) to 90 d (IQR: 60 d). One or more of the investigated factors influenced the return to each of the 14 activities examined, with R² values ranging from 0.013 to 0.127.
CONCLUSIONS: Approximately 80% of patients can RTA, RTW, and RTS within 6 mo after TKA. Return is not consistently influenced by predictive factors. Results help set realistic pre- and postoperative expectations.

We report two cases wherein rotating hinge knee (RHK) arthroplasty was performed for Charcot joints that developed secondary to Charcot-Marie-Tooth disease (CMT).  Case 1 was of a 74-year-old woman with CMT. She presented with muscle weakness and sensory disturbances of the distal lower limbs, deformity, and significant medial instability of the bilateral knees. She was then diagnosed with Charcot joints of the knees secondary to CMT, which were treated with RHK arthroplasty. Five years postoperatively, there was no instability, and she was able to stand unassisted without pain. Case 2 was a 90-year-old woman with CMT who presented with muscle weakness and sensory disturbances of the distal lower limbs, deformity, and significant medial instability of the bilateral knees. She was then diagnosed with Charcot joints of the knees secondary to CMT, which were also treated with RHK arthroplasty. One year postoperatively, there was no instability, and she was able to walk smoothly using a walker. These clinical cases indicate that RHK arthroplasty can be a good therapeutic option for Charcot joints of the knees in patients with CMT.

UNASSIGNED: Cervical cancer is one of the most common gynecological malignancies worldwide. The incidence of cervical cancer ranks second for female malignancies in China. However, human papillomavirus (HPV) prevalence and genotype replacement for a long time in Beijing were not yet evaluated.
UNASSIGNED: Women patients who visited clinical departments, especially the gynecology department, were included in this study from 2014 to 2020. They suffered from different kinds of cervical abnormalities even cervical cancer. Thirteen types of HPV were detected in cervical samples by using multiple fluorescence polymerase chain reactions. All patients were divided into four groups according to age (15-30, 31-45, 46-60, and >60 years old).
UNASSIGNED: The study included data from four certain years (2014, 2016, 2018, and 2020). Overall HPV prevalence was 18.0%, 16.7%, 21.9%, and 19.1%, respectively. Of the 13 genotypes, the top one infection type was HPV52, followed by HPV58 and HPV16 or HPV16 and HPV58 in different years. HPV56 prevalence raised from 2018, which replaced HPV39 into the top five list. Only HPV prevalence of 46-60 years age group declined, mainly resulting from the reduced prevalence of HPV39 and HPV58 (p < 0.001 and p = 0.020). The proportions of HPV dual-infection across the four years varied significantly in statistics (p = 0.001), whereas the most common dual-infection HPV39/68 disappeared after 2018.
UNASSIGNED: The prevalence of two HPV genotypes (HPV39 and HPV58) and dual-infection HPV39/68 showed a declining trend, especially in the 46-60 years age group. The trends need to be observed continuously.

BACKGROUND: A series of interesting literature reports acknowledges the notable loss of essential and non-essential amino acids (EAAs and NEAAs) during hemodialysis sessions. These losses may exceed 800 g/year, thus contributing towards accelerating the onset of malnutrition in hemodialysis patients (HD).
OBJECTIVE: A novel tailored amino acid formula for oral administration was developed to replace total amounts of each individual amino acid lost during dialysis diffusive/convective HD strategies, monitoring the effects produced on nutritional and hematological status.
METHODS: A three-month randomized double-blind study was conducted on 30 subjects over the age of 70 years extrapolated from a total population of 86 hemodialysis patients. The 30 patients were randomly assigned to two groups: a treatment group of 15 HD patients (TG) to whom a novel mixture containing 5.4 g of AAs was administered solely on interdialytic days, and a control group of 15 HD patients (CG) who received no amino acid supplementation. The AAs mixture was administered post-dialysis at an extended interval from the end of solute and compartmental rebound to replace AA losses and optimize their role in protein anabolism.
RESULTS: The results obtained highlighted a significant improvement in protein intake g/kg/day (Protein Catabolic Rate, p = 0.014), and increased IgG (p = 0.008) and C3 serum levels (p = 0.003) in the TG group alone. Fat mass losses were initially confirmed by means of bioelectrical impedance analysis (BIA) (p = 0.011) and plicometry (p < 0.001) in the CG group alone, although the main objective was to preserve nutritional status and, particularly, muscle mass. The study was extended to investigate the effects produced on anemia, yielding evidence of continued positive effects three months after the end of the study in the TG group alone based on an increase in Hb levels from 11.2 ± 0.6 to 12.1 ± 0.6 (p = 0.004) associated with a reduced demand for erythropoietin i.v. from 12928 ± 9033 to 9286 ± 5398 U.I/week (p = 0.012) and iron i.v. from 75.9 ± 55 to 71.4 ± 33.4 mg/week (p = 0.045).
CONCLUSIONS: The results obtained following oral administration of this novel tailored AA replacement mixture aimed at reinstating the high AA losses produced during hemodialysis suggest the mixture should be prescribed as a standard procedure to all HD patients.

The effect of diets with various dietary MUFA content and n-6/n-3 ratios, diets 1 (55.33, 1.00), 2 (25.30, 1.00), 3 (55.13, 2.05), 4 (24.92, 2.03), 5 (54.94, 8.06) and 6 (24.91, 8.06) and a control diet with fish oil (FO), diet 7 (33.60, 5.97), was studied on growth and digestive physiology of rainbow trout, Oncorhynchus mykiss. Juveniles, 14.65 g ± 0.17, were fed the experimental diets for eight weeks. Those fish fed diet 1 (55.33, 1.00) had the lowest growth and nutritional indices, while fish fed diet 6 (24.91, 8.06) possessed the highest indices. However, fish fed D7 (33.60, 5.97) was intermediate in this regard. Proximate body composition results revealed no significant differences among various experimental groups (P > 0.05). Fish fed on diet 1 possessed the highest alkaline protease activity, while fish raised on diet 2 showed the lowest enzyme activity (P < 0.05). Fish fed on diets 1, 3 and 4 had the highest lipase activity (P > 0.05). Amylase activity and intestinal parameters did not differ among groups (P > 0.05). MUFA contents of liver and muscle reflected the MUFA contents of the diets; however, liver PUFA contents was not affected by dietary PUFA contents (P < 0.05). However, 18:3n-3 contents of liver decreased as dietary n-6/n-3 ratio increased (P < 0.05). Furthermore, the liver 20:4n-6 contents considerably increased as dietary n-6/n-3 increased to 8.06 (P < 0.05). Muscle 22:6n-3 content of groups 1 to 6 was lower than group 7 (P < 0.05). In conclusion, rainbow trout was considerably capable of de novo synthesis of 22:6n-3. Meanwhile, increasing dietary n-6/n-3 ratio to 8.06 decreased the muscle 22:6n-3 content which requires further considerations regarding fish immune competence and nutritional quality for human consumption.

BACKGROUND: Total shoulder arthroplasty is performed by orthopedic surgeons with various fellowship training backgrounds. Whether surgeons performing shoulder arthroplasty with different types of fellowship training have differing rates of complications and reoperation remains unknown.
METHODS: The PearlDiver Mariner database was retrospectively queried from the years 2010-2022. Patients undergoing shoulder arthroplasty were selected using the CPT code 23472. Those undergoing revision arthroplasty and those with a history of fracture, infection, or malignancy were excluded. Fellowship was determined and verified via online search. Only surgeons who performed a minimum of 10 cases were selected; and PearlDiver was queried using their provider ID codes. Primary outcome measures included 90-day, 1-year, and 5-year rates of complication and reoperation. A Bonferroni correction was utilized in which the significance threshold was set at p≤0.00023 RESULTS: In total, 150,385 patients met the inclusion criteria and were included in the study. Analysis of surgical trends revealed that Sports Medicine and Shoulder and Elbow fellowship- trained surgeons are performing an increasing percentage of all shoulder arthroplasty over time, with each cohort exhibiting am 11.3% and 4.2% increase from 2010 to 2022, respectively. The geographic region with the highest proportion of cases performed by Sports Medicine surgeons was the West, while the Northeast has the highest proportion of cases performed by Shoulder and Elbow surgeons. Shoulder and Elbow surgeons operated on patients that were significantly younger and had fewer comorbidities. Both Shoulder and Elbow and Sports Medicine surgeons had lower rates of postoperative complications at 90 days, 1 year and 5 years in comparison to surgeons who completed another type of fellowship or no fellowship. Across each time point, the rates of individual complications between Sports Medicine and Shoulder and Elbow were comparable, but the pooled complication rate was lowest in the Shoulder and Elbow cohort.
CONCLUSIONS: Surgeons who have completed either a Sports Medicine or Shoulder and Elbow fellowship are performing an increasing proportion of shoulder arthroplasty over time. Sports Medicine and Shoulder and Elbow-trained surgeons have significantly lower complication rates at 90 days, 1 year and 5 years postoperatively. The individual complication rates between Sports Medicine and Shoulder and Elbow are comparable, but Shoulder and Elbow has the lowest pooled complication rates overall.