Genomic landscape of TCRαß and TCRγδ T-large granular lymphocyte leukemia.

Large granular lymphocyte (LGL) leukemia comprises a group of rare lymphoproliferative disorders whose molecular landscape is incompletely defined. We leveraged paired whole-exome and transcriptome sequencing in the largest LGL leukemia cohort to date, which included 105 patients (93 T-cell receptor αß [TCRαß] T-LGL and 12 TCRγδ T-LGL). Seventy-six mutations were observed in 3 or more patients in the cohort, and out of those, STAT3, KMT2D, PIK3R1, TTN, EYS, and SULF1 mutations were shared between both subtypes. We identified ARHGAP25, ABCC9, PCDHA11, SULF1, SLC6A15, DDX59, DNMT3A, FAS, KDM6A, KMT2D, PIK3R1, STAT3, STAT5B, TET2, and TNFAIP3 as recurrently mutated putative drivers using an unbiased driver analysis approach leveraging our whole-exome cohort. Hotspot mutations in STAT3, PIK3R1, and FAS were detected, whereas truncating mutations in epigenetic modifying enzymes such as KMT2D and TET2 were observed. Moreover, STAT3 mutations co-occurred with mutations in chromatin and epigenetic modifying genes, especially KMT2D and SETD1B (P < .01 and P < .05, respectively). STAT3 was mutated in 50.5% of the patients. Most common Y640F STAT3 mutation was associated with lower absolute neutrophil count values, and N647I mutation was associated with lower hemoglobin values. Somatic activating mutations (Q160P, D170Y, L287F) in the STAT3 coiled-coil domain were characterized. STAT3-mutant patients exhibited increased mutational burden and enrichment of a mutational signature associated with increased spontaneous deamination of 5-methylcytosine. Finally, gene expression analysis revealed enrichment of interferon-γ signaling and decreased phosphatidylinositol 3-kinase-Akt signaling for STAT3-mutant patients. These findings highlight the clinical and molecular heterogeneity of this rare disorder.

The impact of tubular dysfunction and its relationship with acute kidney injury in children.

BACKGROUND: Tubular dysfunction can cause electrolyte disturbances with potentially serious consequences. We studied the epidemiology and outcomes of electrolyte disturbances and tubular dysfunction among critically ill children and evaluated their relationships with acute kidney injury (AKI). METHODS: We conducted a prospective cohort study recruiting children aged 1 month to ≤ 18 years old admitted to the pediatric intensive care unit (PICU) from 6/2020 to 6/2021. The serum levels of sodium, potassium, calcium, phosphate, and magnesium were reviewed and simultaneous urinary investigations for tubular function were performed among children with electrolyte disturbances. RESULTS: Altogether there were 253 episodes of admission. The median (interquartile) age was 4.9 (1.3-11.0) years and 58.1% were male. The median number of electrolyte disorders was 3 (2-4) types. Hypophosphatemia (74.2%), hypocalcemia (70.3%) and hypermagnesemia (52.9%) were the three commonest types of disturbances. Urinary electrolyte wasting was commonly observed among children with hypomagnesemia (70.6%), hypophosphatemia (67.4%) and hypokalemia (28.6%). Tubular dysfunction was detected in 82.6% of patients and urinary ß2-microglobulin level significantly correlated with the severity of tubular dysfunction (p < 0.001). The development of tubular dysfunction was independent of AKI status. Tubular dysfunction was associated with mortality (p < 0.001) and was an independent predictor of PICU length of stay (LOS) (p < 0.001). The incorporation of the tubular dysfunction severity into the AKI staging system improved the prediction of PICU LOS. CONCLUSIONS: Tubular dysfunction was associated with both morbidity and mortality in critically ill children and its assessment may help to capture a more comprehensive picture of acute kidney insult.

A Longitudinal Assessment of a Physician Performance Enhancement Program Using Health Data, to Improve Quality of Care and Facilitate Lifelong Learning.

The Personal Quality Index (PQI) provides individual annual reports of benchmarked clinical data to inform practice development. This 5-year longitudinal retrospective study of PQI performance indicators also surveyed department members (n = 104) on utility, using t test, and Wilcoxon test. Technicity increased from 59% in 2014 to 72% in 2018 (P < 0.001). The vaginal birth after cesarean delivery rate did not improve, but the combined forceps/vacuum delivery rate decreased for sites and physicians (P < 0.001). Survey response was 35%. Most physicians (62%) found it valuable, and it informed professional development in 23% of cases. Nevertheless, 42% did not trust the data, and 39% found the process provoked anxiety.

Quality of Life Associated with Nausea and Vomiting from Anthracycline-Based Chemotherapy: A Pooled Data Analysis from Three Prospective Trials.

BACKGROUND: There is limited work on the impact of chemotherapy-induced nausea and vomiting (CINV) on quality of life (QoL) in adriamycin-cyclophosphamide (AC)-treated patients with breast cancer. The objectives of the study were the following: (a) to confirm if symptoms of CINV led to lower QoL during AC; (b) to evaluate the pattern of changes in patients' QoL during multiple cycles of AC; and (c) to assess if the QoL in an earlier cycle affected the QoL in subsequent cycles of AC. MATERIALS AND METHODS: This is a secondary pooled data analysis that included 303 Chinese patients with breast cancer who received 1,177 cycles of adjuvant AC in three prospective antiemetic studies. QoL data were based on Functional Living Index-emesis (FLIE) scored over three to four AC cycles. CINV symptoms assessed included "no significant nausea" (NSN), "significant nausea" (SN), "no vomiting" (NoV), "vomiting" (V), and complete response (CR). RESULTS: Across all AC cycles, the mean scores for the FLIE nausea domain for patients who experienced NSN versus SN were 10.92 versus 53.92, respectively (p < .0001), with lower scores indicating better QoL; the mean scores for the FLIE vomiting domain for patients who experienced NoV versus V were 1.44 versus 19.11, respectively (p < .0001), with similar results across subsequent cycles. Analysis of the effect of the QoL in cycle 1 on the QoL of subsequent cycles revealed the following: for the nausea domain, among patients who had cycle 1 FLIE scores ≥ versus < the mean, the corresponding scores in cycle 2 were 6.87 versus 36.71 (p < .0001); whereas those for cycle 3 were 7.07 versus 36.87 (p < .0001); and those for cycle 4 were 5.92 versus 21.48 (p < .0001). Similar findings were observed for the vomiting domain. Netupitant + palonosetron- or aprepitant/olanzapine-based antiemetics had significantly better QoL outcomes. CONCLUSION: CINV had a significant impact on the QoL of patients with breast cancer treated with AC over multiple cycles. IMPLICATIONS FOR PRACTICE: In this post-hoc analysis of three prospective studies on chemotherapy-induced nausea and vomiting (CINV), quality of life (QoL) using contemporary antiemetic regimens in Chinese breast cancer patients receiving doxorubicin-cyclophosphamide (AC) was evaluated. During the first and subsequent AC cycles, QoL was significantly better for patients who did not experience vomiting or significant nausea. QoL in an earlier cycle affected the QoL in subsequent AC cycles. Furthermore, recent regimens involving olanzapine/aprepitant or netupitant-palonosetron were associated with a positive impact in QoL. Antiemetic guideline-consistent practice and higher clinician awareness of the impact of CINV on QoL can further mitigate the negative effects of CINV on QoL.

Lysozyme Deposition on Contact Lenses in an In Vitro Blink-Simulation Eye Model Versus a Static Vial Deposition Model.

PURPOSE: To evaluate active lysozyme deposition on daily disposable (DD) contact lenses (CL) using a novel in vitro blink model. METHODS: Three conventional hydrogel DD CL materials (etafilcon A, omafilcon A, nelfilcon A) and three silicone hydrogel DD CL materials (delefilcon A, senofilcon A, somofilcon A) were tested. The device blink rate was set to 6 blinks/min with a tear flow rate of 1 µL/min using an artificial tear solution (ATS) containing lysozyme and other typical tear film components. After incubation at 2, 4, or 8 hr, lenses were removed, and lysozyme activity was measured. A separate experiment was conducted with lenses incubated in a static vial containing 480 µL of ATS. RESULTS: Etafilcon A deposited significantly higher amounts of active lysozyme (402±102 µg/lens) than other lens materials after 8 hr (P<0.0001). Etafilcon A had a higher amount of active lysozyme using the blink model compared with the static vial (P=0.0435), whereas somofilcon A (P=0.0076) and senofilcon A (P=0.0019) had a higher amount of lysozyme activity in the vial compared with the blink model. CONCLUSION: The blink model can be tuned to provide quantitative data that closely mimics ex vivo studies and can be used to model deposition of lysozyme on CL materials.

Uptake and Release of a Multipurpose Solution Biocide (MAP-D) From Hydrogel and Silicone Hydrogel Contact Lenses Using a Radiolabel Methodology.

PURPOSE: The purpose of this study was to evaluate the uptake and release of radiolabelled myristamidopropyl dimethylamine (MAP-D) on reusable daily wear contact lenses (CLs) over 7 days. METHODS: Three silicone hydrogel (SH) CL materials (lotrafilcon B, balafilcon A, senofilcon A) and two conventional hydrogel (CH) materials (etafilcon A, omafilcon A) were tested. A short-term (experiment 1, N=4) and a longer-term (experiment 2, N=3) study was conducted. In experiment 1, the CLs were incubated in 2 mL of phosphate buffered solution (PBS) containing 14C MAP-D (5 µg/mL) for 8 hrs. The release of 14C MAP-D was measured at t=0.25, 0.5, 1, 2, 4, 8, and 24 hr in PBS. In experiment 2, the CLs were incubated in the 14C MAP-D solution for 8 hrs followed by a 16-hr release in PBS. This cycle was repeated daily for 7 days. At the end of both experiments, lenses were extracted to determine the total uptake of MAP-D. The radioactivity was measured using a beta scintillation counter. RESULTS: In experiment 1, all three SH lenses sorbed similar amounts of MAP-D (P=0.99), all of which were higher than the two CH materials (P<0.01). However, the CH materials released a greater amount of MAP-D than the SH materials (P<0.01). In experiment 2, the uptake of MAP-D in SH materials increased over 7 days, whereas the amount of MAP-D remained constant in the CH materials (P=0.99). Similar to experiment 1, the CH lenses released more MAP-D than SH lenses after 7 days (P<0.01). CONCLUSION: The SH materials absorbed greater amounts of MAP-D compared to CH materials. However, the CH materials released the greatest amount of MAP-D. Radioactive labelling of MAP-D offers a highly sensitive method of assessing the uptake and release profiles of biocides to CL materials.

Reducing the Volume of Low-Value Outpatient MRI Joint Examinations in Patients ≥55 Years of Age.

PURPOSE: Magnetic resonance imaging (MRI) is not beneficial in patients with joint pain and concomitant osteoarthritis (OA). We attempt to determine whether evaluation of OA via X-rays can reduce inappropriate MRI and computed tomography (CT) arthrogram use. In our jurisdiction, CT arthrograms are used as surrogate tests because of MRI wait times. MATERIALS AND METHODS: Our intervention required patients ≥55 years of age scheduled for outpatient MRI of the knee/hip/shoulder at an urban hospital to have X-rays (weight bearing when appropriate) from within 1 year. Red flags (ie, neoplasm, infection) were identified for which MRI would be indicated regardless. Through review of radiographs on picture archiving and communication system/digital media and use of the validated Kellgren-Lawrence (KL) OA scale, radiologists assessed the presence and degree of OA. A finding of significant OA (KL > 2) without red flags would preclude MRI. Monthly averages of MRI and CT arthrogram examinations were measured 33 months before and 23 months following introduction of the intervention. RESULTS: The proportion of protocoled MRI requisitions that were avoided was 21%. If extrapolated to the province of British Columbia, 2419 of 11 700 examinations could have been prevented in the past year. The average monthly number of knee/hip/shoulder MRI examinations as a percentage of total MRI examinations decreased from 4.9% to 4.3% (P < .02) following the intervention. The average monthly number of knee/hip/shoulder CT arthrogram examinations decreased from 20.6 to 12.1 (P < .0001). CONCLUSION: We were able to decrease the number of MRI and CT arthrogram examinations in patients ≥55 years of age with joint pain by implementing an evaluation for OA via recent X-ray imaging.

Exploratory study on the relationship between smoking and other risk behaviours among young smokers.

AIMS AND OBJECTIVES: To explore the relationship between smoking and other risk behaviours among Chinese young people in Hong Kong. BACKGROUND: There is growing concern about coexisting risk behaviours in young smokers. Information about smoking and other risk behaviours is crucial for developing interventions to promote smoking abstinence and adoption of healthy lifestyles. The relationship between smoking and other risk behaviours among Chinese young people in Hong Kong has not been explored. DESIGN: This is a mixed-method retrospective population-based study. METHODS: A retrospective population-based study was conducted with 1,147 young smokers through Youth Quitline between November 2011-July 2016. Attitudes, behaviours and experiences related to smoking and risk behaviours among Chinese young smokers were examined in semi-structured qualitative interviews with 30 participants randomly selected from the retrospective population-based study. RESULTS: In total, 45.5% participants reported engaging in at least one other risk behaviour. The interviews revealed that drinking alcohol may have a significant impact on quitting smoking. In addition, smoking may be a gateway for more serious risk behaviours during adolescence. Low health awareness may explain the unhealthy lifestyles among young smokers. CONCLUSIONS: This study bridges a gap in existing literature by exploring relationships between smoking and other risk behaviours among young people in Hong Kong. RELEVANCE TO CLINICAL PRACTICE: Given the interrelationships between smoking and other risk behaviours, a holistic approach should be used to promote smoking cessation and healthy lifestyles among young smokers. If young smokers improve their health and quit smoking at the same time, their physical and mental development will benefit as a secondary outcome.

Video Education on Hereditary Breast and Ovarian Cancer (HBOC) for Physicians: an Interventional Study.

The National Comprehensive Cancer Network (NCCN) guidelines are the gold standard in hereditary cancer risk assessment, screening, and treatment. A minority of physicians follow NCCN guidelines for BRCA1 or BRCA2 mutations. This study assesses the impact of an interventional educational program on HBOC in terms of knowledge. Physicians were sent an invite to join either an intervention survey (web-training offered prior to the knowledge survey) or control survey (web-training offered after the knowledge survey). Sixty-nine physicians in the intervention arm and 67 physicians in the control arm completed the survey. The interventional group regularly answered items correctly at a higher frequency than the control group. For example, 64.71% (n = 44) of physicians in the intervention group knew that multi-gene testing does not have to include only highly penetrant genes compared to 32.84% (n = 22) of the control group (p < 0.01). Similar results were seen with other specific survey items. The current study is important in that it shows web-based education to be a feasible and effective modality for training on hereditary breast cancer. This type of education may be incorporated into CME programs and can be used as a foundation for further studies as well.

A three-miRNA signature as promising non-invasive diagnostic marker for gastric cancer.

BACKGROUND: Despite the declining incidence of gastric cancer, mortality rate remains high due to late presentation. We aimed to evaluate the sensitivity of miRNA as a diagnostic marker for gastric cancer in the circulation. METHODS: Plasma samples from 3 independent groups comprise 123 gastric cancer patients and 111 healthy controls for miRNA profiling from microarray screening. RESULTS: Microarray data showed that 25 miRNAs were upregulated in gastric cancer patients and 6 highly expressed miRNAs (miR-18a, miR-140-5p, miR-199a-3p, miR-627, miR-629 and miR-652) were selected for validation. In an independent validation set, levels of miR-627, miR-629 and miR-652 were significantly higher in gastric cancer patients than healthy controls (P <0.0001). An algorithm with improved sensitivity and specificity as gastric cancer classifier was adopted and validated in another random set of 15 plasma samples. Results showed that combination of 3 miRNAs obtained the highest area under curve, with a cut-off at 0.373, with a sensitivity of 86.7% and a specificity of 85.5%. CONCLUSION: This study revealed a three-miRNA signature as a promising classifier for gastric cancer, and greatly enhances the feasibility of circulating miRNAs as non-invasive diagnostic marker for this disease.

'Let's talk about sex' - A Knowledge, Attitudes and Practice study among Paediatric Nurses about Teen Sexual Health in Hong Kong.

AIMS AND OBJECTIVES: To explore the knowledge, attitudes and practices of paediatric nurses in Hong Kong towards adolescent sexual health issues. BACKGROUND: In Hong Kong, teens are becoming more sexually permissive. As a result, early sexual activity, Sexually transmitted diseases (STD) and unplanned pregnancies among adolescents are increasing. Paediatric nurses are potentially excellent sexual health educators; however, studies in other countries have reported that nurses have inadequate knowledge and skills about sexual health. Little is known about the knowledge, attitudes and practices of nurses in Hong Kong related to teen sexual health. DESIGN: This is a cross-sectional survey study. The survey was developed after an extensive literature review and partially adapted from previously validated questionnaires on nursing needs, knowledge, attitude and practice. METHODS: An anonymous self-administered questionnaire in Chinese was distributed to 500 nurses in Hong Kong attending a local paediatric conference. Participants (n = 394) were recruited using convenience sampling methods. Survey data were analysed using descriptive statistics, correlation tests and logistic regression analyses. RESULTS: The majority of nurses had a high awareness of the importance of sexual healthcare, but rarely felt knowledgeable or comfortable discussing sexual health issues with adolescents. Higher comfort level was associated with higher frequency of practice with an average adjusted odds ratios of 2·64. Inadequate or lack of training (39·4%) was the most significant barrier in providing adolescent sexual health screening and counselling. CONCLUSION: Nurses' clinical practices towards adolescent's sexual health issues were influenced by their perceived comfort level followed by their self-ranked knowledge and training experience. Further specific training on communication, counselling and general sexual health should be provided to nurses in Hong Kong. RELEVANCE TO CLINICAL PRACTICE: Nurses' comfort level was the most important factor influencing their clinical practice with teens. Further specific training should be provided to nurses in Hong Kong to improve adolescent sexual health.

Physician Risk Assessment Knowledge Regarding BRCA Genetics Testing.

The study aim was to evaluate the association between genetics referrals, training in medical school, residency, or continuing medical education and physician knowledge of hereditary breast and ovarian cancer (HBOC). A survey of 55 questions was administered to 140 physicians evaluating knowledge and practice patterns regarding HBOC. Physicians with genetics training during residency were more likely to recognize that most instances of ovarian cancer are not hereditary (odds ratio (OR) = 3.16; 95 % confidence interval (CI) 1.32, 7.58). Physicians with continuing medical education (CME) training on genetics were more likely to identify that screening can be improved for those with a hereditary mutation (OR = 4.28; 95 % CI 1.32, 13.90). Primary care physicians who frequently referred for genetics were more likely to recognize that maternal history is not more important than paternal history (OR = 2.51; 95 % CI 1.11, 5.66), that screening can be improved for those with hereditary risk (OR = 4.06; 95 % CI 1.08, 15.22), and that females with a hereditary breast cancer risk would have different recommendations for screening than someone without this risk (OR = 4.91; 95 % CI 1.04, 23.25). Our data suggest that training and frequency of genetics referrals may be associated with knowledge of general risk assessment for HBOC.

Trainees' Self-Reported Challenges in Knowledge Translation, Research and Practice.

BACKGROUND: Knowledge translation (KT) refers to the process of moving evidence into healthcare policy and practice. Understanding the experiences and perspectives of individuals who develop careers in KT is important for designing training programs and opportunities to enhance capacity in KT research and practice. To date, however, limited research has explored the challenges that trainees encounter as they develop their careers in KT. AIMS: The purpose of this study is to identify the challenges that KT trainees face in their KT research or practice. METHODS: An online survey was conducted with a sample of trainees associated with the Knowledge Translation Trainee Collaborative or the KT Canada Summer Institutes, with written responses thematically analyzed. FINDINGS: A total of 35 individual responses were analyzed, resulting in the identification of six interrelated themes, listed in descending order of prevalence: limited availability of KT-specific resources (54%), difficulty inherent in investigating KT (34%), KT not recognized as a distinct field (23%), colleagues' limited knowledge and understanding of KT (20%), competing priorities and limited time (20%), and difficulties in relation to collaboration (14%). DISCUSSION: KT trainees experience specific challenges in their work: limited understanding of KT in other stakeholder groups; limited structures or infrastructure to support those who do KT; the inherently interdisciplinary and applied nature of KT; and the resultant complexities of scientific inquiry in this field, such as designing and testing multifaceted, multilevel implementation strategies and accounting for contextual factors. LINKING EVIDENCE TO ACTION: KT training and capacity-building efforts are needed to better position health systems to routinely adopt knowledge into healthcare policy and practice.

The Knowledge Exchange-Decision Support Model: application to cancer navigation programs.

PURPOSE: The Knowledge Exchange-Decision Support (KE-DS) Model provides a framework outlining essential components of knowledge generation and exchange. The purpose of this research was to illustrate how the Model makes explicit the different contextual aspects implicit in the planning and implementation of two cancer navigation programs in Canada. METHODS: The KE-DS Model guided the collection and analysis of interviews with program personnel and narrative data. A qualitative thematic analysis was conducted wherein we compared and contrasted the planning and implementation of these two navigation programs. RESULTS: The planning and implementation of these two programs was conceptualized differently and adapted to meet local contingencies. The KE-DS Model highlighted three factors that influenced program delivery. First, the structure of health services was shaped by the interaction of professionals and services operating in the region, and the existing health services influenced the program's approach to navigation. Second, while there were similarities in the professional roles and responsibilities of the navigators, these roles and responsibilities also reflected local context in their approaches to patient assessment, referral, education, coordination of services, and advocacy. Third, these two distinct approaches to navigation have responded to the needs of diverse populations being served by improving access to care. CONCLUSIONS: Evidence generated using the KE-DS Model could ensure a more robust and structured approach to the planning and implementation of future navigation programs. The Model prompts users to make explicit the different types of evidence utilized during program planning and implementation. The systematic collection of new information on program implementation using the KE-DS Model in future initiatives will contribute to an improved understanding of the science of knowledge exchange.

Outcomes of Mastectomy and Immediate Reconstruction Managed with Closed-incision Negative Pressure Therapy Applied Over the Whole Breast.

Background: Incision healing after mastectomy and immediate reconstruction can be supported with closed-incision negative pressure therapy (ciNPT). Studies have reported patients receiving postoperative care with ciNPT after breast surgery exhibited lower rates of dehiscence, infection, necrosis, and seroma, compared with standard dressings. A recent approach to ciNPT involves the application of negative pressure to the incision and a wider area of surrounding tissue. In this retrospective review, we investigated the outcomes of ciNPT using full-coverage dressings over the entire breast after mastectomy and reconstruction. Methods: Patients underwent mastectomies and immediate prepectoral breast reconstruction with an implant or tissue expander. After surgery, patients received oral antibiotics and ciNPT with full-coverage foam dressings at -125 mm Hg. Results: All 54 patients (N = 105 incisions) were women, with a mean age of 53.5 years and 29.1 kg per m2 body mass index. Common comorbidities included prior chemotherapy (31.3%) or radiation (21.6%), hypertension (14.8%), and diabetes (5.6%). Procedures included skin-reducing (34.3%), skin-sparing (7.6%), and nipple-sparing (58.1%) mastectomies. Lymph nodes were removed in 38 (36.2%) incisions. All patients were discharged home with ciNPT on postoperative day (POD) 1, and ciNPT was discontinued on POD 5-7. At POD 30, three patients developed seromas, requiring revision. Of these, one required removal of the left tissue expander. The remaining 102 incisions (97.1%) healed without complication. Conclusions: Among this cohort, the use of ciNPT with full-dressing coverage of the breast incisions and surrounding soft tissue was effective in supporting incisional healing after mastectomy and immediate reconstruction.

Invasive fungal infections in critically ill children: epidemiology, risk factors and antifungal drugs.

Background: Invasive fungal infections (IFIs) are important infectious complications amongst critically ill children. The most common fungal infections are due to Candida species. Aspergillus, Zygomycetes and Fusarium are also emerging because of the empirical use of antifungal drugs. This updated review discusses the epidemiology of IFIs as well as antifungal drugs, dosing and potential adverse effects in critically ill children. Methods: A PubMed search was conducted with Clinical Queries using the key terms "antifungal", "children", "critical care" AND "paediatric intensive care unit" OR "PICU". The search strategy included clinical trials, randomized controlled trials, meta-analyses, observational studies and reviews and was limited to the English literature in paediatrics. Results: Candida and Aspergillus spp. are the most prevalent fungi in paediatric IFIs, causing invasive candidiasis infections (ICIs) and invasive aspergillosis infections (IAIs), respectively. These IFIs are associated with high morbidity, mortality and healthcare costs. Candida albicans is the principal Candida spp. associated with paediatric ICIs. The risks and epidemiology for IFIs vary if considering previously healthy children treated in the paediatric intensive care unit or children with leukaemia, malignancy or a severe haematological disease. The mortality rate for IAIs in children is 2.5-3.5-fold higher than for ICIs. Four major classes of antifungals for critically ill children are azoles, polyenes, antifungal antimetabolites and echinocandins. Conclusions: Antifungal agents are highly efficacious. For successful treatment outcomes, it is crucial to determine the optimal dosage, monitor pharmacokinetics parameters and adverse effects, and individualized therapeutic monitoring. Despite potent antifungal medications, ICIs and IAIs continue to be serious infections with high mortality rates. Pre-emptive therapy has been used for IAIs. Most guidelines recommend voriconazole as initial therapy of invasive aspergillosis in most patients, with consideration of combination therapy with voriconazole plus an echinocandin in selected patients with severe disease. The challenge is to identify critically ill patients at high risks of ICIs for targeted prophylaxis. Intravenous/per os fluconazole is first-line pre-emptive treatment for Candida spp. whereas intravenous micafungin or intravenous liposomal amphotericin B is alternative pre-emptive treatment.This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.

Pattern and prognostic factors for kidney function progression in survivors of children with acute kidney injury: a cohort study.

OBJECTIVE: To examine the pattern of kidney function progression after acute kidney injury (AKI) and identify the associated risk factors. DESIGN: A prospective cohort study was conducted from June 2020 to June 2021 on children aged 1 month to <18 years admitted to the paediatric intensive care unit (PICU). Acute kidney disease (AKD) was defined as AKI persisting from 7 to 90 days after diagnosis. The natural history and prognostic factors of kidney function progression were determined. RESULTS: Among the 253 admissions with a median (IQR) age of 4.9 (9.7) years, the AKI and AKD incidence was 41.9% and 52.2% respectively. The incidence of estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2 was 6.7% at 90 days and 11.9% at latest follow-up. Severe and prolonged AKI and higher degree of nephrotoxic medication exposure were associated with AKD development. The severity and duration of AKI and AKD significantly predicted kidney function non-recovery. Children with both entities exhibited a higher peak-to-baseline serum creatinine level ratio at 90 days (1.6 vs 1.0, p<0.001), and a more pronounced decline in eGFR (21% vs 19%, p=0.028) during the follow-up period compared with those without AKI/AKD. They also had an increased risk of having eGFR <90 mL/min/1.73 m2 at 90 days (HR 14.9 (95% CI 1.8 to 124.0)) and latest follow-up (HR 3.8 (95% CI 1.1 to 13.1)). CONCLUSIONS: AKI and AKD are prevalent among critically ill children and pose substantial risk for non-recovery of kidney function among PICU survivors. A structural follow-up visit for AKI survivors to monitor kidney function progression is advocated.

Evaluating the in vitro wettability and coefficient of friction of a novel and contemporary reusable silicone hydrogel contact lens materials using an in vitro blink model.

PURPOSE: To evaluate the in vitro wettability and coefficient of friction of a novel amphiphilic polymeric surfactant (APS), poly(oxyethylene)-co-poly(oxybutylene) (PEO-PBO) releasing silicone hydrogel (SiHy) contact lens material (serafilcon A), compared to other reusable SiHy lens materials. METHODS: The release of fluorescently-labelled nitrobenzoxadiazole (NBD)-PEO-PBO was evaluated from serafilcon A over 7 days in a vial. The wettability and coefficient of friction of serafilcon A and three contemporary SiHy contact lens materials (senofilcon A; samfilcon A; comfilcon A) were evaluated using an in vitro blink model over their recommended wearing period; t = 0, 1, 7, 14 days for all lens types and t = 30 days for samfilcon A and comfilcon A (n = 4). Sessile drop contact angles were determined and in vitro non-invasive keratographic break-up time (NIKBUT) measurements were assessed on a blink model via the OCULUS Keratograph 5 M. The coefficient of friction was measured using a nano tribometer. RESULTS: The relative fluorescence of NBD-PEO-PBO decreased in serafilcon A by approximately 18 % after 7 days. The amount of NBD-PEO-PBO released on day 7 was 50 % less than the amount released on day 1 (6.5±1.0 vs 3.4±0.5 µg/lens). The reduction in PEO-PBO in the lens also coincided with an increase in contact angles for serafilcon A after 7 days (p < 0.05), although there were no changes in NIKBUT or coefficient of friction (p > 0.05). The other contact lens materials had stable contact angles and NIKBUT over their recommended wearing period (p > 0.05), with the exception of samfilcon A, which had an increase in contact angle after 14 days as compared to t = 0 (p < 0.05). Senofilcon A and samfilcon A also showed an increase in coefficient of friction at 14 and 30 days, respectively, compared to their blister pack values (p < 0.05). CONCLUSION: The results indicate that serafilcon A gradually depletes its reserve of PEO-PBO over 1 week, but this decrease did not significantly change the lens performance in vitro during this time frame.

A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression.

Fetal hemoglobin (HbF) is regulated as a multigenic trait. By genome-wide association study, we confirmed that HBS1L-MYB intergenic polymorphisms (HMIP) and BCL11A polymorphisms are highly associated with HbF in Chinese ß-thalassemia heterozygotes. In this population, the variance in HbF resulting from the HMIP is 13.5%; that resulting from the BCL11A polymorphism is 6.4%. To identify the functional variant in HMIP, we used 1000 Genomes Project data, single nucleotide polymorphism imputation, comparisons of association results across populations, potential transcription factor binding sites, and analysis of phylogenetic conservation. Based on these studies, a hitherto unreported association between HbF expression and a 3-bp deletion, between 135 460 326 and 135 460 328 bp on chromosome 6q23 was found. This 3-bp deletion is in complete linkage disequilibrium with rs9399137, which is the single nucleotide polymorphism in HMIP most significantly associated with HbF among Chinese, Europeans, and Africans. Chromatin immunoprecipitation assays confirmed erythropoiesis-related transcription factors binding to this region in K562 cells. Based on transient expression of a luciferase reporter plasmid, the DNA fragment encompassing the 3-bp deletion polymorphism has enhancer-like activity that is further augmented by the introduction of the 3-bp deletion. This 3-bp deletion polymorphism is probably the most significant functional motif accounting for HMIP modulation of HbF in all 3 populations.

An RNA degradosome assembly in Caulobacter crescentus.

In many bacterial species, the multi-enzyme RNA degradosome assembly makes key contributions to RNA metabolism. Powering the turnover of RNA and the processing of structural precursors, the RNA degradosome has differential activities on a spectrum of transcripts and contributes to gene regulation at a global level. Here, we report the isolation and characterization of an RNA degradosome assembly from the α-proteobacterium Caulobacter crescentus, which is a model organism for studying morphological development and cell-cycle progression. The principal components of the C. crescentus degradosome are the endoribonuclease RNase E, the exoribonuclease polynucleotide phosphorylase (PNPase), a DEAD-box RNA helicase and the Krebs cycle enzyme aconitase. PNPase and aconitase associate with specific segments in the C-terminal domain of RNase E that are predicted to have structural propensity. These recognition 'microdomains' punctuate structurally an extensive region that is otherwise predicted to be natively disordered. Finally, we observe that the abundance of RNase E varies through the cell cycle, with maxima at morphological differentiation and cell division. This variation may contribute to the program of gene expression during cell division.