Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers.

Lariat ethers are macrocyclic polyethers-crown ethers-to which sidearms are appended. 4,13-Diaza-18-crown-6 having twin alkyl chains at the nitrogens show biological activity. They exhibit antibiotic activity, but when co-administered at with an FDA-approved antibiotic, the latter's potency is often strongly enhanced. Potency enhancements and resistance reversals have been documented in vitro for a range of Gram-negative and Gram-positive bacteria with a variety of antimicrobials. Strains of E. coli and Staphylococcus aureus having resistance to a range of drugs have been studied and the potency enhancements (checkerboards) are reported here. Drugs included in the present study are ampicillin, cefepime, chlortetracycline, ciprofloxacin, doxycycline, kanamycin, minocycline, norfloxacin, oxycycline, penicillin G, and tetracycline. Enhancements of norfloxacin potency against S. aureus 1199B of up to 128-fold were observed. The properties of these lariat ethers have been studied to determine solubility, their membrane penetration, cytotoxicity and mammalian cell survival, and their effect on bacterial efflux pumps. It is shown that in some cases, the lariat ethers have complex antimicrobials with considerable selectivity. Based on these observations, including 1:1 complexation between lariat ethers and antimicrobials and the cytotoxicity of the MeI salts showing a separation index of 32-fold, they hold significant potential for further development.

Critical reagent inventory management system and web portal specifically optimized for supporting external clients.

High-quality critical reagents are essential for the establishment of robust ligand binding assays to support regulated bioanalysis. To ensure consistency in assay performance over the lifetime of a project, a well-defined set of processes is needed for critical reagent life cycle management. Moreover, contract research organizations must support reagent life cycle management for diverse global clients. To address these needs, the authors designed and implemented a customized inventory management system, known as LCM+. This software solution provides external clients with efficient, secure access via a web portal to their critical reagent information, pertinent documentation and inventory tracking. Hence, the authors believe that LCM+ can serve as a useful prototype to aid the design of future inventory management systems for optimal management of critical reagents.

An Eye on Gender Equality: A Review of the Evolving Role and Representation of Women in Ophthalmology.

PURPOSE: In recent decades, women have achieved greater representation in ophthalmology. Globally, women now constitute approximately 25%-30% of ophthalmologists and 35%-45% of trainees. Nevertheless, women remain under-represented in key areas, including positions of professional and academic leadership and ophthalmic surgical subspecialization. Furthermore, there is evidence that women in ophthalmology encounter more bias and discrimination across multiple domains than men, including a gender-pay gap that is wider than in many other surgical subspecialties. Women ophthalmologists and trainees report sharply differing training experiences from male peers, including fewer opportunities to operate, more bullying and harassment, less access to mentorship, and contrasting expectations around contributions to family life. DESIGN: Perspective. METHODS: An extensive literature search was undertaken to compile and review papers published with a focus on gender equity across ophthalmology, surgery, and medicine. RESULTS: We identified 8 broad domains that were widely discussed: leadership, research and academics, income, surgical exposure and subspecialization, harassment, career satisfaction, mentorship, and family and marital differences. We have summarized the current research across each of these areas, and discussed possible solutions to reduce the inequities reported. CONCLUSIONS: This review draws on current research published around representation and experiences of women in ophthalmology and suggests that there are opportunities to improve gender inequity.

Surgical-PEARL protocol: a multicentre prospective cohort study exploring aetiology, management and outcomes for patients with congenital anomalies potentially requiring surgical intervention.

INTRODUCTION: Congenital anomalies affect over 2% of pregnancies. Surgical advances have reduced mortality and improved survival for patients with congenital anomalies potentially requiring surgical (CAPRS) intervention. However, our understanding of aetiology, diagnostic methods, optimal management, outcomes and prognostication is limited. Existing birth cohorts have low numbers of individual heterogenous CAPRS. The Surgical Paediatric congEnital Anomalies Registry with Long term follow-up (Surgical-PEARL) study aims to establish a multicentre prospective fetal, child and biological parent cohort of CAPRS. METHODS AND ANALYSIS: From 2022 to 2027, Surgical-PEARL aims to recruit 2500 patients with CAPRS alongside their biological mothers and fathers from up to 15 UK centres. Recruitment will be antenatal or postnatal dependent on diagnosis timing and presentation to a recruitment site. Routine clinical data including antenatal scans and records, neonatal intensive care unit (NICU) records, diagnostic and surgical data and hospital episode statistics will be collected. A detailed biobank of samples will include: parents' blood and urine samples; amniotic fluid if available; children's blood and urine samples on admission to NICU, perioperatively or if the child has care withdrawn or is transferred for extracorporeal membrane oxygenation; stool samples; and surplus surgical tissue. Parents will complete questionnaires including sociodemographic and health data. Follow-up outcome and questionnaire data will be collected for 5 years. Once established we will explore the potential of comparing findings in Surgical-PEARL to general population cohorts born in the same years and centres. ETHICS AND DISSEMINATION: Ethical and health research authority approvals have been granted (IRAS Project ID: 302251; REC reference number 22/SS/0004). Surgical-PEARL is adopted onto the National Institute for Health Research Clinical Research Network portfolio. Findings will be disseminated widely through peer-reviewed publication, conference presentations and through patient organisations and newsletters. TRIAL REGISTRATION NUMBER: ISRCTN12557586.

Bis(Tryptophan) Amphiphiles Form Ion Conducting Pores and Enhance Antimicrobial Activity against Resistant Bacteria.

The compounds referred to as bis(tryptophan)s (BTs) have shown activity as antimicrobials. The hypothesis that the activity of these novel amphiphiles results from insertion in bilayer membranes and transport of cations is supported by planar bilayer voltage-clamp studies reported herein. In addition, fluorescence studies of propidium iodide penetration of vital bacteria confirmed enhanced permeability. It was also found that BTs having either meta-phenylene or n-dodecylene linkers function as effective adjuvants to enhance the properties of FDA-approved antimicrobials against organisms such as S. aureus. In one example, a BT-mediated synergistic effect enhanced the potency of norfloxacin against S. aureus by 128-fold. In order to determine if related compounds in which tryptophan was replaced by other common amino acids (H2N-Aaa-linker-Aaa-NH2) we active, a family of analogs have been prepared, characterized, and tested as controls for both antimicrobial activity and as adjuvants for other antimicrobials against both Gram-negative and Gram-positive bacteria. The most active of the compounds surveyed remain the bis(tryptophan) derivatives.

Gender differences in surgical case volume among ophthalmology trainees.

BACKGROUND: The number of females in ophthalmology has steadily increased over recent decades. The aim of this study was to evaluate whether there is a difference in procedural volume and cataract surgery between male and female trainees in the Royal Australian and New Zealand College of Ophthalmologists (RANZCO). METHODS: A longitudinal retrospective review of de-identified surgical RANZCO trainee logbook data from 2008 to 2020 was undertaken. Data from 241 trainee logbooks were analysed for: location of training, gender, date of commencement of training, maternity/paternity leave status, number of surgeries observed, assisted, supervised and unsupervised. Surgical cases were grouped as: (1) all surgical cases; (2) complete cataract cases and (3) partial cataract cases. RESULTS: Among 241 trainees (40.7% females), 197 263 procedures were performed. Total surgical volume was 21.1% lower at 4 years for females (median 665.5 vs. 843.5; p = 0.036). Completed cataract surgery was 21.5% lower at 18 months (median 87.5 vs. 111.5; p = 0.022) and 41.7% lower at 4 years (median 216 vs. 369; p < 0.001). Interrupted training was significantly more common in females (30.6% vs. 0.7%; p < 0.001). However, linear regression analysis did not identify parental leave or duration as a significant predictor for number of completed cataracts (p = 0.206). Complication rate was not different between males and females (p = 0.35). CONCLUSIONS: Female trainees completed 41.7% fewer cataract operations at the end of their training compared to male counterparts with the gap widening between years 1 and 4 of training. The current data demonstrates that female and male RANZCO trainees are not receiving equivalent operating experiences.

Early Childhood General Anesthesia and Neurodevelopmental Outcomes in the Avon Longitudinal Study of Parents and Children Birth Cohort.

BACKGROUND: Most common anesthetic agents have been implicated in causing neurodegeneration in the developing animal brain, leading to warnings regarding their use in children. The hypothesis of this study was that exposure to general anesthesia and surgery before 4 yr would associate with adverse neurodevelopmental outcomes at age 7 to 16 yr. METHODS: This cohort study comprised 13,433 children enrolled in the Avon Longitudinal Study of Parents and Children, a prospective, population-based birth cohort born between 1991 and 1993 in southwest England. Children were grouped by none, single, or multiple exposures to general anesthesia and surgery by 4 yr. Motor, cognitive, linguistic, educational, social, and behavioral developmental outcomes were evaluated at 7 to 16 yr using school examination results, validated parent/teacher questionnaires, or clinic assessments. Continuous outcomes were z-scored. P-value thresholds were corrected using false discovery rate procedures. RESULTS: This study compared 46 neurodevelopmental outcomes in 13,433 children: 8.3% (1,110) exposed singly and 1.6% (212) exposed multiply to general anesthesia and surgery. Of these, the following reached predefined levels of statistical significance (corrected P < 0.00652): dynamic balance scores were 0.3 SD (95% CI, 0.1, 0.5; P < 0.001) lower in multiply exposed children; manual dexterity performance was 0.1 SD (95% CI, 0.0, 0.2; P = 0.006) lower in singly and 0.3 SD (95% CI, 0.1, 0.4; P < 0.001) lower in multiply exposed children; and social communication scores were 0.1 SD (95% CI, 0.0, 0.2; P = 0.001) and 0.4 SD (95% CI, 0.3, 0.5; P < 0.001) lower in singly and multiply exposed children, respectively. General anesthesia and surgery were not associated with impairments in the remaining neurodevelopmental measures including: general cognitive ability; attention; working memory; reading, spelling, verbal comprehension and expression; behavioral difficulties; or national English, mathematics, and science assessments (all ≤0.1 SD; corrected P ≥ 0.00652). CONCLUSIONS: Early childhood general anesthesia and surgery were not associated with a global picture of clinically and statistically significant neurodegenerative effects, providing reassurance about the neurotoxic potential of general anesthesia. Exposure to anesthesia and surgery was associated with significantly lower motor and social linguistic performance.

Ocular syphilis in Pacific peoples-are we making misdiagnoses secondary to yaws?

AIMS: To determine the demographic and clinical features of patients with ocular disease consistent with syphilis and positive treponemal serology in Auckland, and to compare patients who lived in a Pacific nation before 1960 with all other patients with regard to these features, considering a possible history of yaws infection. METHODS: Retrospective review of subjects seen in uveitis and neuroophthalmology clinics at Auckland District Health Board between January 2006 and June 2019. RESULTS: Two thousand four hundred and ninety-three subjects were reviewed in uveitis clinics during the timeframe, of whom 45 were diagnosed with syphilitic uveitis (1.8%). Mean age was 56.2±14.8 years and 34 (75.5%) were male. Ethnicity was Caucasian in 16 (35.5%), Pacific peoples in 16 (35.5%), Maori in two (4.4%), Asian in six (13.3%) and other in five (11.1%). Pacific peoples were older at presentation (p=0.001) and 75.0% were aged >60 compared to 24.1% of non-Pacific peoples (p=0.002). Comparing Pacific people born prior to 1960 (aged >60) to the rest of the cohort, older Pacific subjects had lower RPR titres (median 3 vs 32 p=0.004), less optic nerve swelling (0% vs 28.0% eyes p=0.014) and less posterior uveitis (6.25% vs 32.0% eyes p = 0.033). No difference was observed in anterior and intermediate uveitis between the groups. No difference was observed in the resolution or recurrence of inflammation between the groups. CONCLUSION: Syphilitic uveitis is common in New Zealand, occurring in 1 in 55 patients seen in consultant uveitis clinics. Clinicians should consider a history of yaws in Pacific peoples presenting with ocular inflammation and positive treponemal serology. In these cases alternative causes of ocular pathology should be included as differentials. In cases of diagnostic uncertainty, the risk of treatment versus the potentially severe sequelae of untreated syphilis need to be considered.

Assessing Long-term Neurodevelopmental Outcome Following General Anesthesia in Early Childhood: Challenges and Opportunities.

Neurodegeneration has been reported in young animals after exposure to all commonly used general anesthetic agents. The brain may be particularly vulnerable to anesthetic toxicity during peak synaptogenesis (in gestation and infancy). Human studies of long-term neurodevelopmental outcome following general anesthesia in early childhood report contradictory findings. This review assesses the strengths and deficiencies in human research methodologies to inform future studies. We identified 76 studies, published between 1990 and 2017, of long-term neurodevelopmental outcome following early childhood or in utero general anesthesia exposure: 49 retrospective, 9 ambidirectional, 17 prospective cohort studies, and 1 randomized controlled trial. Forty-nine studies were explicitly concerned with anesthetic-induced neurotoxicity. Full texts were appraised for methodological challenges and possible solutions. Major challenges identified included delineating effects of anesthesia from surgery, defining the timing and duration of exposure, selection of a surgical cohort and intervention, addressing multiple confounding life course factors, detecting modest neurotoxic effects with small sample sizes (median, 131 children; interquartile range, 50-372), selection of sensitive neurodevelopmental outcomes at appropriate ages for different developmental domains, insufficient length of follow-up (median age, 6 years; interquartile range, 2-12 years), and sample attrition. We discuss potential solutions to these challenges. Further adequately powered, multicenter, prospective randomized controlled trials of anesthetic-induced neurotoxicity in children are required. However, we believe that the inherent methodological challenges of studying anesthetic-induced neurotoxicity necessitate the parallel use of well-designed observational cohort studies.

Xenon depresses aEEG background voltage activity whilst maintaining cardiovascular stability in sedated healthy newborn pigs.

BACKGROUND: Changes in electroencephalography (EEG) voltage range are used to monitor the depth of anaesthesia, as well as predict outcome after hypoxia-ischaemia in neonates. Xenon is being investigated as a potential neuroprotectant after hypoxic-ischaemic brain injury, but the effect of Xenon on EEG parameters in children or neonates is not known. This study aimed to examine the effect of 50% inhaled Xenon on background amplitude-integrated EEG (aEEG) activity in sedated healthy newborn pigs. METHODS: Five healthy newborn pigs, receiving intravenous fentanyl sedation, were ventilated for 24 h with 50%Xenon, 30%O2 and 20%N2 at normothermia. The upper and lower voltage-range of the aEEG was continuously monitored together with cardiovascular parameters throughout a 1 h baseline period with fentanyl sedation only, followed by 24 h of Xenon administration. RESULTS: The median (IQR) upper and lower aEEG voltage during 1 h baseline was 48.0 µV (46.0-50.0) and 25.0 µV (23.0-26.0), respectively. The median (IQR) aEEG upper and lower voltage ranges were significantly depressed to 21.5 µV (20.0-26.5) and 12.0 µV (12.0-16.5) from 10 min after the onset of 50% Xenon administration (p=0.002). After the initial Xenon induced depression in background aEEG voltage, no further aEEG changes were seen over the following 24h of ventilation with 50% xenon under fentanyl sedation. Mean arterial blood pressure and heart rate remained stable. CONCLUSION: Mean arterial blood pressure and heart rate were not significantly influenced by 24h Xenon ventilation. 50% Xenon rapidly depresses background aEEG voltage to a steady ~50% lower level in sedated healthy newborn pigs. Therefore, care must be taken when interpreting the background voltage in neonates also receiving Xenon.

The effect of resuscitation in 100% oxygen on brain injury in a newborn rat model of severe hypoxic-ischaemic encephalopathy.

AIM: Infants with birth asphyxia frequently require resuscitation. Current guidance is to start newborn resuscitation in 21% oxygen. However, infants with severe hypoxia-ischaemia may require prolonged resuscitation with oxygen. To date, no study has looked at the effect of resuscitation in 100% oxygen following a severe hypoxic-ischaemic insult. METHODS: Postnatal day 7 Wistar rats underwent a severe hypoxic-ischaemic insult (modified Vannucci unilateral brain injury model) followed by immediate resuscitation in either 21% or 100% oxygen for 30 min. Seven days following the insult, negative geotaxis testing was performed in survivors, and the brains were harvested. Relative ipsilateral cortical and hippocampal area loss was assessed histologically. RESULTS: Total area loss in the affected hemisphere and area loss within the hippocampus did not significantly differ between the two groups. The same results were seen for short-term neurological assessment. No difference was seen in weight gain between pups resuscitated in 21% and 100% oxygen. CONCLUSION: Resuscitation in 100% oxygen does not cause a deleterious effect on brain injury following a severe hypoxic-ischaemic insult in a rat model of hypoxia-ischaemia. Further work investigating the effects of resuscitation in 100% oxygen is warranted, especially for newborn infants with severe hypoxic-ischaemic encephalopathy.

The feasibility of using a portable xenon delivery device to permit earlier xenon ventilation with therapeutic cooling of neonates during ambulance retrieval.

BACKGROUND: Therapeutic hypothermia is the standard of care after perinatal asphyxia. Preclinical studies show 50% xenon improves outcome, if started early. METHODS: During a 32-patient study randomized between hypothermia only and hypothermia with xenon, 5 neonates were given xenon during retrieval using a closed-circuit incubator-mounted system. RESULTS: Without xenon availability during retrieval, 50% of eligible infants exceeded the 5-hour treatment window. With the transportable system, 100% were recruited. Xenon delivery lasted 55 to 120 minutes, using 174 mL/h (117.5-193.2) (median [interquartile range]), after circuit priming (1300 mL). CONCLUSIONS: Xenon delivery during ambulance retrieval was feasible, reduced starting delays, and used very little gas.