Lower Urinary Tract Symptoms in a prospective cohort of COVID-19 survivors

ABSTRACT Purpose: To analyze the prevalence of lower urinary tract symptoms (LUTS) in patients who survived moderate and severe forms of COVID-19 and the risk factors for LUTS six months after hospitalization. Materials and Methods: In this prospective cohort study, patients were evaluated six months after hospitalization due to COVID-19. LUTS were assessed using the International Prostate Symptom Score. General health was assessed through the Hospital Anxiety and Depression Scale and the EQ5D-L5 scale, which evaluates mobility, ability to perform daily activities, pain and discomfort and completed a self-perception health evaluation. Results: Of 255 participants, 54.1% were men and the median age was 57.3 [44.3 - 66.6] years. Pre-existing comorbidities included diabetes (35.7%), hypertension (54.5%), obesity (30.2%) and physical inactivity (65.5%). One hundred and twenty-four patients (48.6%) had a hospital stay >15 days, 181 (71.0%) were admitted to an ICU and 124 (48.6%) needed mechanical ventilation. Median IPSS was 6 [3-11] and did not differ between genders. Moderate to severe LUTS affected 108 (42.4%) patients (40.6% men and 44.4% women; p=0.610). Nocturia (58.4%) and frequency (45.9%) were the most prevalent symptoms and urgency was the only symptom that affected men (29.0%) and women (44.4%) differently (p=0.013). LUTS impacted the quality of life of 60 (23.5%) patients with women more severely affected (p=0.004). Diabetes, hypertension, and self-perception of worse general health were associated with LUTS. Conclusions: LUTS are highly prevalent and bothersome six months after hospitalization due to COVID-19. Assessment of LUTS may help ensure appropriate diagnosis and treatment in these patients.

Electrocardiographic Abnormalities in Nigerian Hypertensives With Echocardiographic Left Ventricular Hypertrophy.

Introduction To enhance the diagnosis of anatomic left ventricular hypertrophy (LVH) using electrocardiography (ECG), we aimed to identify common ECG amplitude and non-amplitude abnormalities in Nigerian patients with hypertensive echocardiographic LVH. Method The study included 1,765 patients with essential hypertension aged 18 years and older from the Federal Medical Centre Abuja Hypertension Registry (FMCAHR). Participants underwent echocardiography and ECG following the American College of Cardiology and the American Society of Echocardiography guidelines. Results The prevalence of overall ECG LVH amplitude criteria (43.8%) and individual criteria of Cornell voltage (27.1%), Sokolow-Lyon voltage (23.2%), and Gubner-Ungerleider (13.9%) were higher than non-amplitude ECG abnormalities among patients with echocardiographic LVH. The sensitivity and specificity of LVH criteria were 43.8% and 79.5% for overall ECG LVH, 23.2% and 87.2% for Sokolow-Lyon voltage, 27.1% and 93.3% for Cornell voltage, and 13.9% and 95.4% for Gubner-Ungerleider criteria, respectively. After multivariable adjustment, non-amplitude ECG changes, including prolonged corrected QT (QTc) (odds ratio (OR): 1.68, 95% confidence interval (CI): 1.06-2.66), left ventricular (LV) strain pattern (OR: 1.83, CI: 1.23-2.72), left axis deviation (OR: 1.56, CI: 1.09-2.24), poor R wave progression (OR: 2.36, CI: 1.40-3.97), premature ventricular contractions (OR: 1.80, CI: 1.10-2.91), premature atrial contractions (OR: 2.06, CI: 1.10-3.87), atrial fibrillation (OR: 2.40, CI: 1.20-4.82), and left atrial abnormality (OR: 8.43, CI: 2.95-24.05), were associated with echocardiographic LVH (p < 0.05). Conclusion In our cohort of hypertensive patients, ECG LVH amplitude criteria were the most frequently observed abnormalities associated with echocardiographic LVH. Our findings suggest that despite the low sensitivity, ECG LVH amplitude criteria may remain valuable in diagnosing echocardiographic LVH.

Direct bandgap quantum wells in hexagonal Silicon Germanium.

Silicon is indisputably the most advanced material for scalable electronics, but it is a poor choice as a light source for photonic applications, due to its indirect band gap. The recently developed hexagonal Si1-xGex semiconductor features a direct bandgap at least for x > 0.65, and the realization of quantum heterostructures would unlock new opportunities for advanced optoelectronic devices based on the SiGe system. Here, we demonstrate the synthesis and characterization of direct bandgap quantum wells realized in the hexagonal Si1-xGex system. Photoluminescence experiments on hex-Ge/Si0.2Ge0.8 quantum wells demonstrate quantum confinement in the hex-Ge segment with type-I band alignment, showing light emission up to room temperature. Moreover, the tuning range of the quantum well emission energy can be extended using hexagonal Si1-xGex/Si1-yGey quantum wells with additional Si in the well. These experimental findings are supported with ab initio bandstructure calculations. A direct bandgap with type-I band alignment is pivotal for the development of novel low-dimensional light emitting devices based on hexagonal Si1-xGex alloys, which have been out of reach for this material system until now.

Helminthiasis and malaria co-infection among women of reproductive age in a rural setting of Kilifi County, coastal Kenya: A mixed method study.

Soil transmitted helminthiasis (STH), Schistosoma haematobium and malaria co-infection lead to increased susceptibility to other infections and poor pregnancy outcomes among women of reproductive age (WRA). This study sought to establish risk factors, burden of co-infection with STH, S. haematobium and Plasmodium sp. among WRA in Kilifi County, Kenya.A mixed method cross-sectional study was conducted on 474 WRA in 2021. Simple random sampling was used to select WRA from four villages in two purposively sampled sub-counties. Study participants were interviewed, and stool samples collected and analysed using Kato-Katz technique for STH. Urine samples were collected for examination of S. haematobium while malaria microscopic test was done using finger prick blood samples. Further, 15 focus group discussions (FGDs) were conducted with purposively selected WRA and qualitative data analyzed thematically using Nvivo software. Quantitative and qualitative methods were triangulated to comprehensively strengthen the study findings. Prevalence of S. haematobium was 22.3% (95%CI: 13.5-36.9), any STH 5.2% (95%CI: 1.9-14.3) and malaria 8.3% (95%: 3.8-18.2). Co-infections between any STH and S. haematobium was 0.8% (95%CI: 0.2-3.2) and between S. haematobium and malaria 0.8% (95%CI: 0.2-3.1). Multivariable analysis showed increased odds of any STH infections among participants in Rabai Sub-County, (aOR = 9.74; p = 0.026), businesswomen (aOR = 5.25; p<0.001), housewives (aOR = 2.78; p = 0.003), and casual laborers (aOR = 27.03; p<0.001). Qualitative analysis showed that the three parasitic diseases were common and responsible for possible causes of low birth weight, susceptibility to other infections and complications such as infertility and cancer later in life.The study demonstrated that STH, S. haematobium and malaria are still a public health problem to WRA. Some of the associated risks of infection were geographical location, socio-economic and WASH factors. Hence the need to implement integrated control efforts of the three parasitic infection.

A comparison of the activity, lysosomal stability, and efficacy of legumain-cleavable and cathepsin cleavable ADC linkers.

1. Over the past two decades antibody-drug conjugates (ADCs) have emerged as a highly effective drug delivery technology. ADCs utilize a monoclonal antibody, a chemical linker, and a therapeutic payload to selectively deliver highly potent pharmaceutical agents to specific cell types.2. Challenges such as premature linker cleavage and clearance due to linker hydrophobicity have adversely impacted the stability and safety of ADCs. While there are various solutions to these challenges, our team has focused on replacement of hydrophobic ValCit linkers (cleaved by CatB) with Asn-containing linkers that are cleaved by lysosomal legumain.3. Legumain is abundantly present in lysosomes and is known to play a role in tumor microenvironment dynamics. Herein, we directly compare the lysosomal cleavage, cytotoxicity, plasma stability, and efficacy of a traditional cathepsin cleavable ADC to a matched Asn-containing legumain-cleavable ADC.4. We demonstrate that Asn-containing linker sequences are specifically cleaved by lysosomal legumain and that Asn-linked MMAE ADCs are broadly active against a variety of tumors, even those with low legumain expression. Finally, we show that AsnAsn-linked ADCs exhibit comparable or improved efficacy to traditional ValCit-linked ADCs. Our study paves the way for replacement of the traditional ValCit linker technology with more hydrophilic Asn-containing peptide linker sequences.

A Cohort Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms: Results from ECOG-ACRIN E1Z11.

PURPOSE: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS. PATIENTS AND METHODS: Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972). RESULTS: Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS. CONCLUSIONS: We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.

Deep learning-assisted smartphone-based quantitative microscopy for label-free peripheral blood smear analysis.

Hematologists evaluate alterations in blood cell enumeration and morphology to confirm peripheral blood smear findings through manual microscopic examination. However, routine peripheral blood smear analysis is both time-consuming and labor-intensive. Here, we propose using smartphone-based autofluorescence microscopy (Smart-AM) for imaging label-free blood smears at subcellular resolution with automatic hematological analysis. Smart-AM enables rapid and label-free visualization of morphological features of normal and abnormal blood cells (including leukocytes, erythrocytes, and thrombocytes). Moreover, assisted with deep-learning algorithms, this technique can automatically detect and classify different leukocytes with high accuracy, and transform the autofluorescence images into virtual Giemsa-stained images which show clear cellular features. The proposed technique is portable, cost-effective, and user-friendly, making it significant for broad point-of-care applications.

Ambiphilicity of ring-expanded N-heterocyclic carbenes.

N-heterocyclic carbenes, such as imidazole-2-ylidenes and imidazolin-2-ylidenes, the popular class of singlet carbenes introduced by Arduengo in 1991 have not been shown to be ambiphilic owing to the two σ-withdrawing, π-donating amino groups flanking the carbene centre. However, our experimental data suggest that ring-expanded N-heterocyclic carbenes (RE-NHCs), especially the seven and eight membered rings, are significantly ambiphilic. Our results also show that the steric environment in RE-NHCs can become a determining factor for controlling the E-H bond activation.

Prospective evaluation of acute neurological events after paediatric cardiac surgery.

OBJECTIVES: Children with CHD are at heightened risk of neurodevelopmental problems; however, the contribution of acute neurological events specifically linked to the perioperative period is unclear. AIMS: This secondary analysis aimed to quantify the incidence of acute neurological events in a UK paediatric cardiac surgery population, identify risk factors, and assess how acute neurological events impacted the early post-operative pathway. METHODS: Post-operative data were collected prospectively on 3090 consecutive cardiac surgeries between October 2015 and June 2017 in 5 centres. The primary outcome of analysis was acute neurological event, with secondary outcomes of 6-month survival and post-operative length of stay. Patient and procedure-related variables were described, and risk factors were statistically explored with logistic regression. RESULTS: Incidence of acute neurological events after paediatric cardiac surgery in our population occurred in 66 of 3090 (2.1%) consecutive cardiac operations. 52 events occurred with other morbidities including renal failure (21), re-operation (20), cardiac arrest (20), and extracorporeal life support (18). Independent risk factors for occurrence of acute neurological events were CHD complexity 1.9 (1.1-3.2), p = 0.025, longer operation times 2.7 (1.6-4.8), p < 0.0001, and urgent surgery 3.4 (1.8-6.3), p < 0.0001. Unadjusted comparison found that acute neurological event was linked to prolonged post-operative hospital stay (median 35 versus 9 days) and poorer 6-month survival (OR 13.0, 95% CI 7.2-23.8). CONCLUSION: Ascertainment of acute neurological events relates to local measurement policies and was rare in our population. The occurrence of acute neurological events remains a suitable post-operative metric to follow for quality assurance purposes.

Lower Urinary Tract Symptoms in a prospective cohort of COVID-19 survivors.

PURPOSE: To analyze the prevalence of lower urinary tract symptoms (LUTS) in patients who survived moderate and severe forms of COVID-19 and the risk factors for LUTS six months after hospitalization. MATERIALS AND METHODS: In this prospective cohort study, patients were evaluated six months after hospitalization due to COVID-19. LUTS were assessed using the International Prostate Symptom Score. General health was assessed through the Hospital Anxiety and Depression Scale and the EQ5D-L5 scale, which evaluates mobility, ability to perform daily activities, pain and discomfort and completed a self-perception health evaluation. RESULTS: Of 255 participants, 54.1% were men and the median age was 57.3 [44.3 - 66.6] years. Pre-existing comorbidities included diabetes (35.7%), hypertension (54.5%), obesity (30.2%) and physical inactivity (65.5%). One hundred and twenty-four patients (48.6%) had a hospital stay >15 days, 181 (71.0%) were admitted to an ICU and 124 (48.6%) needed mechanical ventilation. Median IPSS was 6 [3-11] and did not differ between genders. Moderate to severe LUTS affected 108 (42.4%) patients (40.6% men and 44.4% women; p=0.610). Nocturia (58.4%) and frequency (45.9%) were the most prevalent symptoms and urgency was the only symptom that affected men (29.0%) and women (44.4%) differently (p=0.013). LUTS impacted the quality of life of 60 (23.5%) patients with women more severely affected (p=0.004). Diabetes, hypertension, and self-perception of worse general health were associated with LUTS. CONCLUSIONS: LUTS are highly prevalent and bothersome six months after hospitalization due to COVID-19. Assessment of LUTS may help ensure appropriate diagnosis and treatment in these patients.

Changes in Pulmonary Vascular Resistance and Obstruction Score Following Acute Pulmonary Embolism in Pigs.

OBJECTIVES: To investigate the contribution of mechanical obstruction and pulmonary vasoconstriction to pulmonary vascular resistance (PVR) in acute pulmonary embolism (PE) in pigs. DESIGN: Controlled, animal study. SETTING: Tertiary university hospital, animal research laboratory. SUBJECTS: Female Danish slaughter pigs (n = 12, ~60 kg). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PE was induced by infusion of autologous blood clots in pigs. CT pulmonary angiograms were performed at baseline, after PE (first experimental day [PEd0]) and the following 2 days (second experimental day [PEd1] and third experimental day [PEd2]), and clot burden quantified by a modified Qanadli Obstruction Score. Hemodynamics were evaluated with left and right heart catheterization and systemic invasive pressures each day before, under, and after treatment with the pulmonary vasodilators sildenafil (0.1 mg/kg) and oxygen (Fio2 40%). PE increased PVR (baseline vs. PEd0: 178 ± 54 vs. 526 ± 160 dynes; p < 0.0001) and obstruction score (baseline vs. PEd0: 0% vs. 45% ± 13%; p < 0.0001). PVR decreased toward baseline at day 1 (baseline vs. PEd1: 178 ± 54 vs. 219 ± 48; p = 0.16) and day 2 (baseline vs. PEd2: 178 ± 54 vs. 201 ± 50; p = 0.51). Obstruction score decreased only slightly at day 1 (PEd0 vs. PEd1: 45% ± 12% vs. 43% ± 14%; p = 0.04) and remained elevated throughout the study (PEd1 vs. PEd2: 43% ± 14% vs. 42% ± 17%; p = 0.74). Sildenafil and oxygen in combination decreased PVR at day 0 (-284 ± 154 dynes; p = 0.0064) but had no effects at day 1 (-8 ± 27 dynes; p = 0.4827) or day 2 (-18 ± 32 dynes; p = 0.0923). CONCLUSIONS: Pulmonary vasoconstriction, and not mechanical obstruction, was the predominant cause of increased PVR in acute PE in pigs. PVR rapidly declined over the first 2 days after onset despite a persistent mechanical obstruction of the pulmonary circulation from emboli. The findings suggest that treatment with pulmonary vasodilators might only be effective in the acute phase of PE thereby limiting the window for such therapy.

Low Surface Recombination in Hexagonal SiGe Alloy Nanowires: Implications for SiGe-Based Nanolasers.

Monolithic integration of silicon-based electronics and photonics could open the door toward many opportunities including on-chip optical data communication and large-scale application of light-based sensing devices in healthcare and automotive; by some, it is considered the Holy Grail of silicon photonics. The monolithic integration is, however, severely hampered by the inability of Si to efficiently emit light. Recently, important progress has been made by the demonstration of efficient light emission from direct-bandgap hexagonal SiGe (hex-SiGe) alloy nanowires. For this promising material, realized by employing a nanowire structure, many challenges and open questions remain before a large-scale application can be realized. Considering that for other direct-bandgap materials like GaAs, surface recombination can be a true bottleneck, one of the open questions is the importance of surface recombination for the photoluminescence efficiency of this new material. In this work, temperature-dependent photoluminescence measurements were performed on both hex-Ge and hex-SiGe nanowires with and without surface passivation schemes that have been well documented and proven effective on cubic silicon and germanium to elucidate whether and to what extent the internal quantum efficiency (IQE) of the wires can be improved. Additionally, time-resolved photoluminescence (TRPL) measurements were performed on unpassivated hex-SiGe nanowires as a function of their diameter. The dependence of the surface recombination on the SiGe composition could, however, not be yet addressed given the sample-to-sample variations of the state-of-the-art hex-SiGe nanowires. With the aforementioned experiments, we demonstrate that at room temperature, under high excitation conditions (a few kW cm-2), the hex-(Si)Ge surface is most likely not a bottleneck for efficient radiative emission under relatively high excitation conditions. This is an important asset for future hex(Si)Ge optoelectronic devices, specifically for nanolasers.

Multimethod analysis of large- and low-tapered single file reciprocating instruments: Design, metallurgy, mechanical performance, and irrigation flow.

AIM: To compare eight large- and low-tapered heat-treated reciprocating instruments regarding their design, metallurgy, mechanical properties, and irrigation flow through an in silico model. METHODOLOGY: A total of 472 new 25-mm E-Flex Rex (25/.04 and 25/.06), Excalibur (25/.05), Procodile (25/.06), Reciproc Blue R25 (25/.08v), WaveOne Gold Primary (25/.07v), and Univy Sense (25/.04 and 25/.06) instruments were evaluated regarding their design (stereomicroscopy, scanning electron microscopy, and 3D surface scanning), metallurgy (energy-dispersive X-ray spectroscopy and differential scanning calorimetry), and mechanical performance (cyclic fatigue, torsional resistance, cutting ability, bending and buckling resistance). Computational fluid dynamics assessment was also conducted to determine the irrigation flow pattern, apical pressure, and wall shear stress in simulated canal preparations. Kruskal-Wallis and one-way anova post hoc Tukey tests were used for statistical comparisons (α = 5%). RESULTS: Instruments presented variations in blade numbers, helical angles, and tip designs, with all featuring non-active tips, symmetrical blades, and equiatomic nickel-titanium ratios. Cross-sectional designs exhibited an S-shaped geometry, except for WaveOne Gold. Univy 25/.04 and Reciproc Blue displayed the smallest and largest core diameters at D3. Univy 25/.04 and E-Flex Rec 25/.04 demonstrated the longest time to fracture (p < .05). Reciproc Blue and Univy 25/.04 exhibited the highest and lowest torque to fracture, respectively (p < .05). Univy 25/.04 and Reciproc Blue had the highest rotation angles, whilst E-Flex Rec 25/.06 showed the lowest angle (p < .05). The better cutting ability was observed with E-Flex Rec 25/.06, Procodile, Excalibur, and Reciproc Blue (p > .05). Reciproc R25 and E-Flex Rec showed the highest buckling resistance values (p < .05), with WaveOne Gold being the least flexible instrument. The impact of instruments' size and taper on wall shear stress and apical pressure did not follow a distinct pattern, although Univy 25/.04 and E-Flex Rec 25/.06 yielded the highest and lowest values for both parameters, respectively. CONCLUSIONS: Low-tapered reciprocating instruments exhibit increased flexibility, higher time to fracture, and greater angles of rotation, coupled with reduced maximum bending loads and buckling strength compared to large-tapered instruments. Nevertheless, low-tapered systems also exhibit lower maximum torque to fracture and inferior cutting ability, contributing to a narrower apical canal enlargement that may compromise the penetration of irrigants in that region.

Rapid desensitization through immunoadsorption during cardiopulmonary bypass. A novel method to facilitate human leukocyte antigen incompatible heart transplantation.

BACKGROUND: Anti-human leukocyte antigen (HLA)-antibody production represents a major barrier to heart transplantation, limiting recipient compatibility with potential donors and increasing the risk of complications with poor waiting-list outcomes. Currently there is no consensus to when desensitization should take place, and through what mechanism, meaning that sensitized patients must wait for a compatible donor for many months, if not years. We aimed to determine if intraoperative immunoadsorption could provide a potential desensitization methodology. METHODS: Anti-HLA antibody-containing whole blood was added to a Cardiopulmonary bypass (CPB) circuit set up to mimic a 20 kg patient undergoing heart transplantation. Plasma was separated and diverted to a standalone, secondary immunoadsorption system, with antibody-depleted plasma returned to the CPB circuit. Samples for anti-HLA antibody definition were taken at baseline, when combined with the CPB prime (on bypass), and then every 20 min for the duration of treatment (total 180 min). RESULTS: A reduction in individual allele median fluorescence intensity (MFI) to below clinically relevant levels (<1000 MFI), and in the majority of cases below the lower positive detection limit (<500 MFI), even in alleles with a baseline MFI >4000 was demonstrated. Reduction occurred in all cases within 120 min, demonstrating efficacy in a time period usual for heart transplantation. Flowcytometric crossmatching of suitable pseudo-donor lymphocytes demonstrated a change from T cell and B cell positive channel shifts to negative, demonstrating a reduction in binding capacity. CONCLUSIONS: Intraoperative immunoadsorption in an ex vivo setting demonstrates clinically relevant reductions in anti-HLA antibodies within the normal timeframe for heart transplantation. This method represents a potential desensitization technique that could enable sensitized children to accept a donor organ earlier, even in the presence of donor-specific anti-HLA antibodies.

The association between parental age differences and perinatal outcomes.

STUDY QUESTION: Are there significant associations existing between parental age differences and adverse perinatal outcomes? SUMMARY ANSWER: Large differences in parental age are associated with adverse perinatal outcomes, particularly with older mothers paired with younger fathers. WHAT IS KNOWN ALREADY: The association between advanced maternal age and perinatal outcomes is well-documented with women over 35 years showing an increased risk of several adverse outcomes. Other studies have identified potential associations between advanced paternal age and adverse perinatal outcomes. STUDY DESIGN, SIZE, DURATION: A historical (retrospective) cohort analysis was performed utilizing a multivariable logistic regression model to evaluate the association between varying differences in parental age and adverse perinatal outcomes while controlling for demographic and health-related covariates. Data were compiled from the National Vital Statistics System for 20 613 704 births between 2012 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Parental age differences, categorized into eleven 4-year intervals, were stratified by seven maternal age categories and evaluated for their associations with adverse perinatal outcomes. Main outcome measures included low birth weight, very low birth weight, preterm birth, very preterm birth, small size for gestational age, low 5-min appearance, pulse, grimace, activity, and respiration score, congenital defects, and chromosomal anomalies. MAIN RESULTS AND THE ROLE OF CHANCE: Increased parental age differences, in either direction, were associated with significant risks for all adverse outcomes, aside from congenital defects, even when controlling for maternal age. Restricting maternal age to the reference range of 25-29 years, infants born to fathers aged 9-12 years younger (n = 3773) had 27% (odds ratio (OR) 1.27, 95% CI, 1.17-1.37) higher odds of having any adverse perinatal outcome. Infants born to fathers aged >16 years older (n = 98 555) had 14% (OR 1.14, 95% CI, 1.12-1.16) higher odds of having any adverse perinatal outcome. LIMITATIONS, REASONS FOR CAUTION: Data extracted from US birth certificates may be compromised by errors in reporting or documentation. Information regarding the mother's socioeconomic status was estimated using proxy variables and may be susceptible to uncontrolled factors. Use of a pre-compiled dataset may potentially exclude additional maternal comorbidities that could impact perinatal outcomes. WIDER IMPLICATIONS OF FINDINGS: Older mothers paired with younger fathers demonstrated the highest risk, even when maternal age was below the threshold of 35 years. For the clinical setting, parental age differences should be considered alongside maternal and paternal age when assessing risks of adverse perinatal outcomes for potential parents. This is particularly relevant for older women with younger male partners as this may exacerbate the impact of advanced maternal age. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the NIH Research Fellowship T35 Training Grant. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Average Volume-assured Pressure Support as Rescue Therapy after CPAP Failure in Pediatric Obstructive Sleep Apnea: A Retrospective Case Series Study.

Background: Continuous positive airway pressure (CPAP) is frequently prescribed for patients with residual obstructive sleep apnea (OSA) following adenotonsillectomy. Objectives: The goal was to examine the efficacy of noninvasive ventilation with average volume-assured pressure support (AVAPS) as a potential option for children with failed CPAP titration. Methods: In a single-center retrospective study, we included children aged 1-17 years, with polysomnographically confirmed OSA who underwent AVAPS titration following failed CPAP titration. In addition to describing the clinical characteristics of the included patients, we compared polysomnographic parameters before and after AVAPS. Results: Nine patients met the inclusion criteria; out of them, 8 (89%) were males with an age range of 6.7 ± 3.9 years and a body mass index percentile of 81.0 ± 28.9. Reasons for failed CPAP titration were: 3 (33%) patients due to inability to control apnea-hypopnea index (AHI), 3 (33%) patients due to sleep-related hypoventilation, 2 (22%) patients due to treatment-emergent central sleep apnea, and 1 (11%) patient due to intolerance to CPAP. AVAPS resulted in a greater reduction in AHI than CPAP (reduction following CPAP = 24.6 ± 29.3, reduction following AVAPS = 42.5 ± 37.6, p = 0.008). All patients had resolution of the problems which caused CPAP failure. Conclusion: In this case a series of children with OSA and with failed CPAP titration, AVAPS resulted in a greater reduction in AHI compared with CPAP as well as resolution of the problems which caused CPAP failure.

Patient perspectives on recall period and response options in patient-reported outcome measures for chronic rhinosinusitis symptomatology: An international multi-centered study.

BACKGROUND: Existing patient-reported outcome measures (PROMs) for chronic rhinosinusitis (CRS) use a variety of recall periods and response scales to assess CRS symptom burden. Global perspectives of CRS patients regarding optimal recall periods and response scales for CRS PROMs are unknown. METHODS: This was a multi-center, cross-sectional study recruiting 461 CRS patients from sites across the United States, Saudi Arabia, New Zealand, and Austria. Participants chose which CRS symptom recall period (1 day, 2 weeks, 1 month, >1 month) was most reflective of their current disease state and upon which to best base treatment recommendations (including surgery). Participants also chose which of six response scales (one visual analogue scale and five Likert scales ranging from four to eight items) was easiest to use, understand, and preferred. RESULTS: A plurality of participants (40.0%) felt their CRS symptoms' current state was best reflected by a 1-month recall period. However, most patients (56.9%) preferred treatment recommendations to be determined by symptoms experienced over a >1 month period. The four- and five-item Likert scales were the easiest to understand (26.0% and 25.4%, respectively) and use (23.4% and 26.7%, respectively). The five-item (26.4% rating it most preferred and 70.9% rating it preferred) and four-item Likert (22.3% rating it most preferred and 56.4% rating it preferred) response scales were most preferred. CONCLUSION: Future PROMs for CRS should consider assessment of symptoms over a 1-month period and use a four- or five-item Likert response scale to reflect global patient preferences. These findings also inform interpretation of current CRS PROMs.

Physical compatibility of lipid emulsions and intravenous medications used in neonatal intensive care settings.

OBJECTIVE: The purpose of this study was to investigate the physical compatibility of intravenous lipid emulsions with parenteral medications used in neonatal intensive care. METHODS: Lipid emulsion and drug solutions were combined 1:1 in glass vials, inspected for physical incompatibility at 0, 1 and 2 hours, and assessed on the basis of lipid droplet size at 0 and 2 hours after mixing. Intravenous fluid controls (Water for Injection, sodium chloride 0.9% w/v, glucose 5% w/v), positive controls (gentamicin, albumin), negative controls (metronidazole, paracetamol, vancomycin) and 21 previously untested drug combinations were evaluated. RESULTS: No phase separation, change in colour, gas production or other visible anomaly was observed. The between-run mean droplet diameter (MDD) for SMOFlipid20% alone (0.301±0.008 µm) was comparable to the lipid emulsion/intravenous fluid and lipid emulsion/drug solution combinations. In addition to gentamicin and albumin, caffeine citrate (20 mg/mL) was shown to be incompatible with the lipid emulsion. All other lipid:drug combinations were compatible, based on the MDD data. CONCLUSION: Intravenous lipid emulsions were found to be compatible with 20 parenteral medications, including antimicrobial agents, inotropes, anti-inflammatory drugs and caffeine base, in simulated Y-site conditions. The lipid emulsion was incompatible with caffeine citrate injection.

To flat or not to flat? Exploring the impact of flat-side design on rotary instruments using a comprehensive multimethod investigation.

AIM: To assess the influence of a flat-side design on the geometry, metallurgy, mechanical performance and shaping ability of a novel nickel-titanium rotary instrument. METHODOLOGY: Sixty-five new 25-mm flat-side rotary instruments (size 25, taper 0.04) and their nonflat-side prototypes (n = 65) were assessed for major deformations and examined regarding macroscopic and microscopic design, determination of nickel and titanium elements ratio, measurement of phase transformation temperature and evaluation of mechanical performance parameters including time/cycles to fracture, maximum torque, angle of rotation, maximum bending and buckling strengths and cutting ability. Additionally, unprepared canal areas, volume of hard tissue debris and percentage reduction of dentine thickness were calculated for each tested instrument after preparing mesial canals of mandibular molars (n = 12), using micro-CT imaging. Statistical analyses were performed using the U-Mann-Whitney test and independent Student t-test (α = 5%). RESULTS: The number of spirals (n = 8) and blade direction (clockwise) were similar between both flat and nonflat instruments, whilst the helical angles were equivalent (⁓25°). Flat-instruments showed inconsistencies in the homogeneity of the gold colour on the flat-side surface, blade discontinuity, and incomplete and variable S-shaped cross-sections. The titanium-to-nickel ratios were equivalent, but significant differences in the R-phase finish and austenitic start phase transformation temperatures were observed between the flat and nonflat-side instruments. The flat-side instruments demonstrated superior cutting ability compared to the nonflat instruments, as well as, significantly lower values for time to fracture, rotation to fracture and maximum torque to fracture (p < .001). No statistical difference was observed between tested instruments regarding angle of rotation (p = .437), maximum bending (p = .152) and buckling load (p = .411). Preparation protocols using flat and nonflat instruments did not show any statistically significant differences (p > .05). All flat-side instruments exhibited deformation after shaping procedures. CONCLUSIONS: The flat-side instrument showcased enhanced cutting ability compared to its nonflat counterpart. However, it exhibited inferior performance in terms of time, rotation and maximum torque to fracture, along with distinct phase transformation temperatures. No differences were observed in the titanium-to-nickel ratios, angle of rotation, maximum bending, buckling load, preparation time, percentage of untouched canal walls, volume of hard tissue debris and percentage reduction of dentine thickness.

Synthesis and biological evaluation of novel ß-lactam-metallo ß-lactamase inhibitors.

ß-lactamases are enzymes that deactivate ß-lactam antibiotics through a hydrolysis mechanism. There are two known types of ß-lactamases: serine ß-lactamases (SBLs) and metallo ß-lactamases (MBLs). The two existing strategies to overcome ß-lactamase-mediated resistance are (a) to develop novel ß-lactam antibiotics that are not susceptible to hydrolysis by these enzymes; or (b) to develop ß-lactamase inhibitors that deactivate the enzyme and thereby restore the efficacy of the co-administered antibiotics. Many commercially available SBL inhibitors are used in combination therapy with antibiotics to treat antimicrobial resistant infections; however, there are only a handful of MBL inhibitors undergoing clinical trials. In this study, we present 11 novel potential MBL inhibitors (via multi-step chemical synthesis), that have shown to completely restore the efficacy of meropenem (≤2 mg L-1) against New Delhi metallo-ß-lactamase (NDM) producing Klebsiella pneumoniae in vitro. These compounds contain a cyclic amino acid zinc chelator conjugated to various commercially available ß-lactam antibiotic scaffolds with the aim to improve the overall drug transport, lipophilicity, and pharmacokinetic/pharmacodynamic properties as compared to the chelator alone. Biological evaluation of compounds 24b and 24c has further highlighted the downstream application of these MBLs, since they are non-toxic at the selected doses. Time-kill assays indicate that compounds 24b and 24c exhibit sterilizing activity towards NDM producing Klebsiella pneumoniae in vitro using minimal concentrations of meropenem. Furthermore, 24b and 24c proved to be promising inhibitors of VIM-2 (Ki = 0.85 and 1.87, respectively). This study has revealed a novel series of ß-lactam MBLIs that are potent, efficacious, and safe leads with the potential to develop into therapeutic MBLIs.