In vitro activity of cefepime/taniborbactam and comparator agents against Gram-negative bacterial bloodstream pathogens recovered from patients with cancer.

Background: Taniborbactam is a ß-lactamase inhibitor that, when combined with cefepime, may offer a potential treatment option for patients with serious and resistant Gram-negative bacterial (GNB) pathogens. Objectives: This study evaluated in vitro activity of cefepime/taniborbactam and comparator agents against GNB pathogens isolated from patients with cancer at our institution. Methods: A total of 270 GNB pathogens (2019-23) isolated from patients with cancer were tested against cefepime/taniborbactam and comparator agents commonly used for these patients. CLSI-approved broth microdilution methods were used. MIC50, MIC90, MIC range and percentage of susceptibility calculations were made using FDA breakpoints when available. Results: Cefepime/taniborbactam showed highly potent activity against tested Enterobacterales, including isolates producing ESBLs and carbapenem-resistant Enterobacterales. At a provisional breakpoint of ≤16/4 mg/L, cefepime/taniborbactam inhibited most tested species of GNB pathogens, with overall 98.9% susceptibility, which was significantly (P < 0.0001) higher than the susceptibility of the GNB isolates to all other tested comparator agents, ranging from 39.6% for cefepime to 86.3% for ceftazidime/avibactam. Conclusions: Our results showed that taniborbactam in combination with cefepime improved in vitro activity against GNB pathogens isolated from patients with cancer, including MDR Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, ESBL-producing Enterobacterales and Stenotrophomonas maltophilia isolates, with highest activity compared with all tested comparator agents, including other ß-lactam/ß-lactamase inhibitor combinations. Further studies are warranted to explore the efficacy of cefepime/taniborbactam for empirical initial treatment of GNB infections in cancer patients with high rates of febrile neutropenia requiring hospitalization.

Review of allergic reactions from use of chlorhexidine on medical products in clinical settings over 40 years: Risks and mitigations.

Chlorhexidine is an antimicrobial agent widely used for infection prevention in medical settings. Nevertheless, allergic reactions ranging from mild to severe have been reported following its use. In this review, we analyzed all case reports published between the introduction of chlorhexidine and the end of 2019 for allergic responses associated with the use of medical devices and or other medical products containing chlorhexidine (CHX) to ascertain the prevalence of severe CHX allergic reactions and what practices might best mitigate those risks.In total, 77 publications containing 124 reported cases of allergic reactions were grouped into 3 product categories, catheters, semisolids, and fluid products. The country, type of reaction, route of sensitization, allergy confirmation, and intervention or mitigation was extracted for each case. Overall, 30 cases were associated with catheters, 46 cases were associated with semisolid products, and 48 cases were associated with the use of other medical products. Severe cases were managed with intravenous fluids, steroids, and epinephrine (adrenaline). None of the reported cases were fatal. The allergy risks can be mitigated by better warning and training clinicians and by recording and screening patient histories for CHX presensitization from prior exposure. For patients undergoing pre-use blood tests, IgE antibody screens can also be performed. Finally, as a precaution in the event a rare severe allergic reaction occurs, procedure carts and rooms can be prestocked with injectable epinephrine and other rapidly acting anti-inflammatory medications.

Enhanced Biofilm Eradication and Reduced Cytotoxicity of a Novel Polygalacturonic and Caprylic Acid Wound Ointment Compared with Common Antiseptic Ointments.

Antiseptic wound ointments are widely used to treat dermal wounds that are microbially contaminated. Polygalacturonic acid (PG)+caprylic acid (CAP) is a novel combination that has been shown to eradicate biofilms. We developed a novel PG+CAP ointment and compared the biofilm eradication capability and cytotoxicity of PG+CAP with that of commercially available antiseptic wound ointments. We used a well-established biofilm model to quantitatively assess the eradication of organisms following exposure to the wound ointments for 2 hours. PG+CAP ointment completely eradicated Candida albicans, multidrug-resistant Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus biofilms, whereas MediHoney, polyhexamethylene biguanide (PHMB), and benzalkonium chloride (BZK) ointments failed to eradicate all biofilms within 2 hours. We assessed cytotoxicity by exposing L-929 fibroblasts to extracts of each ointment; Trypan blue exclusion was used to assess cell viability, and Alamar blue conversion was used to assess metabolic function. After exposure to PG+CAP and MediHoney, fibroblast viability was 96.23% and 95.23%, respectively (Trypan blue), and was comparable to untreated cells (98.77%). PHMB and BZK showed reduced viability (83.25% and 77.83%, respectively, p < 0.05). Metabolic activity results followed a similar pattern. Cytotoxicity of PG+CAP ointment towards erythrocytes was comparable to saline. PG+CAP ointment seems to be safe and can rapidly eradicate microbial biofilm; thus, PG+CAP ointment merits further in vivo testing as a potential antimicrobial wound ointment.

Predicting birth weight in fetuses with gastroschisis.

OBJECTIVE: To determine the accuracy of commonly utilized ultrasound formulas for estimating birth weight (BW) in fetuses with gastroschisis. STUDY DESIGN: A retrospective review was conducted of all inborn pregnancies with gastroschisis within the five institutions of the University of California Fetal Consortium (UCfC) between 2007 and 2012. Infants delivered at ⩾28 weeks who had an ultrasound within 21 days before delivery were included. Prediction of BW was evaluated for each of the five ultrasound formulas: Hadlock 1 (abdominal circumference (AC), biparietal diameter (BPD), femur length (FL) and head circumference (HC)) and Hadlock 2 (AC, BPD and FL), Shepard (AC and BPD), Honarvar (FL) and Siemer (BPD, occipitofrontal diameter (OFD), and FL) using Pearson's correlation, mean difference and percent error and Bland-Altman analysis. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the ultrasound diagnosis of intrauterine growth restriction (IUGR) were assessed. RESULTS: We identified 191 neonates born with gastroschisis within the UCfC, with 111 neonates meeting the inclusion criteria. The mean gestational age at delivery was 36.3±1.7 weeks and the mean BW was 2448±460 g. Hadlock (1) formula was found to have the best correlation (r=0.81), the lowest mean difference (8±306 g) and the lowest mean percent error (1.4±13%). The Honarvar and Siemer formulas performed significantly worse when compared with Hadlock 1, with a 13.7% (P<0.001) and 3.9% (P=0.03) difference, respectively, between estimated and actual BW. This was supported by Bland-Altman plots. For Hadlock 1 and 2, sensitivity was 80% with a NPV of 91%. CONCLUSION: The widely used Hadlock (1) and (2) formulas provided the best estimated BW in infants with gastroschisis despite its inclusion of abdominal circumference. Furthermore, this formula performs well with diagnosis of IUGR.

The association between interdelivery interval and adverse perinatal outcomes in a diverse US population.

OBJECTIVE: The objective of this study was to investigate the association between interdelivery interval (IDI) and subsequent perinatal outcomes in a large population-based cohort. STUDY DESIGN: Retrospective cohort study of primiparous women with singleton gestations giving birth in the US in 2011 to 2012. IDI was defined as the time between last live birth and index live birth. IDI was categorized as 4 to 17 months, 18 to 36 months (referent), 37 to 60 months and >60 months. Statistical comparisons were made using chi-square tests and multivariable logistic regression models to control for confounding. Covariates included maternal age, prior preterm birth, prior cesarean and medical comorbidities. RESULTS: Of the 1 964 523 women meeting study criteria, 9.0% had an IDI of 4 to 17 months, 39.7% 18 to 36 months, 26.8% 37 to 60 months and 24.5% >60 months. Short IDI was associated with preterm delivery (<37 weeks; 13.8 vs 8.8%, (adjusted odds ratio (aOR) 1.51, 95% confidence interval (CI) 1.48 to 1.53)) and adverse perinatal outcomes including low 5-min Apgar, small for gestational age (SGA) status and neonatal intensive care unit (NICU) admission. Women with long IDI had a higher risk of induction of labor, cesarean delivery, chorioamnionitis, maternal ICU admission, preterm delivery and SGA status, 5-min Apgar score <4, and NICU admission. CONCLUSIONS: Compared with women with 18 to 36 month IDIs, women with either shorter or very long IDIs were at an increased risk of adverse maternal and neonatal outcomes.

Engineering a multimodal nerve conduit for repair of injured peripheral nerve.

Injury to nerve tissue in the peripheral nervous system (PNS) results in long-term impairment of limb function, dysaesthesia and pain, often with associated psychological effects. Whilst minor injuries can be left to regenerate without intervention and short gaps up to 2 cm can be sutured, larger or more severe injuries commonly require autogenous nerve grafts harvested from elsewhere in the body (usually sensory nerves). Functional recovery is often suboptimal and associated with loss of sensation from the tissue innervated by the harvested nerve. The challenges that persist with nerve repair have resulted in development of nerve guides or conduits from non-neural biological tissues and various polymers to improve the prognosis for the repair of damaged nerves in the PNS. This study describes the design and fabrication of a multimodal controlled pore size nerve regeneration conduit using polylactic acid (PLA) and (PLA):poly(lactic-co-glycolic) acid (PLGA) fibers within a neurotrophin-enriched alginate hydrogel. The nerve repair conduit design consists of two types of PLGA fibers selected specifically for promotion of axonal outgrowth and Schwann cell growth (75:25 for axons; 85:15 for Schwann cells). These aligned fibers are contained within the lumen of a knitted PLA sheath coated with electrospun PLA nanofibers to control pore size. The PLGA guidance fibers within the nerve repair conduit lumen are supported within an alginate hydrogel impregnated with neurotrophic factors (NT-3 or BDNF with LIF, SMDF and MGF-1) to provide neuroprotection, stimulation of axonal growth and Schwann cell migration. The conduit was used to promote repair of transected sciatic nerve in rats over a period of 4 weeks. Over this period, it was observed that over-grooming and self-mutilation (autotomy) of the limb implanted with the conduit was significantly reduced in rats implanted with the full-configuration conduit compared to rats implanted with conduits containing only an alginate hydrogel. This indicates return of some feeling to the limb via the fully-configured conduit. Immunohistochemical analysis of the implanted conduits removed from the rats after the four-week implantation period confirmed the presence of myelinated axons within the conduit and distal to the site of implantation, further supporting that the conduit promoted nerve repair over this period of time. This study describes the design considerations and fabrication of a novel multicomponent, multimodal bio-engineered synthetic conduit for peripheral nerve repair.

Pharmacodynamics, pharmacokinetics, and safety of AM211: a novel and potent antagonist of the prostaglandin D2 receptor type 2.

The prostaglandin D(2) receptor type 2 (DP2) and its ligand, PGD(2), have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose-dependent inhibition of eosinophil shape change in blood with near-complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased in a greater-than-dose-proportional manner after single and multiple dosing. After multiple dosing, the exposures on day 7 were higher than on day 1 with accumulation ratio values ranging from 1.4 to 1.5. Mean terminal half-life values ranged from 14 to 25 hours across the dose range of 100 to 600 mg. AM211 was well tolerated at all doses in both the single- and multiple-dose cohorts. These data support additional clinical studies to evaluate AM211 in asthma and other inflammatory diseases.

Atmospheric radionuclides from the Fukushima Dai-ichi nuclear reactor accident observed in Vietnam.

Radionuclides from the reactor accident at the Fukushima Dai-ichi Nuclear Power Plant were observed in the surface air at stations in Hanoi, Dalat, and Ho Chi Minh City (HCMC) in Vietnam, about 4500 km southwest of Japan, during the period from March 27 to April 22, 2011. The maximum activity concentrations in the air measured at those three sites were 193, 33, and 37 µBq m(-3) for (131)I, (13)(4)Cs, and (13)(7)Cs, respectively. Peaks of radionuclide concentrations in the air corresponded to arrival of the air mass from Fukushima to Vietnam after traveling for 8 d over the Pacific Ocean. Cesium-134 was detected with the (134)Cs/(137)Cs activity ratio of about 0.85 in line with observations made elsewhere. The (131)I/(137)Cs activity ratio was observed to decrease exponentially with time as expected from radioactive decay. The ratio at Dalat, where is 1500 m high, was higher than those at Hanoi and HCMC in low lands, indicating the relative enrichment of the iodine in comparison to cesium at high altitudes. The time-integrated surface air concentrations of the Fukushima-derived radionuclides in the Southeast Asia showed exponential decrease with distance from Fukushima.

Differential involvement of striato- and cerebello-thalamo-cortical pathways in tremor- and akinetic/rigid-predominant Parkinson's disease.

Parkinson's disease (PD) presents clinically with varying degrees of resting tremor, rigidity, and bradykinesia. For decades, striatal-thalamo-cortical (STC) dysfunction has been implied in bradykinesia and rigidity, but does not explain resting tremor in PD. To understand the roles of cerebello-thalamo-cortical (CTC) and STC circuits in the pathophysiology of the heterogeneous clinical presentation of PD, we collected functional magnetic resonance imaging (fMRI) data from 17 right-handed PD patients [nine tremor predominant (PDT) and eight akinetic-rigidity predominant (PDAR)] and 14 right-handed controls while they performed internally-guided (IG) sequential finger tapping tasks. The percentage of voxels activated in regions constituting the STC and CTC [divided as cerebellar hemisphere-thalamo-cortical (CHTC) and vermis-thalamo-cortical (CVTC)] circuits was calculated. Multivariate analysis of variance compared the activation patterns of these circuits between study groups. Compared to controls, both PDAR and PDT subjects displayed an overall increase in the percentage of voxels activated in both STC and CTC circuits. These increases reached statistical significance in contralateral STC and CTC circuits for PDT subjects, and in contralateral CTC pathways for PDAR subjects. Comparison of PDAR and PDT subjects revealed significant differences in ipsilateral STC (P=0.005) and CTC (P=0.043 for CHTC and P=0.003 for CVTC) circuits. These data support the differential involvement of STC and CTC circuits in PD subtypes, and help explain the heterogeneous presentation of PD symptoms. These findings underscore the importance of integrating CTC circuits in understanding PD and other disorders of the basal ganglia.

Dynamic changes in cerebello-thalamo-cortical motor circuitry during progression of Parkinson's disease.

Both the basal ganglia and cerebellum are known to influence cortical motor and motor-associated areas via the thalamus. Whereas striato-thalamo-cortical (STC) motor circuit dysfunction has been implicated clearly in Parkinson's disease (PD), the role of the cerebello-thalamo-cortical (CTC) motor circuit has not been well defined. Functional magnetic resonance imaging (fMRI) is a convenient tool for studying the role of the CTC in vivo in PD patients, but large inter-individual differences in fMRI activation patterns require very large numbers of subjects in order to interpret data from cross-sectional, case control studies. To understand the role of the CTC during PD progression, we obtained longitudinal fMRI 2 years apart from 5 PD (57+/-8 yr) and five Controls (57+/-9 yr) performing either externally- (EG) or internally-guided (IG) sequential finger movements. All PD subjects had unilateral motor symptoms at baseline, but developed bilateral symptoms at follow-up. Within-group analyses were performed by comparing fMRI activation patterns between baseline and follow-up scans. Between-group comparisons were made by contrasting fMRI activation patterns generated by the more-affected and less-affected hands of PD subjects with the mean of the dominant and non-dominant hands of Controls. Compared to baseline, Controls showed changes in CTC circuits, but PD subjects had increased recruitment of both cortical motor-associated and cerebellar areas. Compared to Controls, PD subjects demonstrated augmented recruitment of CTC circuits over time that was statistically significant when the IG task was performed by the hand that transitioned from non-symptomatic to symptomatic. This longitudinal fMRI study demonstrates increased recruitment of the CTC motor circuit concomitant with PD progression, suggesting a role of the CTC circuit in accommodation to, or pathophysiology of, PD.

Dietary diversity scores can be improved through the use of portion requirements: an analysis in young Filipino children.

OBJECTIVES: Early childhood malnutrition is a pressing international concern which dietary diversity scores (summary scores of food groups in the diet) may be helpful in addressing. We explored three current research needs surrounding diversity scores: the impact of portion size on score function, the relationship of scores to nutrient adequacy and density and the ability of scores to function as screening tools. SUBJECTS/METHODS: 1810 children, age 24 months. Cross sectional study of a birth cohort. RESULTS: We evaluated two nine food group dietary diversity scores based on 0 and 10 g minimum food group requirements for their relationship to nutrient adequacy and nutrient density. Both scores were significantly correlated with nutrient adequacy and density and predicted statistically significant increases (P<0.05) in the probability of adequacy for all nutrients. However, correlations and predicted increases were somewhat larger for the 10 g score. We also considered the sensitivity and specificity of each score for detecting low and high nutrient adequacy in the population. The 10 g cutoff improved score ability to predict low nutrient adequacy, and reduced the misclassification of subjects for all comparisons. CONCLUSIONS: This research suggests that the score without portion requirements reflects dietary adequacy, but when feasible, further refinement of diversity scores is desirable through the application of minimum portion requirements.

Task specific influences of Parkinson's disease on the striato-thalamo-cortical and cerebello-thalamo-cortical motor circuitries.

The motor deficits in Parkinson's disease (PD) have been primarily associated with internally guided (IG), but not externally guided (EG), tasks. This study investigated the functional mechanisms underlying this phenomenon using genetically-matched twins. Functional magnetic resonance images were obtained from a monozygotic twin pair discordant for clinical PD. Single-photon emission computed tomography neuroimaging using [(123)I](-)-2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane confirmed their disease-discordant status by demonstrating a severe loss of transporter binding in the PD-twin, whereas the non-PD-twin was normal. Six runs of functional magnetic resonance imaging (fMRI) data were acquired from each twin performing EG and IG right-hand finger sequential tasks. The percentage of voxels activated in each of several regions of interest (ROI) was calculated. Multiple analysis of variance was used to compare each twin's activity in ROIs constituting the striato-thalamo-cortical motor circuits [basal ganglia (BG)-cortical circuitry, but including the globus pallidus/putamen, thalamus, supplementary motor area, and primary motor cortex] and cerebello-thalamo-cortical circuits (cerebellar-cortical circuitry, including the cerebellum, thalamus, somatosensory cortex, and lateral premotor cortex). During the EG task, there were no significant differences between the twins in bilateral BG-cortical pathways, either basally or after levodopa, whereas the PD-twin had relatively increased activity in the cerebellar-cortical pathways basally that was normalized by levodopa. During the IG task, the PD-twin had less activation than the non-PD-twin in ROIs of the bilateral BG-cortical and cerebellar-cortical pathways. Levodopa normalized the hypoactivation in the contralateral BG-cortical pathway, but "over-corrected" the activation in the ipsilateral BG-cortical and bilateral cerebellar-cortical pathways. In this first fMRI study of twins discordant for PD, the data support the hypothesis that BG-cortical and cerebellar-cortical pathways are task-specifically influenced by PD. The levodopa-induced "over-activation" of BG-cortical and cerebellar-cortical pathways, and its relevance to both compensatory changes in PD and the long-term effects of levodopa in PD, merit further exploration.

Nonparametric regression estimates with censored data: local linear smoothers and their applications.

For censored time-to-event data, Beran (unpublished manuscript), followed by Doksum and Yandell (1982, Properties of Regression Estimates Based on Censored Survival Data) and Dabrowska (1987, Scandinavian Journal of Statistics 14, 181-197), suggested a nonparametric regression technique based on the kernel method to estimate the conditional survival function. We propose to improve the bias term and boundary effects of their procedure by using local linear fits. This is illustrated in this paper with simulated and real data. Moreover, consistency results for the local linear-based estimates of the conditional survival, cumulative hazard, mean, and median functions are also established.

A general statistical framework for frequency-domain analysis of EEG topographic structure.

A wide variety of rhythmic electrophysiological phenomena--including driven, induced, and endogenous activities of cortical neuronal masses--lend themselves naturally to analysis using frequency--domain techniques applied to multichannel recordings that discretely sample the overall spatial pattern of the rhythmic activity. For such cases, a large but so far poorly utilized body of statistical theory supports a third major approach to topographic analysis, complementing the more familiar mapping and source-recovery techniques. These methods, many of which have only recently become computationally feasible, collectively provide general solutions to the problem of detecting and characterizing systematic differences that arise--not only in the spatial distribution of the activity, but also in its frequency-dependent between-channel covariance structure--as a function of multiple experimental conditions presented in conformity with any of the conventional experimental designs. This application-oriented tutorial review provides a comprehensive outline of these resources, including: (1) real multivariate analysis of single-channel spectral measures (and measures of between-channel relationships such as coherence and phase), (2) complex multivariate analysis based on multichannel Fourier transforms, and (3) complex multivariate analysis based on multichannel parametric models. Special emphasis is placed on the potential of the multichannel autoregressive model to support EEG (and MEG) studies of perceptual and cognitive processes.

Cotinine concentrations in semen, urine, and blood of smokers and nonsmokers.

Cotinine levels in the semen, urine, and blood of 88 male smokers and nonsmokers, aged 18 to 35, were analyzed via radioimmunoassay. Detectable cotinine levels were found in all three body fluids, and cotinine levels in all three fluids were highly correlated. Cotinine levels in semen and blood were of similar magnitude; cotinine levels in urine were an order of magnitude or more higher. In all three fluids, cotinine levels increased with an increase in cigarette smoke exposure.

Sensitivity of exercise electrocardiography for acute cardiac events during moderate and strenuous physical activity. The Lipid Research Clinics Coronary Primary Prevention Trial.

We determined whether the exercise electrocardiogram predicted acute cardiac events during moderate or strenuous physical activity among 3617 asymptomatic, hypercholesterolemic men (age range, 35 to 59 years) who were followed up in the Coronary Primary Prevention Trial. Submaximal exercise test results were obtained at entry and at annual follow-up visits in years 2 through 7. ST-segment depression or elevation (greater than or equal to 1 mm or 10 microV-sec) was considered to be a positive test result. The circumstances that surrounded each nonfatal myocardial infarction and coronary heart disease death were determined through a record review. The cumulative incidence of activity-related acute cardiac events was 2% during a mean follow-up period of 7.4 years. The risk was increased 2.6-fold in the presence of clinically silent, exercise-induced, ST-segment changes at entry (95% confidence interval [Cl], 1.3 to 5.2) after adjustment for 11 other potential risk factors. Of 62 men who experienced an activity-related event, 11 had a positive test result at entry (sensitivity, 18%; 95% Cl, 8 to 27). The specificity of the entry exercise test was 92% (95% Cl, 91 to 93). The sensitivity and specificity were similar when the length of follow-up was restricted to 1 year after testing. For a newly positive test result on a follow-up visit, the sensitivity was 24% (95% Cl, 12 to 36), and the specificity was 85% (95% Cl, 84 to 86); for any positive test result during the study (mean number of tests per subject, 6.2), the sensitivity was 37% (95% Cl, 25 to 49), and the specificity was 79% (95% Cl, 77 to 80). Our findings suggested that the presence of clinically silent, exercise-induced, ischemic ST-segment changes on a submaximal test was associated with an increased risk of activity-related acute cardiac events. However, this test was not sensitive when used to predict the occurrence of activity-related events among asymptomatic, hypercholesterolemic men. For this reason, the utility of the submaximal exercise test to assess the safety of physical activity among asymptomatic men at risk of coronary heart disease is likely to be limited.