Olfactory dysfunction and training in children with COVID-19 infection: A prospective study Post-COVID pediatric olfactory training.

OBJECTIVE: Postviral olfactory dysfunction (OD) including corona 2019 viral disease (COVID-19) OD occurs in both adults and children. Despite limited reports of efficacy in treating adult postviral including COVID-19 OD with olfactory training (OT), its effects on children in general, and post-COVID-19 in specific, is unknown. The study aimed at evaluating the effects of OT in a COVID-19 OD pediatric cohort. METHODS: A single-arm prospective study of pediatric COVID-19 OD subjects confirmed by the University of Pennsylvania Smell Identification Test (UPSIT), was conducted. All subjects underwent OT by sniffing 4 odorants (lavender, orange, peppermint, and eucalyptus) for 1 min twice a day for 3 months. Subjects underwent an odorant identification test (OIT) of the 4 odorants each visit. A repeat UPSIT was administered at the 4th visit. RESULTS: The study enrolled a total of 37 subjects [11 males/26 females with mean age/standard deviation (std) of 15.6(2.1) years]. The time interval between COVID-19 and entry was 5.3(2.4) months. The mean pre/post study UPSIT score improvement was 2.3(4.7), p = .09. OIT scores between entry and 3 subsequent visits showed a mean improvement of 1.8(1.5), 1.8(1.9) and 2.3(1.9) odorants, respectively, with P < .001 for all 3 comparisons. CONCLUSIONS: OT subjects were predominantly female teens with substantial OD lasting greater than 5 months. OT did not affect OD as measured by UPSIT but OIT scores improved during OT. We postulate that OT likely has a role in pediatric post-COVID OD recovery, but UPSIT likely is too rigid to detect disparate odorant improvement.

The Impact of Mental Health Symptoms in Children With Tinnitus and Misophonia: A Multi-disciplinary Approach.

Tinnitus and misophonia are important "sound annoyance" disorders in pediatric otolaryngology and audiology practices. There is scant published literature to suggest increased anxiety and depression symptoms in these disorders. This study aimed at assessing the clinical characteristics of these 2 disorders and their prevalence in mental health-related symptoms in a 2-year retrospective chart review of a multi-disciplinary (otolaryngology, audiology, and psychology) clinic cohort. Analyses were based on 54 (tinnitus = 33 and misophonia = 21) children consisting of 19 males and 35 females with a mean age (standard deviation) of 14.3 (3.0) years. The entire cohort was negatively affected by diagnosis-based symptom severity instruments as assessed by Tinnitus Functional Index and Amsterdam Misophonia Scale. Both subgroups exhibited elevated anxiety and depression symptoms in psychometric instruments as assessed by Screen for Child Anxiety Related Emotional Disorders and Short Mood and Feelings Questionnaire. Evidence-based management of these disorders is lacking, and clinical trials are needed.

Public appreciation of lifestyle risk factors for colorectal cancer and awareness of bowel cancer screening: A cross-sectional study.

INTRODUCTION: Prevention of colorectal cancer (CRC) via reduction of lifestyle risk factors, and participation in bowel screening are two ways in which public engagement could lower mortality from colorectal cancer. This study examined public awareness of lifestyle risk factors and bowel screening, with determination of the factors affecting this. METHODS: A representative population sample (n = 1969) was surveyed using a study specific postal questionnaire to determine demographics, experience of bowel problems, awareness of lifestyle risk factors, knowledge about the incidence of CRC and potential benefits of screening, as well as personal experience of screening. RESULTS: The majority of respondents were aged over 50 (74%). 77% had either personal experience or a relative/friend with experience of a bowel problem. Knowledge of dietary advice was better than risks relating to weight and physical activity. Awareness of lifestyle risk factors was significantly worse in those less than 50 years old (p = 0.0004) and with a lower level of education (p = 0.0021). Awareness of bowel cancer diagnosis was significantly lower in those less than 50 years old (p=<0.0001). The most frequent reason for non-completion of a screening kit was that the process was dirty and unpleasant. CONCLUSION: Initiatives are required to improve awareness of younger people with regard to lifestyle risk factors for CRC, especially since this group stand to benefit most from risk reduction. Those with a lower educational level also had poor awareness but felt that the NHS should not prescribe exercise and lifestyle change; targeting this group would need to take this into account.

Double-blind randomised controlled trial of percutaneous tibial nerve stimulation versus sham electrical stimulation in the treatment of faecal incontinence: CONtrol of Faecal Incontinence using Distal NeuromodulaTion (the CONFIDeNT trial).

BACKGROUND: Faecal incontinence (FI) is a common condition which is often under-reported. It is distressing for those suffering from it, impacting heavily on their quality of life. When conservative strategies fail, treatment options are limited. Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive outpatient treatment, shown in preliminary case series to have significant effectiveness; however, no randomised controlled trial has been conducted. OBJECTIVES: To assess the effectiveness of PTNS compared with sham electrical stimulation in the treatment of patients with FI in whom initial conservative strategies have failed. DESIGN: Multicentre, parallel-arm, double-blind randomised (1 : 1) controlled trial. SETTING: Eighteen UK centres providing specialist nurse-led (or equivalent) treatment for pelvic floor disorders. PARTICIPANTS: Participants aged > 18 years with FI who have failed conservative treatments and whose symptoms are sufficiently severe to merit further intervention. INTERVENTIONS: PTNS was delivered via the Urgent(®) PC device (Uroplasty Limited, Manchester, UK), a hand-held pulse generator unit, with single-use leads and fine-needle electrodes. The needle was inserted near the tibial nerve on the right leg adhering to the manufacturer's protocol (and specialist training). Treatment was for 30 minutes weekly for a duration of 12 treatments. Validated sham stimulation involved insertion of the Urgent PC needle subcutaneously at the same site with electrical stimulation delivered to the distal foot using transcutaneous electrical nerve stimulation. MAIN OUTCOME MEASURES: Outcome measures were assessed at baseline and 2 weeks following treatment. Clinical outcomes were derived from bowel diaries and validated, investigator-administered questionnaires. The primary outcome classified patients as responders or non-responders, with a responder defined as someone having achieved ≥ 50% reduction in weekly faecal incontinence episodes (FIEs). RESULTS: In total, 227 patients were randomised from 373 screened: 115 received PTNS and 112 received sham stimulation. There were 12 trial withdrawals: seven from the PTNS arm and five from the sham arm. Missing data were multiply imputed. For the primary outcome, the proportion of patients achieving a ≥ 50% reduction in weekly FIEs was similar in both arms: 39 in the PTNS arm (38%) compared with 32 in the sham arm (31%) [odds ratio 1.28, 95% confidence interval (CI) 0.72 to 2.28; p = 0.396]. For the secondary outcomes, significantly greater decreases in weekly FIEs were observed in the PTNS arm than in the sham arm (beta -2.3, 95% CI -4.2 to -0.3; p = 0.02), comprising a reduction in urge FIEs (p = 0.02) rather than passive FIEs (p = 0.23). No significant differences were found in the St Mark's Continence Score or any quality-of-life measures. No serious adverse events related to treatment were reported. CONCLUSIONS: PTNS did not show significant clinical benefit over sham electrical stimulation in the treatment of FI based on number of patients who received at least a 50% reduction in weekly FIE. It would be difficult to recommend this therapy for the patient population studied. Further research will concentrate on particular subgroups of patients, for example those with pure urge FI. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88559475. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 77. See the NIHR Journals Library website for further project information.

Maintenance steroid use at 30 days post-transplant and outcomes of pediatric heart transplantation: A propensity matched analysis of the Pediatric Heart Transplant Study database.

BACKGROUND: Maintenance steroid (MS) use in pediatric heart transplantation is variable. The purpose of this study was to evaluate the impact of MS use on graft outcomes. METHODS: All patients <18 years old in the Pediatric Heart Transplant Study database at the time of first heart transplant between 1993 and 2011 who survived ≥30 days post-transplant and were from centers with a protocolized approach to MS use were included (N = 2,178). Patients were grouped by MS use at 30 days post-transplant as MS+ or MS- (no MS use). Propensity score analysis was used to generate matched groups of MS+ and MS- patients based on pre-transplant and peri-transplant factors. Kaplan-Meier survival analysis was used to compare freedom from graft loss, graft loss secondary to rejection, rejection, rejection with severe hemodynamic compromise (RSHC), malignancy, and infection between groups. RESULTS: Of patients, 1,393 (64%) were MS+ and 785 (36%) were MS-. There were 315 MS- patients who had propensity matched MS+ controls. Kaplan-Meier estimates showed no difference in graft loss (p = 0.9) or graft loss secondary to rejection (p = 0.09). At 1 year post-transplant, there was no difference in freedom from rejection (p = 0.15) or malignancy (p = 0.07), but there was lower freedom from RSHC and infection in the MS- group (p = 0.05 and p = 0.02, respectively). CONCLUSIONS: MS use at 30 days post-transplant was not associated with enhanced graft survival after pediatric heart transplant. MS- patients had a higher incidence of RSHC and infection. These risks should be taken into consideration when determining MS use for pediatric recipients of heart transplants.

Outcomes of fetal listed patients awaiting heart transplantation.

HTx in neonates is mainstay therapy for those with severe cardiomyopathies and congenital heart disease. Fetal listing for HTx has been proposed as a way to increase the potential window for a donor with outcomes predicted to be similar to the neonatal population. Data from the PHTS, a prospective multicenter study, were used to examine the outcomes of fetuses listed between 1993 and 2009. Four thousand three hundred and sixty-five children were listed for HTx during this period. Fetuses comprised 1% and neonates 19.8% of listed patients. In those patients listed as fetus and transplanted, the median wait time from listing to HTx was 55 days (range 4-255), with a median of 25 days (range 0-233) after birth. By six months post-listing, a higher proportion of fetal listed patients had undergone HTx with a lower waitlist mortality when compared with neonate. There was no significant difference in survival following HTx between the two group (p = 0.4). While the results of this study may be less applicable to current practice due to changes in referrals for fetal listing, they do indicate that fetal listing can be a reasonable option. These results are of particular interest at the present time given the ongoing public discourse on the proposed elimination of fetal listing within UNOS.

Concentration-resistance relationships with Pseudomonas aeruginosa exposed to doripenem and ciprofloxacin in an in vitro model.

OBJECTIVES: To compare the abilities of doripenem and ciprofloxacin to restrict the enrichment of resistant Pseudomonas aeruginosa, multiple antibiotic dosing regimens were simulated in an in vitro model at comparable ratios of the 24 h AUC (AUC24) to the MIC. METHODS: Three clinical isolates of ciprofloxacin-resistant P. aeruginosa (MIC of doripenem 1 mg/L, MIC of ciprofloxacin 4 mg/L) were exposed to thrice-daily doripenem or twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios from 50 to 170 h (doripenem) and from 55 to 180 h (ciprofloxacin). RESULTS: Doripenem- and ciprofloxacin-resistant mutants were enriched at antibiotic concentrations that fell into the mutant selection window for ≥ 45% and ≥ 60% of the dosing interval, respectively. The anti-mutant effects of doripenem and ciprofloxacin expressed by the area under the bacterial mutant concentration-time curve (AUBCM) depended on the AUC24/MIC ratio, and the AUBCM-log AUC24/MIC relationships were antibiotic specific. CONCLUSION: Based on AUC24/MIC relationships with AUBCM, a greater anti-mutant potential was predicted for doripenem compared with ciprofloxacin.

Comparative pharmacodynamics and antimutant potentials of doripenem and imipenem with ciprofloxacin-resistant Pseudomonas aeruginosa in an in vitro model.

To compare the antipseudomonal efficacy of doripenem and imipenem as well as their abilities to restrict the enrichment of resistant Pseudomonas aeruginosa, multiple-dosing regimens of each drug were simulated at comparable values of the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (T(>MIC)) and ratios of the 24-hour area under the curve (AUC(24)) to the MIC. Three clinical isolates of ciprofloxacin-resistant P. aeruginosa (MIC of doripenem, 1 µg/ml; MICs of imipenem, 1, 2, and 2 µg/ml) were exposed to thrice-daily doripenem or imipenem for 3 days at AUC(24)/MIC ratios of from 50 to 170 h (doripenem) and from 30 to 140 h (imipenem). The antimicrobial effects for susceptible and resistant subpopulations of bacteria were expressed by the areas between control growth and time-kill curves (I(E)s) and areas under the bacterial mutant concentration curves (AUBC(M)s), respectively. With each antibiotic, the I(E) and AUBC(M) versus log AUC(24)/MIC relationships were bacterial strain independent. At similar AUC(24)/MIC ratios, doripenem was slightly less efficient than imipenem against susceptible and resistant subpopulations of bacteria. However, doripenem appeared to be somewhat more efficient than imipenem at clinically achievable AUC(24)s related to the means of the MICs for the three studied strains and had higher antimutant potentials for two of the three strains.

Selection of linezolid-resistant Enterococcus faecium in an in vitro dynamic model: protective effect of doxycycline.

OBJECTIVES: To relate the enrichment of linezolid-resistant Enterococcus faecium with linezolid pharmacokinetics, the pharmacodynamics of linezolid and its ability to prevent the selection of resistant mutants were studied in an in vitro model that simulates antibiotic concentrations in and out of the mutant selection window (MSW), i.e. the concentration range from the MIC to the mutant prevention concentration (MPC). METHODS: A clinical isolate of E. faecium (MIC 1.8 mg/L and MPC 7 mg/L) at a starting inoculum of 8 log cfu/mL was exposed to twice-daily linezolid, alone and in combination with once-daily doxycycline (MIC 0.2 mg/L and MPC 3.4 mg/L), for 3 consecutive days in a hollow-fibre two-compartment model. RESULTS: The ratios of 24 h area under the curve (AUC24) to MIC of linezolid were estimated at 70, 100 and 230 h and those of doxycycline were estimated at 230 and 720 h. At the two lower AUC24/MIC ratios of linezolid given alone, E. faecium resistant to 2 x MIC-16 x MIC and 2 x MIC-8 x MIC of linezolid, respectively, were selectively enriched with a concomitant slight loss in susceptibility. Neither growth on linezolid-containing media nor changes in susceptibility occurred at the high AUC24/MIC ratio. A similar protective effect was observed with the minimal AUC24/MIC ratio of linezolid (70 h) combined with doxycycline at an AUC24/MIC of 230 h. CONCLUSIONS: This study suggests that selection of linezolid-resistant enterococci can be predicted from the MSW concept and can be prevented by linezolid given in combination with doxycycline, each at suboptimal AUC24/MIC ratios.

Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrations inside and outside the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing.

OBJECTIVES: According to the mutant selection window (MSW) hypothesis, resistant mutants are selected or enriched at antibiotic concentrations above the MIC but below the mutant prevention concentration (MPC). To test this hypothesis, Streptococcus pneumoniae ATCC 49619 (MIC 0.1 mg/L; MPC 0.5 mg/L) was exposed to moxifloxacin concentrations below the MIC, above the MPC and between the MIC and MPC, i.e. within the MSW. METHODS: Daily administration of moxifloxacin for 3 consecutive days was mimicked using a two-compartment dynamic model with peripheral units containing a starting inoculum of 10(8) cfu/mL S. pneumoniae. Changes in susceptibility were examined by repeated MIC determinations and by plating the specimens on agar containing zero, 2 x MIC, 4 x MIC and 8 x MIC of moxifloxacin. RESULTS: Both in terms of the MIC and resistance frequency, S. pneumoniae resistance developed at concentrations that fell inside the MSW [ratios of 24 h area under the curve (AUC24) to MIC between 24 and 47 h]. A Gaussian-like function fitted the AUC24/MIC-dependent increases in MIC and resistance frequency with central points at AUC24/MICs of 38 and 42 h, respectively, where resistant mutants are enriched selectively. Selective enrichment of resistant mutants was not seen at AUC24/MICs <10 h or >100 h. CONCLUSIONS: These data suggest that AUC24/MICs >100 h may protect against the selection of resistant S. pneumoniae mutants. Since the usual 400 mg dose of moxifloxacin provides much higher AUC24/MIC (270 h), it is expected to prevent mutant selection at clinically achievable concentrations. Also, these data provide further support for the MSW hypothesis.

The antibacterial effects of ciprofloxacin and trovafloxacin against Streptococcus pneumoniae in an in vitro dynamic model.

OBJECTIVE: To determine whether the newer fluoroquinolone antibiotics such as trovafloxacin posses enhanced activity against Gram-positive organisms, including Streptococcus pneumoniae, because the clinical activity of older quinolones against pneumococci has been questioned. METHODS: In this study, the bactericidal activities of ciprofloxacin and trovafloxacin against six strains of penicillin-resistant and -sensitive strains of Streptococcus pneumoniae were compared using an in vitro model that simulates human pharmacokinetics. Ciprofloxacin was administered at 750 mg every 12 h, higher than the usual daily dose of 500 mg twice a day. Trovafloxacin was administered at 300 mg every 24 h for the six strains and at 200 mg every 24 h for three of the strains. RESULTS: The single 300-mg dose of trovafloxacin killed five of the six strains in 4 h, with no bacterial regrowth. Ciprofloxacin reduced the initial inoculum by 3--5 logs by 24 h. Although the 300-mg dose of trovafloxacin more rapidly eradicated susceptible strains, the activity of trovafloxacin at 200 mg every 24 h was similar to that of ciprofloxacin at 750 mg every 12 h against the three strains tested. CONCLUSION: Trovafloxacin (and ciprofloxacin at high doses) eradicates susceptible strains of pneumococci in an in vitro dynamic model.

In-vitro interaction of azithromycin and fluoroquinolones against gram-positive and gram-negative bacteria.

OBJECTIVE: To determine the combined in-vitro effects of azithromycin plus the fluoroquinolone ofloxacin or lomefloxacin against gram-positive and gram-negative bacteria. METHODS: Fractional inhibitory (FIC) and fractional bactericidal concentration indices of azithromycin and the fluoroquinolone were determined using a microtiter-checkerboard method. Clinical isolates of Staphylococcus aureus, Streptococcus pneumoniae, Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Pseudomonas cepacia, Haemophilus influenzae, Xanthomonas maltophilia and Acinetobacter calcoaceticus were studied. Fourteen strains of S. aureus were also studied in time-kill curves with azithromycin (4 mg/L), lomefloxacin (6 mg/L) and the two in combination. RESULTS: No synergism or antagonism was found in inhibitory assays. However, bactericidal assays revealed antagonism with some strains of S. aureus, S. pneumoniae, X. maltophilia, A. calcoaceticus, P. aeruginosa, P. cepacia, K. pneumoniae and E. coli. Kill-curve results with 14 strains of S. aureus showed no antagonism with four strains of methicillin-resistant S. aureus (MRSA), and antagonism with one strain of MRSA and seven methicillin-susceptible S. aureus (MSSA). CONCLUSIONS: In-vitro exposure to combinations of azithromycin and a fluoroquinolone does not produce a synergistic effect. Antagonism was found in bactericidal assays against some gram-negative bacteria and MSSA; caution is therefore recommended in the use of macrolides and quinolones against these organisms.