Epidemiological and clinical insights into the enterovirus D68 upsurge in Europe 2021/22 and the emergence of novel B3-derived lineages, ENPEN multicentre study.

Enterovirus D68 (EV-D68) infections are associated with severe respiratory disease and acute flaccid myelitis (AFM). The European Non-Polio Enterovirus Network (ENPEN) aimed to investigate the epidemiological and genetic characteristics of EV-D68 and its clinical impact during the fall-winter season of 2021/22. From 19 European countries, 58 institutes reported 10,481 (6.8%) EV-positive samples of which 1,004 (9.6%) were identified as EV-D68 (852 respiratory samples). Clinical data was reported for 969 cases. 78.9% of infections were reported in children (0-5 years); 37.9% of cases were hospitalised. Acute respiratory distress was commonly noted (93.1%) followed by fever (49.4%). Neurological problems were observed in 6.4% of cases with six reported with AFM. Phylodynamic/Nextstrain and phylogenetic analyses based on 694 sequences showed the emergence of two novel B3-derived lineages, with no regional clustering. In conclusion, we describe a large-scale EV-D68 European upsurge with severe clinical impact and the emergence of B3-derived lineages.

Influence of phosphate on bacterial release from activated carbon point-of-use filters and on biofilm characteristics.

Point-of-use (POU) filters certified to remove lead are often composed of activated carbon and have been shown to release high concentrations of bacteria, including opportunistic pathogens. In this study, we examine the impacts of the common corrosion inhibitor phosphate on biofilm characteristics and the relationship between biofilm structure and bacterial release from POU filters. This knowledge is essential for understanding how best to use the filters and where these filters fit in a system where other lead contamination prevention measures may be in place. We measured the bacterial release from activated carbon POU filters fed with groundwater - a common source of drinking water - with and without phosphate. We used optical coherence tomography (OCT) to quantitatively characterize biofilm growing on activated carbon filter material in which the biofilms were fed groundwater with and without phosphate. Phosphate filters released significantly less (57-87 %) bacteria than groundwater filters, and phosphate biofilms (median thickness: 82-331 µm) grew to be significantly thicker than groundwater biofilms (median thickness: 122-221 µm). The phosphate biofilm roughness ranged from 97 to 142 % of the groundwater biofilm roughness and was significantly greater in most weeks. Phosphate biofilms also had fewer pores per biofilm volume and shorter channels connecting those pores.

Effects of phosphate and silicate on stiffness and viscoelasticity of mature biofilms developed with simulated drinking water.

Biofilms, a porous matrix of cells aggregated with extracellular polymeric substances under the influence of chemical constituents in the feed water, can develop a viscoelastic response to mechanical stresses. In this study, the roles of phosphate and silicate, common additives in corrosion control and meat processing, on the stiffness, viscoelasticity, porous structure networks, and chemical properties of biofilm were investigated. Three-year biofilms on PVC coupons were grown from sand-filtered groundwater with or without one of the non-nutrient (silicate) or nutrient additives (phosphate or phosphate blends). Compared with non-nutrient additives, the phosphate and phosphate-blend additives led to a biofilm with the lowest stiffness, most viscoelastic, and more porous structure, including more connecting throats with greater equivalent radii. The phosphate-based additives also led to more organic species in the biofilm matrix than the silicate additive did. This work demonstrated that nutrient additives could promote biomass accumulation but also reduce mechanical stability.

Human parainfluenza 2 & 4: Clinical and genetic epidemiology in the UK, 2013-2017, reveals distinct disease features and co-circulating genomic subtypes.

BACKGROUND: Human Parainfluenza viruses (HPIV) comprise of four members of the genetically distinct genera of Respirovirus (HPIV1&3) and Orthorubulavirus (HPIV2&4), causing significant upper and lower respiratory tract infections worldwide, particularly in children. However, despite frequent molecular diagnosis, they are frequently considered collectively or with HPIV4 overlooked entirely. We therefore investigated clinical and viral epidemiological distinctions of the relatively less prevalent Orthorubulaviruses HPIV2&4 at a regional UK hospital across four autumn/winter epidemic seasons. METHODS: A retrospective audit of clinical features of all HPIV2 or HPIV4 RT-PCR-positive patients, diagnosed between 1st September 2013 and 12th April 2017 was undertaken, alongside sequencing of viral genome fragments in a representative subset of samples. RESULTS: Infection was observed across all age groups, but predominantly in children under nine and adults over 40, with almost twice as many HPIV4 as HPIV2 cases. Fever, abnormal haematology, elevated C-reactive protein and hospital admission were more frequently seen in HPIV2 than HPIV4 infection. Each of the four seasonal peaks of either HPIV2, HPIV4 or both, closely matched that of RSV, occurring in November and December and preceding that of Influenza A. A subset of viruses were partially sequenced, indicating co-circulation of multiple subtypes of both HPIV2&4, but with little variation between each epidemic season or from limited global reference sequences. CONCLUSIONS: Despite being closest known genetic relatives, our data indicates a potential difference in associated disease between HPIV2 and HPIV4, with more hospitalisation seen in HPIV2 mono-infected individuals, but a greater overall number of HPIV4 cases.

Enterovirus D68 epidemic, UK, 2018, was caused by subclades B3 and D1, predominantly in children and adults, respectively, with both subclades exhibiting extensive genetic diversity.

Enterovirus D68 (EV-D68) has recently been identified in biennial epidemics coinciding with diagnoses of non-polio acute flaccid paralysis/myelitis (AFP/AFM). We investigated the prevalence, genetic relatedness and associated clinical features of EV-D68 in 193 EV-positive samples from 193 patients in late 2018, UK. EV-D68 was detected in 83 (58 %) of 143 confirmed EV-positive samples. Sequencing and phylogenetic analysis revealed extensive genetic diversity, split between subclades B3 (n=50) and D1 (n=33), suggesting epidemiologically unrelated infections. B3 predominated in children and younger adults, and D1 in older adults and the elderly (P=0.0009). Clinical presentation indicated causation or exacerbation of respiratory distress in 91.4 % of EV-D68-positive individuals, principally cough (75.3 %), shortness of breath (56.8 %), coryza (48.1 %), wheeze (46.9 %), supplemental oxygen required (46.9 %) and fever (38.9 %). Two cases of AFM were observed, one with EV-D68 detectable in the cerebrospinal fluid, but otherwise neurological symptoms were rarely reported (n=4). Both AFM cases and all additional instances of intensive care unit (ICU) admission (n=5) were seen in patients infected with EV-D68 subclade B3. However, due to the infrequency of severe infection in our cohort, statistical significance could not be assessed.

Chlorine decay and disinfection by-products formation during chlorination of biofilms formed with simulated drinking water containing corrosion inhibitors.

Corrosion inhibitors used to reduce pipe corrosion can alter the physical structure and biochemical components of the biofilm in premise plumbing systems. We studied the effects of corrosion inhibitors on chlorine decay and associated disinfection by-products (DBPs) formation by biofilms grown with simulated drinking water amended with silicate, phosphate, and the phosphate blends. Experiments were conducted with either intact biofilms or biofilm materials dispersed in solution during sonication (referred to as biomass). While there was no significant difference in chlorine decay among biomass from different biofilms, biomass from the phosphate blend biofilm showed the lowest trihalomethane (THMs) and haloacetic acids (HAAs) formation. The chlorine decay rate constants from the biofilm experiment were ranked as: phosphate blends > phosphate ≈ groundwater (GW) > silicate. The kinetics of chlorine decay and formation of DBPs were successfully described by pseudo-first-order kinetics. These fitting parameters were used to predict the DBPs formation in a realistic premise plumbing system. The results showed that biofilm-derived THMs and HAAs increased with increasing chlorine concentration, while THMs and HAAs first increased and then stabilized to a maximum with increasing biofilm total organic carbon (TOC) concentration. In general, the biofilms grown with phosphate-based corrosion inhibitors resulted in lower DBPs formation yield but higher bacterial release, which could potentially increase the risk of user exposure to opportunistic pathogens in drinking water. The silicate biofilms showed the largest yield coefficient of DBPs formation but had the least biomass and lower bacterial release.

Influence of point-of-use filters and stagnation on water quality at a preschool and under laboratory conditions.

A local preschool installed NSF/ANSI 42 and 53 certified point-of-use (POU) filters in its classroom sinks and drinking fountains to protect children from the possibility of elevated lead (Pb) levels in drinking water. We examined the effects of these filters during flowing water and immediately following stagnation periods on Pb, chlorine, and bacterial concentrations in the field and the laboratory. Before and after typical school stagnation periods, we collected samples from filtered classroom sinks, a filtered drinking fountain and nearby unfiltered sinks for a year. No unfiltered samples exceeded Illinois State limits of 5 µg/L for Pb in pre-K through 5th grade schools. However, following stagnation periods as short as overnight (14.5 h), over half of post-stagnation filtered samples from classroom sinks exceeded 5 µg/L while post-stagnation unfiltered samples remained below 5 µg/L. Laboratory testing showed no significant increases in Pb with stagnation, suggesting that the preschool classrooms may have had Pb-bearing plumbing downstream of the filters which released Pb into the filtered drinking water. The filters effectively removed free chlorine (99% decrease) in both the preschool and laboratory. Installing the filters had the unintended consequence of significantly increasing the bacterial concentrations (as measured by qPCR) in the preschool's drinking water and in laboratory filter effluent. Legionella pneumophila, Pseudomonas aeruginosa, and Mycobacterium spp. were not detected in pre-stagnation unfiltered and post-stagnation filtered samples. These results suggest that the installation of POU filters be considered as one component of an overall strategy to decrease Pb concentrations in school drinking water that holistically considers the premise plumbing system. A 5-minute flush significantly decreased concentrations of Pb and bacteria in filtered sinks. Replacing Pb-bearing plumbing components downstream of a POU filter may also be needed to combat Pb levels in drinking water.

Retrospective screening of routine respiratory samples revealed undetected community transmission and missed intervention opportunities for SARS-CoV-2 in the United Kingdom.

In the early phases of the SARS coronavirus type 2 (SARS-CoV-2) pandemic, testing focused on individuals fitting a strict case definition involving a limited set of symptoms together with an identified epidemiological risk, such as contact with an infected individual or travel to a high-risk area. To assess whether this impaired our ability to detect and control early introductions of the virus into the UK, we PCR-tested archival specimens collected on admission to a large UK teaching hospital who retrospectively were identified as having a clinical presentation compatible with COVID-19. In addition, we screened available archival specimens submitted for respiratory virus diagnosis, and dating back to early January 2020, for the presence of SARS-CoV-2 RNA. Our data provides evidence for widespread community circulation of SARS-CoV-2 in early February 2020 and into March that was undetected at the time due to restrictive case definitions informing testing policy. Genome sequence data showed that many of these early cases were infected with a distinct lineage of the virus. Sequences obtained from the first officially recorded case in Nottinghamshire - a traveller returning from Daegu, South Korea - also clustered with these early UK sequences suggesting acquisition of the virus occurred in the UK and not Daegu. Analysis of a larger sample of sequences obtained in the Nottinghamshire area revealed multiple viral introductions, mainly in late February and through March. These data highlight the importance of timely and extensive community testing to prevent future widespread transmission of the virus.

Enterovirus subtyping in a routine UK laboratory setting between 2013 and 2017.

BACKGROUND: Human enteroviruses (EV) are the leading cause of viral meningitis. EV genotyping is predominantly performed through amplification and sequencing of viral capsid protein-1 (VP1), frequently by national reference laboratories (NRLs). OBJECTIVE: To determine the frequency of genotyping failure in our NRL-submitted samples and apply a superior alternative assay to resolve untyped specimens. STUDY DESIGN: We initially audited genotyping data received for a cohort of patients in the East Midlands, UK by the NRL between 2013 and 2017, then identified an alternative RT-PCR typing method by literature review and evaluated primers from both assays in silico against comprehensive publicly available genomic data. The alternative assay was further optimised and applied to archived nucleic acids from previously untypable samples. RESULTS: Genotyping data showed a significant increase in untypable EV strains through the study period (p = 0.0073). Typing failure appeared unrelated to sample type or viral load. In silico analyses of 2,201 EV genomes showed high levels of mismatch between reference assay primers and clinically significant EV-species, in contrast to a selected alternative semi-nested RT-PCR VP1-typing assay. This alternative assay, with minor modifications, successfully genotyped 23 of 24 previously untypable yet viable archived specimens (EV-A, n = 4; EV-B, n = 19). Phylogenetic analyses identified no predominant strain within NRL untypable isolates, suggesting sub-optimal reference assay sensitivity across EV species, in agreement with in silico analyses. CONCLUSION: This modified highly sensitive RT-PCR assay presents a suitable alternative to the current English national reference VP1-typing assay and is recommended in other settings experiencing typing failure.

Human Bocavirus infection and respiratory tract disease identified in a UK patient cohort.

BACKGROUND: Since its first isolation in 2005, Human Bocavirus (HBoV) has been repeatedly associated with acute respiratory tract infections, although its role in pathogenicity remains unclear due to high co-infection rates. OBJECTIVES: To assess HBoV prevalence and associated disease in a cohort of respiratory patients in the East Midlands, UK between 2015 and 2019. STUDY DESIGN: We initially investigated the undiagnosed burden of HBoV in a retrospective paediatric cohort sampled between 2015 and 2017 using an in-house PCR assay. HBoV was subsequently incorporated into the standard respiratory diagnostic pathway and we audited a calendar year of HBoV positive results between 2018 and 2019. RESULTS: Our retrospective PCR screening of previously routine diagnostic-negative samples from juvenile patients identified a 9% (n = 30) prevalence of HBoV type 1. These apparent HBoV1 mono-infections were frequently associated with respiratory tract symptoms, often severe requiring ventilation, oxygen and steroid intervention with 31% (n = 9) of individuals requiring intensive care. When HBoV screening was subsequently adopted into the routine respiratory diagnostic pathway, year-round infections were observed in both children and adults peaking in February. 185 of 9098 (2.03%) individuals were found to be HBoV positive with children aged 12-24 months the principally infected group. However, HBoV infection was also observed in patients aged over 60, predominantly as a mono-infection. 23% of the 185 unique patients were HBoV monoinfected and persistent low-level DNA positivity was observed in 15 individuals up to 6-months after initial presentation. CONCLUSION: HBoV1 is a prevalent respiratory infection in the UK capable of causing serious monoinfections.

Dry Heat as a Decontamination Method for N95 Respirator Reuse.

A pandemic such as COVID-19 can cause a sudden depletion of the worldwide supply of respirators, forcing healthcare providers to reuse them. In this study, we systematically evaluated dry heat treatment as a viable option for the safe decontamination of N95 respirators (1860, 3M) before their reuse. We found that the dry heat generated by an electric cooker (100 °C, 5% relative humidity, 50 min) effectively inactivated Tulane virus (TV, >5.2-log10 reduction), rotavirus (RV, >6.6-log10 reduction), adenovirus (AdV, >4.0-log10 reduction), and transmissible gastroenteritis virus (TGEV, >4.7-log10 reduction). The respirator integrity (determined on the basis of the particle filtration efficiency and quantitative fit testing) was not compromised after 20 cycles of a 50 min dry heat treatment. On the basis of these results, dry heat decontamination generated by an electric cooker (e.g., rice cookers, instant pots, and ovens) could be an effective and accessible decontamination method for the safe reuse of N95 respirators. We recommend users measure the temperature during decontamination to ensure the respirator temperature can be maintained at 100 °C for 50 min.

The SAMe-TT2R2 Score Predicts Warfarin Control in an Australian Population with Atrial Fibrillation.

BACKGROUND: Warfarin requires regular monitoring with the time in therapeutic range (TTR), a common indicator of control and TTR > 70% is indicative of efficient anticoagulation. The SAMe-TT2R2 (sex, age, medical history, treatment, tobacco use, race) model has been utilised as a predictor of warfarin control, with a score ≥ 2 indicative of poor control. However, it has been suggested that race may be over-represented in this model. To date, no Australian studies have applied this model, possibly because race is not routinely recorded. Therefore, the aim of this study was to apply the SAMe-TT2R2 model in an Australian population on warfarin managed by both a warfarin care program (WCP) and general practitioner (GP). METHODS: Retrospective data was collected for patients receiving warfarin via a WCP in Queensland and whilst being managed by a GP. Patient data was used to calculate the SAMe-TT2R2 score and the TTR for each patient. Mean TTR was used for analysis and comparison with the categorised SAMe-TT2R2 score. RESULTS: Of the 3911 patients managed by a WCP, there was a significantly lower mean TTR for patients with a SAMe-TT2R2 score ≥ 2 compared to 0-1 (78.6 ± 10.7% vs. 80.9 ± 9.5%, p < 0.0001). Of these patients, 200 were analysed whilst managed by a GP and the categorised SAMe-TT2R2 score did not result in a statistically different mean TTR (69.3 ± 16.3% with 0-1 vs. 63.6 ± 15.0% with ≥2, p = 0.089), but a score ≥2 differentiated patients with a TTR less than 65%. CONCLUSIONS: The SAMe-TT2R2 model differentiated Australian patients with reduced warfarin control, despite the exclusion of race. In Australia, the SAMe-TT2R2 score could assist clinicians in identifying Australian patients who may obtain reduced warfarin control and benefit from additional interventions such as a dedicated WCP.

Roofing material and irrigation frequency influence microbial risk from consuming homegrown lettuce irrigated with harvested rainwater.

Rooftop harvested rainwater has become an alternative, potable, and non-potable water source used around the world. In the United States, rooftop harvested rainwater is most commonly used for irrigation. Rooftop harvested rainwater may contain contaminants from bird or animal feces that may present a risk to water users. Different roofing materials may influence the survival of fecal bacteria on the rooftop prior to runoff during rainfall. In this study, three pathogen groups (E. coli, enterococci and Salmonella enterica) in rooftop runoff from three, replicated roof types (asphalt shingle, synthetic slate, and wood shake) were quantified in multiple rain events. Matched roofs were selected from locations with differing amounts of tree cover. Enterococci were the most frequently detected bacteria from all roof types. Wood shake and asphalt shingle roofing materials had the poorest microbial water quality. Rainwater runoff from two of the six buildings failed to meet United States Food and Drug Administration microbial standards for irrigation water. A quantitative microbial risk assessment indicated that the annual probability of illness from consuming lettuce irrigated with rooftop harvested rainwater varied by roofing material, irrigation water withholding period, and exposure frequency. Consuming lettuce immediately after irrigation with rooftop rainwater presented the highest human health risk based on the probability of illness from E. coli and enterococci exposure. Withholding irrigation by 1 day prior to harvest decreased the annual probability of illness from E. coli by 2 log, but had a minimal effect on the risk from enterococci.

Trichodysplasia Spinulosa Polyomavirus in Respiratory Tract of Immunocompromised Child.

Trichodysplasia spinulosa polyomavirus causes trichodysplasia spinulosa, a skin infection, in immunocompromised persons, but the virus is rarely detected in respiratory samples. Using PCR, we detected persistent virus in respiratory and skin samples from an immunocompromised boy with respiratory signs but no characteristic skin spicules. This virus may play a role in respiratory illness.

Improving the use of treatment escalation plans: a quality-improvement study.

OBJECTIVES: Treatment escalation plans (TEPs) are vital in communicating a ceiling of care. However, many patients still deteriorate and die without a pre-established ceiling of care for attending clinicians to rely on. We aimed to increase the proportion of suitable patients that have TEPs in place in a rural district general hospital. METHODS: We undertook three 'Plan-Do-Study-Act' (PDSA) cycles between 1 December 2016 and 9 June 2017. These cycles aimed to assess the problem, implement a solution and monitor its sustainability. We sampled all acute medical admissions at different time points, focusing on the acute medical unit. We identified patients requiring TEP forms using SupportiveandPalliative Care Indicators Tool. Stakeholders were surveyed during the project, and a process communication map was developed to understand the human interfaces that occur when producing a TEP. RESULTS: We sampled a total of 323 patients (PDSA 1, n=128; PDSA 2, n=95; PDSA 3, n=100). Following implementation of a 'talking to your doctor about treatment' leaflet, the proportion of patients who did not have a TEP but required one fell from 43% (n=38, PDSA 1) to 27% (n=20, PDSA 3) then to 23% (n=77, PDSA 3) (CI 0.6631 to 39.917, p=0.028). CONCLUSIONS: This study highlights the challenges of TEP form completion. The impact of our intervention appeared to raise awareness of advanced care planning. The information contained in our leaflet could be distributed in more innovative ways to ensure patients unable to access textual information are able to receive this message.

Measuring and modelling the response of Klebsiella pneumoniae KPC prey to Bdellovibrio bacteriovorus predation, in human serum and defined buffer.

In worldwide conditions of increasingly antibiotic-resistant hospital infections, it is important to research alternative therapies. Bdellovibrio bacteriovorus bacteria naturally prey on Gram-negative pathogens, including antibiotic-resistant strains and so B. bacteriovorus have been proposed as "living antibiotics" to combat antimicrobially-resistant pathogens. Predator-prey interactions are complex and can be altered by environmental components. To be effective B. bacteriovorus predation needs to work in human body fluids such as serum where predation dynamics may differ to that studied in laboratory media. Here we combine mathematical modelling and lab experimentation to investigate the predation of an important carbapenem-resistant human pathogen, Klebsiella pneumoniae, by B. bacteriovorus in human serum versus buffer. We show experimentally that B. bacteriovorus is able to reduce prey numbers in each environment, on different timescales. Our mathematical model captures the underlying dynamics of the experimentation, including an initial predation-delay at the predator-prey-serum interface. Our research shows differences between predation in buffer and serum and highlights both the potential and limitations of B. bacteriovorus acting therapeutically against K. pneumoniae in serum, informing future research into the medicinal behaviours and dosing of this living antibacterial.

In silico and in vitro interrogation of a widely used HEV RT-qPCR assay for detection of the species Orthohepevirus A.

Hepatitis E virus (HEV) infection is a public health concern worldwide, associated with waterborne outbreaks in developing countries and reported as an emerging zoonotic infection in high-income countries. A recent consensus proposal classified the isolates from human, swine, wild boar, deer, mongoose, rabbit and camel in seven genotypes within the species Orthohepevirus A. In this report a popular HEV RT-qPCR assay was assessed for the detection of the species Orthohepevirus A. In silico analysis of 189 complete genome sequences showed that the assay targets a highly conserved region in the Orthohepevirus A genome. Additionally, plasmid standards were constructed to test the effect of probe- and primer-binding site mutations in the assay performance. The assay proved robust enough to detect strains with mutations in the probe-binding site and in the 3' end primer-binding site regions. A degenerate version of the reverse primer improves the performance of the assay particularly in the detection of HEV-5 and 6. The addition and detection of MS2 RNA in each RT-qPCR reaction monitored for amplification inhibition and did not affect the performance of the assay in the detection of the HEV RNA international standard. Therefore, the RT-qPCR assay can be confidently used for the RNA detection of the seven genotypes within the species Orthohepevirus A.

Phenotypic microarrays suggest Escherichia coli ST131 is not a metabolically distinct lineage of extra-intestinal pathogenic E. coli.

Extraintestinal pathogenic E. coli (ExPEC) are the major aetiological agent of urinary tract infections (UTIs) in humans. The emergence of the CTX-M producing clone E. coli ST131 represents a major challenge to public health worldwide. A recent study on the metabolic potential of E. coli isolates demonstrated an association between the E. coli ST131 clone and enhanced utilisation of a panel of metabolic substrates. The studies presented here investigated the metabolic potential of ST131 and other major ExPEC ST isolates using 120 API test reagents and found that ST131 isolates demonstrated a lower metabolic activity for 5 of 120 biochemical tests in comparison to non-ST131 ExPEC isolates. Furthermore, comparative phenotypic microarray analysis showed a lack of specific metabolic profile for ST131 isolates countering the suggestion that these bacteria are metabolically fitter and therefore more successful human pathogens.

Nitroglycerin 0.4% ointment vs placebo in the treatment of pain resulting from chronic anal fissure: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Complications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF. METHODS: In this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (≥50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14-18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application. RESULTS: A total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of -7.0 mm in favor of NTG 0.4% (95% CI -13.6, -0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups. CONCLUSIONS: This was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to-severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00522041.

Use of transdermal and intravenous granisetron and the ability of the Hesketh score to assess nausea and vomiting induced by multiday chemotherapy.

PURPOSE: Hesketh scores define emetogenicity of single-agent and multiagent single-day chemotherapy. This analysis determined the emetogenicity of multiagent, multiday chemotherapy and the Granisetron Transdermal System (GTDS; Sancuso(®)). METHODS: This was a retrospective analysis of a multicenter, randomized, double-blind, phase III noninferiority trial of GTDS versus oral granisetron in patients receiving 3 days of multiagent moderately or highly emetogenic chemotherapy, regardless of granisetron formulation. Emesis was defined as vomiting/retching or the use of rescue medication. Logistic regression and classification trees were used to determine the optimal combination of Hesketh scores over the multiagent, multiday regimens for the prediction of emesis. RESULTS: Of 393 patients, 272 (69.2%) were chemotherapy naïve. The most common types of cancer were lung (30.5%) and gynecologic (21.9%). The most common chemotherapeutic regimen (in 14.2% of patients) was cisplatin plus etoposide on days 1-3. The best binary emesis predictor was day 1 Hesketh score. Patients with a day 1 Hesketh score of 5 had the highest rate of emesis (62.5%) versus patients with a score < 5 (31.7%). For patients with day 1 Hesketh score < 5, only 14.3% of those receiving only one drug on day 1 experienced emesis. CONCLUSION: Hesketh emetogenicity scores of individual agents are applicable to multiday, multiagent chemotherapeutic regimens in patients receiving antiemetics.