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Introduction: Protonitazene is an opioid belonging to the 2-benzylbenzimidazole structural class. We describe two cases of opioid toxicity involving the reported inhalation of a delta-9-tetrahydrocannabinol vape product in which protonitazene was detected., Case Reports: Case 1 was a young male found unconscious after the reported use of a delta-9-tetrahydrocannabinol vape. He suffered two subsequent apnoeic episodes requiring bag-valve-mask ventilation before eventual recovery. Only protonitazene was detected in blood at a concentration of 0.74 µg/L. Case 2 was a young male who died shortly after being found unresponsive. The postmortem femoral blood concentrations of protonitazene and delta-9-tetrahydrocannabinol were 0.33 µg/L and 2 µg/L, respectively. Analysis of a pod vaping device found in the decedent's hand and a separate e-liquid bottle labelled as delta-9-tetrahydrocannabinol showed a mixture of protonitazene and delta-9-tetrahydrocannabinol., Discussion: The opioid effects of protonitazene are mediated through β-arrestin2 and mu opioid receptor signalling pathways. Benzimidazole opioids are lipophilic and, when mixed with a suitable solvent, can be used in a vape device. It is anticipated that naloxone would have provided effective reversal of toxicity in our cases., Conclusions: Novel routes of opioid administration, like vaping, may appear relatively innocuous in comparison to intravenous administration, but opioids may still be absorbed at high concentrations, resulting in severe opioid toxicity or death.

N,N-Diformylmescaline, a novel analogue of mescaline, has recently been detected in Australia in two unrelated seizures. To confirm the identification, a three-step synthesis from 3,4,5-trimethoxyphenylacetic acid was devised. However, purification of the final product proved problematic with the compound prone to degradation in solution. Analysis of the compound by LC-MS indicated that the compound was unstable under acidic and basic conditions, breaking down to N-formylmescaline. Further degradation to mescaline was observed when the compound was dissolved in hydrochloric acid for an extended period of time suggesting that N,N-diformylmescaline may be a prodrug for mescaline. The GC-MS, NMR and FTIR data for the seized compound are presented along with details of the synthesis and studies of the compound's stability in solution., (© 2022 Commonwealth of Australia. Drug Testing and Analysis © 2022 John Wiley & Sons Ltd.)

The identification of a range of different drugs within counterfeit benzodiazepine tablets has been widely reported; however, limited information is available on the dosage of these products. A rapid dosage survey of 46 counterfeit benzodiazepine tablets from 20 seizures was conducted over a 6-month period between April and September 2020. Existing methods utilised for the determination of benzodiazepines in toxicology specimens were applied to assess the dosage of four benzodiazepines detected across five different counterfeit benzodiazepine presentations. The highest dosage variation was observed for etizolam with a range of 0.7-8.3 mg per tablet. This report demonstrates the variability in drug content and dosage that can occur between visually similar counterfeit tablets, even when co-packaged within the same seizure, highlighting the potential public harm posed by these counterfeit medications., (© 2021 John Wiley & Sons, Ltd.)

Synthetic cannabinoid receptor agonists (SCRAs) remain a prolific class of new psychoactive substances (NPS) and continue to expand rapidly. Despite the recent identification of hydroxybenzotriazole (HOBt) containing SCRAs in synthetic cannabis samples, there is currently no information regarding the pharmacological profile of these NPS with respect to human CB 1 and CB 2 receptors. In the current study, a series consisting of seven HOBt indole-, indazole-, and 7-azaindole-carboxylates bearing a range of N -alkyl substituents were synthesized and pharmacologically evaluated. Competitive binding assays at CB 1 and CB 2 demonstrated that all analogues except a 2-methyl-substituted derivative had low affinity for CB 1 ( K i = 3.80-43.7 μM) and CB 2 ( K i = 2.75-18.2 μM). A fluorometric functional assay revealed that 2-methylindole- and indole-derived HOBt carboxylates were potent and efficacious agonists of CB 1 (EC 50 = 12.0 and 63.7 nM; E max = 118 and 120%) and CB 2 (EC 50 = 10.9 and 321 nM; E max = 91 and 126%). All other analogues incorporating indazole and 7-azaindole cores and bearing a range of N1-substituents showed relatively low potency for CB 1 and CB 2 . Additionally, a reporter assay monitoring β-arrestin 2 (βarr2) recruitment to the receptor revealed that the 2-methylindole example was the most potent and efficacious at CB 1 (EC 50 = 131 nM; E max = 724%) and the most potent at CB 2 (EC 50 = 38.2 nM; E max = 51%). As with the membrane potential assay, the indazole and other indole HOBt carboxylates were considerably less potent at both receptors, and analogues comprising a 7-azaindole core showed little activity. Taken together, these data suggest that NNL-3 demonstrates little CB1 receptor activity and is unlikely to be psychoactive in humans. NNL-3 is likely an unintended SCRA manufacturing byproduct. However, the synthesis of NNL-3 analogues proved simple and general, and some of these showed potent cannabimetic profiles in vitro , indicating that HOBt esters of this type may represent an emerging class of SCRA NPS.

Background: The etiology of most cases of congenital hypothyroidism (CHT) due to thyroid dysgenesis (DG) is unknown. If transient environmental factors can impact on thyroid gland development, then clustering of cases in time and/or space may occur, and this would be more likely in thyroid DG than dyshormonogenesis (DHG). Methods: The newborn screening program for CHT in Scotland is linked to a central database that includes case details such as postcode. The etiology of CHT is investigated in many cases of CHT using scintigraphy and/or ultrasonography. We looked for evidence of a change in CHT incidence with year of birth and according to season of the year. We then undertook space-time clustering analysis (using a method based on K -functions, with nearest neighbor thresholds) of CHT in Scotland between 1979 and 2015. We also looked for evidence of overall changes associated with sex and area-based birth density. Results: Of 531 cases with CHT during the study period, 290 cases had been categorized as DG ( n  = 229) or DHG ( n  = 61) following more detailed investigation. The incidence of CHT increased with year of birth and was in part linked to changing methodology, but there was no seasonality. There was no evidence of overall space-time clustering ( p  = 0.06), but there was evidence of clustering in babies with DG ( p  = 0.007). This picture appeared to be most closely linked to underlying thyroid gland hypoplasia rather than thyroid gland agenesis or ectopia. There was significant space-time clustering for both males and females, but clustering was restricted to lesser birth density areas. There was also evidence of clustering for unknown cases ( p  < 0.001). Clustering of these cases was restricted to females but was present for cases from both greater and lesser birth density areas. There was no evidence of clustering in cases of DHG. Conclusions: These data suggest that an unidentified environmental factor or factors may be involved in the etiology of thyroid DG in Scotland. The variation in CHT incidence observed internationally may reflect environmental as well as genetic factors.

Background: Studies have shown marked improvements in survival between 1981 and 2000 for Ewing sarcoma patients but not for osteosarcoma. This study aimed to explore socio-economic patterning in early mortality rates for both tumours., Procedure: The study analysed all 2432 osteosarcoma and 1619 Ewing sarcoma cases, aged 0-49 years, diagnosed in Great Britain 1985-2008 and followed to 31/12/2009. Logistic regression models were used to calculate risk of dying within three months, six months, one year, three years and five years after diagnosis. Associations with Townsend deprivation score and its components were examined at small-area level. Urban/rural status was studied at larger regional level., Results: For osteosarcoma, after age adjustment, mortality at three months, six months and one year was associated with higher area unemployment, OR = 1.05 (95% CI 1.00, 1.10), OR = 1.04 (95% CI 1.01, 1.08) and OR = 1.04 (95% CI 1.02, 1.06) respectively per 1% increase in unemployment. Mortality at six months was associated with greater household non-car ownership, OR = 1.02 (95% CI 1.00, 1.03). For Ewing sarcoma, there were no significant associations between mortality and overall Townsend score, nor its components for any time period. For both tumours increasing mortality was associated with less urban and more remote rural areas., Conclusions: This study found that for osteosarcoma, early mortality was associated with residence at diagnosis in areas of higher unemployment, suggesting risk of early death may be socio-economically determined. For both tumours, distance from urban centres may lead to greater risk of early death., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Previously excesses in incident cases of leukaemia and non-Hodgkin lymphoma have been observed amongst young people born or resident in Seascale, Cumbria. These excesses have not been seen more recently. It is postulated that the former apparent increased risk was related to 'unusual population mixing', which is not present in recent years. This study investigated changes in measures of population mixing from 1951-2001. Comparisons were made between three specified areas. Area-based measures were calculated (migration, commuting, deprivation, population density). All areas have become more affluent, although Seascale was consistently the most affluent. Seascale has become less densely populated, with less migration into the ward and less diversity with respect to migrants' origin. There have been marked changes in patterns of population mixing throughout Cumbria. Lesser population mixing has been observed in Seascale in recent decades. Changes in pattern and nature of population mixing may explain the lack of recent excesses., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Article Title and Bibliographic Information: Community water fluoridation and health outcomes in England: a cross-sectional study. Young N, Newton J, Morris J, Morris J, Langford J, Iloya J, Edwards D, Makhani S, Verne J. Community Dent Oral Epidemiol 2015; 43:550-9., Source of Funding: Public Health England TYPE OF STUDY/DESIGN: Ecological (area based)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In 2012, seized capsules containing white powder were analyzed to show the presence of unknown steroid-related compounds. Subsequent gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) investigations identified a mixture of 3α- and 3β- isomers of the novel compound; 3-chloro-17α-methyl-5α-androstan-17β-ol. Synthesis of authentic reference materials followed by comparison of NMR, GC-MS and gas chromatography-tandem mass spectrometry (GC-MS/MS) data confirmed the finding of a new 'designer' steroid. Furthermore, in vitro androgen bioassays showed potent activity highlighting the potential for doping using this steroid. Due to the potential toxicity of the halogenated steroid, in vitro metabolic investigations of 3α-chloro-17α-methyl-5α-androstan-17β-ol using equine and human S9 liver fractions were performed. For equine, GC-MS/MS analysis identified the diagnostic 3α-chloro-17α-methyl-5α-androstane-16α,17β-diol metabolite. For human, the 17α-methyl-5α-androstane-3α,17β-diol metabolite was found. Results from these studies were used to verify the ability of GC-MS/MS precursor-ion scanning techniques to support untargeted detection strategies for designer steroids in anti-doping analyses. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

The identification and structural elucidation of the novel synthetic cannabimimetic 8-quinolinyl 4-methyl-3-(1-piperidinylsulfonyl)benzoate (QMPSB) by GC-MS, LC-MS and NMR is reported. QMPSB was identified in Queensland, Australia on plant material packaged as herbal incense. The identification of QMPSB was initially hampered due to trans-esterification occurring in the extraction solvent. An investigation of the trans-esterification of QMPSB in methanol and ethanol was conducted and analytical data for the respective methyl and ethyl esters are reported. Analytical data is presented for two other compounds detected on seized plant material packaged as herbal incense: the synthetic cannabimimetic 1-[(N-methylpiperidin-2-yl)methyl]-3-(4-methyl-1-naphthoyl)indole (MAM-1220) and the JWH-081 analogue 1-(cyclohexylmethyl)-3-(4-methoxy-1-naphthoyl)indole (CHM-081)., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Artificial fluoridation of drinking water to improve dental health has long been a topic of controversy. Opponents of this public health measure have cited the possibility of bone cancer induction. The study objective was to examine whether increased risk of primary bone cancer was associated with living in areas with higher concentrations of fluoride in drinking water., Methods: Case data on osteosarcoma and Ewing sarcoma, diagnosed at ages 0-49 years in Great Britain (GB) (defined here as England, Scotland and Wales) during the period 1980-2005, were obtained from population-based cancer registries. Data on fluoride levels in drinking water in England and Wales were accessed through regional water companies and the Drinking Water Inspectorate. Scottish Water provided data for Scotland. Negative binomial regression was used to examine the relationship between incidence rates and level of fluoride in drinking water at small area level., Results: The study analysed 2566 osteosarcoma and 1650 Ewing sarcoma cases. There was no evidence of an association between osteosarcoma risk and fluoride in drinking water [relative risk (RR) per one part per million increase in the level of fluoride = 1·001; 90% confidence interval (CI) 0·871, 1·151] and similarly there was no association for Ewing sarcoma (RR = 0·929; 90% CI 0·773, 1·115)., Conclusions: The findings from this study provide no evidence that higher levels of fluoride (whether natural or artificial) in drinking water in GB lead to greater risk of either osteosarcoma or Ewing sarcoma.

Increases in the incidence of thyroid cancer have been previously reported. The purpose of the present study was to examine temporal trends in the incidence of primary thyroid cancer diagnosed in 0-49 year olds in parts of Great Britain during 1976-2005. Data on 4,337 cases of thyroid cancer were obtained from regional cancer registries. Age-standardized incidence rates (ASRs) were calculated. Negative binomial regression was used to examine effects of age, sex, drift (linear trend), non-linear period and non-linear cohort. The best fitting negative binomial regression model included age (P < 0.001), sex (P < 0.001) and drift (P < 0.001). Non-linear period (P = 0.648) and non-linear cohort (P = 0.788) were not statistically significant. For males aged 0-14, the ASR increased from 0.2 per million persons per year in 1976-1986 to 0.6 in 1997-2005. For males aged 15-29 and 30-49 the ASRs increased from 1.9 to 3.3 and from 7.4 to 12.7, respectively. For females aged 0-14, the corresponding ASR increased from 0.3 to 0.5. For females aged 15-29 and 30-49 the ASRs increased from 6.9 to 12.4 and from 21.2 to 42.3, respectively. For all age groups, there has been a linear increase in incidence of thyroid cancer, which has led to a doubling of the number of cases diagnosed over a twenty year span. The reasons for this increase are not well understood, but it is consistent with findings from other countries.

4-Methylmethamphetamine has been detected in samples submitted for analysis in several states throughout Australia. Six ring substituted methyl isomers of methamphetamine and amphetamine were synthesised and analysed. As the regioisomeric 2-, 3- and 4-methylmethamphetamine and 2-, 3- and 4-methylamphetamine have virtually identical mass spectra, the use of MS is an ineffective technique to discriminate between these closely related compounds. We set out to determine whether the regioisomers could be differentiated by a combination of GC-MS, acetyl derivatisation and GC-IRD. We demonstrate that the three isomers of methylmethamphetamine and methylamphetamine can be separated by GC, and a combination of acetyl derivatisation and vapour phase IR can identify the specific ring substituted compound., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The aetiology of bone cancers is poorly understood. This study examined geographical patterning in incidence of primary bone cancers diagnosed in 0-49 year olds in Great Britain during 1980-2005 to provide information on factors linked with disease development. We investigated putative associations with deprivation and population density., Methods: Data on osteosarcoma and Ewing sarcoma were obtained from national population-based registries. Negative binomial regression was used to examine the relationship between incidence rates and the Townsend deprivation score (and its component variables) and small-area population density., Results: The study analyzed 2566 osteosarcoma and 1650 Ewing sarcoma cases. For females with osteosarcoma, statistically significant decreased risk was associated with higher levels of deprivation (relative risk [RR] per unit increase in deprivation score = 0.969; 95% confidence interval [CI] 0.946-0.993). For all Ewing sarcoma combined, statistically significant decreased risk was associated with greater area-level population density and higher levels of non-car ownership (RR per person per hectare increase = 0.984; 95% CI 0.976-0.993, RR per 1% increase in non-car ownership = 0.994; 95% CI 0.991-0.998)., Conclusions: Higher incidence of osteosarcoma was observed for females in areas with lower deprivation levels indicating increased risk is linked to some aspect of affluent living. Higher incidence of Ewing sarcoma occurred in areas of low population density and where more people owned cars, both characteristic of rural environments. The study adds substantially to evidence associating Ewing sarcoma risk with rural environmental exposures. Putative risk factors include agricultural exposures, such as pesticides and zoonotic agents.

Background: There is a paucity of recent epidemiological data on bone cancers. The aim of this study was to describe incidence and survival patterns for bone cancers diagnosed during 1981 - 2002., Methods: Cases aged 0 - 39 years (236 osteosarcomas, 166 Ewing sarcomas and 73 chondrosarcomas) were analysed using Poisson and Cox regressions., Results: Incidence rates (per million persons per year) for osteosarcoma were 2.5 at age 0 - 14 years; 4.5 at age 15 - 29 years and 1.0 at age 30 - 39 years. Similarly, for Ewing sarcoma the incidence rates were 2.2; 2.9; 0.4 and for chondrosarcoma rates were 0.1; 1.2; 1.8 respectively. Incidence of osteosarcoma increased at an average annual rate of 2.5% (95% CI 0.4 - 4.7; P = 0.02), but there was no change in incidence of Ewing sarcoma or chondrosarcoma. There was a marginally statistically significant improvement in survival for Ewing sarcoma (hazard ratio (HR) per annum = 0.97; 95% CI 0.94 - 1.00; P = 0.06), although patients aged 15 - 39 years (n = 93) had worse overall survival than those aged 0 - 14 (n = 73; HR = 1.46; 95% CI 0.98 - 2.17; P = 0.06). There was no significant improvement in osteosarcoma survival (HR per annum = 0.98; 95% CI 0.95 - 1.01; P = 0.18)., Conclusions: Reasons for poorer survival in Ewing sarcoma patients aged 15 - 39 years and failure to significantly improve survival for osteosarcoma patients requires further investigation.

Objective: Current imaging recommendations for investigating any infantile febrile urinary tract infection (UTI) are ultrasound scan (US), micturating cystourethrogram (MCUG) and dimercaptosuccinic acid (DMSA) scan. The aim of this retrospective cohort study was to determine the need and indications for MCUG in the investigation of a first febrile infantile UTI, as doubts have been raised over its benefit., Patients and Methods: Information on 427 infants who had undergone US, MCUG and DMSA following a first febrile UTI was prospectively recorded. The infants were divided into two groups: A (354) with normal renal US and B (73) with abnormal US. DMSA findings were correlated with findings on MCUG. Main outcome measures were incidence of recurrent UTIs, change in management or intervention as a result of MCUG, and outcome at discharge., Results: Only 21/354 (6%) infants in Group A had both scarring on DMSA and vesicoureteric reflux (VUR), predominantly low-grade on MCUG. In Group B (abnormal US), 23/73 (32%) had scarring on DMSA and vesicoureteric reflux, predominantly high grade on MCUG. Of the infants with non-scarred kidneys, 73% had dilating reflux. Successful conservative treatment was performed in 423 infants, and 4 infants in Group B required surgery., Conclusion: We recommend US and DMSA in all infantile febrile UTI cases. Where US is normal, MCUG should be reserved for those cases with abnormal DMSA. Where US is abnormal, MCUG should be performed irrespective of findings on DMSA scan. A randomized prospective study is necessary to evaluate this further., (Copyright © 2009 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: A recent report highlights the need for clear standards of practice regarding working-age health. Despite this, little is known about training or performance of sickness certification by junior doctors in secondary care., Aims: To see what sickness certification training had been received by practising hospital postgraduate trainees and establish how confident and knowledgeable they were in this area. We also evaluated the feasibility and face validity of a paper-based educational module., Methods: We surveyed 51 junior doctors in a variety of specialties, at all grades. Questions concerned training and practice of sickness certification and assessing capacity for work. A knowledge test regarding formal guidelines, use of forms and self-certification was undertaken, before participants evaluated a 10 min training module., Results: Seventy-nine per cent of participants lacked knowledge in sickness certification, and 55% were not confident to assess capacity for work; 66% had received no training at all and 71% participants followed no guideline. Many could not identify or explain the use of certificates: MED-3 (50 or 71%, respectively), MED-5 (42 or 38%, respectively), MED-10 (0 or 17%, respectively), RM-7 (2 or 6%, respectively) and DS-1500 (6 or 8%, respectively). Majority of participants thought that an educational module could increase knowledge and skill in sickness certification (96%) and in assessing work capacity (74%)., Conclusions: Junior doctors are involved in sickness certification, but there is a lack of training at undergraduate and postgraduate level, and many are unaware of formal guidance. The majority of junior doctors are concerned about lack of knowledge in this area and to a lesser extent in assessing patients' capacity to work. A simple educational module could improve confidence, knowledge and skills in sickness certification.

Asthma control, defined by asthma symptoms and lung function, and asthma medication use, was assessed in 123 adolescent asthmatics. Sputum eosinophilia (>or= 2.5% eosinophils) and bronchial hyperresponsiveness (BHR) to hypertonic saline were also measured to assess whether these additional objective parameters might aid in determining asthma control; 54.5% of subjects had adequately controlled asthma; 50.4% of all subjects reported inhaled corticosteroid use in the preceding 12 months; however, only 22.3% reported regular use. Although BHR and median eosinophil numbers were significantly higher in the inadequately controlled asthmatics, BHR and sputum eosinophilia had poor sensitivity for detecting inadequate asthma control.

Non-Maori Pacific people constitute a significant and rapidly growing population in New Zealand. An accompanying change in lifestyle associated with changing socio-economic environments results in a change in disease patterns including cancer. The paucity of reliable data on cancer necessitates our effort to contribute to the control of cancer by reviewing the available information. Our study indicates a high incidence among non-Maori Pacific people of some cancers of public health importance as well as a disproportionately high mortality rate compared to non-Maori, non-Pacific people in New Zealand. In addition, we challenge previous documentation of a significant and high incidence of cervical cancer among Pacific women compared to non-Pacific people in New Zealand. We also identified the need to remedy the inadequacy in data quality as part of any strategy to prevent and control the rising incidence and mortality attributed to cancer among non-Maori Pacific people. In addition we have commenced regional training on cancer epidemiology and propose further cancer studies in both New Zealand and the Pacific Islands.