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Professor of Orthopaedic and Tropical Surgery and Consultant Orthopaedic and Spine Surgeon Chris Lavy has been awarded a prestigious honorary fellowship by the British Orthopaedic Association (BOA).
Longitudinal modelling of growth in neonates exposed to antenatal steroids to quantify associations with final height: a cohort study.
OBJECTIVE: To assess the associations of antenatal steroids with child growth. DESIGN: Longitudinal observational cohort study started in 1994. SETTING: A single tertiary neonatal centre in Sheffield, UK. PARTICIPANTS: Of 254 individuals recruited, two were excluded, 48 born at term; 202 (57% boys, 87% white ethnicity) modelled had a median of 19 height measurements each (Q1:12 to Q3:21) up to median age 15.8 years (Q1:9.9 to Q3:16.9). INTERVENTIONS: Data on administration of antenatal steroids were collected alongside gestational age and parental height. MAIN OUTCOME MEASURES: Height was modelled with SuperImposition by Translation and Rotation (SITAR) to extract each person's peak velocity and age at peak velocity via the SITAR random effects of 'size', 'timing' and 'intensity' and to predict height at 18 years. The association of each random effect and final height with exposure to antenatal steroids was assessed by multiple regression to adjust for covariates. RESULTS: In girls with covariates available (n=59/87), exposure to antenatal steroids was positively associated with SITAR 'size' and 'intensity' of growth when adjusted for gestational age, maternal and paternal height, equating to a final height 2.8 cm (95% CI 0.3 to 5.3 cm) greater than for those not exposed to antenatal steroids. In boys (n=66/115), exposure to antenatal steroids had no association with final height. CONCLUSIONS: This observational cohort study showed greater height of girls exposed to antenatal steroids not seen in boys. Analysis of existing long-term follow-up data from neonates is indicated to increase understanding of the associations of neonatal interventions on growth.
A 3-week pause versus continued Bruton tyrosine kinase inhibitor use during COVID-19 vaccination in individuals with chronic lymphocytic leukaemia (IMPROVE trial): a randomised, open-label, superiority trial.
BACKGROUND: Chronic lymphocytic leukaemia is the commonest leukaemia and is associated with profound immunosuppression. Bruton tyrosine kinase inhibitors (BTKi) have revolutionised chronic lymphocytic leukaemia management; however, therapy impairs vaccine-induced immunity. We evaluated whether a 3-week pause of BTKi treatment improved spike protein receptor binding domain (RBD) immunity to SARS-CoV-2 booster vaccination while maintaining disease control. METHODS: We performed an open-label, two-arm, parallel-group, randomised trial in secondary-care haematology clinics in 11 UK hospitals. Participants aged 18 years or older, diagnosed with chronic lymphocytic leukaemia, and currently taking BTKi therapy (frontline or relapsed setting) for at least 12 months were eligible. Participants were randomly allocated (1:1, by a centralised computer randomisation program, stratified by BTKi therapy line) to pause BTKi for 3 weeks, starting 6 days before their SARS-CoV-2 vaccination booster date, or to continue therapy as usual. Neither participants nor clinical staff were blinded but laboratory staff were. Intramuscular injection of either original BA.1 or original BA.4/5 bivalent mRNA vaccine (50 μg mRNA-1273 or 30 μg BNT162b2), or 5 μg protein-based Vidprevtyn Beta (Sanofi Pasteur, Lyon, France) were received according to the national vaccination programme schedule. The primary outcome measure was anti-spike-RBD-specific antibody titre 3 weeks after vaccination and analysis performed by intention to treat (as randomly allocated, irrespective of compliance) following trial completion. This trial is registered with ISRCTN, 14197181, and has been completed. FINDINGS: Between Oct 10, 2022, and June 8, 2023, 99 individuals (71 [72%] male and 28 [28%] female, with 89 [90%] of White ethnicity) were randomly allocated to groups pausing (n=50 [51%]) or continuing (n=49 [49%]) their BTKi therapy, and followed up for 12 weeks. At 3 weeks after vaccination, the geometric mean anti-spike-RBD-specific antibody titre was 218·8 U/mL (SD 122·9) in the continue group and 153·4 U/mL (103·2) in the pause group, with geometric mean ratio 1·104 (95% CI 0·565-2·158, p=0·77) using a mixed-effects model. The only serious adverse event during the 12-week follow-up was the death of one participant in the pause group due to COVID-19 infection 2 months after randomisation. INTERPRETATION: Although the study was slightly underpowered, the results suggest that pausing BTKi around the time of vaccination is not beneficial for immunity and should not be recommended in clinical practice. FUNDING: National Institute for Health and Care Research.
Impact of Climate Change and Extreme Temperature on the Incidence of Infectious Disease Among Children and Adolescents in China: A Nationwide Case-crossover Study with over 8.7 million cases between 2008 and 2019.
BACKGROUND: The relationship between ambient temperature and infectious disease incidence lacks comprehensive documentation. Our study, therefore, sought to systematically determine the national association between temperature and the incidence of infectious diseases, categorized into respiratory, gastrointestinal and enterovirus, and vector-borne categories. We aimed to study the association between extreme cold and heat extreme temperature on infectious disease occurrence among children and teenagers, and to evaluate the secular trends in these diseases in relation to temperature extremes. METHODS: We accessed the dataset encompassing 8,731,930 cases of 27 distinct infectious diseases, spanning respiratory, gastrointestinal and enterovirus infections, and vector-borne categories, across 507 Chinese cities from 2008 to 2019. Employing a time-stratified case-crossover design, we quantified the association between temperature exposure and the risk of infectious diseases specific to each city. The attributable fractions for temperature-related risks were determined by identifying extreme temperatures exceeding the 90th percentile and falling below the 10th percentile of the respective city-specific temperature distributions, indicative of heat and cold effects. A comparative analysis of these attributable fractions between the periods 2008-2010 and 2017-2019 was conducted to evaluate the secular changes of infectious diseases associated with cold and heat. FINDINGS: Our analysis revealed significant non-linear associations between temperature and the incidence of specific infectious diseases. Cold temperatures were found to be responsible for 1.35% (95% CI: 1.18 to 1.51%) of respiratory infectious disease cases. In contrast, heat was attributed to a lower proportion, with 0.29% (95% CI: 0.25 to 0.33%) of such cases. Among gastrointestinal and enterovirus diseases, a more substantial 4.93% (95% CI: 4.82 to 5.04%) of cases were linked to heat exposure. Notably, vector-borne diseases demonstrated the highest attributable fraction to heat, with 22.12% (95% CI: 21.82 to 22.41%) of cases affected. Specifically, five diseases-scarlet fever, tuberculosis, mumps, leprosy, and typhus-exhibited an increased incidence associated with cold temperatures. Notably, for scarlet fever, leprosy, and typhus, the attributable fraction escalated from the period 2008-2010 to 2017-2019. However, findings for leprosy should be interpreted with caution due to its low incidence. As for heat-related diseases, thirteen were identified, with the attributable fraction for nine diseases-tuberculosis, pertussis, hand, foot, and mouth disease, infectious diarrhea, dysentery, hepatitis A, typhoid and paratyphoid, dengue, and Japanese encephalitis-showing a marked increase over the same comparative timeframes. INTERPRETATION: The temperature increase observed from 2008-2010 to 2017-2019 has been accompanied by a rising trend in heat-related infections. Among all infectious diseases in Chinese children and adolescents, more than half (13 out of 24) are heat-related, compared to five infections linked to extreme cold. The risk of gastrointestinal and enterovirus infections was associated with extreme hot temperatures, with vector-borne diseases particularly responsive to extreme heat. These findings highlight an urgent requirement for proactive public health measures to address the potential impact of temperature variability on infectious disease outbreaks, safeguarding vulnerable demographics in the context of climate change.
Association between the serotonin transporter gene and alcohol consumption in social drinkers
Relatively few studies have investigated the role of the 5HTT gene in intermediate phenotypes such as alcohol consumption in non-alcohol dependent populations. A recent study reported an association with alcohol consumption in a student population. We attempted to replicate these findings and extend on this work in a representative, ethnically homogenous, non-alcohol dependent sample of social drinkers in the United Kingdom. The short allele of the 5HTT gene was significantly associated with, increased alcohol consumption (P = 0.03). There was suggestive evidence of a genotype-sex interaction (P = 0.04). Post-hoc tests indicated higher alcohol consumption in men with one or more copies of the short allele, while in women consumption was highest among heterozygotes compared to both homozygote groups. Age at time of data collection and cigarette consumption were entered as covariates. These results replicate recent previous findings and suggest a possibility that this association may differ in men and women. © 2005 Wiley-Liss, Inc.
Zyban for smoking cessation in a general practice setting: the response to an invitation to make a quit attempt.
The objective of this study was to assess the feasibility and success of Zyban as part of a moderately supported smoking cessation programme within UK general practice. Treatment was offered to 479 moderately dependent smokers (smoking 15 or more cigarettes per day) who had never used Zyban, and who had taken part in a previous NRT trial (the PATCH study). Main outcome measures were point prevalence and continuous abstinence from smoking at 6 and at 12 months. Two hundred and forty were excluded because of medical reasons or prescribing contraindication. Of the remainder (n=239) only 54 (23%) made an active quit attempt. Thirty percent (16/54) were abstinent at six months, and 22% (12/54) at 12 months (biochemically validated point prevalence rates). Age, socio-economic status, nicotine dependence, and genetic profile appeared to have little impact on success rates, but male quit-attempters were significantly more successful than female (40% vs. 10% at 12 months, p<0.05). In conclusion, a real-world smoking cessation programme using Zyban with moderate support within a general practice setting may achieve satisfactory quit rates without widening existing disparities in cessation.
The dopamine D2 receptor C32806T polymorphism (DRD2 Taq1A RFLP) exhibits no association with smoking behaviour in a healthy UK population.
A single nucleotide polymorphism (SNP) in the Taq1A site near the DRD2 gene has been associated in several studies with smoking behaviour. We genotyped 732 current smokers (241 low, one to nine cigarettes a day, 250 mid, 10-19 cigarettes, 241 high, 20+cigarettes) and 243 never-smokers at this site (C32806T), to test for effects on smoking initiation and amount of tobacco consumed. No significant association between minor allele frequency and smoking status was detected. Multiple regression analysis including DRD2 genotype, sex, age and alcohol consumption as predictors showed that level of cigarette consumption was associated with sex (p=0.003) and age (p=0.002) but not with alcohol consumption (p=0.25) or DRD2 genotype (p=0.76).
Pharmacogenomics of Tobacco Addiction
The precise mechanism of nicotine addiction and the influence of genetics on smoking behavior are beginning to be elucidated. A major challenge for the new science of pharmacogenomics is to utilize recent discoveries in genetics to improve existing smoking cessation therapies. Traditional candidate gene studies show that genetic polymorphisms affecting nicotine metabolism and dopaminergic transmission increase the susceptibility to tobacco dependence. Chromosomal regions in which other relevant genes may be located have recently been identified by genome scans. Combining these techniques may open the door to largescale rationally designed studies to identify new genes that are important in the development of nicotine dependence. Animal models have also been used to unravel genetic influences on the behavioral effects of nicotine and highlight in particular the important role that the acetylcholine receptor plays in nicotine action. This chapter reviews these various approaches to elucidating the genetic basis of nicotine dependence. We explore the potential benefits of classifying smokers according to the molecular etiology of their habit in order to plan individually targeted cessation strategies.
Synthesis, biological evaluation and mechanism study based on network pharmacology of amino acids esters of 20(S)-protopanaxadiol as novel anticancer agents.
As one of the metabolites of ginseng, 20(S)-protopanaxadiol (PPD) is a compound with dammarane-type tetracyclic triterpene, which performs a wide range of anticancer activities. In this study, PPD was used as a lead. A series of compounds were synthesized respectively with 11 amino acids through esterification and were evaluated for their cytotoxicity against several cancer cell lines. One of the synthetic products (PL) exhibited potent inhibitory effect on Huh-7 cells relative to that of PPD in vitro. Subsequently, the Annexin V-FITC /PI staining assay was used to verify that PL induced apoptosis of Huh-7 cells in a dose-dependent manner. A UPLC-Q/TOF-MS analysis method was established and validated for assessing pharmacokinetic properties after the administration of PPD and PL in rats. The results showed that compared with PPD, T1/2of PL in rats was prolonged, and the peak time was delayed, resulting in broader tissue distribution of the compound in the body. In addition, the targets of PL against several cancers were predicted and analyzed via network pharmacology. Molecular docking simulations demonstrated that PL interacted with the active sites of the above targets. In conclusion, this study provided a theoretical basis for the development and clinical application of anti-tumor activity of PPD.
Aberrant P53 expression lacks prognostic or predictive significance in colorectal cancer: results from the VICTOR trial.
AIM: Biomarkers with prognostic and predictive value can help stratify patients with colorectal cancer (CRC) into appropriate treatment groups. We sought to evaluate the clinical utility of P53 protein expression as a biomarker in VICTOR, a large phase III trial of rofecoxib in stage II and III CRC. PATIENTS AND METHODS: Tissue micro arrays were constructed from 884 tumors and the expression of P53 was examined by immunohistochemistry. Tumors were dichotomised as either P53-positive (nuclear expression in >10% of cells or the 'absent' pattern, both representing TP53 mutation) or P53-negative (nuclear expression in <10% of cells). RESULTS: Aberrant P53 expression was found in 65% (482/740) of patients. It was associated with distal location (p<0.001) and stage III disease (p<0.001). No effect was observed on disease-free or overall survival, and there was no interaction with chemotherapy or radiotherapy. CONCLUSION: Analysis of P53 expression in the patients recruited to the VICTOR trial confirmed that P53 expression is associated with site and stage of CRC. However, independently, this biomarker has neither prognostic nor predictive utility in this cohort of patients.
PTEN loss in the continuum of common cancers, rare syndromes and mouse models.
PTEN is among the most frequently inactivated tumour suppressor genes in sporadic cancer. PTEN has dual protein and lipid phosphatase activity, and its tumour suppressor activity is dependent on its lipid phosphatase activity, which negatively regulates the PI3K-AKT-mTOR pathway. Germline mutations in PTEN have been described in a variety of rare syndromes that are collectively known as the PTEN hamartoma tumour syndromes (PHTS). Cowden syndrome is the best-described syndrome within PHTS, with approximately 80% of patients having germline PTEN mutations. Patients with Cowden syndrome have an increased incidence of cancers of the breast, thyroid and endometrium, which correspond to sporadic tumour types that commonly exhibit somatic PTEN inactivation. Pten deletion in mice leads to Cowden syndrome-like phenotypes, and tissue-specific Pten deletion has provided clues to the role of PTEN mutation and loss in specific tumour types. Studying PTEN in the continuum of rare syndromes, common cancers and mouse models provides insight into the role of PTEN in tumorigenesis and will inform targeted drug development.
What is the role and impact of molecular markers on treatment decisions for colorectal cancer in the adjuvant setting?
The new mantra for delivering optimal cancer treatment is "personalized care." This extends beyond the holistic to using germline and somatic tumoral mutations to link a specific therapy to some prognostic or predictive factor which defines a particularly responsive patient subgroup who might benefit most from treatment. Furthermore, inherited polymorphisms have the potential to greatly modulate the side effects of treatment, especially for chemotherapy which has a notoriously narrow therapeutic window.
Smoking cessation, weight gain, and DRD4 −521 genotype
AbstractWe investigated change in body mass index following long‐term smoking cessation in a representative cohort of treatment‐seeking heavy smokers in the United Kingdom, to determine the extent of long‐term weight gain in successful quitters versus continuing smokers. We further investigated whether DRD4 genotype moderated any weight gain in either group. Smoking cessation was associated with an increase in BMI, and persisted up to 8 years after smoking cessation. Ex‐smokers at 8‐year follow‐up weighed over 2.5 kg/m3 more on average than they did at baseline, while participants who were smokers at both baseline and 8‐year follow‐up did not demonstrate any change in BMI. We did not observe an interaction between smoking status and DRD4 genotype. However, independently of the weight gain among those who stopped smoking during the course of the study, DRD4 genotype was significantly associated with BMI, with possession of the −521 C‐allele associated with increased BMI. The magnitude of increase in BMI following smoking cessation, and the persistence of this change at 8‐year follow‐up, suggests that health benefits associated with smoking cessation may to some extent be negated by the detrimental effects on health of associated weight gain. Smoking cessation programmes should therefore consider incorporating follow‐up support to promote weight loss among those who successfully stop smoking. © 2006 Wiley‐Liss, Inc.
Neurophysiological effects of high-frequency spinal cord stimulation on cortico-sensory areas in large ovine animal model.
Spinal Cord Stimulation (SCS) has been a cornerstone in managing chronic pain since the late 1960s. However, traditional SCS is often associated with variable efficacy and side effects, driving the development of advanced techniques like high-frequency SCS (hSCS). Previous studies have demonstrated that the power of high-frequency cerebral oscillations increases as a function of stimulus intensity and plays a critical role in local neural processing of peripheral sensory stimuli. Extending from the current body of literature, we hypothesized that hSCS could selectively influence stimulus-triggered neural oscillations involved in sensory processing and perception. Using electrocorticography (ECoG) in sheep (n = 4), we investigated the effects of 8.2 KHz hSCS on low-frequency (4-30 Hz) and high-frequency (70-150 Hz) oscillations in ovine somatosensory and association cortices. Neural signals were recorded before, and after hSCS application to assess frequency-specific modulation of cortical activity. Our findings reveal that hSCS induces broad suppression of high-frequency oscillations across both cortical regions. In contrast, low-frequency oscillations were selectively suppressed or enhanced in both cortices. Furthermore, a linear mixed model analysis revealed that low-frequency oscillations better predict high-frequency modulation in the association than the somatosensory cortex, highlighting a reciprocal low-/high-frequency relationship between cortices. These distinct effects on cortical oscillations suggest potential supraspinal mechanisms through which hSCS may exert its analgesic effects. Our findings provide new insights for optimizing neuromodulation strategies in pain management, emphasizing the role of frequency-specific modulation in sensory and cognitive pain processing. PERSPECTIVE: This study demonstrates that high-frequency spinal cord stimulation modulates cortical oscillations in a frequency- and region-specific manner, suggesting a supraspinal mechanism of pain. These findings advance our understanding of how neuromodulation influences sensory components of pain, with implications for optimizing stimulation protocols in chronic pain management.
Meet Chris
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Chris Lavy
Professor of Orthopaedic and Tropical Surgery and Consultant Orthopaedic and Spine Surgeon
