Aberrant p16, p53 and Ki-67 immunohistochemistry staining patterns can distinguish solitary keratoacanthoma from cutaneous squamous cell carcinoma.

Keratoacanthoma (KA) is widely considered a benign, usually self-resolving, neoplasm distinct from cutaneous squamous cell carcinoma (cSCC), while some consider KA to be indistinguishable from cSCC. Published studies indicate utility for p16, p53, Ki-67 immunostaining and elastic van Gieson (EVG) in the assessment of KA and cSCC. We compared clinical features and staining patterns for p16, p53, Ki-67 and EVG in fully excised KA, cSCC with KA-like features (cSCC-KAL) and other cSCC (cSCC-OTHER). Significant differences between KA, cSCC-KAL and cSCC-OTHER were found for head and neck location (20%, 86%, 84%), and duration <5 months (95%, 63%, 36%). KA shows both a mosaic pattern for p16 (>25-90% of neoplasm area) and peripheral graded pattern for p53 (up to 50% moderate and strong nuclear staining) in 92% compared with 0% of cSCC-KAL and 0% of cSCC-OTHER. In contrast, a highly aberrant pattern (usually null) for one or both p16 and p53, was present in 0% of KA, 83.8% of cSCC-KAL and 90.9% of cSCC-OTHER. Abnormal distribution of Ki-67 beyond the peripheral 1-3 cells was uncommon in KA (4.2%) and common in cSCC-KAL (67.6%) and cSCC-OTHER (88.4%). Moderate to striking entrapment of elastic and collagen fibres was present in the majority of KA (84%), cSCC-KAL (81%) and cSCC-OTHER (65%). KA are clinically distinct neoplasms typically of short duration occurring preferentially outside the head and neck and generally lacking aberrations of p16, p53 and Ki-67, compared with cSCC that have high rates of aberrant or highly aberrant p16, p53 and Ki-67, but EVG lacked specificity.

Association of Onset-to-Treatment Time With Discharge Destination, Mortality, and Complications Among Patients With Aneurysmal Subarachnoid Hemorrhage.

Importance: Rapid access to specialized care is recommended to improve outcomes after aneurysmal subarachnoid hemorrhage (SAH), but understanding of the optimal onset-to-treatment time for aneurysmal SAH is limited. Objective: To assess the optimal onset-to-treatment time for aneurysmal SAH that maximized patient outcomes after surgery. Design, Setting, and Participants: This cohort study assessed 575 retrospectively identified cases of first-ever aneurysmal SAH occurring within the referral networks of 2 major tertiary Australian hospitals from January 1, 2010, to December 31, 2016. Individual factors, prehospital factors, and hospital factors were extracted from the digital medical records of eligible cases. Data analysis was performed from March 1, 2020, to August 31, 2021. Exposures: Main exposure was onset-to-treatment time (time between symptom onset and aneurysm surgical treatment in hours) derived from medical records. Main Outcomes and Measures: Clinical characteristics, complications, and discharge destination were extracted from medical records and 12-month survival obtained from data linkage. The associations of onset-to-treatment time (in hours) with (1) discharge destination of survivors (home vs rehabilitation), (2) 12-month survival, and (3) neurologic complications (rebleed, delayed cerebral ischemia, meningitis, seizure, hydrocephalus, and delayed cerebral injury) were investigated using natural cubic splines in multivariable Cox proportional hazards and logistic regression models. Results: Of the 575 patients with aneurysmal SAH, 482 patients (mean [SD] age, 55.0 [14.5] years; 337 [69.9%] female) who received endovascular coiling or neurosurgical clipping were studied. A nonlinear association of treatment delay was found with the odds of being discharged home vs rehabilitation (effective df = 3.83 in the generalized additive model, χ2 test P = .002 for the 4-df cubic spline), with a similar nonlinear association remaining significant after adjustment for sex, treatment modality, severity, Charlson Comorbidity Index, history of hypertension, and hospital transfer (likelihood ratio test: df = 3, deviance = 9.57, χ2 test P = .02). Both unadjusted and adjusted cox regression models showed a nonlinear association between time to treatment and 12-month mortality with the lowest hazard of death with receipt of treatment at 12.5 hours after symptom onset, although the nonlinear term became nonsignificant upon adjustment. The odds of being discharged home were higher with treatment before 20 hours after onset, with the probability of being discharged home compared with rehabilitation or other hospital increased by approximately 10% when treatment was received within the first 12.5 hours after symptom onset and increased by an additional 5% from 12.5 to 20 hours. Time to treatment was not associated with any complications. Conclusions and Relevance: This cohort study found evidence that more favorable outcomes (discharge home and survival at 12 months) were achieved when surgical treatment occurred at approximately 12.5 hours. These findings provide more clarity around optimal timelines of treatment with people with aneurysmal SAH; however, additional studies are needed to confirm the findings.

Sex differences in aneurysmal subarachnoid haemorrhage (aSAH): aneurysm characteristics, neurological complications, and outcome.

BACKGROUND: Women are over-represented in aSAH cohorts, but whether their outcomes differ to men remains unclear. We examined if sex differences in neurological complications and aneurysm characteristics contributed to aSAH outcomes. METHODS: In a retrospective cohort (2010-2016) of all aSAH cases across two hospital networks in Australia, information on severity, aneurysm characteristics and neurological complications (rebleed before/after treatment, postoperative stroke < 48 h, neurological infections, hydrocephalus, seizures, delayed cerebral ischemia [DCI], cerebral infarction) were extracted. We estimated sex differences in (1) complications and aneurysm characteristics using chi square/t-tests and (2) outcome at discharge (home, rehabilitation or death) using multinomial regression with and without propensity score matching on prestroke confounders. RESULTS: Among 577 cases (69% women, 84% treated) aneurysm size was greater in men than women and DCI more common in women than men. In unadjusted log multinomial regression, women had marginally greater discharge to rehabilitation (RRR 1.15 95% CI 0.90-1.48) and similar likelihood of in-hospital death (RRR 1.02 95% CI 0.76-1.36) versus discharge home. Prestroke confounders (age, hypertension, smoking status) explained greater risk of death in women (rehabilitation RRR 1.13 95% CI 0.87-1.48; death RRR 0.75 95% CI 0.51-1.10). Neurological complications (DCI and hydrocephalus) were covariates explaining some of the greater risk for poor outcomes in women (rehabilitation RRR 0.87 95% CI 0.69-1.11; death RRR 0.80 95% CI 0.52-1.23). Results were consistent in propensity score matched models. CONCLUSION: The marginally poorer outcome in women at discharge was partially attributable to prestroke confounders and complications. Improvements in managing complications could improve outcomes.

Incidence of indications for tonsillectomy and frequency of evidence-based surgery: a 12-year retrospective cohort study of primary care electronic records.

BACKGROUND: Neither the incidence of indications for childhood tonsillectomy nor the proportion of tonsillectomies that are evidence-based is known. AIM: To determine the incidence of indications for tonsillectomy in UK children, and the proportion of tonsillectomies meeting evidence-based criteria. DESIGN AND SETTING: A retrospective cohort study of electronic medical records of children aged 0-15 years registered with 739 UK general practices contributing to a research database. METHOD: Children with recorded indications for tonsillectomy were identified from electronic medical records. Evidence-based indications included documented sore throats of sufficient frequency and severity (Paradise criteria); periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA); or tonsillar tumour. Other indications were considered non-evidence-based. The numbers of children subsequently undergoing tonsillectomy was then identified. The numbers with evidence-based and non-evidence-based indications for surgery among children who had undergone tonsillectomy were determined. RESULTS: The authors included 1 630 807 children followed up for 7 200 159 person-years between 2005 and 2016. Incidence of evidence-based indications for tonsillectomy was 4.2 per 1000 person years; 13.6% (2144/15 760) underwent tonsillectomy. Incidence of childhood tonsillectomy was 2.5 per 1000 person years; 11.7% (2144/18 281) had evidence-based indications, almost all with Paradise criteria. The proportion of evidence-based tonsillectomies was unchanged over 12 years. Most childhood tonsillectomies followed non-evidence-based indications: five to six sore throats (12.4%) in 1 year, two to four sore throats (44.6%) in 1 year, sleep disordered breathing (12.3%), or obstructive sleep apnoea (3.9%). CONCLUSION: In the UK, few children with evidence-based indications undergo tonsillectomy and seven in eight of those who do (32 500 of 37 000 annually) are unlikely to benefit.

Implementing a Primary Healthcare Framework: The Importance of Nursing Leadership in Developing and Maintaining a Brain Tumor Support Group.

BACKGROUND: Although brain tumor support groups have been available internationally for many years, Liverpool Hospital in Australia has not traditionally provided this service. As a leadership initiative, the development of a brain tumor support group that incorporates a primary healthcare framework is a sustainable approach that showcases the role of nursing leaders in changing attitudes and improving outcomes. OBJECTIVES: The purpose of this review of the literature and reflection of clinical experience is to explore nursing leadership within brain tumor-specific support groups. METHODS: This article will showcase a nurse-led group that incorporated a coordinated approach to delivering patient-centered care. FINDINGS: The initiation of activities and interventions that reflected the five tenets of primary health care resulted in improved outcomes for individuals and their family caregivers throughout the trajectory of their illness. Vital to the success of this project was moving from a standalone leader to building collective and collaborative leadership more conducive to facilitating change. The support group successfully demonstrated that individuals and family caregivers may see ongoing and long-term improvements during and following treatment.

The association between smoking cessation and glycaemic control in patients with type 2 diabetes: a THIN database cohort study.

BACKGROUND: Smoking increases the risk of developing type 2 diabetes. However, several population studies also show a higher risk in people 3-5 years after smoking cessation than in continuing smokers. After 10-12 years the risk equates to that of never-smokers. Small cohort studies suggest diabetes control deteriorates temporarily during the first year after quitting. We examined whether or not quitting smoking was associated with altered diabetes control in a population study, for how long this association persisted, and whether or not this association was mediated by weight change. METHODS: We did a retrospective cohort study (Jan 1, 2005, to Dec 31, 2010) of adult smokers with type 2 diabetes using The Health Improvement Network (THIN), a large UK primary care database. We developed adjusted multilevel regression models to investigate the association between a quit event, smoking abstinence duration, change in HbA1c, and the mediating effect of weight change. FINDINGS: 10 692 adult smokers with type 2 diabetes were included. 3131 (29%) quit smoking and remained abstinent for at least 1 year. After adjustment for potential confounders, HbA1c increased by 0·21% (95% CI 0·17-0·25; p<0·001; [2·34 mmol/mol (95% CI 1·91-2·77)]) within the first year after quitting. HbA1c decreased as abstinence continued and became comparable to that of continual smokers after 3 years. This increase in HbA1c was not mediated by weight change. INTERPRETATION: In type 2 diabetes, smoking cessation is associated with deterioration in glycaemic control that lasts for 3 years and is unrelated to weight gain. At a population level, this temporary rise could increase microvascular complications. FUNDING: National Institute for Health Research School for Primary Care Research.

Lack of attentional retraining effects in cigarette smokers attempting cessation: a proof of concept double-blind randomised controlled trial.

BACKGROUND: Observational studies have shown that attentional bias for smoking-related cues is associated with increased craving and relapse. Laboratory experiments have shown that manipulating attentional bias may change craving. Interventions to reduce attentional bias could reduce relapse in smokers seeking to quit. We report a clinical trial of attentional retraining in treatment-seeking smokers. METHODS: This was a double-blind randomised controlled trial that took place in UK smoking cessation clinics. Smokers interested in quitting were randomised to five weekly sessions of attentional retraining (N=60) or placebo training (N = 58) using a modified visual probe task from one week prior to quit day. Both groups received 21 mg nicotine patches (from quit day onwards) and behavioural support. Primary outcomes included change in attentional bias reaction times four weeks after quit day on the visual probe task and craving measured weekly using the Mood and Physical Symptoms Scale. Secondary outcomes were changes in withdrawal symptoms, time to first lapse and prolonged abstinence. RESULTS: No attentional bias towards smoking cues was found in the sample at baseline (mean difference = 3 ms, 95% CI = -2, 9). Post-training bias was not significantly lower in the retraining group compared with the placebo group (mean difference = -9 ms, 95% CI = -20, 2). There was no difference between groups in change in craving (p = 0.89) and prolonged abstinence at four weeks (risk ratio = 1.00, 95% CI = 0.70, 1.43). CONCLUSIONS: Taken with one other trial, there appears to be no effect from clinic-based attentional retraining using the visual probe task. Attentional retraining conducted out of clinic may prove more effective. CLINICAL TRIAL REGISTRATION: UK Clinical Trials ISRCTN 54375405.

Smoking and Smoking Increase in Caregivers of Alzheimer's Patients.

PURPOSE OF THE STUDY: The relationship between stress and smoking has been established, but there is little research on the effects of stress and coping on smoking in caregivers of Alzheimer's disease patients. This study examines how caregiver stressors and coping resources explain smoking status and recent smoking increase. DESIGN AND METHODS: Data were obtained from the Resources for Enhancing Alzheimer's Caregivers Health (REACH II) study. Analyses identified differences between caregiver smokers and nonsmokers and between caregiver smokers who reported a recent smoking increase and those who did not. Variables that were significantly different between the groups were examined in two logistic regression analyses to explain smoking status and smoking increase. RESULTS: Of 642 caregivers, nearly 40% reported smoking and 25% of smokers reported recent increase in smoking. Younger caregivers were more likely to report smoking. Explanatory variables for smoking increase were being Caucasian or African-American, higher depression scores, and less caregiving skills. IMPLICATIONS: This study demonstrates that smoking among caregivers is a valid public health concern. Further investigation of ways that explanatory variables affect smoking status and increase in caregivers, and incorporation of smoking cessation strategies that address depression and low caregiving skills, seem warranted in future caregiver interventions.

Attentional bias retraining in cigarette smokers attempting smoking cessation (ARTS): study protocol for a double blind randomised controlled trial.

BACKGROUND: Smokers attend preferentially to cigarettes and other smoking-related cues in the environment, in what is known as an attentional bias. There is evidence that attentional bias may contribute to craving and failure to stop smoking. Attentional retraining procedures have been used in laboratory studies to train smokers to reduce attentional bias, although these procedures have not been applied in smoking cessation programmes. This trial will examine the efficacy of multiple sessions of attentional retraining on attentional bias, craving, and abstinence in smokers attempting cessation. METHODS/DESIGN: This is a double-blind randomised controlled trial. Adult smokers attending a 7-session weekly stop smoking clinic will be randomised to either a modified visual probe task with attentional retraining or placebo training. Training will start 1 week prior to quit day and be given weekly for 5 sessions. Both groups will receive 21 mg transdermal nicotine patches for 8-12 weeks and withdrawal-orientated behavioural support for 7 sessions. Primary outcome measures are the change in attentional bias reaction time and urge to smoke on the Mood and Physical Symptoms Scale at 4 weeks post-quit. Secondary outcome measures include differences in withdrawal, time to first lapse and prolonged abstinence at 4 weeks post-quit, which will be biochemically validated at each clinic visit. Follow-up will take place at 8 weeks, 3 months and 6 months post-quit. DISCUSSION: This is the first randomised controlled trial of attentional retraining in smokers attempting cessation. This trial could provide proof of principle for a treatment aimed at a fundamental cause of addiction. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN54375405.

Assessing the predictive value of HIV indicator conditions in general practice: a case-control study using the THIN database.

BACKGROUND: UK HIV guidelines identify 37 clinical indicator conditions for adult HIV infection that should prompt an HIV test. However, few data currently exist to show their predictive value in identifying undiagnosed HIV. AIM: To identify symptoms and clinical diagnoses associated with HIV infection and assess their relative importance in identifying HIV cases, using data from The Health Improvement Network (THIN) general practice database. DESIGN AND SETTING: A case-control study in primary care. METHOD: Cases (HIV-positive patients) were matched to controls (not known to have HIV). Data from 939 cases and 2576 controls were included (n = 3515). Statistical analysis assessed the incidence of the 37 clinical conditions in cases and controls, and their predictive value in indicating HIV infection, and derived odds ratios (ORs) for each indicator condition. RESULTS: Twelve indicator conditions were significantly associated with HIV infection; 74.2% of HIV cases (n = 697) presented with none of the HIV indicator conditions prior to diagnosis. The conditions most strongly associated with HIV infection were bacterial pneumonia (OR = 47.7; 95% confidence interval [CI] = 5.6 to 404.2) and oral candidiasis (OR = 29.4; 95% CI = 6.9 to 125.5). The signs and symptoms most associated with HIV were weight loss (OR = 13.4; 95% CI = 5.0 to 36.0), pyrexia of unknown origin (OR = 7.2; 95% CI = 2.8 to 18.7), and diarrhoea (one or two consultations). CONCLUSION: This is the first study to quantify the predictive value of clinical diagnoses related to HIV infection in primary care. In identifying the conditions most strongly associated with HIV, this study could aid GPs in offering targeted HIV testing to those at highest risk.

Evaluating the effectiveness of GP endorsement on increasing participation in the NHS Bowel Cancer Screening Programme in England: study protocol for a randomized controlled trial.

BACKGROUND: The success and cost-effectiveness of bowel cancer screening depends on achieving and maintaining high screening uptake rates. The involvement of GPs in screening has been found to improve patient compliance. Therefore, the endorsement of screening by GPs may increase uptake rates amongst non-responders. METHODS/DESIGN: A two-armed randomised controlled trial will evaluate the effectiveness of a GP endorsed reminder in improving patient participation in the NHS Bowel Cancer Screening Programme (NHSBCSP). Up to 30 general practices in the West Midlands with a screening uptake rate of less than 50% will be recruited and patients identified from the patient lists of these practices. Eligible patients will be those aged 60 to 74, who have previously been invited to participate in bowel screening but who have been recorded by the Midlands and North West Bowel Cancer Screening Hub as non-responders. Approximately 4,380 people will be randomised in equal numbers to either the intervention (GP letter and duplicate FOBt kit) or control (no additional contact) arms of the trial. The primary outcome measure will be the difference in the uptake rate of FOBt screening for bowel cancer between the intervention and control groups at 13 weeks after the GP endorsed reminder and duplicate FOBt kit are sent. Secondary outcome measures will be subgroup analyses of uptake according to gender, age and deprivation quartile, and the validation of methods for collecting GP, NHSBCSP and patient costs associated with the intervention. Qualitative work (30 to 40 semi-structured interviews) will be undertaken with individuals in the intervention arm who return a FOBt kit, to investigate the relative importance of the duplicate FOBt kit, reminder to participate, and GP endorsement of that reminder in contributing to individuals' decisions to participate in screening. DISCUSSION: Implementing feasible, acceptable and cost-effective strategies to improve screening uptake amongst non-responders to invitations to participate is fundamentally important for the success of screening programmes. If this feasibility study demonstrates a significant increase in uptake of FOBt screening in individuals receiving the intervention, a definitive, appropriately powered future trial will be designed. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN86784060.

Molecular monitoring of chronic myeloid leukemia: a personalized approach to optimizing treatment response.

Personalized medicine is rapidly developing a purposeful niche in the field of oncology. Monitoring the activity of the oncogenic fusion gene BCR-ABL1 in chronic myeloid leukemia (CML) is a good example of individualizing CML treatment for patients using patient-specific genetic information. However, the frequency at which molecular monitoring for BCR-ABL1 transcripts occurs during treatment with tyrosine kinase inhibitors (TKIs) for CML in clinical practice is much lower than that recommended by either the National Cancer Center Network or the European LeukemiaNet guidelines. Adherence, one of the most critical factors affecting response to TKIs, is often less than desirable and rarely communicated to physicians by patients or managed by care providers. Less than optimal molecular monitoring and low adherence to TKI treatment can lead to rising transcripts levels, that when not detected, have been shown to contribute to poor outcomes. This review reports the basis for and describes the design of a state-of-the-art program intended to improve communication with physicians through real-time messaging about sequential test results for BCR-ABL1 and patients' adherence to TKI therapy.

Cancer incidence and cancer mortality in a cohort of UK semiconductor workers, 1970-2002.

OBJECTIVE: To examine cancer risks in a cohort of workers employed in the manufacture of semiconductors. METHODS: The mortality (1970-2002) and cancer morbidity (1971-2001) experienced by a cohort of 1807 male and female workforce employees from a semiconductor factory in the West Midlands (UK) have been investigated. Standardized mortality ratios (SMRs) and standardized registration ratios (SRRs) were used to assess mortality and morbidity, respectively. RESULTS: Overall mortality was close to expectation in males [SMR 99, 95% (confidence interval) CI 79-122] and significantly below expectation in females (SMR 74, 95% CI 65-85). Incidence of all sites of cancer was somewhat elevated in males (SRR 130, 95% CI 95-173) but close to expectation in females (SRR 94, 95% CI 82-109). There were significant deficits of deaths from cancer of the oesophagus in males and females combined and from cancer of the breast in females. Significantly elevated SRRs were found in males for cancer of the rectum [Observed (Obs) 6, SRR 284, 95% CI 104-619], in females for cancer of the pancreas (Obs 10, SRR 226, 95% CI 108-415) and malignant melanoma (Obs 11, SRR 221, 95% CI 110-396) and in males and females combined for cancer of the rectum (Obs 19, SRR 199, 95% CI 120-310) and malignant melanoma (Obs 12, SRR 217, 95% CI 112-379). Detailed work history data were unavailable for analysis. The finding of excess morbidity was not mirrored in the corresponding mortality findings. CONCLUSIONS: The study found elevated morbidity for a number of cancer sites that may be unconnected with occupation. Elimination of all possible occupational causes will, however, require more detailed analyses of cancer risks in relation to exposure histories.

Mortality of UK electricity generation and transmission workers, 1973-2002.

OBJECTIVE: To examine mortality from cancer and non-malignant causes among a large cohort of UK electricity generation and transmission workers. METHODS: The mortality experienced by a cohort of 83,923 employees of the former Central Electricity Generating Board of England and Wales was investigated for the period 1973-2002. All employees had worked for at least 6 months with some employment between 1973 and 1982. Standardized mortality ratios (SMRs) were used to assess mortality in the total cohort and in three sub-cohorts: power station workers, substation and transmission workers and workers at non-operational locations. These classifications were based on the place of work of the first known job. RESULTS: Overall mortality was significantly below that expected, based on national rates [males: observed (Obs) 18,773, expected (Exp) 22,497.9, SMR 83; females: Obs 1122, Exp 1424.9, SMR 79]. Statistically significant deficits of deaths were also found for most of the major disease groupings. However, significant excesses of deaths were found in male power station workers for cancer of the pleura (Obs 129, Exp 30.3, SMR 426) and in male workers from non-operational locations for cancer of the brain (Obs 55, Exp 36.0, SMR 153). There was also a non-significant excess of deaths from cancer of the breast in male power station workers (Obs 10, Exp 5.3, SMR 190). CONCLUSIONS: Mortality was exceptionally low for most causes of death but late health effects from earlier asbestos exposure were still in evidence.