Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells.

We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.

Cancer cells employ an evolutionarily conserved polyploidization program to resist therapy.

Unusually large cancer cells with abnormal nuclei have been documented in the cancer literature since 1858. For more than 100 years, they have been generally disregarded as irreversibly senescent or dying cells, too morphologically misshapen and chromatin too disorganized to be functional. Cell enlargement, accompanied by whole genome doubling or more, is observed across organisms, often associated with mitigation strategies against environmental change, severe stress, or the lack of nutrients. Our comparison of the mechanisms for polyploidization in other organisms and non-transformed tissues suggest that cancer cells draw from a conserved program for their survival, utilizing whole genome doubling and pausing proliferation to survive stress. These polyaneuploid cancer cells (PACCs) are the source of therapeutic resistance, responsible for cancer recurrence and, ultimately, cancer lethality.

Engaging male students with mental health support: a qualitative focus group study.

BACKGROUND: Males are less likely to seek help for mental health difficulties compared to females. Despite considerable interest, a paucity of evidence-based solutions exists to address this. Concerns about students' mental health has led to the United Kingdom's Department of Education to make this a priority. Studies have shown that male students hold more negative attitudes towards the use of psychological services compared to female students and are less likely to seek help. A major concern is that male students make up 69% of university suicides, which is often associated with lower rates of help-seeking. This focus group study therefore sought to identify potential approaches that would be relevant to improving mental health help-seeking in male students. METHODS: Three focus groups comprising of 24 male students at a London University were conducted. Participants were asked questions exploring: the barriers to seeking help, what would encourage help-seeking, how an appropriate intervention should be designed, and how to publicise this intervention to male students. Thematic analysis was conducted to evaluate participants responses. RESULTS: Five distinct themes were identified. These were: 1) protecting male vulnerability, 2) providing a masculine narrative of help-seeking, 3) differences over intervention format, 4) difficulty knowing when and how to seek help, and 5) strategies to sensitively engage male students. CONCLUSIONS: These themes represent important considerations that can be used, together with the existing literature about male help-seeking, to develop more male friendly interventions that are suitable for male students. This could help improve help-seeking attitudes and the uptake of mental health interventions for male students experiencing emotional distress.

A clinical approach to respiratory disease in patients with hematological malignancy, with a focus on respiratory infection.

Respiratory complications, in particular infections, are common in the setting of hematological malignancy and after hematopoetic stem cell transplant. The symptoms can be nonspecific; therefore, it can be difficult to identify and treat the cause. However, an understanding of the specific immune defect, clinical parameters such as speed of onset, and radiological findings, allows the logical diagnostic and treatment plan to be made. Radiological findings can include consolidation, nodules, and diffuse changes such as ground glass and tree-in-bud changes. Common infections that induce these symptoms include bacterial pneumonia, invasive fungal disease, Pneumocystis jirovecii and respiratory viruses. These infections must be differentiated from inflammatory complications that often require immune suppressive treatment. The diagnosis can be refined with the aid of investigations such as bronchoscopy, computed tomography (CT) guided lung biopsy, culture, and serological tests. This article gives a schema to approach patients with respiratory symptoms in this patient group; however, in the common scenario of a rapidly deteriorating patient, treatment often has to begin empirically, with the aim to de-escalate treatment subsequently after targeted investigations.

Viscosity, density, and thermal conductivity of aluminum oxide and zinc oxide nanolubricants.

This paper presents liquid kinematic viscosity, density, and thermal conductivity measurements of eleven different synthetic polyolester-based nanoparticle nanolubricants (dispersions) at atmospheric pressure over the temperature range 288 K to 318 K. Aluminum oxide (Al2O3) and zinc oxide (ZnO) nanoparticles with nominal diameters of 127 nm and 135 nm, respectively, were investigated. A good dispersion of the spherical and non-spherical nanoparticles in the lubricant was maintained with a surfactant. Viscosity, density, and thermal conductivity measurements were made for the neat lubricant along with eleven nanolubricants with differing nanoparticle and surfactant mass fractions. Existing models were used to predict kinematic viscosity (±20%), thermal conductivity (±1%), and specific volume (±6%) of the nanolubricant as a function of temperature, nanoparticle mass fraction, surfactant mass fraction, and nanoparticle diameter. The liquid viscosity, density and thermal conductivity were shown to increase with respect to increasing nanoparticle mass fraction.

Glycaemic control and risk of incident urinary incontinence in women with Type 1 diabetes: results from the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.

AIMS: To study the impact of glycaemic control on urinary incontinence in women who participated in the Diabetes Control and Complications Trial (DCCT; 1983-1993) and its observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC; 1994-present). METHODS: Study participants were women who completed, at both years 10 (2003) and 17 (2010) of the EDIC follow-up, the urological assessment questionnaire (UroEDIC). Urinary incontinence was defined as self-reported involuntary leakage of urine that occurred at least weekly. Incident urinary incontinence was defined as weekly urinary incontinence present at EDIC year 17 but not at EDIC year 10. Multivariable regression models were used to examine the association of incident urinary incontinence with comorbid prevalent conditions and glycaemic control (mean HbA1c over the first 10 years of EDIC). RESULTS: A total of 64 (15.3%) women with Type 1 diabetes (mean age 43.6 ± 6.3 years at EDIC year 10) reported incident urinary incontinence at EDIC year 17. When adjusted for clinical covariates (including age, DCCT cohort assignment, DCCT treatment arm, BMI, insulin dosage, parity, hysterectomy, autonomic neuropathy and urinary tract infection in the last year), the mean EDIC HbA1c was associated with increased odds of incident urinary incontinence (odds ratio 1.03, 95% CI 1.01-1.06 per mmol/mol increase; odds ratio 1.41, 95% CI 1.07-1.89 per % HbA1c increase). CONCLUSIONS: Incident urinary incontinence was associated with higher HbA1c levels in women with Type 1 diabetes, independent of other recognized risk factors. These results suggest the potential for women to modify their risk of urinary incontinence with improved glycaemic control. (Clinical Trials Registry no: NCT00360815 and NCT00360893).

What is the impact of mental health-related stigma on help-seeking? A systematic review of quantitative and qualitative studies.

BACKGROUND: Individuals often avoid or delay seeking professional help for mental health problems. Stigma may be a key deterrent to help-seeking but this has not been reviewed systematically. Our systematic review addressed the overarching question: What is the impact of mental health-related stigma on help-seeking for mental health problems? Subquestions were: (a) What is the size and direction of any association between stigma and help-seeking? (b) To what extent is stigma identified as a barrier to help-seeking? (c) What processes underlie the relationship between stigma and help-seeking? (d) Are there population groups for which stigma disproportionately deters help-seeking? METHOD: Five electronic databases were searched from 1980 to 2011 and references of reviews checked. A meta-synthesis of quantitative and qualitative studies, comprising three parallel narrative syntheses and subgroup analyses, was conducted. RESULTS: The review identified 144 studies with 90,189 participants meeting inclusion criteria. The median association between stigma and help-seeking was d = - 0.27, with internalized and treatment stigma being most often associated with reduced help-seeking. Stigma was the fourth highest ranked barrier to help-seeking, with disclosure concerns the most commonly reported stigma barrier. A detailed conceptual model was derived that describes the processes contributing to, and counteracting, the deterrent effect of stigma on help-seeking. Ethnic minorities, youth, men and those in military and health professions were disproportionately deterred by stigma. CONCLUSIONS: Stigma has a small- to moderate-sized negative effect on help-seeking. Review findings can be used to help inform the design of interventions to increase help-seeking.

How equitable are psychological therapy services in South East London now? A comparison of referrals to a new psychological therapy service with participants in a psychiatric morbidity survey in the same London borough.

PURPOSE: Psychological therapy services are sometimes characterised as being small and inequitable, with an over-representation of white middle class women. The 'Improving Access to Psychological Therapies (IAPT)' initiative is a programme in England that attempts to make evidence-based therapies accessible to more people more equitably. The aim of this study is to assess whether an IAPT service is delivering an equitable service a London borough. Patients using services at the Southwark IAPT service (n = 4,781) were compared with a sub-group of participants in the South East London Community Health study (SELCOH) with diagnosable mental health problems and who were also resident in Southwark (n = 196). METHODS: We compared Southwark IAPT patients and SELCOH participants on equity criteria of age, gender, ethnicity, occupational status and benefits status. To investigate if referral pathways influenced equity, patients referred by their general practitioner (GP pathway) (n = 3,738) or who self-referred (self-referral pathway) (n = 482) were compared with SELCOH participants. RESULTS: Southwark IAPT patients significantly differed from SELCOH participants on all our equity criteria and similar differences were found with GP pathway patients. However, self-referrals did not differ from the SELCOH group on age, gender, ethnicity and benefit status. CONCLUSIONS: When compared to a community sample with diagnosable mental disorders, health disparities were found with the overall Southwark IAPT service and with GP pathway patients. Although unemployed people did access IAPT, fewer disparities were found with the self-referral pathway patients, suggesting that the IAPT self-referral pathway may be important in reducing inequitable access to services.

A new classification of mandibular fractures.

There is no accepted method of reporting mandibular fracture that reflects incidence, treatment and outcome for individual cases. As most series include anatomical site only for all fractures, the aim was to establish a new method to report fractures based on a systematic review of the literature and an internal audit. The classification proposed is: Class I; condyle, II; angle, IIc; II+condyle, III; body/symphysis, IIIc; III+condyle, IV; multiple fractures not including condyle, IVc; IV+condyle, V; bilateral condyle±other fracture(s). A total of 10,971 adult and 914 paediatric cases were analyzed through systematic review, and 833 from the regional audit. Only 32% (14/44) of reported series could be reclassified which, when added to the audit data, showed Class IV was most common (29%), with similar proportions of Class III, Class IIIc and Class II (18-23%). External validation (literature review) in terms of treatment and outcome was non-informative, but the internal validation (audit) demonstrated an increasing requirement for adding maxillomandibular fixation (MMF) to open reduction and internal fixation (ORIF) as class increased. The heterogeneity of data reporting found in the systematic review confirms the need for a classification such as this, likely to enhance comparison of varying management protocols.

Outcomes of microvascular composite reconstruction for mandibular osteoradionecrosis.

The aim of this retrospective study was to compare outcomes and reconstruction-related complications in patients receiving a composite free flap reconstruction of the mandible for ORN with those reconstructed for other indications. The records of all patients who underwent composite reconstruction of a mandibular defect at Aintree University Hospital, Liverpool, were reviewed and analysed. Based on radiotherapy exposure and ORN history, the study cohort was divided into three separate case-matched groups. Local wound healing issues were markedly more common in the ORN setting, as was infection and subsequent osteosynthesis plate(s) removal. Free flap survival was similar among all three case-matched groups. Advanced mandibular ORN may be safely and predictably reconstructed with composite free flaps, and that while the rate of local complications is greater than non-irradiated, and non-ORN case-matched controls, the free flap survival rate compares favourably.

Systematic review of lingual nerve retraction during surgical mandibular third molar extractions.

The lingual nerve is at risk of damage during mandibular third molar (M3M) surgery. Current trends to avoid lingual retraction and prevent injury to the nerve run counter to the surgical principles of locating and protecting important structures. To our knowledge, the last review of this subject only considered repurposed lingual retractors such as the Howarth. Other studies have reported the use of purpose-built retractors with improved outcomes for lingual nerve injuries. This systematic review aims to assess the current view regarding lingual nerve retraction in M3M surgery. A search of PubMed and Web of Science using the key words "lingual", "nerve", "retractor", and "retraction" returned 118 results, 10 of which were selected for inclusion (nine original research papers and one systematic review). The data comprised 16,133 M3M extractions using no lingual retractor, repurposed, and purpose-built retractors. No lingual retraction showed a 0.60% risk of temporary and a 0.08% risk of permanent injury to the nerve. Repurposed retractors showed a 7.9% risk of temporary and 0.41% risk of permanent injury, and purpose-built retractors a 0.56% risk of temporary injury. No reported cases of permanent injury were associated with the use of purpose-built instruments. The evidence suggests that whilst the use of repurposed retractors increases the risk of injury to the nerve, there is no such risk with purpose-built retractors. Current data sets are confounded by the limitations of non-randomised, non-blinded studies, but trends show that lingual nerve retraction with purpose-built retractors may help to prevent permanent injury to the lingual nerve.

Training in oral and maxillofacial surgery: a medicine-first perspective.

Specialist registration in oral and maxillofacial surgery (OMFS) requires dual medical and dental qualification involving at least eight years of undergraduate study. Training has continued to evolve since dual qualification was introduced and has often resulted in unwarranted repetition. If a time-based curriculum is necessary, second degree trainees should be allowed to pursue research and audit, and gain relevant clinical experience in lieu of repeating previously covered material. Junior surgical training could be integrated into the second degree. A programme that records competencies during the second degree may demonstrate equivalent to other aspects of junior training. One barrier is timetabling, which often restricts the integration of second degree trainees with OMFS units. Junior training in OMFS could be streamlined if the content was agreed nationally. This would also offer the opportunity for those key institutions that implement these changes to take on a prominent role in OMFS training.

Role of live animals in the training of microvascular surgery: a systematic review.

As training in microvascular surgery often involves the use of live animals, it is important that such a practice is regularly revisited and justified, particularly in the context of emerging training strategies such as virtual simulation. This systematic review was therefore designed to assess the ongoing need for their use over other methods. A search of PubMed and MEDLINE using the major MeSH terms: anastomosis, surgical vascular procedures, microsurgery, and training, yielded 1386 titles from which 153 abstracts were read, 70 papers analysed, and 17 included. Nine of these papers were randomised studies that compared different methods of training. Other publications were included if the use of live animals was assessed or commented upon, or both (8 publications). Only one study randomised trainees to a non-living animal model or a living model, with detailed assessment that included clinical transfer to live surgery. It showed no significant difference in the quality of training, and excellent techniques of assessment. There was much discussion on the advantage of regular training and opportunities to practise without tuition, but there was no clear advantage for the use of live animals. Our review emphasises the lack of evidence regarding the need for live animals in the training of microsurgical or microvascular skills. Although the assumption remains that the use of live rats is essential, there is a clear need for a high-quality, comparative study to justify the continued use of such models given the quality of the alternatives now available.

Longitudinal patterns of mental health service utilisation by those with mental-physical comorbidity in the community.

OBJECTIVE: Successful healthcare integration demands an understanding of current service utilisation by people with comorbidity. Physical illness may impact on mental health service use (MHSU), but longitudinal studies of comorbidity and MHSU are rare. This study 1) estimated associations between mental-physical comorbidity and longitudinal MHSU patterns; 2) tested whether associations between comorbidity and continuous MHSU are driven by "need". METHODS: Survey data from a South East London community cohort were used (N = 1052). Common mental disorder symptoms (CMDS) were measured using the Clinical Interview Schedule Revised and self-report of long-standing disorders. A checklist of common conditions measured chronic physical conditions. MHSU captured self-reported use of mental health services in the past year at two time points. "Need" indicators included CMDS at follow-up, suicidal ideation, somatic symptom severity, self-rated health, daily functioning problems and perceived functioning limitations due to emotional health. Analyses used logistic and multinomial regression. RESULTS: Continuous MHSU (at both time-points) was twice as commonly reported by those with comorbidity than those without physical comorbidity (30.9% vs 12.3%). CMDS at follow-up, suicidal ideation, and perceived functioning limitations due to emotional health only partially explained the association between CMDS-physical comorbidity and continuous MHSU. In the adjusted model, comorbidity remained associated with continuous MHSU (RRR = 3.23, 95% CI: 1.39-7.51; p = .002), while the association for non-comorbid CMDS was fully attenuated (RRR = 1.08, 95% CI: 0.40-2.93; p = .85). CONCLUSION: CMDS-physical comorbidity was strongly associated with continuous MHSU, and "need" did not account for this association, suggesting that comorbidity itself represents a "need" indicator.

Natural human antibodies to pneumococcus have distinctive molecular characteristics and protect against pneumococcal disease.

The molecular and functional characteristics of natural antibody from the preimmune repertoire have not been explored in detail in man. We describe seven human IgM monoclonal antibodies selected on the basis of pneumococcal polysaccharide binding that share both molecular and functional characteristics with natural antibody, suggesting a common B cell lineage origin. Unlike class-switched antibodies, which are serotype-specific, the antibodies were polyreactive and bound all pneumococcal polysaccharide capsular serotypes tested. Some bound endogenous antigens, including blood group antigens and intermediate filament proteins. All the antibodies used unmutated heavy chain V (IGHV) that are expressed at an increased frequency in the elderly and in the preimmune repertoire. The CDR3 was characterized by long length (mean aa 18.4 (+/-4.2) and selective use of IGHD6 (P < 0.001) and IGHJ6 (P < 0.01) family genes. The clones expressing IGHV1-69 and IGHV 3-21 provided significant passive protection against invasive pneumococcal disease in vivo.

Effects of urinary incontinence, comorbidity and race on quality of life outcomes in women.

PURPOSE: We investigated the effects of comorbidity and urinary incontinence on both generic and incontinence specific quality of life outcome measures, and investigated whether the association between urinary incontinence and quality of life varies by race. MATERIALS AND METHODS: Study participants were 2,109 women 40 to 69 years old randomly selected from an urban health maintenance organization and interviewed in person for a study of risk factors for urinary incontinence. The sample was racially diverse consisting of 48% white, 18% black, 17% Hispanic and 16% Asian-American women. In addition to incontinence, reproductive and medical history questionnaires, all participants completed the Medical Outcomes Study Short Form 36, a measure of health related quality of life. All participants with daily and weekly incontinence (29%) completed the Incontinence Impact Questionnaire, an incontinence specific quality of life measure. The health maintenance organization's inpatient and outpatient electronic databases were used to calculate a Charlson comorbidity index score for each participant. ANCOVA was used to produce a model adjusting for sociodemographic variables, comorbidity and incontinence frequency. The same model was run for each of 4 racial groupings to examine differences by race/ethnicity. RESULTS: Urinary incontinence is significantly associated with a decreased quality of life and those with more frequent incontinence have significantly lower quality of life scores. In our model the Charlson score, an objective measure of comorbidity based on hospital and physician records, also has a significant negative impact on quality of life. When comorbidity is controlled, incontinence frequency continues to have a significant negative association with quality of life except among the sickest women. For women with the greatest extent of comorbidity, incontinence frequency is not significantly associated with negative quality of life outcomes. We did not find clear patterns of variation by race. CONCLUSIONS: Urinary incontinence and comorbidity each have an independent and significant role in reducing quality of life outcomes for all but the sickest women.

Previous abortion and the risk of low birth weight and preterm births.

OBJECTIVE: To investigate the association between previous abortion and low birth weight (LBW) and preterm birth (PB). METHOD: The study examined live, singleton births using data from the United States Collaborative Perinatal Project. Logistic regression was used to control for obstetric and medical history, and lifestyle and demographic factors. RESULT: Compared with women with no history of abortion, women who had one, two and three or more previous abortions were 2.8 (95% CI 2.48 to 3.07), 4.6 (95% CI 3.94 to 5.46) and 9.5 (95% CI 7.72 to 11.67) times more likely to have LBW, respectively. The risk for PB was also 1.7 (95% CI 1.52 to 1.83), 2.0 (95% CI 1.73 to 2.37) and 3.0 (95% CI 2.47 to 3.70) times higher for women with a history of one, two and three or more previous abortions, respectively. CONCLUSION: Previous abortion is a significant risk factor for LBW and PB, and the risk increases with the increasing number of previous abortions. Practitioners should consider previous abortion as a risk factor for LBW and PB.

Introducing correlations into carrier transport simulations of disordered materials through seeded nucleation: impact on density of states, carrier mobility, and carrier statistics.

Disorder in organic semiconductors has made it challenging to achieve performance gains; this is a result of the many competing and often nuanced mechanisms effecting charge transport. In this article, we attempt to illuminate one of these mechanisms in the hopes of aiding experimentalists in exceeding current performance thresholds. Using a heuristic exponential function, energetic correlation has been added to the Gaussian disorder model (GDM). The new model is grounded in the concept that energetic correlations can arise in materials without strong dipoles or dopants, but may be a result of an incomplete crystal formation process. The proposed correlation has been used to explain the exponential tail states often observed in these materials; it is also better able to capture the carrier mobility field dependence, commonly known as the Poole-Frenkel dependence, when compared to the GDM. Investigation of simulated current transients shows that the exponential tail states do not necessitate Montroll and Scher fits. Montroll and Scher fits occur in the form of two distinct power law curves that share a common constant in their exponent; they are clearly observed as linear lines when the current transient is plotted using a log-log scale. Typically, these fits have been found appropriate for describing amorphous silicon and other disordered materials which display exponential tail states. Furthermore, we observe the proposed correlation function leads to domains of energetically similar sites separated by boundaries where the site energies exhibit stochastic deviation. These boundary sites are found to be the source of the extended exponential tail states, and are responsible for high charge visitation frequency, which may be associated with the molecular turnover number and ultimately the material stability.

An assessment of deprivation as a factor in the delays in presentation, diagnosis and treatment in patients with oral and oropharyngeal squamous cell carcinoma.

This study explores the relationship between deprivation and patient and professional delays in presentation and treatment of oral and oropharyngeal squamous cell carcinoma. The cohort comprised 559 consecutive previously untreated patients presenting to the Regional Maxillofacial Unit, Liverpool from 1 January 1992 to 31 December 2002. All had primary surgery. The head and neck database was searched together with a review of casenotes. Deprivation was scored using the Index of Multiple Deprivation 2000 (IMD 2000) from patient post codes. PATIENT DELAY: Similar numbers of patients presented to general dental and general medical practitioners. The predominant presenting symptom was either an ulcer or swelling and 38% had symptoms for 3 or more months. Patients with shorter duration of symptoms tended to be smokers, drinkers, with lower gum and floor of mouth tumours, and more advanced disease. Primary health professional, patient age, gender, marital status, and deprivation showed no obvious correlation with patient delay. PROFESSIONAL DELAY: For 78% of patients a referral letter from GPs and GDPs was sent to the MFU on the same day as the primary consultation. There was on average about 3 weeks from referral to definitive diagnosis and about another 3 weeks before having surgery. Professional delay was shorter in patients with more advanced tumours and for patients living in the most deprived of wards. Deprivation did not seem to significantly lengthen presentation or referral however it may be that it is associated with more rapidly growing tumours.

A comparison of outcomes for patients with oral squamous cell carcinoma at intermediate risk of recurrence treated by surgery alone or with post-operative radiotherapy.

Controversy remains about which patients at intermediate risk of recurrence of oral squamous cell carcinoma would benefit from radiotherapy. A retrospective review of computerised database and medical records for 462 consecutive patients at the Regional Maxillofacial Unit in Liverpool who were treated with primary surgery with or without post-operative radiotherapy was carried out. We classified 29% (134) of patients as being at 'low' risk of disease recurrence (pT1-2, N0 with clear margins), 29% (135) at 'high' risk (involved margins or lymph node extracapsular spread) and the remaining 42% (193) at 'intermediate' risk. Of those at intermediate risk, 41% (80/193) received adjuvant radiotherapy and their 5 year survival (SE) was 54% (6%) compared to 71% (5%) for those with primary surgery alone (P=0.002). A higher proportion of patients having radiotherapy had loco-regional recurrence (19/80 24%) compared to those treated by surgery alone (17/113 15%). The improved salvage rate for recurrent disease in the surgery alone group (8/17 53%), compared to those receiving radiotherapy (2/19 13%, P=0.05), indicates an advantage in withholding radiotherapy for patients at intermediate risk of recurrence. This study indicates a potential disadvantage associated with the use of postoperative radiotherapy for patients at intermediate risk of recurrence. A randomised trial comparing a watch and wait policy to postoperative radiotherapy in patients with an intermediate risk of recurrence is required to confirm the trend indicated in this retrospective data.