Understanding the relationship between patient language and outcomes in internet-enabled cognitive behavioural therapy: A deep learning approach to automatic coding of session transcripts.

Objective: Understanding patient responses to psychotherapy is important in developing effective interventions. However, coding patient language is a resource-intensive exercise and difficult to perform at scale. Our aim was to develop a deep learning model to automatically identify patient utterances during text-based internet-enabled Cognitive Behavioural Therapy and to determine the association between utterances and clinical outcomes. Method: Using 340 manually annotated transcripts we trained a deep learning model to categorize patient utterances into one or more of five categories. The model was used to automatically code patient utterances from our entire data set of transcripts (∼34,000 patients), and logistic regression analyses used to determine the association between both reliable improvement and engagement, and patient responses. Results: Our model reached human-level agreement on three of the five patient categories. Regression analyses revealed that increased counter change-talk (movement away from change) was associated with lower odds of both reliable improvement and engagement, while increased change-talk (movement towards change or self-exploration) was associated with increased odds of improvement and engagement. Conclusions: Deep learning provides an effective means of automatically coding patient utterances at scale. This approach enables the development of a data-driven understanding of the relationship between therapist and patient during therapy.

Meaning in Life in Earlier and Later Older-Adulthood: Confirmatory Factor Analysis and Correlates of the Meaning in Life Questionnaire.

OBJECTIVE: To validate the Meaning in Life Questionnaire (MLQ) in earlier and later older-adulthood, and examine its correlates. METHOD: Participants in earlier ( n = 341, M age = 68.5) and later older-adulthood ( n = 341, M age = 78.6) completed the MLQ and other measures. Confirmatory multigroup analysis, correlations, and regression models were conducted. RESULTS: A two-factor (presence and search), eight-item model of the MLQ had a good fit and was age-invariant. Presence and search for meaning were largely unrelated. Meaning was associated with life satisfaction, well-being across a range of domains, and psychological resources. Searching for meaning correlated negatively with these variables, but to a lesser degree in later older-adulthood. DISCUSSION: The MLQ is valid in older-adulthood. Meaning in life is psychologically adaptive in older-adulthood. Searching for meaning appears less important, especially in later older-adulthood. Findings are discussed in the context of aging and psychosocial development.

Caregiver perceptions about the impact of caring for patients with wet age-related macular degeneration.

PURPOSE: Caregivers of older persons with eye disease, namely age-related macular degeneration (AMD), have been reported to have a higher than expected distress. Very few studies have explored caregiver perceptions as to what is important when providing care. The aim of this study was to explore the perceptions of caregivers of persons with neovascular AMD in relation to the most important aspects of caring, as described in extended answers to self-administered survey questions. METHODS: A cross-sectional, self-administered survey of 643 caregivers of people with neovascular AMD, comprising 27 closed-response questions and 2 open ended questions. The latter were analysed as part of this study utilising and 'inductive' Grounded Theory approach. RESULTS: Six-hundred and forty-three caregiver responses to 2 open ended questions were analysed using an inductive approach and sorted into thematic networks. Three discrete categories arose: The Impact of Caring; Injections and Information and Activities of Daily Living. CONCLUSIONS: Most caregivers were family caregivers and were found to be compassionate and self-sacrificing. They accepted additional responsibility whilst providing an encouraging environment for their care recipient. As a result, they experience distress and consider their own needs as secondary. Very few seek or receive respite and this added burden can have a negative impact upon the relationship between caregiver and care recipient.

The prognostic value of tumour regression grade following neoadjuvant chemoradiation therapy for rectal cancer.

AIM: To date, there is no uniform consensus on whether tumour regression grade (TRG) is predictive of outcome in rectal cancer. Furthermore, the lack of standardization of TRG grading is a major source of variability in published studies. The aim of this study was to evaluate the prognostic impact of TRG in a cohort of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation therapy (CRT). In addition to the Mandard TRG, we utilized four TRG systems modified from the Mandard TRG system and applied them to the cohort to assess which TRG system is most informative. METHOD: One-hundred and fifty-three patients with a T3/T4 and/or a node-positive rectal cancer underwent neoadjuvant 5-fluorouracil-based CRT followed by surgical resection. RESULTS: Thirty-six (23.5%) patients achieving complete pathological response (ypCR) had a 5-year disease-free survival (DFS) rate of 100% compared with a DFS rate of 74% for 117 (76.5%) patients without ypCR (P = 0.003). The Royal College of Pathologists (RCPath) TRG best condenses the Mandard five-point TRG by stratifying patients into three groups with distinct 5-year DFS rates of 100%, 86% and 67%, respectively (P = 0.001). In multivariate analysis, pathological nodal status and circumferential resection margin (CRM) status, but not TRG, remained significant predictors of DFS (P = 0.002, P = 0.035 and P = 0.310, respectively). CONCLUSION: Our findings support the notion that ypCR status, nodal status after neoadjuvant CRT and CRM status, but not TRG, are predictors of long-term survival in patients with locally advanced rectal cancer.

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer.

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

Multivariate analysis of MLH1 c.1664T>C (p.Leu555Pro) mismatch repair gene variant demonstrates its pathogenicity.

Genetic testing of an Irish kindred identified an exonic nucleotide substitution c.1664T>C (p.Leu555Pro) in the MLH1 mismatch repair (MMR) gene. This previously unreported variant is classified as a "variant of uncertain significance" (VUS). Immunohistochemical (IHC) analysis and microsatellite instability (MSI) studies, genetic testing, a literature and online MMR mutation database review, in silico phenotype prediction tools, and an in vitro MMR activity assay were used to study the clinical significance of this variant. The MLH1 c.1664T>C (p.Leu555Pro) VUS co-segregated with three cases of classic Lynch syndrome-associated malignancies over two generations, with consistent loss of MLH1 and PMS2 protein expression on IHC, and evidence of the MSI-High mutator phenotype. The leucine at position 555 is well conserved across a number of species, and this novel variant has not been reported as a normal polymorphism in the general population. In silico and in vitro analyses suggest that this variant may have a deleterious effect on the MLH1 protein and abrogate MMR activity. Evidence from clinical, histological, immunohistochemical, and molecular genetic data suggests that MLH1 c.1664T>C (p.Leu555Pro) is likely to be the pathogenic cause of Lynch syndrome in this family.

Adaptive autobiographical memory in younger and older adults: the indirect association of integrative and instrumental reminiscence with depressive symptoms.

Despite the established effectiveness of reminiscence-based interventions for depression, little research exists into the pathways through which specific reminiscence functions are related to depressive symptoms. Drawing on theory of the mechanisms of change in cognitive-reminiscence therapy, the current study tests the hypothesised indirect associations of adaptive integrative and instrumental reminiscence functions with depressive symptoms and whether these relationships might differ among younger and older adults. Questionnaires were completed by a large community sample of the Australian population. Multiple mediation models were tested in two groups: younger adults (n = 730, M age = 52.24, SD=9.84) and older adults (n = 725, M age= 73.59, SD=6.29). Results were consistent across age groups, indicating that there was direct relationship between these reminiscence functions and depressive symptoms, but that integrative reminiscence is indirectly associated with depressive symptoms through meaning in life, self-esteem, and optimism, and that instrumental reminiscence is indirectly associated with depressive symptoms through primary control and self-efficacy. This study provides support for the relationships between constructs underlying the proposed mechanisms of change in cognitive-reminiscence therapy for the treatment of depression, and suggests these relationships are similar for younger and older adults.

Ultrasonic dissection versus electrocautery in mastectomy for breast cancer - a meta-analysis.

BACKGROUND: Electrocautery has advanced the practice of mastectomy but significant morbidity, such as seroma and blood loss, remains a concern. This has led to newer forms of dissection being introduced including the ultrasonic dissection devices, which are thought to reduce tissue damage. The aim of this systematic review was to compare the outcomes after mastectomy using novel ultrasonic dissection or standard electrocautery in published trials. METHODS: Medline, Embase, trial registries, conference proceedings and reference lists were searched for comparative trials of ultrasonic dissection versus electrocautery for mastectomy. The primary outcomes were total postoperative drainage, seroma development and intra-operative blood loss. Secondary outcomes were operative time and wound complications. Odds ratios were calculated for categorical outcomes and standardised mean differences for continuous outcomes. RESULTS: Six trials were included in the analysis of 287 mastectomies. There was no effect in total postoperative drainage (pooled analysis weight mean difference: -0.21 (95% CI: -0.70-0.29); p = 0.41) or seroma development (pooled analysis odds ratio: 0.77 (95% CIs 0.43-1.37); p = 0.37). Intra-operative blood was slightly less for ultrasonic dissection compared to standard electrocautery (pooled analysis weight mean difference: -1.04 (95% CI: -2.00 to -0.08); p = 0.03). Ultrasonic dissection and standard electrocautery had similar outcomes with regard to operative time and wound complications. CONCLUSION: Ultrasonic dissection and standard electrocautery appear to deliver similar results in the mastectomy setting. Further cost-effectiveness analysis may guide surgeon selection in the use of new technologies for mastectomy.

Apoptosome-dependent caspase activation proteins as prognostic markers in Stage II and III colorectal cancer.

BACKGROUND: Critical to successful execution of mitochondrial-mediated apoptosis is apoptosome formation and subsequent activation of caspases. Defects in this pathway have an important role in colorectal carcinogenesis and chemoresistance; therefore, the expression of apoptosome-associated proteins may be associated with clinical outcome and response to chemotherapy. METHODS: Here we performed a systematic analysis of the immunohistochemical expression of the key proteins involved in apoptosome-dependent caspase activation (APAF1, Pro-caspases 9 and 3, SMAC, and XIAP) in a cohort of Stage II and III colorectal cancer patients from a Phase III trial of adjuvant 5-fluorouracil-based chemotherapy vs postoperative observation alone. RESULTS: Survival analysis indicated that of the apoptosome-associated proteins examined here, Pro-caspase 3 and APAF1 have potential clinical utility as predictive markers in Stage II and III colorectal cancer, respectively. Interestingly, we identified APAF1 staining to be associated with better recurrence-free and overall survival in patients receiving chemotherapy. CONCLUSION: These studies reveal the importance of the apoptosome-dependent caspase activation pathway, specifically Pro-caspase 3 and APAF1 proteins, for predicting both prognosis and response to therapy.

PEA3/ETV4-related transcription factors coupled with active ERK signalling are associated with poor prognosis in gastric adenocarcinoma.

BACKGROUND: Transcription factors often play important roles in tumourigenesis. Members of the PEA3 subfamily of ETS-domain transcription factors fulfil such a role and have been associated with tumour metastasis in several different cancers. Moreover, the activity of the PEA3 subfamily transcription factors is potentiated by Ras-ERK pathway signalling, which is itself often deregulated in tumour cells. METHODS: Immunohistochemical patterns of PEA3 expression and active ERK signalling were analysed and mRNA expression levels of PEA3, ER81, MMP-1 and MMP-7 were determined in gastric adenocarcinoma samples. RESULTS: Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in gastric adenocarcinomas. PEA3 is upregulated at the protein level in gastric adenocarcinomas and both PEA3/ETV4 and ER81/ETV1 are upregulated at the mRNA level in gastric adenocarcinoma tissues. This increased expression correlates with the expression of a target gene associated with metastasis, MMP-1. Enhanced ERK signalling is also more prevalent in late-stage gastric adenocarcinomas, and the co-association of ERK signalling and PEA3 expression also occurs in late-stage gastric adenocarcinomas. Furthermore, the co-association of ERK signalling and PEA3 expression correlates with decreased survival rates. CONCLUSIONS: This study shows that members of the PEA3 subfamily of transcription factors are upregulated in gastric adenocarcinomas and that the simultaneous upregulation of PEA3 expression and ERK pathway signalling is indicative of late-stage disease and a poor survival prognosis.

Impact of dose adjustment for normal eating in Australia (OzDAFNE) on subjective wellbeing, coping resources and negative affects in adults with type 1 diabetes: a prospective comparison study.

AIM: This prospective study examined the impact of a structured education program (OzDAFNE) on subjective wellbeing, coping resources, and negative affects in adults with type 1 diabetes. Participants completing the OzDAFNE program were compared to those using continuous subcutaneous insulin (CSII) and multiple daily injections (MDI) over the same time period. METHODS: Participants in the OzDAFNE group (N=144) were recruited from diabetes centres throughout Australia. The comparison groups were recruited from Diabetes Australia-Victoria's membership database and comprised 383 people using MDI and 64 people using CSII. All participants completed self-report questionnaires at baseline and 12-months later. Additional assessments for OzDAFNE participants were conducted at the end of the education program and at three and six-months following the training. RESULTS: The results demonstrated that participants completing the OzDAFNE program experienced improved subjective wellbeing (p<.01), a greater sense of mastery and control in managing their diabetes (p<.001), and reduced diabetes-related distress (p<.001) compared to the CSII and MDI groups. However, the CSII group recorded a significant drop in self-esteem (p<.001) over the duration of the study. CONCLUSIONS/INTERPRETATIONS: The OzDAFNE program provides a powerful mastery experience for participants, positively influencing subjective wellbeing and diabetes-related distress.

Aberrant DNA methylation associated with MTHFR C677T genetic polymorphism in cutaneous squamous cell carcinoma in renal transplant patients.

BACKGROUND: Changes in genomic DNA methylation associated with cancer include global DNA hypomethylation and gene-specific hyper- or hypomethylation. We have previously identified a genetic variant in the MTHFR gene involved in the methylation pathway which confers risk for the development of squamous cell carcinoma (SCC) in renal transplant patients. This genetic variant has also been discovered to confer SCC risk in nontransplant patients with low folate status. OBJECTIVES: To explore the methylation profile of SCC compared with adjacent non-neoplastic skin using pyrosequencing, and to elucidate whether the MTHFR polymorphism impacts upon the methylation patterns in SCC. METHODS: We used pyrosequencing to evaluate global (using long interspersed nuclear element 1) and gene-specific (p16 and MGMT) methylation status in 47 SCCs and 40 adjacent autologous non-neoplastic skin samples in those with (n = 16) and without (n = 17) the MTHFR polymorphism. RESULTS: Pyrosequencing methylation analysis revealed that SCC was hypomethylated compared with adjacent non-neoplastic skin (P < 0.04). Patients with the MTHFR polymorphism had higher levels of global methylation in tumours and non-neoplastic skin compared with those without the MTHFR polymorphism (P < 0.002). There was no association between levels of methylation in tumour and non-neoplastic skin for the genes MGMT and p16. CONCLUSIONS: Global hypomethylation appears to be a feature of SCC. Aberrant methylation of DNA appears related to polymorphisms of MTHFR. Such findings suggest that intervention in the form of demethylating agents or folate supplementation might be beneficial in the treatment or prevention of SCC.

Human IgG antibody profiles differentiate between symptomatic patients with and without colorectal cancer.

OBJECTIVE: Patients with cancer have antibodies against tumour antigens. Characterising the antibody repertoire may provide insights into aberrant cellular mechanisms in cancer development, ultimately leading to novel diagnostic or therapeutic targets. The aim of this study was to characterise the antibody profiles in patients whose symptoms warranted colonoscopy, to see if there was a difference in patients with and without colorectal cancer. METHODS: Patients were recruited from a colonoscopy clinic. Individual serum samples from 43 patients with colorectal cancer and 40 patients with no cancer on colonoscopy were profiled on a 37 830 clone recombinant human protein array. Antigen expression was evaluated by quantitative reverse transcription-PCR and by immunohistochemistry on tissue microarrays. RESULTS: Using a sex- and age-matched training set, 18 antigens associated with cancer and 4 associated with the absence of cancer (p<0.05) were identified and confirmed. To investigate the mechanisms triggering antibody responses to these antigens, antigen expression was examined in normal colorectal mucosa and colorectal carcinoma of the same patients. The identified antigens showed cellular accumulation (p53), aberrant cellular expression (high mobility group B1 (HMGB1)) and overexpression (tripartite motif-containing 28 (TRIM28), p53, HMGB1, transcription factor 3 (TCF3), longevity assurance gene homologue 5 (LASS5) and zinc finger protein 346 (ZNF346)) in colorectal cancer tissue compared with normal colorectal mucosa. CONCLUSIONS: It is demonstrated for the first time that screening high-density protein arrays identifies unique antibody profiles that discriminate between symptomatic patients with and without colorectal cancer. The differential expression of identified antigens suggests their involvement in aberrant cellular mechanisms in cancer.

Recommendations to achieve rapid therapeutic teicoplanin plasma concentrations in adult hospitalised patients treated for sepsis.

The optimum teicoplanin loading dose and duration of therapy required for rapid attainment of a therapeutic trough plasma concentration (C(min)) (> or = 10mg/L for serious Gram-positive infections and > or = 20mg/L for deep-seated infections) are not known. In this open-label, multicentre, observational study, teicoplanin levels were determined following administration of loading doses of 6 mg/kg every 12h on Day 1 followed by 6 mg/kg once or twice daily to hospitalised patients with suspected or diagnosed Gram-positive infections. C(min) levels for the first 4 days of treatment were collected 15min prior to drug administration. Levels were determined with an Abbott TDx/FLx Analyzer and Seradyn Teicoplanin Innofluor Assay Kit. The two target trough values (> or = 10mg/L and > or = 20mg/L) were only achieved by Day 4 in the once-daily group (n=34; mean 9.55 mg/L, 95% confidence interval (CI) 8.17-10.94 mg/L) and in the twice-daily group (n=40; mean 21.8 mg/L, 95% CI 17.21-26.39 mg/L), respectively. However, the mean C(min) in the twice-daily group was > or = 10mg/L (11.03 mg/L) by Day 2. To achieve rapid therapeutic C(min) concentrations targeted for the majority of serious Gram-positive infections, we recommend teicoplanin loading doses of 6 mg/kg every 12h for 48h followed by once-daily for infections other than infective endocarditis, septic arthritis and osteomyelitis. Regarding the latter infections, higher loading doses might be warranted to reach rapid steady-state concentrations.

Moving from the quality of life concept to a theory.

BACKGROUND: The Special Interest Quality of Life Group has updated its set of statements defining the quality of life (QOL) construct to reflect emerging areas of agreement and the framework for understanding better the QOL construct. METHOD: This article examines the major areas currently under discussion involving the objective-subjective dichotomy, needs, and core domains. RESULTS: It is concluded that while the new statements constitute a significant advance, further progress requires testable theory. In order to facilitate such future research, a conceptual model is proposed that distinguishes causal and indicator variables within the framework of a homeostatic management system. CONCLUSION: Several lines of empirical investigation are suggested to test this and similar theoretical models with a view to taking our conceptualization of QOL to the next level.

Ovulating ovary in an inguinal hemia.

BACKGROUND: An ovary can, occasionally, be found in an inguinal hernia in the newborn female. This is extremely rare in premenopausal women. We report a case of an ovulating ovary in an incarcerated inguinal hernia. There is only one similar case of incarcerated ovulating ovary reported in the literature. METHOD AND FINDINGS: A 23-year-old Turkish woman, mother of three children, presented with a painful swelling over the upper part of left labia majora of 48 hours duration. She was diagnosed as having an obstructed left inguinal hernia. At operation the left ovary and fallopian tube were seen in the left inguinal canal. The ovary and fallopian tube were congested but viable and mature ovarian follicles could be seen on the ovary. A biopsy was taken from the ovary, the ovary and the fallopian tube were easily reduced back into the abdominal cavity and the hernia repaired. DISCUSSION: The presence of an ovary in the inguinal canal is very rare and should be a differential diagnosis in women presenting with an irreducible lump in the inguinal area. It should be treated as a surgical emergency.

Intra-operative specimen analysis using faxitron microradiography for excision of mammographically suspicious, non-palpable breast lesions.

Recent advances in digital imaging have made Faxitron microradiography an attractive alternative to intra-operative conventional specimen radiography (CSR) for the excision of wire-localized breast lesions. Faxitron specimen analysis time, usefulness of digital image manipulation and re-excision rates were evaluated in comparison to CSR in 299 consecutive wire-localized excisions for mammographically suspicious non-palpable breast lesions (172 procedures with Faxitron, 127 with CSR) in a non-randomized study. The corresponding mean operation times were 34.7 vs. 42.7 min and the respective re-excision rates were 19.8% vs. 31.5% (no significant difference on chi analysis P < 0.1). Faxitron digital image manipulation led to cavity biopsies in 50% (60/121) of the cancer excisions. In 19 of these (16%), histological excision margins were converted from incomplete to complete. The shorter Faxitron mean operating time enables an additional wire-localized operation per theatre list. Digital imaging guides the surgeon for additional cavity biopsies, resulting in re-excision rates as good as CSR.

Reduction in heat-induced gastrointestinal hyperpermeability in rats by bovine colostrum and goat milk powders.

Male Sprague-Dawley rats were assigned to one of three dietary groups [standard diet (Cont; n = 8), standard diet plus bovine colostrum powder (BColost 1.7 g/kg; n = 8), or goat milk powder (GMilk 1.7 g/kg; n = 8)] to determine the ability of these supplements to reduce gastrointestinal hyperpermeability induced by heat. Raising core body temperature of rats to 41.5 degrees C increased transfer of (51)Cr-EDTA from gut into blood 34-fold relative to the ambient temperature value (P < 0.05) in the Cont group of rats, indicative of increased gastrointestinal permeability. Significantly less (P < 0.01) (51)Cr-EDTA was transferred into the blood of rats in either the BColost (27% of Cont) or GMilk group (10% of Cont) after heating, showing that prior supplementation with either bovine colostrum or goat milk powder significantly reduced the impact of heat stress on gastrointestinal permeability. The changes in the BColost group were not significantly different than those of the GMilk group. The potential mechanism of the protective effect of bovine colostrum and goat milk powders may involve modulation of tight junction permeability, because both powders were able to maintain transepithelial resistance in Madin Darby canine kidney cells challenged with EGTA compared with cells maintained in media only. The results show that bovine colostrum powder can partially alleviate the effects of hyperthermia on gastrointestinal permeability in the intact animal. Moreover, goat milk powder was equally as effective as bovine colostrum powder, and both may be of benefit in other situations where gastrointestinal barrier function is compromised.

Defining quality of life for Chinese elderly stroke survivors.

PURPOSE: This study aimed to identify the constituents and conceptual characteristics of the quality of life (QOL) of Chinese elderly stroke survivors, living in the community in Hong Kong. METHOD: A triangulated approach was used to identify the QOL components for this population. This process involved a comparison of QOL components gathered from three different methods, namely, focus group interviews, review of the literature and the contents of the generic Hong Kong Chinese version of the World Health Organization Quality of Life Scale (CWHOQOL-HK). Five health professionals were involved in the comparison process. A percentage of inter-judge agreement was used to determine the reliability of the comparisons made between the judges. RESULTS: This study identified 36 components considered to contribute to the QOL of Chinese elderly stroke survivors in Hong Kong. The conceptual characteristics of their QOL generally concurred with those identified in the literature. CONCLUSION: Both similarities and differences were found in the QOL components identified in this study when compared to those identified in studies of Western populations who are elderly and had a stroke. The contents of the CWHOQOL-HK scale were found to lack adequacy in representing the QOL of Chinese elderly stroke survivors in Hong Kong. Recommendations are given, based on the findings of this study, to overcome this limitation for its application as a QOL measure for this population.