Certifying Higher-Order Polynomial Interpretations

Higher-order rewriting is a framework in which one can write higher-order programs and study their properties. One such property is termination: the situation that for all inputs, the program eventually halts its execution and produces an output. Several tools have been developed to check whether higher-order rewriting systems are terminating. However, developing such tools is difficult and can be error-prone. In this paper, we present a way of certifying termination proofs of higher-order term rewriting systems. We formalize a specific method that is used to prove termination, namely the polynomial interpretation method. In addition, we give a program that processes proof traces containing a high-level description of a termination proof into a formal Coq proof script that can be checked by Coq. We demonstrate the usability of this approach by certifying higher-order polynomial interpretation proofs produced by Wanda, a termination analysis tool for higher-order rewriting

Retention during the first year of HIV care and the effect of an interactive text-messaging service on patient engagement in care

Background: Retention in HIV care is critical to ensure timely treatment initiation, viral suppression, reduced transmission, and to prevent AIDS-related deaths. Retention in care is low and falls short of the level needed to meet the UNAIDS 90-90-90 targets. There are few interventions designed to improve retention in HIV care and quantifying retention in care has been mostly limited to quantifying ‘retention in clinic’. ‘Retention in clinic’ accounts for those who return to the clinic at which they were originally enrolled but does not consider informal or formal transfers, which are common in sub-Saharan Africa. The overall aim of this thesis was to quantify retention in HIV care and to investigate whether the WelTel text-messaging intervention, previously found to improve antiretroviral therapy adherence, improved retention during the first year of HIV care. Ancillary studies using baseline data were also conducted as part of this thesis. Methods: Between April 2013 and June 2015, adults testing HIV-positive were recruited at two clinics in informal settlements in Nairobi, Kenya. Individuals ineligible for the trial because they did not meet phone-related trial eligibility criteria were invited to participate in a supplementary cohort study. In the trial, intervention arm participants received a weekly text-message and were asked to respond within 48 hours. The primary outcome was retention in care at 12-months (clinic attendance 10-14 months after the first visit). Participants who did not attend this 12-month appointment were traced and those confirmed active in care elsewhere were considered retained. All participants, both in the trial and cohort study, were followed for up to 14 months to quantify retention in care at one year. Baseline data for the entire study population were used to conduct additional studies on advanced HIV at presentation to care and a gender analysis of health-related quality of life at the time of a positive HIV test. Results: Of 700 individuals recruited for the trial, 349 were allocated to the intervention and 351 to the control arm. At 12 months, 79.4% (n=277/349) of intervention arm participants were retained in care compared to 81.2% (n=285/351) of control arm participants (risk ratio 0.98, 95% confidence interval [CI] 0.91 – 1.05). In the larger cohort study (n=775), 62.7% (95% CI 59.2% - 66.1%) of participants returned to the clinic for their 12-month appointment (retained in clinic) and 609 (78.6%, 95% CI 75.7% - 81.5%) were retained in care at any HIV clinic. In the first ancillary study, 248/753 (32.9%) participants presented to care with advanced HIV, 59.0% (146/248) of whom had been previously diagnosed with HIV. In the second ancillary study, the mean physical composite score was statistically significantly higher in women than men at the time of an HIV diagnosis (adjusted mean difference [AMD] 2.49, 95% CI 0.54 - 4.44). There was no significant difference between the genders in mental composite scores (AMD -0.99, 95% CI -2.71 - 0.73). Conclusions: Presentation to care with advanced HIV was primarily due to delayed diagnosis, rather than delayed linkage to care after diagnosis. Variation by clinic suggests that outreach and other community-based efforts may drive earlier testing and linkage to care. After receiving a positive HIV test, men and women had similar mental health scores, while women reported greater physical health. The weekly WelTel textmessaging service did not improve retention in early HIV care in this setting. Both in the trial and cohort study, retention in clinic substantially underestimated retention in care one year after presenting to care. While the proportion of patients retained in care was greater than expected, interventions to improve retention in care are needed to meet global targets to end the AIDS epidemic

Prevalence and correlates of fatigue in patients with meningioma before and after surgery

Background Fatigue is a common symptom in patients with brain tumors, but comprehensive studies on fatigue in patients with meningioma specifically are lacking. This study examined the prevalence and correlates of fatigue in meningioma patients. Methods Patients with grade I meningioma completed the Multidimensional Fatigue Inventory (MFI-20) before and 1 year after neurosurgery. The MFI consists of 5 subscales: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation, and Reduced Activity. Patients’ scores were compared with normative data. Preoperative fatigue was compared with postoperative fatigue. Correlations with sex, age, education, tumor hemisphere, preoperative tumor volume, antiepileptic drugs (AEDs), symptoms of anxiety/depression, and self-reported cognitive complaints were explored. Results Questionnaires were completed by 65 patients preoperatively, and 53 patients postoperatively. Of 34 patients, data from both time points were available. Patients had significantly higher fatigue levels on all subscales compared to normative values at both time points. Mean scores on General Fatigue, Physical Fatigue, and Mental Fatigue remained stable over time and improvements were observed on Reduced Motivation and Reduced Activity. Preoperatively, the prevalence of high fatigue (Z-score ≥ 1.3) varied between 34% for Reduced Motivation and 43% for General Fatigue/Mental Fatigue. The postoperative prevalence ranged from 19% for Reduced Activity to 49% on Mental Fatigue. Fatigue was associated with cognitive complaints, anxiety and depression, but not with education, tumor lateralization, tumor volume, or AEDs. Conclusion Fatigue is a common and persistent symptom in patients with meningioma undergoing neurosurgery. Findings emphasize the need for more research and appropriate care targeting fatigue for meningioma patients

Distinct Biomarker Profiles and Clinical Characteristics in T1-T2 Glottic and Supraglottic Carcinomas

Background: In early stage laryngeal squamous cell carcinoma (LSCC) radiotherapy with curative intent is a major treatment modality. TNM classification is used to define patients eligible for radiotherapy. Studies in early stage glottic LSCC identified several predictive biomarkers associated with local control. However, we recently reported that this predictive value could not be confirmed in supraglottic LSCC. Objective: To examine whether clinical behavior and protein expression patterns of these biomarkers differ between glottic and supraglottic LSCC. Study Design: Retrospective cohort study. Methods: Tumor tissue sections of 196 glottic and 80 supraglottic T1-T2 LSCC treated primarily with RT were assessed immunohistochemically for expression of pAKT, Ki-67 and β-Catenin. Expression data of HIF-1α, CA-IX, OPN, FADD, pFADD, Cyclin D1, Cortactin and EGFR in the same cohort of glottic and supraglottic LSCC, were retrieved from previously reported data. The relationship between glottic and supraglottic sublocalization and clinicopathological, follow-up, and immunohistochemical staining characteristics were evaluated using logistic regression and Cox regression analyses. Results: Glottic LSCC were correlated with male gender (P =.001), hoarseness as a primary symptom (P <.001), T1 tumor stage (P <.001), negative lymph node status (P <.001), and an older age at presentation (P =.004). Supraglottic LSCC patients developed more post-treatment distant metastasis when adjusted for gender, age, and T-status. While supraglottic LSCC was associated with higher expression of HIF-1α (P =.001), Cortactin (P <.001), EGFR (P <.001), and Ki-67 (P =.027), glottic LSCC demonstrated higher expression of CA-IX (P =.005) and Cyclin D1 (P =.001). Conclusion: Differences in clinicopathological and immunohistochemical staining characteristics suggest that T1-T2 glottic and supraglottic LSCC should be considered as different entities. Level of Evidence: N/A. Laryngoscope, 2020

Neurocognitive functioning in patients with conversion disorder/functional neurological disorder

Neurocognitive symptoms are common in individuals with somatic symptom and related disorders (SSRD), but little is known about the specific impairments in neurocognitive domains in patients with conversion disorder (CD)/functional neurological disorder (FND). This study examines neurocognitive functioning in patients with CD/FND compared to patients with other SSRD. The sample consisted of 318 patients. Twenty-nine patients were diagnosed with CD/FND, mean age 42.4, standard deviation (SD) = 13.8 years, 79.3% women, and 289 patients had other SSRD (mean age 42.1, SD = 13.3, 60.2% women). Patients completed a neuropsychological test battery that addressed a broad range of neurocognitive domains, including information processing speed, attention and executive functioning. Patients with CD/FND had clinically significant neurocognitive deficits in all neurocognitive domains based on normative data comparison. Patients with CD/FND also performed significantly worse than patients with other SSRD on information processing speed (Digit Symbol Substitution Test (V = .115, p = .035), Stroop Color-Word Test (SCWT) card 1 (V = .190, p = .006), and SCWT card 2 (V = .244, p < .001). No CD/FND vs. other SSRD differences were observed in other neurocognitive domains. These findings indicate the patients with CD/FND perform worse on information processing speed tests compared to patients with other SSRD

Standardised Ki-67 proliferation index assessment in early-stage laryngeal squamous cell carcinoma in relation to local control and survival after primary radiotherapy

ObjectivesAmbiguous results have been reported on the predictive value of the Ki-67 proliferation index (Ki-67 PI) regarding local control (LC) and survival after primary radiotherapy (RT) in early-stage laryngeal squamous cell cancer (LSCC). Small study size, heterogenic inclusion, variations in immunostaining and cut-off values are attributing factors. Our aim was to elucidate the predictive value of the Ki-67 PI for LC and disease-specific survival (DSS) using a well-defined series of T1-T2 LSCC, standardised automatic immunostaining and digital image analysis (DIA). MethodsA consecutive and well-defined cohort of 208 patients with T1-T2 LSCC treated with primary RT was selected. The Ki-67 PI was determined using DIA. Mann-Whitney U-tests, logistic and Cox regression analyses were performed to assess associations between Ki-67 PI, clinicopathological variables, LC and DSS. ResultsIn multivariate Cox regression analysis, poor tumour differentiation (HR 2.20; 95% CI 1.06-4.59, P = .04) and alcohol use (HR 2.84, 95% CI 1.20-6.71; P = .02) were independent predictors for LC. Lymph node positivity was an independent predictor for DSS (HR 3.16, 95% CI 1.16-8.64; P = .03). Ki-67 PI was not associated with LC (HR 1.59; 95% CI 0.89-2.81; P = .11) or DSS (HR 0.98; 95% CI 0.57-1.66; P = .97). In addition, continuous Ki-67 PI was not associated with LC (HR 2.03; 95% CI 0.37-11.14, P = .42) or DSS (HR 0.62; 95% CI 0.05-8.28; P = .72). ConclusionThe Ki-67 PI was not found to be a predictor for LC or DSS and therefore should not be incorporated in treatment-related decision-making for LSCC

Biological tumor markers associated with local control after primary radiotherapy in laryngeal cancer:A systematic review

Background The choice of treatment in laryngeal cancer is mainly based on tumor stage, post-treatment morbidity and quality of life. Biological tumor markers might also be of potential clinical relevance. Objective of the review The aim was to systematically review the value of published biological tumor markers to predict local control in laryngeal cancer patients treated with definitive radiotherapy. Type of Review Systematic review. Search strategy PubMed, Embase, Cochrane Library. Evaluation Method A literature search was performed using multiple terms for laryngeal cancer, radiotherapy, biological markers, detection methods and local control or survival. Studies regarding the relation between biological tumor markers and local control or survival in laryngeal cancer patients primarily treated with radiotherapy were included. Markers were clustered on biological function. Quality of all studies was assessed. Study selection, data extraction and quality assessment was performed by two independent reviewers. Results A total of 52 studies out of 618 manuscripts, concerning 118 markers, were included. EGFR and P53 showed consistent evidence for not being predictive of local control after primary radiotherapy, whereas proliferation markers (ie high Ki-67 expression) showed some, but no consistent, evidence for being predictive of better local control. Other clusters of markers (markers involved in angiogenesis and hypoxia, apoptosis markers, cell cycle, COX-2 and DNA characteristics) showed no consistent evidence towards being predictors of local control after primary radiotherapy. Conclusions Cell proliferation could be of potential interest for predicting local control after primary radiotherapy in laryngeal cancer patients, whereas EGFR and p53 are not predictive in contrast to some previous analyses. Large diversity in research methods is found between studies, which results in contradictory outcomes. Future studies need to be more standardised and well described according to the REMARK criteria in order to have better insight into which biomarkers can be used as predictors of local control after primary radiotherapy

Relationship between petal abscission and programmed cell death in Prunus yedoensis and Delphinium belladonna

Depending on the species, the end of flower life span is characterized by petal wilting or by abscission of petals that are still fully turgid. Wilting at the end of petal life is due to programmed cell death (PCD). It is not known whether the abscission of turgid petals is preceded by PCD. We studied some parameters that indicate PCD: chromatin condensation, a decrease in nuclear diameter, DNA fragmentation, and DNA content per nucleus, using Prunus yedoensis and Delphiniumbelladonna which both show abscission of turgid petals at the end of floral life. No DNA degradation, no chromatin condensation, and no change in nuclear volume was observed in P. yedoensis petals, prior to abscission. In abscising D.belladonna petals, in contrast, considerable DNA degradation was found, chromatin was condensed and the nuclear volume considerably reduced. Following abscission, the nuclear area in both species drastically increased, and the chromatin became unevenly distributed. Similar chromatin changes were observed after dehydration (24 h at 60°C) of petals severed at the time of flower opening, and in dehydrated petals of Ipomoea nil and Petunia hybrida, severed at the time of flower opening. In these flowers the petal life span is terminated by wilting rather than abscission. It is concluded that the abscission of turgid petals in D. belladonna was preceded by a number of PCD indicators, whereas no such evidence for PCD was found at the time of P. yedoensis petal abscission. Dehydration of the petal cells, after abscission, was associated with a remarkable nuclear morphology which was also found in younger petals subjected to dehydration. This nuclear morphology has apparently not been described previously, for any organism