Body mass index and nutritional intake following Elexacaftor/Tezacaftor/Ivacaftor modulator therapy in adults with cystic fibrosis.

BACKGROUND: Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy is often associated with increased body mass index (BMI) in people with cystic fibrosis (CF). This is thought to reflect improved clinical stability and increased appetite and nutritional intake. We explored the change in BMI and nutritional intake following ETI modulator therapy in adults with CF. METHODS: Dietary intake, measured with myfood24®, and BMI were collected from adults with CF at baseline and follow-up as part of an observational study. Changes in BMI and nutritional intake in participants who commenced ETI therapy between time points were assessed. To contextualize findings, we also assessed changes in BMI and nutritional intake between study points in a group on no modulators. RESULTS: In the pre and post ETI threapy group (n = 40), BMI significantly increased from 23.0 kg/m2 (IQR 21.4, 25.3) at baseline to 24.6 kg/m2 (IQR 23.0, 26.7) at follow-up (p<0.001), with a median of 68 weeks between time points (range 20-94 weeks) and median duration of ETI therapy was 23 weeks (range 7-72 weeks). There was a significant decrease in energy intake from 2551 kcal/day (IQR 2107, 3115) to 2153 kcal/day (IQR 1648, 2606), p<0.001. In the no modulator group (n = 10), BMI and energy intake did not significantly change between time points (p>0.05), a median of 28 weeks apart (range 20-76 weeks). CONCLUSIONS: These findings tentatively suggest that the increase in BMI with ETI therapy may not simply be attributable to an increase in oral intake. Further exploration into the underlying aetiology of weight gain with ETI therapy is needed.

Substance Use in U.S. Vietnam War Era Veterans and Nonveterans: Results from the Vietnam Era Health Retrospective Observational Study.

Background: Substance use (SU) is associated with physical injury and mental health disorders in older persons, but recent research has scarcely examined SU in U.S. Vietnam-era veterans who are mostly in or near their eighth decade of life. Objectives: We compared the prevalence of self-reported lifetime and current SU and modeled current usage patterns in a nationally representative sample of veterans versus a matched nonveteran cohort. Methods: Cross-sectional, self-reported survey data were analyzed from the 2016-2017 Vietnam Era Health Retrospective Observational Study (VE-HEROeS) (n = 18,866 veterans, n = 4,530 nonveterans). We assessed lifetime and current alcohol and drug use disorders; lifetime and current use of cannabis, opioids, stimulants, sedatives, "other drugs" (psychedelics, prescription or over-the-counter drugs not prescribed/used as intended); and current SU patterns (alcohol-use-only, drug-use-only, dual-SU, no SU). Weighted descriptive, bivariable, and multivariable statistics were calculated. Covariates in multinomial modeling included sociodemographic characteristics, lifetime cigarette smoking, depression, potentially traumatic events (PTEs), and current pain (SF-8TM). Results: Prevalence of lifetime opioid and sedative use (p ≤ .01), drug and alcohol use disorders (p < .001), and current "other drug" use (p < .001) were higher in veterans versus nonveterans. Current use of alcohol and cannabis was high in both cohorts. In veterans, very severe/severe pain, depression, and PTEs were highly associated with drug-use-only (p < .001) and dual-SU (p < .01), but these associations were fewer for nonveterans. Conclusion: This research confirmed existing concerns over substance misuse in older individuals. Vietnam-era veterans may be at particular risk due to service-related experiences and later-life tribulations. Era veterans' unique perceptions toward healthcare assistance for SU may need greater provider focus to maximize self-efficacy and treatment.

U.S. Blue Water Navy Veterans of the Vietnam War: Comparisons from the Vietnam Era Health Retrospective Observational Study (VE-HEROeS).

Background: US Vietnam War Blue Water Navy veterans (BWN) conducted military operations on Vietnam's offshore waters and likely experienced various war-related exposures. The overall health of the BWN has never been systematically studied. Purpose: Describe and compare BWN's health with other servicemembers and non-veterans of the Vietnam era. Materials and methods: Survey of 45 067 randomly selected US Vietnam War theatre and non-theatre veterans and 6885 non-veterans. Results: For 22 646 male respondents, self-reported health was contrasted by veteran status defined as BWN (n=985), theatre veterans (n=6717), non-theatre veterans (n=10 698) and non-veterans (n=4246). Exposure was service in the Vietnam War theatre. Collected were demographics, military service characteristics, lifestyle factors and health conditions. Adjusted odds ratios (aOR) were calculated using multivariable logistic regression. Controlling for cigarette smoking and other covariates, respiratory cancer risk was highest in BWN vs other veterans (theatre: aOR 1.65; 95% CI 1.09, 2.50; non-theatre: aOR 1.77; 1.13, 2.77) and to non-veterans (aOR 1.78; 1.15, 2.74). Other findings showed BWN's health risks between theatre and non-theatre veterans. Conclusion: There was a higher risk for respiratory cancers in BWN. Other risks were less than theatre veterans but greater than non-theatre or non-veterans, indicating a potential role of military exposures in BWN's health.

Outcomes for Patients with Non-metastatic Triple-negative Breast Cancer in New Zealand.

AIMS: Triple-negative breast cancer (TNBC) has inferior outcomes to other subtypes of breast cancer. We studied the demographics and baseline breast cancer characteristics of patients in New Zealand with TNBC and assessed survival outcomes and prognostic/predictive factors. MATERIALS AND METHODS: We searched the New Zealand breast cancer registry database and identified patients with TNBC without distant metastatic disease. We retrieved demographic, tumour characteristic and treatment information. Locoregional recurrence-free survival, breast cancer-specific survival (BSS), metastasis-free survival (MRFS) and overall survival were determined. Predefined univariate and multivariate analyses were carried out investigating the association of survival outcomes with treatment and tumour characteristics. RESULTS: In total, 1390 patients were identified, with a median follow-up of 3.5 years. The median age was 55 years. Thirty-eight per cent were node positive and 79% were grade III. Mastectomy was carried out in 53%, adjuvant radiation delivered in 66% and chemotherapy in 69%. The significant predictive factors for overall survival, BSS and MRFS were radiotherapy, chemotherapy and neoadjuvant chemotherapy. The significant prognostic indicators were lymphovascular invasion, nodal status and tumour size. On Kaplan-Meier analysis, the 5 year overall survival was 72%. The median time to death for those who died was 3.55 years with 92% of deaths within 5 years. Seventy-four per cent of patients had distant metastasis as a first recurrence and isolated local recurrences occurred in only 4.5%. Metastatic disease occurred in lung (55.9%) and was in multiple sites in 51%. CONCLUSION: We report a large population-based series of TBNC without distant metastatic disease at diagnosis highlighting the unique behavioural characteristics of TNBC. Traditional therapies are positively associated with survival outcomes, and yet, particularly in the setting of recurrent disease, prognosis remains poor. Increased research into more effective systemic agents and the most effective timing of delivery of these may result in improved outcomes.

Adherence to Adjuvant Endocrine Therapy in Christchurch Women with Early Breast Cancer.

AIMS: To assess adherence to adjuvant endocrine therapy by a real-world cohort of women in Christchurch and to determine any associated factors. MATERIALS AND METHODS: Records were retrieved of all women newly diagnosed with early breast cancer and registered on the Christchurch Breast Cancer Patient Register over 4 years from June 2009. Demographic and pathological factors, dates of starting and stopping endocrine therapies and reported side-effects were collected. The proportion remaining on endocrine therapy was analysed by Kaplan-Meier curve; Cox regression analysis was used to identify independent factors influencing adherence. RESULTS: Of 1213 women, 1018 (83.9%) had oestrogen receptor-positive tumours, of whom 674 (66.2%) started adjuvant endocrine therapy, including 62 (9.2%) neoadjuvantly. Uptake was 52.4% of those with T1 tumours, 89% with T2 tumours, 93% with T3/T4 tumours, 92.7% with node-positive tumours and 49.7% with node-negative tumours. The initial endocrine therapy was an aromatase inhibitor in 254 (38%) and tamoxifen for 412 (61%). At 1 year, 90% remained adherent, at 2 years 84%, at 3 years 81%, at 4 years 76%, at 4.5 years 71% and at 5 years 50%, with a median duration of 60 months (56-64 months, 95% confidence interval) and a median follow-up of 33 months. Overall, 135 (20%) women stopped treatment for adverse events or poor tolerability. A longer persistence with endocrine therapy was associated with node-positive tumours (hazard ratio 1.38, P = 0.003), but not first hormone used; aromatase inhibitor compared with tamoxifen, P = 0.76. CONCLUSION: Adjuvant endocrine therapy use fell to 50% by 5 years, limiting possible survival benefits, providing support for efforts to increase compliance.

The weight debate.

Therapeutic interventions administered on Critical Care are often dosed on the basis of patient body size, to ensure treatments are effective in achieving their goals and to prevent harm from overdose. Many treatment modalities use predicted weights estimated from descriptors such as sex, weight and height to reduce error that is associated with using total body weight in critically ill patients. In this article we review the size descriptors that have been described, their origin and calculation. We then examine the role they play in dosing of common therapies utilised in Critical Care and potential areas of research for the future.

Evaluation of CD4+ T cell function In vivo in HIV-infected patients as measured by bacteriophage phiX174 immunization.

Bacteriophage phiX174 immunization was used to measure CD4(+) T cell function in vivo in human immunodeficiency virus (HIV)-infected patients across all disease stages. Function was evaluated by measuring the ability of T cells to provide help to B cells in antibody production, amplification, and isotype switching. A total of 33 patients and 10 controls received 3 bacteriophage phiX174 immunizations 6 weeks apart. The patients' responses regarding bacteriophage-specific total antibody titers and IgG titers were quantitatively and qualitatively inferior to the controls' responses. Overall, 7 of 33 patients had normal T cell function. Baseline CD4 counts provided the strongest correlation with total antibody and IgG titers. HIV RNA had a weaker association with responses but had some predictive power among patients with a CD4 count >200 cells/microL. Bacteriophage phiX174 immunization seems to be a useful tool for measuring immune function in vivo, which suggests that most HIV-infected patients may have abnormal CD4(+) T cell function despite adequate antiretroviral treatment.

Observational learning in children with Down syndrome and developmental delays: the effect of presentation speed in videotaped modelling.

Children with severe developmental delays (three with Down syndrome and three with autism as the primary diagnosis) observed a videotaped model performing two basic dressing skills without prompting, verbal or otherwise, or explanation by an instructor. In a within-subjects design, dressing skills that were presented at a relatively slow presentation speed through videotaped modelling were eventually performed better than those presented at a relatively fast speed. These data in combination with evidence from this laboratory that passive modelling of basic skills is more effective than interactive modelling (e.g., Biederman, Fairhall, Raven, & Davey, 1998; Biederman, Davey, Ryder, & Franchi, 1994; Biederman, Ryder, Davey, & Gibson, 1991) suggest that standard instructional techniques warrant reexamination both from the basis of instructional effectiveness and the efficient use of the allotment of teacher time.

Conditioned antisickness: indirect evidence from rats and direct evidence from ferrets that conditioning alleviates drug-induced nausea and emesis.

In a direct test of conditioned antisickness (CAS; B. T. Lett, 1983) theory, the authors measured emesis in ferrets and found those with a history of forward pairings of pentobarbital and lithium to have fewer and shorter bouts of emesis on test, whether induced by lithium or, in a subsequent test, by the highly emetogenic anticancer drug cisplatin. In an indirect test of her CAS theory, B. T. Lett (1992) paired interoceptive (drug) or place cues with lithium chloride toxicosis and found that rats with a forward-pairings history ate less food than controls on a forward-pairing test, consistent with conditioned sickness rather than CAS. But rats eat dirt or clay in response to sickness and adaptively eat small amounts of food when clay is not available. We substituted clay (kaolin) for food in a partial procedural replication of B. T. Lett's (1992, Experiment 1) experiment and found that rats with a history of forward pairings of pentobarbital and lithium ate less kaolin, which is consistent with CAS.

The role of stimulus preexposure in problem solving by Octopus vulgaris.

Octopus vulgaris is able to open transparent glass jars closed with plastic plugs and containing live crabs. The decrease in performance times for removing the plug and seizing the prey with increasing experience of the task has been taken to indicate learning. However, octopuses' attack behaviors are typically slow and variable in novel environmental situations. In this study the role of preexposure to selected features of the problem-solving context was investigated. Although octopuses failed to benefit from greater familiarity with the training context or with selected elements of the task of solving the jar problem, the methodological strategies used are instructive in potentially clarifying the role of complex problem-solving behaviors in this species including stimulus preexposure and social learning.

Teaching basic skills to children with Down syndrome and developmental delays: the relative efficacy of interactive modeling with social rewards for benchmark achievements and passive observation.

In interventions attempting to remediate deficiencies in the skills repertoire of developmentally delayed children, no less than in medical interventions, it may be fairly said that less is more. That is, the instructor should intervene as little as possible both from the perspective of efficient instructional practice and from time allotment concerns which modern classrooms face. Evidence from this laboratory has indicated that in skills training for children with severe developmental delays the passive observation of a model demonstrating the target skill is more effective than interactive modeling involving hand-over-hand instruction with verbal prompting. We have considered the role of verbal prompting in interactive modeling and have found that prompts intended to provide typical social reinforcers are counterproductive (e.g., Biederman, Davey, Ryder, & Franchi, 1994). The present study examines the efficacy of hand-over-hand modeling with response-contingent verbal prompts. In such instruction, tasks are divided into identifiable sequential components, and the achievement of each component is marked by the delivery of some form of verbal prompt. In a within-subjects design, children were trained in one skill with response-contingent verbal prompts and in a second skill with simple passive observation. A separate group of children were trained with less rigorous verbal prompting in one skill and with passive observation in a second. Consistent with previous research, we found that passive modeling was overall significantly more effective than hand-over-hand modeling and moreover that passive modeling was significantly more effective than hand-over-hand modeling with response-contingent prompting. Our evidence therefore indicates that current classroom practice in training basic skills to children with severe developmental delays may require reassessment in that simple observation of modeled skills appears to be more effective than more labor-intensive instruction.

Conditioned antisickness: heat as an internal stimulus in conditioning taste aversion and aversion failure in rats.

Heat was found to be effective as a conditional stimulus in the aversion failure procedure (S. Revusky, H. K. Taukulis, L. A. Parker, & S. Coombes, 1979) and was also found to be effective as an unconditional stimulus using a taste aversion procedure in which rats exposed to high ambient temperature following saccharin consumption showed robust saccharin aversions relative to unpaired and unheated controls. The antisickness and taste aversion conditioning evidence force reexamination of the view that toxic heat effects are referred to the external environment. Together with other recent evidence from this laboratory, these data support the hypothetical antisickness mechanism of aversion failure, which requires that toxic heat serve as an internal stimulus.

Combination therapy with didanosine and interferon-alpha in human immunodeficiency virus-infected patients: results of a phase I/II trial.

A nonrandomized trial was undertaken to evaluate the combination of didanosine and interferon-alpha (INF-alpha) in human immunodeficiency virus (HIV)-infected patients. Thirty-six volunteers with >200 x 10(6) CD4 cells/L received didanosine (one 100-, 250-, or 375-mg sachet twice daily) for at least 6 weeks, following which IFN-alpha (1, 5, 10, or 15 MU/day) was begun. Didanosine (one 375-mg sachet twice daily) was substituted for zidovudine in 14 additional patients who had received IFN-alpha and zidovudine for 7-45 months. Thirty-five patients completed the 34-week study. Clinical or chemical pancreatitis was the most common (6 patients) dose-limiting toxicity. CD4 cell counts increased with didanosine but declined following the addition of IFN-alpha; CD4 cell percents tended to increase and remain elevated. Thus, combination therapy with didanosine and IFN-alpha can be safely administered to patients with HIV infection. The clinical benefit of this combination therapy will require further evaluation.

Transfer of HIV-1-specific cytotoxic T lymphocytes to an AIDS patient leads to selection for mutant HIV variants and subsequent disease progression.

An HIV-1-seropositive volunteer was infused with an expanded autologous cytotoxic T lymphocyte (CTL) clone directed against the HIV-1 nef protein. This clone was adoptively transferred to determine whether supplementing CTL activity could reduce viral load or improve clinical course. Unexpectedly, infusion was followed by a decline in circulating CD4+ T cells and a rise in viral load. Some of the HIV isolates obtained from the plasma or CD4+ cells of the patient were lacking the nef epitope. These results suggest that active CTL selection of viral variants could contribute to the pathogenesis of AIDS and that clinical progression can occur despite high levels of circulating HIV-1-specific CTLs.

The effect of caloric restriction on lipofuscin accumulation in mouse brain with age.

Caloric restriction (CR), has been shown to extend average and maximum lifespan in rodents and other animals as well as to delay a wide variety of manifestations of aging. The purpose of this study was to further elucidate the relationship between lipofuscin (LF) accumulation and the aging process by examining the effect of lifelong CR on LF accumulation in brain cells. Specifically, 1) we include age groups of CR (CR1 approximately equal to 90 kcal/wk and CR2 approximately equal to 58 kcal/wk) and ad libidum fed (AL; approximately 120 kcal/wk) mice including groups at maximum lifespan; 2) CR was the major dietary manipulation; 3) LF was identified using EM; 4) LF was quantified by areal measurement; and 5) the results were analyzed by inferential statistics. We have found that 1) LF increased with age and 2) that animals in the CR2 group had significantly less overall LF in the perikarya of the granule cells of the dentate gyrus when compared to CR1 or AL animals at equivalent ages. In addition, CR2 mice at maximum lifespan (45 mo.) had slightly less LF than did CR1 or AL mice at their maximum lifespans (36 mo.). Our results clearly demonstrate that CR (at 52%, but not 25% of AL diet) retards the overall accumulation of LF with time and, further, suggest that LF accumulation is not simply a linear function of age.

Antisickness conditioning using a nausea-producing nondrug cue.

Most drugs induce conditioned taste aversions and are therefore commonly supposed to produce nausea or sickness. Paradoxically, some drugs appear to lose induction capability when made to serve as a cue for a second drug that produces more severe sickness, perhaps through selective association with a hypothetical homeostatic or antisickness aftereffect of sickness. Using drug-drug pairings had made antisickness conditioning theory difficult to validate. We report here that rotation serves in lieu of a drug cue in rats. Rotation-drug pairings eliminate drug interactions and enable the sorts of parametric manipulations required to validate the theory. By postulating a common sickness mechanism to explain both taste aversion and aversion failure, the theory places the phenomenon within an adaptive evolutionary framework. Successful application could yield a direct countermeasure to severe nausea in clinical settings.

Methodological issues in drug-drug conditioning in rats: nonassociative factors in heart rate and avfail.

Sodium pentobarbital injections followed 30 min later by d-amphetamine sulfate produce an effect over trials in the form of an increase in heart rate in response to pentobarbital in relation to rats that receive the 2 drugs 24 hr apart (long-delayed control: Revusky, Davey, & Zagorski, 1989). This study found equivalent increases in heart rate in forward and backward groups in relation to a long-delayed control regardless of whether training or testing was carried out in a heart rate recording apparatus or in the home cage, which suggests that a drug interaction due to drug administrations in forward and backward groups has yet to be eliminated in accounting for the heart rate effect. Comparison of backward and long-delayed controls in a drug-drug procedure that used a taste aversion test revealed that both forward and delayed pairings can produce attenuated aversions in relation to a backward group regardless of whether the unconditional stimulus is amphetamine (Experiment 1) or lithium chloride (Experiment 2).