Integrative Oncology Approaches to Reduce Recurrence of Disease and Improve Survival.

PURPOSE OF REVIEW: After a cancer diagnosis, patients ask what they can do in addition to the recommended treatments to increase their survival. Many turn to integrative medicine modalities and lifestyle changes to improve their chances of survival. Numerous studies have demonstrated that lifestyle changes can significantly improve survival rates for cancer patients. Less support exists for the use of natural products or supplements to improve cancer survival. In this manuscript, we review key findings and evidence in the areas of healthy eating habits, physical activity, stress management and social support, and sleep quality, as well as natural products and supplements as they relate to the cancer recurrence and survival. RECENT FINDINGS: While more research is needed to fully understand the mechanisms underlying the associations between lifestyle changes and cancer survival, findings suggest that lifestyle modifications in the areas of diet, physical activity, stress management and social support, and sleep quality improve clinical cancer outcomes. This is especially true for programs that modify more than one lifestyle habit. To date, outside of supplementing with vitamin D to maintain adequate levels, conflicting conclusion within the research remain regarding the efficacy of using natural products or supplement to improve cancer recurrence of disease or cancer survival. A call for further research is warranted. Lifestyle screening and counseling should be incorporated into cancer treatment plans to help improve patient outcomes. While the scientific community strives for the pursuit of high-quality research on natural products to enhance cancer survival, transparency, dialogue, and psychological safety between patients and clinicians must continue to be emphasized. Proactive inquiry by clinicians regarding patients' supplement use will allow for an informed discussion of the benefits and risks of natural products and supplements, as well as a re-emphasis of the evidence supporting diet and other lifestyle habits to increase survival.

Eating breakfast and avoiding late-evening snacking sustains lipid oxidation.

Circadian (daily) regulation of metabolic pathways implies that food may be metabolized differentially over the daily cycle. To test that hypothesis, we monitored the metabolism of older subjects in a whole-room respiratory chamber over two separate 56-h sessions in a random crossover design. In one session, one of the 3 daily meals was presented as breakfast, whereas in the other session, a nutritionally equivalent meal was presented as a late-evening snack. The duration of the overnight fast was the same for both sessions. Whereas the two sessions did not differ in overall energy expenditure, the respiratory exchange ratio (RER) was different during sleep between the two sessions. Unexpectedly, this difference in RER due to daily meal timing was not due to daily differences in physical activity, sleep disruption, or core body temperature (CBT). Rather, we found that the daily timing of nutrient availability coupled with daily/circadian control of metabolism drives a switch in substrate preference such that the late-evening Snack Session resulted in significantly lower lipid oxidation (LO) compared to the Breakfast Session. Therefore, the timing of meals during the day/night cycle affects how ingested food is oxidized or stored in humans, with important implications for optimal eating habits.

Frequencies and predictors of health psychology referrals after integrative oncology consultation.

OBJECTIVE: Health psychology (HP) plays a critical role within a multidisciplinary, integrative oncology team. HP in integrative oncology is not well established and criteria for referral have not been examined. This study examined characteristics of referral to HP. METHODS: A chart review of 1827 patients in the Integrative Medicine Center (IMC) between 2019 and 2020 was conducted. Patient assessments included the Edmonton Symptom Assessment Scale, Measure Yourself Concerns and Well-being, and PROMIS10. Chi-square tests were used to compare categorical variables, Mann-Whitney test for non-normally distributed continuous variables, and t-tests for normally distributed continuous variables comparing those referred and not referred to HP. RESULTS: Patients referred (n = 316) were mostly female (85.4%), White (67.1%), married/partnered (67.7%), obese (42.1%), and with breast cancer (52.2%). When comparing the two groups, patients referred to HP and patients not referred to HP, patients referred had a higher proportion of female and Black patients than expected (p ≤ .01); patients referred were also younger and had higher BMIs (p ≤ .01). Referred patients reported worse fatigue, sleep, depression, anxiety, well-being, spiritual pain, financial distress, memory, overall mental health, physical health, and global health (p ≤ .01). Most common concerns of referrals were diet/nutrition, overall health, and stress/anxiety. Compared to non-referred, HP referrals were more likely to prioritize depression, spirituality, and stress/anxiety (p ≤ .01). CONCLUSIONS: Patient characteristics are well-suited treatment targets for HP, including addressing emotional distress, healthy lifestyle, and quality of life. Our findings can help programs develop strategies to facilitate engagement with psychological counseling.

Multidisciplinary lifestyle modification program (IM-FIT) for cancer survivors: implementation of a reimbursable model in a cancer hospital.

PURPOSE: We examined the initial effects of a real-world application of a multimodal, reimbursable program to improve lifestyle and promote healthy weight loss in cancer survivors as part of their care. METHODS: The lifestyle program (Integrative Medicine Fitness Program; IM-FIT) focusing on increasing physical activity and strength training, improving nutrition, and facilitating stress management and behavior change was delivered in a group format over 12 weeks. Patients met weekly with a physical therapist, dietitian, and psychologist. Body composition and behavioral data were collected at the start and end of 12 weeks, as well as fitness, nutrition, and psychological data. The first cohort started in September 2017, and the last cohort ended in August 2019. RESULTS: Twenty-six patients (92% female; mean age = 62.7, SD = 9) completed the program, which was pre-approved and covered as in-network by their health insurance. Patients lost an average of 3.9% of their body weight (SD = - 2.2). There was a significant reduction in white bread and desserts and increase in legumes and non-dairy milk. Time spent in vigorous exercise (p < .001), strength training (p < .001), and total exercise (p < .001) significantly increased. Patients reported reduction in depression (7.76 to 4.29; p = .01), anxiety (6.14 to 3.29; p < .01), and overall distress (4.70 to 3.40; p < .01). CONCLUSION: We demonstrated that a multi-disciplinary weight loss program can be tailored to cancer survivors leading to weight reduction and improvements in lifestyle factors and mental health. This program showed successful real-world implementation with insurance reimbursement.

CDDO-Me, Sulforaphane and tBHQ attenuate the RANKL-induced osteoclast differentiation via activating the NRF2-mediated antioxidant response.

Metabolic bone diseases are global public health concerns and are primarily caused by uncontrolled osteoclast (OC) formation and activation. During OC differentiation, intracellular reactive oxygen species (ROS) stimulated by receptor activator of nuclear factor kappa-B ligand (RANKL) can serve as the signaling molecules to promote osteoclastic genes expression. Nuclear factor erythroid-2 related factor 2 (NRF2), a master mediator of cellular antioxidant response, also plays a critical role in OC differentiation through the regulation of redox homeostasis. In this study, we investigated the effects of three NRF2 inducers on osteoclastogenesis, including Bardoxolone methyl (CDDO-Me), Sulforaphane (SFN), and tert-butylhydroquinone (tBHQ). By treating RAW cells with three compounds, we found that NRF2 was activated and its downstream antioxidant genes were upregulated, and the RANKL-induced intracellular ROS production and osteoclastogenesis were impaired. Additionally, the expression of nuclear factor of activated T cells c1 (NFATC1), C-FOS and tumor necrosis factor alpha (TNFα) were inhibited after acute exposures (6 h) to the three compounds. Furthermore, suppressed the expression of osteoclast differentiation-associated genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase-9 (MMP-9) and dendritic cell-specific transmembrane protein (DC-STAMP) were observed after prolonged exposures (5 days) to the compounds. Taken together, these results suggest that CDDO-Me, SFN and tBHQ attenuate RANKL-induced osteoclastogenesis via activation of NRF2-mediated antioxidant response. Among these compounds, relatively low concentrations of CDDO-Me showed stronger active and inhibitory effects on antioxidant response and osteoclastogenesis, respectively.

The effects of inpatient music therapy on self-reported symptoms at an academic cancer center: a preliminary report.

PURPOSE: Music therapy has shown benefits for reducing distress in individuals with cancer. We explore the effects of music therapy on self-reported symptoms of patients receiving inpatient care at a comprehensive cancer center. METHODS: Music therapy was available as part of an inpatient integrative oncology consultation service; we examined interventions and symptoms for consecutive patients treated by a board-certified music therapist from September 2016 to May 2017. Patients completed the Edmonton Symptom Assessment Scale (ESAS, 10 symptoms, scale 0-10, 10 most severe) before and after the intervention. Data was summarized by descriptive statistics. Changes in ESAS symptom and subscale scores (physical distress (PHS), psychological distress (PSS), and global distress (GDS)) were evaluated by Wilcoxon signed rank test. RESULTS: Data were evaluable for 96 of 100 consecutive initial, unique patient encounters; 55% were women, average age 50, and majority with hematologic malignancies (47%). Reasons for music therapy referral included anxiety/stress (67%), adjustment disorder/coping (28%), and mood elevation/depression (17%). The highest (worst) symptoms at baseline were sleep disturbance (5.7) and well-being (5.5). We observed statistically and clinically significant improvement (means) for anxiety (- 2.3 ± 1.5), drowsiness (- 2.1 ± 2.2), depression (- 2.1 ± 1.9), nausea (- 2.0 ± 2.4), fatigue (- 1.9 ± 1.5), pain (- 1.8 ± 1.4), shortness of breath (- 1.4 ± 2.2), appetite (- 1.1 ± 1.7), and for all ESAS subscales (all ps < 0.02). The highest clinical response rates were observed for anxiety (92%), depression (91%), and pain (89%). CONCLUSIONS: A single, in-person, tailored music therapy intervention as part of an integrative oncology inpatient consultation service contributed to the significant improvement in global, physical, and psychosocial distress. A randomized controlled trial is justified.

A population-averaged approach to diagnostic test meta-analysis.

The meta-analysis of diagnostic accuracy studies is often of interest in screening programs for many diseases. The typical summary statistics for studies chosen for a diagnostic accuracy meta-analysis are often two dimensional: sensitivities and specificities. The common statistical analysis approach for the meta-analysis of diagnostic studies is based on the bivariate generalized linear-mixed model (BGLMM), which has study-specific interpretations. In this article, we present a population-averaged (PA) model using generalized estimating equations (GEE) for making inference on mean specificity and sensitivity of a diagnostic test in the population represented by the meta-analytic studies. We also derive the marginalized counterparts of the regression parameters from the BGLMM. We illustrate the proposed PA approach through two dataset examples and compare performance of estimators of the marginal regression parameters from the PA model with those of the marginalized regression parameters from the BGLMM through Monte Carlo simulation studies. Overall, both marginalized BGLMM and GEE with sandwich standard errors maintained nominal 95% confidence interval coverage levels for mean specificity and mean sensitivity in meta-analysis of 25 of more studies even under misspecification of the covariance structure of the bivariate positive test counts for diseased and nondiseased subjects.

Acute Hypoxia Induces Enkephalin Production and Release in an Adrenergic Cell Line Model of Neonatal Chromaffin Cell Responses to Hypoxic Stress.

OBJECTIVE: Prior to maturation of the human sympathetic nervous system, the neonatal adrenal medulla senses and responds to hypoxia. In addition to catecholamine release, the adrenal medulla synthesizes and stores opioid peptides, notably enkephalin (ENK). However, it is not known whether acute hypoxia evokes adrenal ENK production and release, as seen in the central nervous system (CNS). We hypothesize that acute hypoxia stimulates synthesis and release of ENK in chromaffin cells. STUDY DESIGN: Cultures of adrenergic mouse pheochromocytoma cells (MPC) 10/9/96CR were incubated in 10% oxygen (O2) at intervals of up to 60 minutes. ENK content and release were measured by Met-ENK enzyme-linked immunosorbent assay (ELISA). ENK messenger ribonucleic acid (mRNA) was analyzed by quantitative reverse-transcriptase polymerase chain reaction (PCR). RESULTS: Incubation of MPC 10/9 cells in 10% O2 evoked rapid release of epinephrine and of Met-ENK which increased approximately twofold in 15 minutes. Reduced [O2] also induced an overall increase (14%) in cellular ENK peptide content within 60 minutes. Acute hypoxia-stimulated release of Met-ENK was accompanied by increased mRNAENK expression in MPC 10/9s, a cell culture model of adrenergic chromaffin cells. CONCLUSION: We speculate that the ability of reduced [O2] to evoke ENK release from chromaffin cells may influence blood pressure regulation and heart contractility, thereby providing an adaptive survival advantage during neonatal asphyxia.

Improving geriatric prescribing in the ED: a qualitative study of facilitators and barriers to clinical decision support tool use.

QUALITY PROBLEM OR ISSUE: Clinical decision support (CDS) may improve prescribing for older adults in the Emergency Department (ED) if adopted by providers. INITIAL ASSESSMENT: Existing prescribing order entry processes were mapped at an initial Veterans Administration Medical Center site, demonstrating cognitive burden, effort and safety concerns. CHOICE OF SOLUTION: Geriatric order sets incorporating 2012 Beers guidelines and including geriatric prescribing advice and prepopulated order options were developed. IMPLEMENTATION: Geriatric order sets were implemented at two sites as part of the multicomponent 'Enhancing Quality of Prescribing Practices for Older Veterans Discharged from the Emergency Department' quality improvement initiative. EVALUATION: Facilitators and barriers to order sets use at the two sites were evaluated. Phone interviews were conducted with two provider groups (n = 20), those 'EQUiPPED' with the interventions (n = 10, 5 at each site) and Comparison providers who were only exposed to order sets through a clickable option on the ED order menu within the patient's medical record (n = 10, 5 at each site). All providers were asked about order set 'use' and 'usefulness'. Users (n = 11) were asked about 'usability'. LESSONS LEARNED: Order set adopters described 'usefulness' in terms of 'safety' and 'efficiency', whereas order set consultants and order set non-users described 'usefulness' in terms of 'information' or 'training'. Provider 'autonomy', 'comfort' level with existing tools, and 'learning curve' were stated as barriers to use. CONCLUSIONS: Quantifying efficiency advantages and communicating safety benefit over preexisting practices and tools may improve adoption of CDS in ED and in other settings of care.

Atypical multiple system atrophy is a new subtype of frontotemporal lobar degeneration: frontotemporal lobar degeneration associated with α-synuclein.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease clinically characterized by cerebellar signs, parkinsonism, and autonomic dysfunction. Pathologically, MSA is an α-synucleinopathy affecting striatonigral and olivopontocerebellar systems, while neocortical and limbic involvement is usually minimal. In this study, we describe four patients with atypical MSA with clinical features consistent with frontotemporal dementia (FTD), including two with corticobasal syndrome, one with progressive non-fluent aphasia, and one with behavioral variant FTD. None had autonomic dysfunction. All had frontotemporal atrophy and severe limbic α-synuclein neuronal pathology. The neuronal inclusions were heterogeneous, but included Pick body-like inclusions. The latter were strongly associated with neuronal loss in the hippocampus and amygdala. Unlike typical Pick bodies, the neuronal inclusions were positive on Gallyas silver stain and negative on tau immunohistochemistry. In comparison to 34 typical MSA cases, atypical MSA had significantly more neuronal inclusions in anteromedial temporal lobe and limbic structures. While uncommon, our findings suggest that MSA may present clinically and pathologically as a frontotemporal lobar degeneration (FTLD). We suggest that this may represent a novel subtype of FTLD associated with α-synuclein (FTLD-synuclein).

Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion.

Although there have been numerous advances in our understanding of how apicomplexan parasites such as Toxoplasma gondii enter host cells, many of the signaling pathways and enzymes involved in the organization of invasion mediators remain poorly defined. We recently performed a forward chemical-genetic screen in T. gondii and identified compounds that markedly enhanced infectivity. Although molecular dissection of invasion has benefited from the use of small-molecule inhibitors, the mechanisms underlying induction of invasion by small-molecule enhancers have never been described. Here we identify the Toxoplasma ortholog of human APT1, palmitoyl protein thioesterase-1 (TgPPT1), as the target of one class of small-molecule enhancers. Inhibition of this uncharacterized thioesterase triggered secretion of invasion-associated organelles, increased motility and enhanced the invasive capacity of tachyzoites. We demonstrate that TgPPT1 is a bona fide depalmitoylase, thereby establishing an important role for dynamic and reversible palmitoylation in host-cell invasion by T. gondii.

Using natural language processing to provide personalized learning opportunities from trainee clinical notes.

OBJECTIVE: Assessment of medical trainee learning through pre-defined competencies is now commonplace in schools of medicine. We describe a novel electronic advisor system using natural language processing (NLP) to identify two geriatric medicine competencies from medical student clinical notes in the electronic medical record: advance directives (AD) and altered mental status (AMS). MATERIALS AND METHODS: Clinical notes from third year medical students were processed using a general-purpose NLP system to identify biomedical concepts and their section context. The system analyzed these notes for relevance to AD or AMS and generated custom email alerts to students with embedded supplemental learning material customized to their notes. Recall and precision of the two advisors were evaluated by physician review. Students were given pre and post multiple choice question tests broadly covering geriatrics. RESULTS: Of 102 students approached, 66 students consented and enrolled. The system sent 393 email alerts to 54 students (82%), including 270 for AD and 123 for AMS. Precision was 100% for AD and 93% for AMS. Recall was 69% for AD and 100% for AMS. Students mentioned ADs for 43 patients, with all mentions occurring after first having received an AD reminder. Students accessed educational links 34 times from the 393 email alerts. There was no difference in pre (mean 62%) and post (mean 60%) test scores. CONCLUSIONS: The system effectively identified two educational opportunities using NLP applied to clinical notes and demonstrated a small change in student behavior. Use of electronic advisors such as these may provide a scalable model to assess specific competency elements and deliver educational opportunities.

Clinical symptoms, signs and tests for identification of impending and current water-loss dehydration in older people.

BACKGROUND: There is evidence that water-loss dehydration is common in older people and associated with many causes of morbidity and mortality. However, it is unclear what clinical symptoms, signs and tests may be used to identify early dehydration in older people, so that support can be mobilised to improve hydration before health and well-being are compromised. OBJECTIVES: To determine the diagnostic accuracy of state (one time), minimally invasive clinical symptoms, signs and tests to be used as screening tests for detecting water-loss dehydration in older people by systematically reviewing studies that have measured a reference standard and at least one index test in people aged 65 years and over. Water-loss dehydration was defined primarily as including everyone with either impending or current water-loss dehydration (including all those with serum osmolality ≥ 295 mOsm/kg as being dehydrated). SEARCH METHODS: Structured search strategies were developed for MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL, LILACS, DARE and HTA databases (The Cochrane Library), and the International Clinical Trials Registry Platform (ICTRP). Reference lists of included studies and identified relevant reviews were checked. Authors of included studies were contacted for details of further studies. SELECTION CRITERIA: Titles and abstracts were scanned and all potentially relevant studies obtained in full text. Inclusion of full text studies was assessed independently in duplicate, and disagreements resolved by a third author. We wrote to authors of all studies that appeared to have collected data on at least one reference standard and at least one index test, and in at least 10 people aged ≥ 65 years, even where no comparative analysis has been published, requesting original dataset so we could create 2 x 2 tables. DATA COLLECTION AND ANALYSIS: Diagnostic accuracy of each test was assessed against the best available reference standard for water-loss dehydration (serum or plasma osmolality cut-off ≥ 295 mOsm/kg, serum osmolarity or weight change) within each study. For each index test study data were presented in forest plots of sensitivity and specificity. The primary target condition was water-loss dehydration (including either impending or current water-loss dehydration). Secondary target conditions were intended as current (> 300 mOsm/kg) and impending (295 to 300 mOsm/kg) water-loss dehydration, but restricted to current dehydration in the final review.We conducted bivariate random-effects meta-analyses (Stata/IC, StataCorp) for index tests where there were at least four studies and study datasets could be pooled to construct sensitivity and specificity summary estimates. We assigned the same approach for index tests with continuous outcome data for each of three pre-specified cut-off points investigated.Pre-set minimum sensitivity of a useful test was 60%, minimum specificity 75%. As pre-specifying three cut-offs for each continuous test may have led to missing a cut-off with useful sensitivity and specificity, we conducted post-hoc exploratory analyses to create receiver operating characteristic (ROC) curves where there appeared some possibility of a useful cut-off missed by the original three. These analyses enabled assessment of which tests may be worth assessing in further research. A further exploratory analysis assessed the value of combining the best two index tests where each had some individual predictive ability. MAIN RESULTS: There were few published studies of the diagnostic accuracy of state (one time), minimally invasive clinical symptoms, signs or tests to be used as screening tests for detecting water-loss dehydration in older people. Therefore, to complete this review we sought, analysed and included raw datasets that included a reference standard and an index test in people aged ≥ 65 years.We included three studies with published diagnostic accuracy data and a further 21 studies provided datasets that we analysed. We assessed 67 tests (at three cut-offs for each continuous outcome) for diagnostic accuracy of water-loss dehydration (primary target condition) and of current dehydration (secondary target condition).Only three tests showed any ability to diagnose water-loss dehydration (including both impending and current water-loss dehydration) as stand-alone tests: expressing fatigue (sensitivity 0.71 (95% CI 0.29 to 0.96), specificity 0.75 (95% CI 0.63 to 0.85), in one study with 71 participants, but two additional studies had lower sensitivity); missing drinks between meals (sensitivity 1.00 (95% CI 0.59 to 1.00), specificity 0.77 (95% CI 0.64 to 0.86), in one study with 71 participants) and BIA resistance at 50 kHz (sensitivities 1.00 (95% CI 0.48 to 1.00) and 0.71 (95% CI 0.44 to 0.90) and specificities of 1.00 (95% CI 0.69 to 1.00) and 0.80 (95% CI 0.28 to 0.99) in 15 and 22 people respectively for two studies, but with sensitivities of 0.54 (95% CI 0.25 to 0.81) and 0.69 (95% CI 0.56 to 0.79) and specificities of 0.50 (95% CI 0.16 to 0.84) and 0.19 (95% CI 0.17 to 0.21) in 21 and 1947 people respectively in two other studies). In post-hoc ROC plots drinks intake, urine osmolality and axillial moisture also showed limited diagnostic accuracy. No test was consistently useful in more than one study.Combining two tests so that an individual both missed some drinks between meals and expressed fatigue was sensitive at 0.71 (95% CI 0.29 to 0.96) and specific at 0.92 (95% CI 0.83 to 0.97).There was sufficient evidence to suggest that several stand-alone tests often used to assess dehydration in older people (including fluid intake, urine specific gravity, urine colour, urine volume, heart rate, dry mouth, feeling thirsty and BIA assessment of intracellular water or extracellular water) are not useful, and should not be relied on individually as ways of assessing presence or absence of dehydration in older people.No tests were found consistently useful in diagnosing current water-loss dehydration. AUTHORS' CONCLUSIONS: There is limited evidence of the diagnostic utility of any individual clinical symptom, sign or test or combination of tests to indicate water-loss dehydration in older people. Individual tests should not be used in this population to indicate dehydration; they miss a high proportion of people with dehydration, and wrongly label those who are adequately hydrated.Promising tests identified by this review need to be further assessed, as do new methods in development. Combining several tests may improve diagnostic accuracy.

Care transitions: a leverage point for safe and effective medication use in older adults--a mini-review.

Older adults often face challenges as they transition out of the acute care hospital, especially with regard to adhering to their medications. In this narrative review, we discuss medication adherence in older adults across the continuum of care, describing reasons for nonadherence, methods to assess adherence and tools to improve adherence, with particular focus on emerging techniques and technologies. Taking steps at care transitions to assess medications and foster adherence to the medication regimen can increase the safety of older adults following hospitalization.

Development of a level 1 geriatric outpatient social work screen in a veterans primary care clinic.

Patient Aligned Care Teams (PACT) provide primary care to veterans. We describe our experience in a PACT (average age 66, 98% men, 8 medications, 16% yearly hospitalization rate) using a nurse-administered screen to identify patients in need of intervention by a Masters-level Social Worker. Our screening results--98% Positive predictive value (included social work concerns) and 73% negative predictive value (excluded social work concerns)--suggest that the nurse accurately identified patients. Another 15% of patients were identified by the social worker. Similar screens used in interprofessional clinics could help target patients in need of further social work care.

Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis.

The mechanistic details of the pathogenesis of Chlamydia, an obligate intracellular pathogen of global importance, have eluded scientists due to the scarcity of traditional molecular genetic tools to investigate this organism. Here we report a chemical biology strategy that has uncovered the first essential protease for this organism. Identification and application of a unique CtHtrA inhibitor (JO146) to cultures of Chlamydia resulted in a complete loss of viable elementary body formation. JO146 treatment during the replicative phase of development resulted in a loss of Chlamydia cell morphology, diminishing inclusion size, and ultimate loss of inclusions from the host cells. This completely prevented the formation of viable Chlamydia elementary bodies. In addition to its effect on the human Chlamydia trachomatis strain, JO146 inhibited the viability of the mouse strain, Chlamydia muridarum, both in vitro and in vivo. Thus, we report a chemical biology approach to establish an essential role for Chlamydia CtHtrA. The function of CtHtrA for Chlamydia appears to be essential for maintenance of cell morphology during replicative the phase and these findings provide proof of concept that proteases can be targeted for antimicrobial therapy for intracellular pathogens.

Effects of hematopoietic stem cell transplantation on acyl-CoA oxidase deficiency: a sibling comparison study.

OBJECTIVE: Acyl-CoA oxidase (ACOX1) deficiency is a rare disorder of peroxisomal very-long chain fatty acid oxidation. No reports detailing attempted treatment, longitudinal imaging, or neuropathology exist. We describe the natural history of clinical symptoms and brain imaging in two siblings with ACOX1 deficiency, including the younger sibling's response to allogeneic unrelated donor hematopoietic stem cell transplantation (HSCT). METHODS: We conducted retrospective chart review to obtain clinical history, neuro-imaging, and neuropathology data. ACOX1 genotyping were performed to confirm the disease. In vitro fibroblast and neural stem cell fatty acid oxidation assays were also performed. RESULTS: Both patients experienced a fatal neurodegenerative course, with late-stage cerebellar and cerebral gray matter atrophy. Serial brain magnetic resonance imaging in the younger sibling indicated demyelination began in the medulla and progressed rostrally to include the white matter of the cerebellum, pons, midbrain, and eventually subcortical white matter. The successfully engrafted younger sibling had less brain inflammation, cortical atrophy, and neuronal loss on neuro-imaging and neuropathology compared to the untreated older sister. Fibroblasts and stem cells demonstrated deficient very long chain fatty acid oxidation. INTERPRETATION: Although HSCT did not halt the course of ACOX1 deficiency, it reduced the extent of white matter inflammation in the brain. Demyelination continued because of ongoing neuronal loss, which may be due to inability of transplant to prevent progression of gray matter disease, adverse effects of chronic corticosteroid use to control graft-versus-host disease, or intervention occurring beyond a critical point for therapeutic efficacy.

Psychiatric illness and resident assaults among veterans in long-term care facilities.

This article describes a quality improvement program to reduce the prevalence of physical assaults in a university-affiliated, 234-bed Veterans Affairs (VA) long-term care (LTC) facility, which experienced a rise in the number of physical assaults to >4 per 1,000 bed days of care in four LTC units. Analysis of 55 events (29 patients) at this VA LTC site during 2007 revealed 19 resident assailants (8% total population), 10 victims, and 30% repeat events. Of the residents who exhibited assaultive behavior, 44% had dementia and 32% had schizophrenia as a major diagnosis. Following a process improvement plan, new occurrence assaultive behaviors declined from >4 to <1 per 1,000 bed days and remained low during 5-year follow up.

Guanfacine for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Down Syndrome: A Retrospective Chart Review.

Study Design: Retrospective case series. Objectives: The objective of this study was to provide naturalistic data on the use of guanfacine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in a clinically referred sample of youth with Down syndrome (DS). Methods: The medical records of children and adolescents with DS who received guanfacine for the treatment of ADHD from a multidisciplinary neurodevelopmental disorder clinic between September 1, 2011, and September 10, 2021, were reviewed. Demographic and clinical characteristics, guanfacine dose and treatment duration, and adverse effects were recorded. Clinical Global Impression Scale (CGI) scores for ADHD symptom severity (S) and improvement (I) were retrospectively assigned by a child and adolescent psychiatrist based on review of the clinic notes. Response to guanfacine was defined as completion of at least 12 weeks of treatment and a Clinical Global Impression Improvement subscale rating ≤2 (1 = "very much improved" or 2 = "much improved"). Results: Twenty-one patients were eligible for inclusion, of whom 17 (81%) completed at least 12 weeks of guanfacine. Ten of the 21 patients (48%; 95% confidence interval [CI]: 28%-68%) responded to treatment. The median time on guanfacine treatment covered by the clinic notes was 50.4 weeks, with a range of 0.3 weeks to 7.5 years. Thirteen patients (62%) remained on guanfacine at the time of their most recent clinic note. Nine patients had adverse events documented in their clinic notes (43%; 95% CI: 24%-63%), most commonly sleepiness (n = 7) and constipation (n = 2). Conclusion: About half of patients with DS responded to guanfacine for the treatment of ADHD and many tolerated long-term use. Study limitations primarily relate to the retrospective nature of the study and small sample size.