Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics.

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.

Safety and efficacy of nightly nitrofurantoin as prophylaxis in dogs with recurrent urinary tract infections: 13 cases (2015-2021).

OBJECTIVES: To report the protocol, efficacy and adverse events in dogs receiving nightly nitrofurantoin therapy as antimicrobial prophylaxis for recurrent urinary tract infections. MATERIALS AND METHODS: Retrospective case series of dogs prescribed nitrofurantoin as prophylaxis for recurrent urinary tract infections. Data on urological history, diagnostic investigation, protocol, adverse events and efficacy (through serial urine cultures) were extracted from medical records. RESULTS: Thirteen dogs were included. Before therapy, dogs had a median of 3 (range 3 to 7) positive urine cultures in the past year. In all but one dog, standard antimicrobial therapy was given before starting the nightly nitrofurantoin. The nightly nitrofurantoin was then prescribed at a median dose of 4.1 mg/kg orally every 24 hours for a median of 166 days (range 44 to 1740). The median infection-free interval on therapy was 268 days (95% confidence interval: 165 to undefined). Eight dogs had no positive urine cultures while on therapy. Of these, five (three which discontinued and two which remained on nitrofurantoin) had no return of clinical signs or bacteriuria at time of last follow-up evaluation or death, and three had suspected or confirmed bacteriuria 10 to 70 days after discontinuation. Five dogs developed bacteriuria on therapy, four of which were nitrofurantoin-resistant Proteus spp. Most other adverse events were minor; none were considered likely caused by the drug on causality assessment. CLINICAL SIGNIFICANCE: Based on this small study group, nightly nitrofurantoin appears well tolerated and might be efficacious prophylaxis for recurrent urinary tract infections in dogs. Infection with nitrofurantoin-resistant Proteus spp. was a common reason for treatment failure.

Association Between Childhood Adversity and Functional Outcomes in People With Psychosis: A Meta-analysis.

BACKGROUND AND HYPOTHESIS: Despite the accepted link between childhood adversity (CA) and psychotic disorders, evidence on the relationship between CA and poor functional outcome remains less consistent and has never been reviewed quantitatively. The aim of this meta-analysis was to systematically examine the association between CA and functional outcomes in people with psychotic disorders. STUDY DESIGN: The study protocol was registered on the International Prospective Register of Systematic Reviews (CRD42021254201). A search was conducted across EMBASE, MEDLINE, PsycINFO, and Cochrane Libraries (CENTRAL) using search terms related to psychosis; CA (general, sexual abuse, physical abuse, emotional abuse, physical neglect, and emotional neglect); and functional outcomes (social, occupational, and general functioning [GF]). We conducted random-effects models, sensitivity and heterogeneity analyses, meta-regressions, and we assessed quality. STUDY RESULTS: Our meta-analysis comprised 35 studies, including 10 568 cases with psychosis. General CA was negatively associated with GF (28 studies; r = -0.109, 95%CI = -0.161 to -0.05, P < .001), with greater effects in prospective data (10 studies; r = -0.151, 95% CI = -0.236 to -0.063, P = .001). General CA was also associated with social functioning (r = -0.062, 95% CI = -0.120 to -0.004, P = .018) but not occupational outcomes. All CA subtypes except sexual abuse were significantly associated with GF, with emotional and physical neglect showing the largest magnitudes of effect (ranging from r = -0.199 to r = -0.250). CONCLUSIONS: This meta-analysis provides evidence for a negative association between general CA, specific subtypes, and general and social functional outcomes in people with psychosis.

Increased rates of hypernatraemia during modest heatwaves in temperate climates.

BACKGROUND: Hypernatraemia is associated with morbidity and mortality, particularly in the older person. Last summer, Ireland experienced prolonged periods of excessive heat. The Irish meteorological service defines a heatwave as temperatures exceeding 25°C for five consecutive days. AIM: This study sought to compare the frequency of hypernatraemia (sodium (Na+) >145 mmol/l) observed during a modest heatwave with that during average ambient temperature in the temperate Irish climate. DESIGN: Retrospective cross-sectional analysis with nested case-control study. METHODS: The 10-day period from 24 June to 3 July in 2017 and 2018 were chosen as the control and heatwave periods, respectively. Patients aged >65 with at least one Na+ value recorded on the laboratory information system were included. Local meteorological data, age, gender and Na+ levels were evaluated. RESULTS: Maximum air temperatures were significantly higher during the heatwave period (mean 27°C vs. 16.8°C, P < 0.0001). Hypernatraemia was present in 3.6% (66/1840) of samples collected during the heatwave compared to 1.4% (23/1593) in the control period. The mean age of affected patients was similar in both groups, 75 years ±7 (P = 1.000). Almost half of participants (49.5%) were male. The frequency of hypernatraemia observed was not influenced by gender, P = 0.33. The median sodium concentrations were similar in both groups, P = 1.00. CONCLUSION: Hypernatraemia was 2.5 times more frequent in samples drawn during the heatwave compared to the control period. In this study, neither age nor gender impacted the profile of patients diagnosed with hypernatraemia. A modest rise in temperatures increases hypernatraemia rates in temperate climates.

Use of Lean Six Sigma methodology shows reduction of inpatient waiting time for peripherally inserted central catheter placement.

AIM: The aim of this study was to assess the use of Lean Six Sigma methodology to improve the turnaround time (TAT) for inpatient peripherally inserted central catheter (PICC) placement. MATERIALS AND METHODS: Value stream mapping was used to analyse the workflow process for inpatient PICC placement and to divide it into its component parts. Unnecessary steps were eliminated and variation minimised in the remaining processes. The TAT for PICC line placement was recorded for the 6 months prior to implementation of changes, and subsequently, at the 6-month and 2-year follow-up points. RESULTS: Prior to implementing the changes, the mean TAT for PICC line placement was 3.74±3.28 days (95% confidence interval [CI]=3.3-4.17). Six months after implementation, the mean TAT was 1.89±1.82 days (95% CI=1.72-2.06, p<0.0001). The reduction was sustained such that at 2 years post-implementation the mean TAT was 1.88±1.87 days (95% CI=1.78-1.99, p<0.0001). This was achieved despite a 13.8% increase in overall interventional radiological activity. CONCLUSION: By applying Lean Six Sigma methodology to the complex multifactorial processes involved from ordering a PICC to its final insertion, it was possible to identify areas for improvement and to introduce simple, effective measures that resulted in a significant sustained decrease in the TAT without additional resources.

A rare three part proximal ulnar shear fracture requiring innovative reduction and fixation in a paediatric elbow.

Fracture of the proximal ulna in children is an uncommon injury with various classification models. An 8-year-old boy presented to our emergency department with an isolated three part intra-articular fracture of his right proximal ulna from an extension injury sustained during skiing which has not been previously described in the literature. He was taken to the operating room for open reduction and internal fixation. Two cannulated screws positioned in a posterior-anterior direction were used to hold the reduction. He was discharged from the hospital 24 h post-reduction in a complete cast. At 5 weeks follow-up, his elbow radiographs indicate no loss of reduction and at 4 months follow-up, he has regained a full range of movement at the elbow joint. The cannulated screws were left in situ as it did not cause him any harm. We propose that the described fracture pattern should be managed by open reduction and internal fixation (cannulated screws used to hold the reduction, position in a posterior-anterior direction).

The metabolism and pharmacokinetics of phospho-sulindac (OXT-328) and the effect of difluoromethylornithine.

BACKGROUND AND PURPOSE: Phospho-sulindac (PS; OXT-328) prevents colon cancer in mice, especially when combined with difluoromethylornithine (DFMO). Here, we explored its metabolism and pharmacokinetics. EXPERIMENTAL APPROACH: PS metabolism was studied in cultured cells, liver microsomes and cytosol, intestinal microsomes and in mice. Pharmacokinetics and biodistribution of PS were studied in mice. KEY RESULTS: PS undergoes reduction and oxidation yielding PS sulphide and PS sulphone; is hydrolysed releasing sulindac, which generates sulindac sulphide (SSide) and sulindac sulphone (SSone), all of which are glucuronidated. Liver and intestinal microsomes metabolized PS extensively but cultured cells converted only 10% of it to PS sulphide and PS sulphone. In mice, oral PS is rapidly absorbed, metabolized and distributed to the blood and other tissues. PS survives only partially intact in blood; of its three major metabolites (sulindac, SSide and SSone), sulindac has the highest C(max) and SSone the highest t(1/2) ; their AUC(0-24h) are similar. Compared with conventional sulindac, PS generated more SSone but less SSide, which may contribute to the safety of PS. In the gastroduodenal wall of mice, 71% of PS was intact; sulindac, SSide and SSone together accounted for <30% of the total. This finding may explain the lack of gastrointestinal toxicity by PS. DFMO had no effect on PS metabolism but significantly reduced drug level in mouse plasma and other tissues. CONCLUSIONS AND IMPLICATIONS: Our findings establish the metabolism of PS define its pharmacokinetics and biodistribution, describe its interactions with DFMO and largely explain its gastrointestinal safety.

Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress.

Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPKα. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.

Development of second-generation VEGFR tyrosine kinase inhibitors: current status.

The vascular endothelial growth factor (VEGF) signaling pathway appears to be the dominant pathway involved in tumor angiogenesis, providing a rationale for targeting the VEGF receptors (VEGFR-1, -2, and -3) in the treatment of cancers. In particular, VEGF signaling is thought to be important in renal cell carcinoma (RCC) because of the deregulation of the pathway through nearly uniform loss of the von Hippel Lindau protein. The tyrosine kinase inhibitors (TKIs) sorafenib, sunitinib, and pazopanib are approved by the US Food and Drug Administration for the treatment of advanced RCC; however, these multitargeted agents inhibit a wide range of kinase targets in addition to the VEGFRs, resulting in a range of adverse effects unrelated to efficient VEGF blockade. This article reviews recent advances in the development of the second-generation VEGFR TKIs, including the more selective VEGFR TKIs tivozanib and axitinib, and focuses on the potential benefits of novel inhibitors with improved potency and selectivity.

Chimeric mouse tumor models reveal differences in pathway activation between ERBB family- and KRAS-dependent lung adenocarcinomas.

To recapitulate the stochastic nature of human cancer development, we have devised a strategy for generating mouse tumor models that involves stepwise genetic manipulation of embryonic stem (ES) cells and chimera generation. Tumors in the chimeric animals develop from engineered cells in the context of normal tissue. Adenocarcinomas arising in an allelic series of lung cancer models containing HER2 (also known as ERBB2), KRAS or EGFR oncogenes exhibit features of advanced malignancies. Treatment of EGFR(L858R) and KRAS(G12V) chimeric models with an EGFR inhibitor resulted in near complete tumor regression and no response to the treatment, respectively, accurately reflecting previous clinical observations. Transcriptome and immunohistochemical analyses reveal that PI3K pathway activation is unique to ERBB family tumors whereas KRAS-driven tumors show activation of the JNK/SAP pathway, suggesting points of therapeutic intervention for this difficult-to-treat tumor category.

De novo discovery of a gamma-secretase inhibitor response signature using a novel in vivo breast tumor model.

Notch pathway signaling plays a fundamental role in normal biological processes and is frequently deregulated in many cancers. Although several hypotheses regarding cancer subpopulations most likely to respond to therapies targeting the Notch pathway have been proposed, clinical utility of these predictive markers has not been shown. To understand the molecular basis of gamma-secretase inhibitor (GSI) sensitivity in breast cancer, we undertook an unbiased, de novo responder identification study using a novel genetically engineered in vivo breast cancer model. We show that tumors arising from this model are heterogeneous on the levels of gene expression, histopathology, growth rate, expression of Notch pathway markers, and response to GSI treatment. In addition, GSI treatment of this model was associated with inhibition of Hes1 and proliferation markers, indicating that GSI treatment inhibits Notch signaling. We then identified a pretreatment gene expression signature comprising 768 genes that is significantly associated with in vivo GSI efficacy across 99 tumor lines. Pathway analysis showed that the GSI responder signature is enriched for Notch pathway components and inflammation/immune-related genes. These data show the power of this novel in vivo model system for the discovery of biomarkers predictive of response to targeted therapies, and provide a basis for the identification of human breast cancers most likely to be sensitive to GSI treatment.

Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice.

Breast cancer development is a complex pathobiological process involving sequential genetic alterations in normal epithelial cells that results in uncontrolled growth in a permissive microenvironment. Accordingly, physiologically relevant models of human breast cancer that recapitulate these events are needed to study cancer biology and evaluate therapeutic agents. Here, we report the generation and utilization of the human breast cancer in mouse (HIM) model, which is composed of genetically engineered primary human breast epithelial organoids and activated human breast stromal cells. By using this approach, we have defined key genetic events required to drive the development of human preneoplastic lesions as well as invasive adenocarcinomas that are histologically similar to those in patients. Tumor development in the HIM model proceeds through defined histological stages of hyperplasia, DCIS to invasive carcinoma. Moreover, HIM tumors display characteristic responses to targeted therapies, such as HER2 inhibitors, further validating the utility of these models in preclinical compound testing. The HIM model is an experimentally tractable human in vivo system that holds great potential for advancing our basic understanding of cancer biology and for the discovery and testing of targeted therapies.

Psychiatric disorders, HIV infection and HIV/hepatitis co-infection in the correctional setting.

Psychiatric disorders such as bipolar disorder, schizophrenia and depression have long been associated with risk behaviors for HIV, hepatitis C virus (HCV) and hepatitis B virus (HBV). The US prison population is reported to have elevated rates of HIV, hepatitis and most psychiatric disorders. This study examined the association of six major psychiatric disorders with HIV mono-infection, HIV/HCV co-infection and HIV/HBV co-infection in one of the nation's largest prison populations. The study population consisted of 370,511 Texas Department of Criminal Justice inmates who were incarcerated for any duration between January 1, 2003 and July 1, 2006. Information on medical conditions and sociodemographic factors was obtained from an institution-wide electronic medical information system. Offenders diagnosed with HIV mono-infection, HIV/HCV, HIV/HBV and all HIV combined exhibited elevated rates of major depression, bipolar disorder, schizophrenia, schizoaffective disorder, non-schizophrenic psychotic disorder and any psychiatric disorder. In comparison to offenders with HIV mono-infection, those with HIV/HCV co-infection had an elevated prevalence of any psychiatric disorder. This cross-sectional study's finding of positive associations between psychiatric disease and both HIV infection and hepatitis co-infection among Texas prison inmates holds both clinical and public health relevance. It will be important for future investigations to examine the extent to which psychiatric disorders serve as a barrier to medical care, communication with clinicians and adherence to prescribed medical regimens among both HIV-mono-infected and HIV/hepatitis-co-infected inmates.

Functional conservation of the telomerase protein Est1p in humans.

Eukaryotic telomerase contains a telomerase reverse transcriptase (TERT) and an RNA template component that are essential for telomerase catalytic activity and several other telomerase-associated factors of which only a few appear to be integral enzyme components [1-3]. The first essential telomerase protein identified was S. cerevisiae Est1p, whose deletion leads to ever-shorter telomeres despite the persistence of telomerase activity [4-6]. Extensive genetic and biochemical data show that Est1p, via its interaction with the telomerase RNA and telomere end DNA binding complex Cdc13p/Stn1p/Ten1p, promotes the ability of telomerase to elongate telomeres in vivo [7-22]. The characterization of Est1p homologs outside of yeast has not been documented. We report the characterization of two putative human homologs of Est1p, hEST1A and hEST1B. Both proteins specifically associated with telomerase activity in human cell extracts and bound hTERT in rabbit reticulocyte lysates independently of the telomerase RNA. Overproduction of hEST1A cooperated with hTERT to lengthen telomeres, an effect that was specific to cells containing telomerase activity. Like Est1p, hEST1A (but not hEST1B) exhibited a single-stranded telomere DNA binding activity. These results suggest that the telomerase-associated factor Est1p is evolutionarily conserved in humans.

Preferential maintenance of critically short telomeres in mammalian cells heterozygous for mTert.

Prolonged growth of murine embryonic stem (ES) cells lacking the telomerase reverse transcriptase, mTert, results in a loss of telomere DNA and an increased incidence of end-to-end fusions and aneuploidy. Furthermore, loss of only one copy of mTert also results in telomere shortening intermediate between wild-type (wt) and mTert-null ES cells [Liu, Y., Snow, B. E., Hande, M. P., Yeung, D., Erdmann, N. J., Wakeham, A., Itie, A., Siderovski, D. P., Lansdorp, P. M., Robinson, M. O. & Harrington, L. (2000) Curr. Biol. 10, 1459-1462]. Unexpectedly, although average telomere length in mTert(+/-) ES cells declined to a similar level as mTert-null ES cells, mTert(+/-) ES cell lines retained a minimal telomeric DNA signal at all chromosome ends. Consequently, no end-to-end fusions and genome instability were observed in the latest passages of mTert(+/-) ES cell lines. These data uncover a functional distinction between the dosage-dependent function of telomerase in average telomere-length maintenance and the selective maintenance of critically short telomeres in cells heterozygous for mTert. In normal and tumor cells, we suggest that telomerase activity insufficient to maintain a given average telomere length may, nonetheless, provide a protective advantage from end-to-end fusion and genome instability.

Telomere dysfunction: multiple paths to the same end.

The molecular cloning of telomerase and telomere components has enabled the analysis and precise manipulation of processes that regulate telomere length maintenance. In mammalian cells and in other organisms, we now recognize that disruption of telomere integrity via any one of a number of perturbations induces chromosome instability and the activation of DNA damage responses. Thus, telomere dysfunction may represent a physiological trigger of the DNA damage or apoptotic response in an analogous fashion to other genotoxic insults that introduce chromosome breaks. Initial studies in mice lacking the murine telomerase RNA and in cells expressing a dominant negative version of the telomere binding protein TRF2 revealed a strong p53-dependent response to telomere dysfunction. Yet, telomere dysfunction exhibits p53-independent effects as well, an observation supported by p53-independent responses to telomere dysfunction in p53 mutant human tumor cell lines and mouse cells. As most tumors are compromised for p53 function, examination of this p53-independent response warrants closer attention. A better understanding of this p53-independent response may prove critical for determining the ultimate utility of telomerase inhibitors in the clinic. This review will summarize our current understanding of the molecular responses to telomere dysfunction in mammalian cells.

Compliance with antidepressant medication among prison inmates with depressive disorders.

This study assessed correlates of antidepressant medication compliance among 5,305 inmates of the Texas Department of Criminal Justice prison system who were diagnosed as having a depressive disorder. Use of tricyclic antidepressants, male gender, and higher age were all positively associated with medication compliance scores. This investigation provided no evidence that broader use of selective serotonin reuptake inhibitors would improve adherence to pharmacologic treatment in this population. The results also suggest that correctional administrators may wish to target younger inmates and women with interventions to improve medication compliance.