A prospective longitudinal study of multidomain resilience among youths with and without maltreatment histories.

The majority of children with maltreatment histories do not go on to develop depression in their adolescent and adult years. These individuals are often identified as being "resilient", but this characterization may conceal difficulties that individuals with maltreatment histories might face in their interpersonal relationships, substance use, physical health, and/or socioeconomic outcomes in their later lives. This study examined how adolescents with maltreatment histories who exhibit low levels of depression function in other domains during their adult years. Longitudinal trajectories of depression (across ages 13-32) in individuals with (n = 3,809) and without (n = 8,249) maltreatment histories were modeled in the National Longitudinal Study of Adolescent to Adult Health. The same "Low," "increasing," and "declining" depression trajectories in both individuals with and without maltreatment histories were identified. Youths with maltreatment histories in the "low" depression trajectory reported lower romantic relationship satisfaction, more exposure to intimate partner and sexual violence, more alcohol abuse/dependency, and poorer general physical health compared to individuals without maltreatment histories in the same "low" depression trajectory in adulthood. Findings add further caution against labeling individuals as "resilient" based on a just single domain of functioning (low depression), as childhood maltreatment has harmful effects on a broad spectrum of functional domains.

Progressive disseminated histoplasmosis with concomitant disseminated nontuberculous mycobacterial infection in a patient with AIDS from a nonendemic region (California).

BACKGROUND: Opportunistic infections, while well studied in the AIDS population, continue to have variable and surprising presentations. Here, we present a case of disseminated histoplasmosis with disseminated nontuberculous mycobacterial infection in a 50 year old man with long standing AIDS living in a non-endemic area. CASE PRESENTATION: Patient presented with a constellation of symptoms, and imaging of the chest showed a pulmonary mass with cavitation, multiple nodules, and ground glass opacities. Further investigations revealed granulomatous lung nodules and fungemia consistent with Histoplasma capsulatum, and coinfection with disseminated nontuberculous mycobateria in a nonendemic area. CONCLUSIONS: Immunocompromised patients risk co-inhabitation by multiple infectious organisms. Some of these organisms may preside in the host for years prior to reactivation. Clinicians in non endemic areas should therefore be careful to not overlook specific organisms based on a lack of a recent travel history. Physicians in nonendemic areas should become more familiar with the clinical findings and diagnostic approach of infectious such as Histoplasmosis, to ensure earlier recognition and treatment in immunocompromised individuals.

Corynebacterium urealyticum: rare urinary tract infection with serious complications.

Corynebacterium urealyticum is an organism associated with a rare chronic urinary tract infection, which can lead to calcification of the urinary tract and promote rapid lithogenesis. This case illustrates the serious complications that can arise from chronic infection with C. urealyticum, which include rapid progression of luminal and parenchymal urinary tract calcification and concomitant renal failure. This case and a review of the literature demonstrate the need for an increased awareness of this organism with early identification, aggressive management, and test of cure that may help avoid the sequela of these infections.

Adjunctive Corticosteroid Therapy in the Treatment of Coccidioidal Meningitis.

Coccidioidal meningitis (CM) has high morbidity, and adjunctive measures to improve outcomes are needed. Using an established multicenter retrospective cohort study of CM (N = 221), we found that patients receiving adjunctive corticosteroids had a significant reduction in secondary cerebrovascular events (P = .0049). Those with CM-associated cerebrovascular events (8%) may benefit from short-term corticosteroids.

Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC), an aggressive disease comprising several subtypes including basal-like and claudin-low, involves frequent deletions or point mutations in TP53, as well as loss of PTEN. We previously showed that combined deletion of both tumor suppressors in the mouse mammary epithelium invariably induced claudin-low-like TNBC. The effect of p53 mutation plus Pten deletion on mammary tumorigenesis and whether this combination can induce basal-like TNBC in the mouse are unknown. METHODS: WAP-Cre:Pten(f/f):p53(lox.stop.lox_R270H) composite mice were generated in which Pten is deleted and a p53-R270H mutation in the DNA-binding domain is induced upon expression of Cre-recombinase in pregnancy-identified alveolar progenitors. Tumors were characterized by histology, marker analysis, transcriptional profiling [GEO-GSE75989], bioinformatics, high-throughput (HTP) FDA drug screen as well as orthotopic injection to quantify tumor-initiating cells (TICs) and tail vein injection to identify lung metastasis. RESULTS: Combined Pten deletion plus induction of p53-R270H mutation accelerated formation of four distinct mammary tumors including poorly differentiated adenocarcinoma (PDA) and spindle/mesenchymal-like lesions. Transplantation assays revealed highest frequency of TICs in PDA and spindle tumors compared with other subtypes. Hierarchical clustering demonstrated that the PDA and spindle tumors grouped closely with human as well as mouse models of basal and claudin-low subtypes, respectively. HTP screens of primary Pten(∆):p53(∆) vs. Pten(∆):p53(R270H) spindle tumor cells with 1120 FDA-approved drugs identified 8-azaguanine as most potent for both tumor types, but found no allele-specific inhibitor. A gene set enrichment analysis revealed increased expression of a metastasis pathway in Pten(∆):p53(R270H) vs. Pten(∆):p53(∆) spindle tumors. Accordingly, following tail vein injection, both Pten(∆):p53(R270H) spindle and PDA tumor cells induced lung metastases and morbidity significantly faster than Pten(∆):p53(∆) double-deletion cells, and this was associated with the ability of Pten(∆):p53(R270H) tumor cells to upregulate E-cadherin expression in lung metastases. CONCLUSIONS: Our results demonstrate that WAP-Cre:Pten(f/f):p53(lox.stop.lox_R270H) mice represent a tractable model to study basal-like breast cancer because unlike p53 deletion, p53(R270H) mutation in the mouse does not skew tumors toward the claudin-low subtype. The WAP-Cre:Pten(f/f):p53(lox.stop.lox_R270H) mice develop basal-like breast cancer that is enriched in TICs, can readily form lung metastasis, and provides a preclinical model to study both basal-like and claudin-low TNBC in immune-competent mice.

Complete genome sequences of Campylobacter jejuni subsp. jejuni strain P4549 isolated from an asymptomatic rhesus monkey (Macaca mulatta).

Campylobacter jejuni subsp. jejuni is a leading bacterial cause of human gastroenteritis. C. jejuni strain P4549 was isolated from an asymptomatic rhesus monkey, Macaca mulatta. We report the genome sequences have a circular chromosome of 1,729,940 bp and two plasmids of 50,482 bp and 7,259 bp, respectively.

Differences in Connected Speech Outcomes Across Elicitation Methods.

Background: Connected speech is often used to assess many aspects of an individual's language abilities after stroke. However, it is unknown the degree to which elicitation methods differ in generating structural and syntactic aspects of connected speech, two critical components of successful communication. Quantifying the degree to which elicitation methods differ in eliciting structurally, syntactically, and lexically complex connected speech at the earliest stage of stroke before reorganization and rehabilitation of function independent of clinical diagnosis of aphasia has not been examined to date. Addressing this gap has implications for early clinical intervention as well as empirical studies of connected speech production. Aims: We compared two common elicitation methods, picture description and storytelling on lexical, structural, and syntactic measures of connected speech in speakers during the acute stage of left hemisphere stroke. Methods & Procedures: We measured connected speech using an automated quantitative production analysis approach (Fromm et al., 2021) in 71 native-English speaking participants (27 female; 59 ± 13 years) within an average 3.9 days from left hemisphere stroke onset. We tested the degree of agreement and consistency between elicitation methods for lexical, structural, and syntactic measures of connected speech, as well as the degree of concordance in classifying deficits across individuals. Outcomes & Results: Storytelling elicited significantly more words and more structurally complex, lexically diverse, and syntactically accurate speech in comparison to picture description. Elicitation methods differed in measuring outcomes across participants for the lexical and syntactic, but not structural complexity aspects of connected speech where storytelling classified more participants with impairments in comparison to picture description. Conclusions: These differences suggest storytelling provides assessment of connected speech abilities more reflective of real-world abilities where its use is particularly critical for examining individual differences and providing diagnoses of acute stroke language deficits. As a result, using storytelling as a connected speech elicitation method more effectively captures a patient's language capabilities after stroke, consequently informing clinical diagnosis and treatment.

Complete genome sequence of two chromosomes of Vibrio metoecus strain ZF102 isolated from the abdominal cavity of moribund laboratory zebrafish (Danio rerio).

Vibrio metoecus was isolated from the abdominal cavity of moribund laboratory zebrafish. We report complete genomic sequences of V. metoecus strain ZF102 that has two circular chromosomes of 2,872,299 and 1,170,691 bp and two plasmids of 5,265 and 2,361 bp.

Complete genome sequence of Delftia tsuruhatensis strain HA60 isolated from a commercial hydroxyapatite nano-particle product (nano-hydroxyapatite).

Delftia tsuruhatensis is a Gram-negative rod-shaped aerobic bacterium with environmental remediation functions. D. tsuruhatensis strain HA60 was isolated from a commercial nano-particle product, nano-hydroxyapatite. We report that the genome of D. tsuruhatensis strain HA60 has a circular genome of 6,922,195 base pairs with a G+C content of 66.45%.

Complete genome sequence of Parabacteroides distasonis strain GP102, isolated from the cecum of a morbid pregnant laboratory guinea pig (Cavia porcellus).

Parabacteroides distasonis is an anaerobic bacterium with ambivalent health effects. P. distasonis strain GP102 was isolated from the cecum content of a morbid pregnant laboratory guinea pig (Cavia porcellus). The genome consists of one circular 5.39-Mbp chromosome with a G + C content of 44.79%.

Genome sequence of Clostridium septicum strain WW106, isolated from influent wastewater at a research center with multiple-species research animal facilities.

Clostridium septicum is an anaerobic Gram-positive rod-shaped bacterial pathogen known as a lethal causative agent of progressive gas gangrene in animals and humans. We report the 3.43-Mbp genome sequence of C. septicum strain WW106, isolated from influent wastewater at a research center with multiple-species laboratory animal facilities.

Real-World Treatment Patterns, Clinical Outcomes, Healthcare Resource Utilization, and Costs in Advanced Hepatocellular Carcinoma in Ontario, Canada.

The therapeutic landscape for aHCC has evolved in recent years, necessitating a comprehensive analysis of treatment patterns, clinical outcomes, HCRU, and costs to contextualize emerging treatments. This study aimed to investigate these outcomes using real-world data from Ontario, Canada. This retrospective cohort study was conducted using linked administrative databases from April 2010 to March 2020. Patients diagnosed with aHCC were included, and their clinical and demographic characteristics were analyzed, as well as treatment patterns, survival, HCRU, and economic burden. Among 7322 identified patients, 802 aHCC patients met the eligibility criteria for inclusion in the study. Treatment subgroups included 1L systemic therapy (53.2%), other systemic treatments (4.5%), LRT (9.0%), and no treatment (33.3%). The median age was 66 years, and the majority were male (82%). The mOS for the entire cohort from diagnosis was 6.5 months. However, patients who received 1L systemic therapy had an mOS of 9.0 months, which was significantly higher than the other three subgroups. The mean cost per aHCC-treated patient was $49,640 CAD, with oral medications and inpatient hospitalizations as the largest cost drivers. The results underscore the need for the continuous evaluation and optimization of HCC management strategies in the era of evolving therapeutic options.

Anosognosia is associated with increased prevalence and faster development of neuropsychiatric symptoms in mild cognitive impairment.

Introduction: Both the loss of awareness for cognitive decline (a. k.a anosognosia) and neuropsychiatric symptoms (NPS) are common in patients with Alzheimer's disease (AD) dementia, even in prodromal stages, and may exacerbate functional impairment and negatively impact caregiver burden. Despite the high impact of these symptoms on patients and their caregivers, our knowledge of how they develop across the AD spectrum is limited. Here, we explored the cross-sectional and longitudinal associations between anosognosia and NPS in individuals with mild cognitive impairment (MCI). Methods: We included 237 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with a baseline clinical diagnosis of MCI. Everyday Cognition (ECog) questionnaire scores were used to measure complaints from participants and study-partners at baseline and annually over a mean of 4.29 years [standard deviation (SD) = 2.72]. Anosognosia was defined as the study-partner having an ECog score ≥2.5/4 and the participant having an ECog score < 2.5/4 on their baseline measure and their last observation without more than two consecutive deviating observations during the follow-up period. The 12-item study-partner-rated Neuropsychiatric Inventory determined the presence or absence of specific NPS. Survival analyses were performed to analyze the frequency and temporal onset of NPS over time in individuals with and without anosognosia. Results: Thirty-eight out of 237 participants displayed anosognosia. Groups had similar lengths of follow-up at baseline (p > 0.9), though participants with anosognosia had lower MMSE scores (p = 0.049) and a higher proportion of amyloid-positivity using PET (p < 0.001. At baseline, the frequencies of agitation (p = 0.029) and disinhibition (p < 0.001) were higher in the anosognosia group compared to the non-anosognosia group. Survival analyses showed earlier onset of seven of the 12 NPS in the anosognosia group (p's < 0.001). Discussion: Loss of awareness for cognitive decline is associated with greater frequency and earlier onset of NPS over time in participants with MCI. These results support the hypothesis of a potential common underlying neurophysiological process for anosognosia and NPS, a finding that needs to be addressed in future studies.

Amyloid and tau burden relate to longitudinal changes in the performance of complex everyday activities among cognitively unimpaired older adults: results from the performance-based Harvard Automated Phone Task.

Background: Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults. Methods: Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education. Results: Amyloid [unstandardized partial regression coefficient estimate (ß) = -0.007, 95% confidence interval (95% CI) = (-0.013, -0.001)], and medial temporal tau [ß = -0.013, 95% CI = (-0.022, -0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time. Conclusion: Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages.

Evaluation of a drug-drug interaction: fax alert intervention program.

BACKGROUND: Clinicians often encounter information about drug-drug interactions (DDIs) during clinical practice. This information is found within product information (hardcopy and electronic) and various electronic systems. Prescribers may receive medication-related communications in practice that are distributed by facsimile (fax), mail, or telephone from pharmacies and pharmacy benefit managers (PBMs). The purpose of this study was to determine if near-real time fax alerts for potential drug-drug interactions (PDDIs) would influence prescribing. METHODS: A prospective study, in cooperation with a pharmacy benefit manager (PBM), was conducted targeting 18 clinically important PDDIs. Fax alerts included an individualized letter to the prescriber with a list of the interacting drugs, PDDI evidence summaries with citations, and recommended clinical management strategies. Among the 18 PDDIs, 13 PDDIs could be assessed for prescription therapy changes using pharmacy claims data. A prospective cohort design was used to evaluate changes in prescription dispensing 90-days following a PDDI fax alert. RESULTS: A total of 8,075 fax alerts were sent to prescribers and there were 4,712 alerts for the 13 PDDIs that could be assessed for change using pharmacy claims data. There were 2,019 patients (interventions) for which fax alerts were sent to their prescribers who were matched with a control group consisting of patients with the same PDDIs but for whom no fax alert was sent. Overall, this study found 154 (7.6%) of patients in the fax alert group compared to 132 (6.5%) in the control group had changes in therapy (p = 0.177). CONCLUSIONS: This fax alert intervention program observed no statistically significant differences in prescribing with a fax alert compared to the control group. If PBMs chose to send individualized, evidence-based information to clinicians regarding drug-drug interactions, this study suggests it may not be an effective intervention to mitigate harm.

Valley fever, mimicker of malignancy.

Coccidioidomycosis rates in endemic areas such as California and Arizona have been increasing in recent years. Most common manifestations in symptomatic individuals involve the lungs. Disseminated disease occurs when the infection spreads beyond the lungs. Disseminated disease occurs in about 1% of all coccidiomycosis cases. Diagnosis in classically non-endemic regions can be difficult as coccidiomycosis can mimic a variety of other illnesses which can lead to delays in initiating appropriate therapy. We report a case of severe disseminated coccidiomycosis involving the soft tissue, bone, and intra-abdominal organs in a previously healthy individual that was initially thought to be a malignancy. With climate change possibly altering the traditional endemic regions and expanding Coccidioides to new territories, this case reinforces the importance of maintaining a broad differential as well as awareness of disease manifestations for healthcare providers who do not regularly treat Coccidioides.

Complete Genome Sequence of Invasive MLST-Untypeable Serotype 3 xpt-Deficient Streptococcus pneumoniae Strain B1900, Isolated from the Brain of an Infant Rhesus Monkey (Macaca mulatta) That Died of Meningitis.

Serotype 3 Streptococcus pneumoniae is associated with major invasive pneumococcal diseases in humans. We report the circularized 2.0-Mbp complete genome sequence of invasive serotype 3 S. pneumoniae strain B1900, untypeable by multilocus sequence typing (MLST). This strain was isolated from the brain of an infant rhesus monkey (Macaca mulatta) that suddenly died of meningitis with no clinical symptoms.

Genome sequence of Gordonia alkaliphila strain WW102, isolated from influent wastewater at a research center with multiple-species research animal facilities.

Gordonia alkaliphila is a little known mesophilic Gram-positive rod-shaped bacterium. We report the 3.85-Mbp genome sequence of G. alkaliphila strain WW102, isolated from wastewater at a research center with multiple-species laboratory animal facilities. The genome predicted FadD32 gene clusters that are involved in the biosynthesis of mycolic acids as found in Mycobacterium tuberculosis.

Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings.

BACKGROUND: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical. OBJECTIVE: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. METHODS: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. RESULTS: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. CONCLUSION: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

Medical diagnosis of cubital tunnel syndrome ameliorated with thrust manipulation of the elbow and carpals.

This case report describes the effectiveness of thrust manipulation to the elbow and carpals in the management of a patient referred with a medical diagnosis of cubital tunnel syndrome (CuTS). The patient was a 45-year-old woman with a 6-week history of right medial elbow pain, ulnar wrist pain, and intermittent paresthesia in the ulnar nerve distribution. Upon initial assessment, she presented with a positive elbow flexion test and upper limb neurodynamic test with ulnar nerve bias. A biomechanical assessment of the elbow and carpals revealed a loss of lateral glide of the humerus on the ulna and a loss of palmar glide of the triquetral on the hamate. After the patient received two thrust manipulations of the elbow and one thrust manipulation of the carpals over the course of four sessions, her pain and paresthesia were resolved. This case demonstrates that the use of thrust manipulation to the elbow and carpals may be an effective approach in the management of insidious onset CuTS. This patient was successfully treated with thrust manipulation when joint dysfunction of the elbow and wrist were appropriately identified. This case report may shed light on the examination and management of insidious onset CuTS.