Autism spectrum disorder diagnosis using a new panel of immune- and inflammatory-related serum biomarkers: A case-control multicenter study.

Background and objectives: Children with autism spectrum disorder (ASD) present with distinctive clinical features. No objective laboratory assay has been developed to establish a diagnosis of ASD. Considering the known immunological associations with ASD, immunological biomarkers might enable ASD diagnosis and intervention at an early age when the immature brain has the highest degree of plasticity. This work aimed to identify diagnostic biomarkers discriminating between children with ASD and typically developing (TD) children. Methods: A multicenter, diagnostic case-control study trial was conducted in Israel and Canada between 2014 and 2021. In this trial, a single blood sample was collected from 102 children with ASD as defined in Diagnostic Statistical Manual of Mental Disorders [DSM)-IV (299.00) or DSM-V (299.00)], and from 97 typically developing control children aged 3-12 years. Samples were analyzed using a high-throughput, multiplexed ELISA array which quantifies 1,000 human immune/inflammatory-related proteins. Multiple logistic regression analysis was used to obtain a predictor from these results using 10-fold cross validation. Results: Twelve biomarkers were identified that provided an overall accuracy of 0.82 ± 0.09 (sensitivity: 0.87 ± 0.08; specificity: 0.77 ± 0.14) in diagnosing ASD with a threshold of 0.5. The resulting model had an area under the curve of 0.86 ± 0.06 (95% CI: 0.811-0.889). Of the 102 ASD children included in the study, 13% were negative for this signature. Most of the markers included in all models have been reported to be associated with ASD and/or autoimmune diseases. Conclusion: The identified biomarkers may serve as the basis of an objective assay for early and accurate diagnosis of ASD. In addition, the markers may shed light on ASD etiology and pathogenesis. It should be noted that this was only a pilot, case-control diagnostic study, with a high risk of bias. The findings should be validated in larger prospective cohorts of consecutive children suspected of ASD.

Principles and philosophies for speech and language therapists working with people with primary progressive aphasia: an international expert consensus.

PURPOSE: Primary progressive aphasia (PPA) is a language-led dementia associated with Alzheimer's pathology and fronto-temporal lobar degeneration. Multiple tailored speech and language interventions have been developed for people with PPA. Speech and language therapists/speech-language pathologists (SLT/Ps) report lacking confidence in identifying the most pertinent interventions options relevant to their clients living with PPA during their illness trajectory. MATERIALS AND METHODS: The aim of this study was to establish a consensus amongst 15 clinical-academic SLT/Ps on best practice in selection and delivery of speech and language therapy interventions for people with PPA. An online nominal group technique (NGT) and consequent focus group session were held. NGT rankings were aggregated and focus groups video recorded, transcribed, and reflexive thematic analysis undertaken. RESULTS: The results of the NGT identified 17 items. Two main themes and seven further subthemes were identified in the focus groups. The main themes comprised (1) philosophy of person-centredness and (2) complexity. The seven subthemes were knowing people deeply, preventing disasters, practical issues, professional development, connectedness, barriers and limitations, and peer support and mentoring towards a shared understanding. CONCLUSIONS: This study describes the philosophy of expert practice and outlines a set of best practice principles when working with people with PPA.Implications for rehabilitationPrimary progressive aphasia (PPA) describes a group of language led dementias which deteriorate inexorably over time.Providing speech and language therapy for people with PPA is complex and must be person centred and bespoke.This study describes the philosophy of expert practice and outlines a set of best practice principles for speech and language therapists/pathologists working with people with people with PPA.

The Effect of Nonpharmaceutical Interventions Implemented in Response to the COVID-19 Pandemic on Seasonal Respiratory Syncytial Virus: Analysis of Google Trends Data.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of respiratory infection in children. Despite usually following a consistent seasonal pattern, the 2020-2021 RSV season in many countries was delayed and changed in magnitude. OBJECTIVE: This study aimed to test if these changes can be attributed to nonpharmaceutical interventions (NPIs) instituted around the world to combat SARS-CoV-2. METHODS: We used the internet search volume for RSV, as obtained from Google Trends, as a proxy to investigate these abnormalities. RESULTS: Our analysis shows a breakdown of the usual correlation between peak latency and magnitude during the year of the pandemic. Analyzing latency and magnitude separately, we found that the changes therein are associated with implemented NPIs. Among several important interventions, NPIs affecting population mobility are shown to be particularly relevant to RSV incidence. CONCLUSIONS: The 2020-2021 RSV season served as a natural experiment to test NPIs that are likely to restrict RSV spread, and our findings can be used to guide health authorities to possible interventions.

Direct comparison shows that mRNA-based diagnostics incorporate information which cannot be learned directly from genomic mutations.

BACKGROUND: Compared to the many uses of DNA-level testing in clinical oncology, development of RNA-based diagnostics has been more limited. An exception to this trend is the growing use of mRNA-based methods in early-stage breast cancer. Although DNA and mRNA are used together in breast cancer research, the distinct contribution of mRNA beyond that of DNA in clinical challenges has not yet been directly assessed. We hypothesize that mRNA harbors prognostically useful information independently of genomic variation. To validate this, we use both genomic mutations and gene expression to predict five-year breast cancer recurrence in an integrated test model. This is accomplished first by comparing the feature importance of DNA and mRNA features in a model trained on both, and second, by evaluating the difference in performance of models trained on DNA and mRNA data separately. RESULTS: We find that models trained on DNA and mRNA data give more weight to mRNA features than to DNA features, and models trained only on mRNA outperform models trained on DNA alone. CONCLUSIONS: The evaluation process presented here may serve as a framework for the interpretation of the relative contribution of individual molecular markers. It also suggests that mRNA has a distinct contribution in a diagnostic setting, beyond and independently of DNA mutation data.

Support following total laryngectomy: Exploring the concept from different perspectives.

Adjustment after total laryngectomy is complex, and the resultant support needs are extensive. Current practice is often guided by health-related quality of life measures. While useful, many of these tools were developed without considering the perspectives of people who have experienced the surgery. To improve understanding of the support needs after total laryngectomy, multiple viewpoints were examined, for example individuals with a laryngectomy (IWL), significant others (SO) and health professionals (HP). A qualitative study explored the perspectives of 28 individuals (IWL-seven men and five women, nine SO and seven HP). Data were collected through in-depth, semi-structured interviews and analysed using constructivist grounded theory and symbolic interactionism. The data suggested that the construct "being supported to develop competence and resilience" is a multidimensional and nonlinear phenomenon underpinned by the interactive processes "perceiving influencing factors," "building trusting relationships" and "sharing and balancing the care." The findings highlight the significant contribution the care triad (i.e., IWL, SO and HP) plays and the factors influencing care, safety and dignity for IWL. Furthermore, support is optimised when all stakeholders are competent with the care. In turn, reduced competence increases the burden for one or all in the triad.

Missing voices: Profile and extent of acquired communication disorders in Aboriginal and non-Aboriginal adult stroke survivors in Western Australia using linked administrative records.

BACKGROUND: Limited data exist on the extent of specific functional sequelae, including acquired communication disorder, among Aboriginal stroke survivors, making planning of multidisciplinary services difficult. AIMS: To obtain estimates of the extent and profile of acquired communication disorder in Aboriginal and non-Aboriginal adult stroke survivors in Western Australia and investigate potential disparities in receiving in-hospital speech pathology services among survivors with acquired communication disorder. METHODS: Stroke cases surviving their first stroke episode during 2002-2011 were identified using Western Australia-wide person-based linked hospital and mortality data, and their five-year comorbidity profiles determined. The mid-year prevalence of stroke cases with acquired communication disorder was estimated for 2011. Regression methods were used to investigate determinants of receiving speech pathology services among acquired communication disorder cases. RESULTS: Of 14,757 stroke survivors aged 15-79 years admitted in 2002-2011, 33% had acquired communication disorder (22% aphasia/dysphasia) and 777 (5.3%) were Aboriginal. Aboriginal patients were more likely to be younger, live remotely, and have comorbidities. A diagnosis of aphasia was more common in Aboriginal than non-Aboriginal patients 15-44 years (p = 0.003). A minimum of 107 Aboriginal and 2324 non-Aboriginal stroke patients with acquired communication disorder lived in Western Australia in 2011. Aboriginal status was not associated with receiving in-hospital speech services among acquired communication disorder patients in unadjusted or adjusted models. CONCLUSIONS: The relative youth, geographical distribution, high comorbidity prevalence, and cultural needs of Aboriginal stroke patients with acquired communication disorder should inform appropriate service design for speech pathology and rehabilitation. Innovative models are required to address workforce issues, given low patient volumes.

Stroke management: updated recommendations for treatment along the care continuum.

The Australian Clinical Guidelines for Stroke Management 2010 represents an update of the Clinical Guidelines for Stroke Rehabilitation and Recovery (2005) and the Clinical Guidelines for Acute Stroke Management (2007). For the first time, they cover the whole spectrum of stroke, from public awareness and prehospital response to stroke unit and stroke management strategies, acute treatment, secondary prevention, rehabilitation and community care. The guidelines also include recommendations on transient ischaemic attack. The most significant changes to previous guideline recommendations include the extension of the stroke thrombolysis window from 3 to 4.5 h and the change from positive to negative recommendations for the use of thigh-length antithrombotic stockings for deep venous thrombosis prevention and the routine use of prolonged positioning for contracture management.

Patterns of regional head and neck lymph node metastasis in primary conjunctival malignant melanoma.

OBJECTIVE: To correlate patterns of regional lymph node metastasis with the site of origin in primary conjunctival malignant melanoma. DESIGN: Retrospective analysis (1990-2003) of clinical data. SETTING: Two London tertiary referral centres. PARTICIPANTS: 12 patients presenting with regional metastases after failed local treatment for conjunctival malignant melanoma. RESULTS: 6 cases predominantly involving the temporal conjunctiva metastasised to the pre-auricular lymph nodes. Two cases predominantly involving the nasal conjunctiva metastasised to the submandibular nodes. Of the two cases with purely multifocal disease, one metastasised to the pre-auricular nodes and another to both submandibular and parotid nodes. One primary conjunctival malignant melanoma had its origin in temporal conjunctiva but metastasised to submandibular nodes, and another case originating from nasal conjunctiva metastasised to pre-auricular nodes. CONCLUSIONS: Temporal conjunctival melanotic lesions tend to metastasise clinically to pre-auricular lymph nodes and nasal conjunctival melanotic lesions metastasise to the submandibular lymph nodes. Patterns appear consistent with laboratory-based anatomically mapped lymphatic drainage basins of the conjunctiva.

Clinical value of postnatal autopsy and genetics consultation in fetal death.

The aim of the present study was to investigate the clinical use of postnatal autopsy and genetics consultation in cases of fetal death in a teaching hospital. A retrospective analysis of medical records including pathology and genetics reports was performed in all cases of fetal death in which a woman delivered at Ben Taub General Hospital, Houston, Texas over a 2-year period. Cases were excluded when gestational age of the fetus was less than 20 weeks. Fetuses were only included when the 1- and 5-min Apgar scores were 0 and 0, respectively. There were 139 fetal deaths and 12,209 live born infants during the study period (stillbirth rate 1.125%). Although pathology services were used in 96.2%, a genetics consultation was obtained in only 12% of cases. Fetal autopsy provided a certain cause of fetal death in 19.4%, a probable cause for death in 36.3%, and was inconclusive in 44.3%. Among the cases in which a genetics consultation was obtained, a certain and probable cause for fetal death was found in 20% and 20% of cases, respectively. The utilization of genetics consultation was found to be independent of multiple clinical variables examined including ultrasound data, identification of maceration, and training level of resident. Our data show a frequent use of pathologic examination in cases of fetal death and an infrequent use of genetics consultation services. The request for genetics consultation seemed to have been made at random.

Experiences of ending aphasia therapy.

Despite a considerable literature on assessment and treatment issues in aphasiology, little has been written about how therapy ends. We lack detail about how clinicians decide to terminate treatment and about how patients and carers view leaving therapy. This paper explores experiences and perceptions of aphasia treatment termination. It uses in-depth interview data gathered in South Australia as part of a doctoral study with a speech pathologist, three ex-patients with aphasia and one spouse. This case study allows comparison of client and professional narratives to each other and also to the official discharge documentation in the medical file. The discharge process arising from this analysis is discussed.

Structure-function analysis of the Shigella virulence factor IpaB.

Infection by the gram-negative bacterium Shigella flexneri results in dysentery, an acute inflammatory disease of the colon. Essential events in the pathogenesis of Shigella infections include bacterial invasion of epithelial cells, escape from the phagosome, and induction of apoptosis in macrophages. The Shigella virulence factor invasion plasmid antigen B (IpaB) is required for all of these processes. Induction of apoptosis is dependent on IpaB binding to the cysteine protease caspase-1 (Casp-1). The activation of this enzyme triggers both apoptosis and release of the proinflammatory cytokine interleukin-1beta. Several IpaB mutants were generated to correlate function with protein subdomains. We determined that the N-terminal portion of IpaB is necessary for stable expression of IpaB. A putative amphipathic alpha-helical domain preserves the structure of IpaB. We found 10 consecutive residues within the amino terminus of the hydrophobic region that play a critical role in invasion, phagosomal escape, and cytotoxicity. An IpaB mutant carrying a mutation in this region binds to Casp-1 yet is not cytotoxic, even following direct delivery to the macrophage cytoplasm. These results indicate that the association between IpaB and Casp-1 is only a step in the activation of macrophage apoptosis.

Salmonella exploits caspase-1 to colonize Peyer's patches in a murine typhoid model.

Salmonella typhimurium invades host macrophages and induces apoptosis and the release of mature proinflammatory cytokines. SipB, a protein translocated by Salmonella into the cytoplasm of macrophages, is required for activation of Caspase-1 (Casp-1, an interleukin [IL]-1beta-converting enzyme), which is a member of a family of cysteine proteases that induce apoptosis in mammalian cells. Casp-1 is unique among caspases because it also directly cleaves the proinflammatory cytokines IL-1beta and IL-18 to produce bioactive cytokines. We show here that mice lacking Casp-1 (casp-1(-/)- mice) had an oral S. typhimurium 50% lethal dose (LD(50)) that was 1,000-fold higher than that of wild-type mice. Salmonella breached the M cell barrier of casp-1(-/)- mice efficiently; however, there was a decrease in the number of apoptotic cells, intracellular bacteria, and the recruitment of polymorphonuclear lymphocytes in the Peyer's patches (PP) as compared with wild-type mice. Furthermore, Salmonella did not disseminate systemically in the majority of casp-1(-/)- mice, as demonstrated by significantly less colonization in the PP, mesenteric lymph nodes, and spleens of casp-1(-/)- mice after an oral dose of S. typhimurium that was 100-fold higher than the LD(50). The increased resistance in casp-1(-/)- animals appears specific for Salmonella infection since these mice were susceptible to colonization by another enteric pathogen, Yersinia pseudotuberculosis, which normally invades the PP. These results show that Casp-1, which is both proapoptotic and proinflammatory, is essential for S. typhimurium to efficiently colonize the cecum and PP and subsequently cause systemic typhoid-like disease in mice.

The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1.

Recently, Salmonella spp. were shown to induce apoptosis in infected macrophages. The mechanism responsible for this process is unknown. In this report, we establish that the Inv-Spa type III secretion apparatus target invasin SipB is necessary and sufficient for the induction of apoptosis. Purified SipB microinjected into macrophages led to cell death. Binding studies show that SipB associates with the proapoptotic protease caspase-1. This interaction results in the activation of caspase-1, as seen in its proteolytic maturation and the processing of its substrate interleukin-1beta. Caspase-1 activity is essential for the cytotoxicity. Functional inhibition of caspase-1 activity by acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone blocks macrophage cytotoxicity, and macrophages lacking caspase-1 are not susceptible to Salmonella-induced apoptosis. Taken together, the data demonstrate that SipB functions as an analog of the Shigella invasin IpaB.

The validity of self-reported cocaine use in two groups of cocaine abusers.

To evaluate the validity of 2 self-report methods for estimating cocaine use, Timeline Follow-Back (TLFB) and weekly calendar reports from 65 patients with a cocaine use disorder were compared with urine drug test results. The TLFB showed fair to moderate validity, and the weekly calendar showed moderate to high validity in measuring the frequency of cocaine use. Similar results were obtained when the self-report measures were used to time specific cocaine use episodes. In addition to evidence for superiority of the weekly calendar, the validity of self-reports was inversely related to the percentage of positive urine test results. Furthermore, there was some evidence that validity increased as the time window over which the comparisons were drawn increased. Given the central role of self-reports in the clinical and research evaluation of drug use, factors affecting their validity warrant further investigation.

Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB.

We report here that the Shigella invasion plasmid antigen (Ipa)B, which is sufficient to induce apoptosis in macrophages, binds to caspase (Casp)-1, but not to Casp-2 or Casp-3. Casp-1 is activated and its specific substrate interleukin-1beta is cleaved shortly after Shigella infection. Macrophages isolated from Casp-1 knock-out mice are not susceptible to Shigella-induced apoptosis, although they respond normally to other apoptotic stimuli. Shigella kills macrophages from casp-3, casp-11, and p53 knock-out mice as well as macrophages overexpressing Bcl-2. We propose that Shigella induces apoptosis by directly activating Casp-1 through IpaB, bypassing signal transduction events and caspases upstream of Casp-1. Taken together these data indicate that Shigella-induced apoptosis is distinct from other forms of apoptosis and seems uniquely dependent on Casp-1.

Naltrexone treatment of comorbid alcohol and cocaine use disorders.

Naltrexone (NTX) has been shown to be efficacious for the treatment of alcohol dependence. Since alcohol and cocaine use disorders commonly co-occur, we conducted a randomized, double-blind, placebo-controlled trial of NTX 50 mg/day in 64 subjects with comorbid alcohol and cocaine use disorders. Although subjects in both groups reduced their consumption of both alcohol and cocaine during the 8-week trial, there was no consistent advantage to NTX over placebo treatment. We conclude that, due to behavioral, neurochemical, or other factors, individuals with both alcohol and cocaine use disorders are distinct from those dependent on alcohol alone, and that NTX at a dosage of 50 mg/day is not efficacious in this patient population. Several factors, including medication dosage, length of treatment, sample size and attrition rate, limit the interpretation of these findings. Consequently, we recommend that subsequent trials of NTX to reduce the risk of relapse in patients with comorbid alcohol and cocaine use disorders take these issues into account.

How bacteria initiate inflammation: aspects of the emerging story.

Recent studies have shown that bacteria possess an array of proinflammatory molecules in addition to the extensively studied lipopolysaccharide and superantigens. These bacterial molecules include soluble and membrane-associated inducers of cytokine release, inducers of host cell apoptosis, and immunostimulatory DNA. There is therefore much greater diversity in the class of molecules and mechanisms by which bacteria engage the host immune system than previously appreciated.