A Data-Driven Latent Variable Approach to Validating the Research Domain Criteria Framework.

Despite the widespread use of the Research Domain Criteria (RDoC) framework in psychiatry and neuroscience, recent studies suggest that the RDoC is insufficiently specific or excessively broad relative to the underlying brain circuitry it seeks to elucidate. To address these concerns of the RDoC framework, our study employed a latent variable approach, specifically utilizing bifactor analysis. We examined a total of 84 whole-brain task-based fMRI (tfMRI) activation maps from 19 studies with a total of 6,192 participants. Within this set of 84 maps, a curated subset of 37 maps with a balanced representation of RDoC domains constituted the training set of our analysis, and the remaining held-out maps formed the internal validation set. External validation was performed with 36 peak coordinate activation maps from Neurosynth, using terms of RDoC constructs as seeds for topic meta-analysis. Our results indicate that a bifactor model with a task-general domain and splitting the cognitive systems domain into sub-domains better fits the current corpus of tfMRI data than the current RDoC framework. Our data-driven validation supports revising the RDoC framework to accurately reflect underlying brain circuitry.

Three-year epidemiology of hospitalised paediatric burn patients in a Malaysian Tertiary Hospital 2016 - 2018.

INTRODUCTION: Burn injuries incur not just significant morbidity but also long-term psychosocial impact. This study aims to identify the clinico-demographics of children hospitalised for burns and factors associated with prolonged hospitalisation. MATERIALS AND METHODS: Written medical records of burn patients admitted to the Sultanah Aminah Hospital paediatric surgical ward, from January 2016 to December 2018, were retrospectively reviewed. Details on the patients' socio-demographic background, burn injuries, management and outcomes were recorded and analysed with logistic regression. RESULTS AND CONCLUSION: Of the 255 children included in the study, the majority were males (62.7%), children aged between 1 to 3 years (43.1%), and of the Malay ethnic group (83.1%). The commonest injury mechanism was scalds burns (81.2%). Staphylococcus aureus remained the commonest organism cultured from paediatric burn wounds. Most patients (66.4%) were hospitalised for less than 1 week. A significant number of patients experienced complications from their injuries. Multivariate analysis showed burns affecting total body surface area > 10% (adjusted OR, 13.45 [95% CI 6.25 - 28.96]; p = < 0.001) and non-scald burns (adjusted OR, 2.70 [95% CI 1.12 - 6.50]; p = 0.027) were the two main factors associated with prolonged hospitalisation of more than 1 week. These findings describing the epidemiology and outcomes of paediatric burn cases in a tertiary centre in Malaysia may inform future practice. More importantly, the information may contribute to the identification of at-risk populations and advise the development of effective prevention strategies to reduce the incidence and morbidity associated with paediatric burns in this region.

Trait Anxiety Mediated by Amygdala Serotonin Transporter in the Common Marmoset.

High trait anxiety is associated with altered activity across emotion regulation circuitry and a higher risk of developing anxiety disorders and depression. This circuitry is extensively modulated by serotonin. Here, to understand why some people may be more vulnerable to developing affective disorders, we investigated whether serotonin-related gene expression across the brain's emotion regulation circuitry may underlie individual differences in trait anxiety using the common marmoset (Callithrix jacchus, mixed sexes) as a model. First, we assessed the association of region-specific expression of the serotonin transporter (SLC6A4) and serotonin receptor (HTR1A, HTR2A, HTR2C) genes with anxiety-like behavior; and second, we investigated their causal role in two key features of the high trait anxious phenotype: high responsivity to anxiety-provoking stimuli and an exaggerated conditioned threat response. While the expression of the serotonin receptors did not show a significant relationship with anxiety-like behavior in any of the targeted brain regions, serotonin transporter expression, specifically within the right ventrolateral prefrontal cortex (vlPFC) and most strongly in the right amygdala, was associated positively with anxiety-like behavior. The causal relationship between amygdala serotonin levels and an animal's sensitivity to threat was confirmed via direct amygdala infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram. Both anxiety-like behaviors, and conditioned threat-induced responses were reduced by the blockade of serotonin reuptake in the amygdala. Together, these findings provide evidence that high amygdala serotonin transporter expression contributes to the high trait anxious phenotype and suggest that reduction of threat reactivity by SSRIs may be mediated by their actions in the amygdala.SIGNIFICANCE STATEMENT Findings here contribute to our understanding of how the serotonin system underlies an individual's expression of threat-elicited negative emotions such as anxiety and fear within nonhuman primates. Exploration of serotonergic gene expression across brain regions implicated in emotion regulation revealed that serotonin transporter gene expression in the ventrolateral prefrontal cortex (vlPFC) and most strongly in the amygdala, but none of the serotonin receptor genes, were predictive of interindividual differences in anxiety-like behavior. Targeting of amygdala serotonin reuptake with selective serotonin reuptake inhibitors (SSRIs) confirmed the causal relationship between amygdala serotonin transporter and an animal's sensitivity to threat by reversing expression of two key features of the high trait-like anxiety phenotype: high responsivity to anxiety-provoking uncertain threat and responsivity to certain conditioned threat.

Role of oral flora in chemotherapy-induced oral mucositis in vivo.

OBJECTIVE: To determine if commensal oral microflora impacts the severity of chemotherapy-induced oral mucositis (OM). DESIGN: Specific-pathogen-free (SPF) and germ-free Swiss Webster mice in the experimental groups were dosed with 5-fluorouracil (5-FU) to induce OM. Mice in the control group received phosphate buffered saline. Comparative analyses of the epithelial thickness and cell proliferation/turnover rates, as well as the expression levels of metalloproteinases and pro-inflammatory mediators in the oral mucosa between the control and experimental groups were determined by histopathological and immunohistochemical analyses. RESULTS: 5-FU-treated SPF and germ-free mice showed characteristic features of OM with reduced oral epithelial thickness, presence of inflammatory cells in the connective tissues, and increased levels of expression of metalloproteinases and pro-inflammatory cytokines compared to the respective control groups. When 5-FU-treated SPF and germ-free mice were compared, 5-FU-treated germ-free mice exhibited less severe epithelial destruction with higher expression of the cell proliferation marker Ki67, coupled with lower expression levels of metalloproteinases and pro-inflammatory cytokine in the oral mucosa. CONCLUSION: This study provides the first histopathological evidence that oral flora has a detrimental effect on chemotherapy-induced OM in vivo.

Bacterial species associated with persistent apical periodontitis exert differential effects on osteogenic differentiation.

AIM: To determine if bacteria associated with persistent apical periodontitis induce species-specific pro-inflammatory cytokine responses in macrophages, and the effects of this species-specific microenvironment on osteogenic differentiation. METHODOLOGY: Macrophages were exposed to Enterococcus faecalis, Streptococcus oralis, Streptococcus mitis, Fusobacterium nucleatum, Treponema denticola or Tannerella forsythia, and levels of TNF-α and IL-1ß elicited were determined by immunoassay. Following treatment of MG-63 pre-osteoblasts with conditioned media from bacteria-exposed macrophages, osteogenic differentiation and viability of osteoblasts were analyzed by Alizarin Red Staining and MTS assay, respectively. Statistical analysis was carried out by one-way anova with the Tukey post-hoc test. Differences were considered to be significant if P < 0.05. RESULTS: Macrophages exposed to Gram-positive bacteria did not produce significant amounts of cytokines. F. nucleatum-challenged macrophages produced up to four-fold more TNF-α and IL-1ß compared to T. denticola or T. forsythia. Only conditioned media from macrophages treated with Gram-negative bacteria decreased mineralization and viability of osteoblasts. CONCLUSIONS: Gram-positive bacteria did not impact osteogenic differentiation and appeared innocuous. Gram-negative bacteria, in particular F. nucleatum elicited an enhanced pro-inflammatory response in macrophages, inhibited osteogenic differentiation and reduced cell viability. The findings suggest that the presence of this organism could potentially increase the severity of persistent apical periodontitis.

Early clinical experience of dolutegravir in an HIV cohort in a larger teaching hospital.

Dolutegravir (DTG) is the third HIV integrase inhibitor (INI) available for prescription in Belfast since July 2014. It has shown high virological efficacy in both treatment-naïve and -experienced patients. We carried out a retrospective case chart analysis of HIV-1-positive adults commenced on DTG between July 2014 and September 2015. Patients were identified from records as either treatment-naïve or antiretroviral therapy (ART) experienced. Outcomes included: (1) virological response (HIV-1 RNA viral load at 0, 4, 8 and 12 weeks), (2) immunological response (CD4+ cell count at 0, 4, 8 and 12 weeks) and (3) tolerability (side effects and discontinuation). The main exclusion criteria were patients transferring care already established on DTG from other treatment centres or inadequate follow-up information (defined as attendance at <50% of clinical and serological follow-up visits). One hundred and fifty-seven commenced DTG out of 823 patients on ART; 106 (68%) were switched to DTG from another regimen, and 51 (32%) were ART-naïve. One naïve and 14 treatment-experienced patients were excluded from the analysis due to failure to attend clinical follow-up. Analysis of HIV-1 RNA viral load (HIV-1 VL) was divided into three groups: 50 new starters, 68 suppressed at switch and 24 not suppressed at switch. New starters: Baseline median HIV-1 RNA VL 71,259 copies/mL (19,536Q25-196,413Q75); 73% were virally undetectable (HIV-1 RNA VL <70 copies/mL) by week 4. Switching patients: Of those with an HIV-1 RNA undetectable viral load prior to switching, two were detectable with a mean viral load of 443,730 copies/mL after four weeks. Of the 24 patients detectable at switch (median HIV-1 VL 2212 [311Q25-43,467Q75]), 10 were detectable after four weeks. For those with a recordable viraemia, the median HIV-1 VL reduced to 376 (220Q25-1181Q75). At week 12, four patients were detectable with a median VL of 12,390 (567Q25-52,285Q75). Overall, 56 (35%) reported side effects; 40 (25%) reported either difficulty with low mood, anxiety or sleep disturbance. Sixteen (10%) discontinued DTG, with 13 (8%) due to intolerable side effects. DTG is a useful drug in naïve or switch patients. It has the potential to effectively suppress the viral load within the first four weeks of treatment and thus reduces infectiousness. Within the cohort, DTG was generally well tolerated but side effects such as low mood, anxiety and sleep disturbance were high, with 8% of patients discontinuing treatment.

Secreted adenosine triphosphate from Aggregatibacter actinomycetemcomitans triggers chemokine response.

Extracellular ATP (eATP) is an important intercellular signaling molecule secreted by activated immune cells or released by damaged cells. In mammalian cells, a rapid increase of ATP concentration in the extracellular space sends a danger signal, which alerts the immune system of an impending danger, resulting in recruitment and priming of phagocytes. Recent studies show that bacteria also release ATP into the extracellular milieu, suggesting a potential role for eATP in host-microbe interactions. It is currently unknown if any oral bacteria release eATP. As eATP triggers and amplifies innate immunity and inflammation, we hypothesized that eATP secreted from periodontal bacteria may contribute to inflammation in periodontitis. The aims of this study were to determine if periodontal bacteria secrete ATP, and to determine the function of bacterially derived eATP as an inducer of inflammation. Our results showed that Aggregatibacter actinomycetemcomitans, but not Porphyromonas gingivalis, Prevotella intermedia, or Fusobacterium nucleatum, secreted ATP into the culture supernatant. Exposure of periodontal fibroblasts to filter sterilized culture supernatant of A. actinomycetemcomitans induced chemokine expression in an eATP-dependent manner. This occurred independently of cyclic adenosine monophosphate and phospholipase C, suggesting that ionotrophic P2X receptor is involved in sensing of bacterial eATP. Silencing of P2X7 receptor in periodontal fibroblasts led to a significant reduction in bacterial eATP-induced chemokine response. Furthermore, bacterial eATP served as a potent chemoattractant for neutrophils and monocytes. Collectively, our findings provide evidence for secreted ATP of A. actinomycetemcomitans as a novel virulence factor contributing to inflammation during periodontal disease.

Fusobacterium nucleatum induces cytokine production through Toll-like-receptor-independent mechanism.

AIM: To determine whether Fusobacterium nucleatum's ability to invade cells allows the bacteria to activate pro-inflammatory response through cytosolic pattern recognition receptors, independent of surface Toll-like receptors (TLRs). METHODOLOGY: HEK293T cells, which lack endogenous TLRs, and overexpressing dominant negative myeloid differentiation primary response gene 88 (MyD88DN) protein, were infected with F. nucleatum and the production of interleukin-8 (IL-8) was determined. The necessity for intracellular invasion of the bacteria for cytokine production was also investigated by blocking bacterial invasion with cytochalasin D. The roles of NFĸB and p38 mitogen-activated protein kinase (MAPK) and nucleotide-binding oligomerization domain-1 (NOD-1) signalling pathways in F. nucleatum-induced IL-8 secretion were determined. RESULTS: Fusobacterium nucleatum-infected HEK293T cells produced IL-8 independent of the MYD88 signalling. This response was inhibited by preventing F. nucleatum invasion into HEK293T cells. p38 MAPK but not the NFĸB signalling pathway was required for F. nucleatum-mediated IL-8 production. HEK293T cells expressed NOD-1 but not NOD-2. Yet, inhibition of NOD-1 signalling did not affect F. nucleatum-induced IL-8 secretion. CONCLUSIONS: Fusobacterium nucleatum invasion led to cytokine production, which is mediated by the p38 MAPK signalling but independent of TLRs, NOD-1, NOD-2 and NFĸB signalling.

Clinical care versus ethical obligations: HIV-1 and -2 co-infection with hepatitis B in a pregnant Jehovah's Witness.

Co-infection with HIV-1 and -2 is rare, even in west Africa. We present the case of a 38-year-old pregnant Jehovah's Witness presenting late in pregnancy with triple infection with HIV-1, HIV-2 and hepatitis B virus. There was a successful outcome in averting vertical transmission despite objections to management based on religious and cultural beliefs.

Managing vaccines: defining the remit of primary care and specialist HIV clinics in the delivery of immunization to individuals with HIV infection.

The British HIV Association (BHIVA) has published guidelines for immunization of HIV-infected adults. A chart review of 200 HIV-infected patients diagnosed was conducted to determine shortcomings in previous practice and determine which vaccines should routinely be given in specialist HIV clinics and which might be able to be delegated to primary care clinics. Data were collected on administration of three categories of vaccinations: (1) vaccines used in all individuals with chronic disease (pneumococcal, influenza, swine flu H1N1); (2) targeted vaccinations used in non-immune individuals with HIV who are at risk of exposure (hepatitis A and hepatitis B); (3) routine vaccines traditionally delivered to the whole population (measles/mumps/rubella [MMR], diphtheria/tetanus/pertussis and meningitis C/ACWY). Pneumococcal vaccine was delivered to 54% of eligible patients, 52% of eligible individuals completed a full hepatitis B programme of vaccination and 21% (42/200) were naturally immune; hepatitis A vaccine was delivered to 36% of eligible individuals. With increasing demands on resources, it seems likely that HIV services will have to harness resources of primary care in vaccine programmes in relation to routine vaccines. By improving communication between primary and secondary care mistakes with live vaccination decisions could be avoided; HIV services should continue to perform targeted and chronic disease vaccines, i.e. for category 1 and category 2 vaccines.

Acute hepatitis B: the limits of maintaining patient confidentiality.

Household contacts of hepatitis B (HBV) are at risk of infection, and guidelines advise vaccination of these contacts in addition to sexual partners (along with traditional high-risk groups). We present a case of intrafamilial transmission of acute hepatitis B virus (HBV) following failure to self-disclose status to family members. Complex confidentiality issues can arise following a diagnosis of HBV infection.

Post-exposure prophylaxis following sexual exposure to HIV: a seven-year retrospective analysis in a regional centre.

An audit of 72 patients presenting for post-exposure prophylaxis following sexual exposure (PEPSE) to HIV (68 genitourinary medicine and 4 accident & emergency) was conducted from 2003 to 2009. The principal indications for PEPSE included 27 (38%) unprotected intercourse (15/27 vaginal and 12/27 anal) with a known HIV-positive partner, 20 (28%) unprotected receptive anal sex with male partner of unknown status, 17 (24%) following sexual assault and three (4%) unprotected sex with a partner from an endemic country. Of those who commenced PEPSE, 92% did so within the recommended 72 hours. Concurrent sexually transmitted infection (STI) was diagnosed in 8.3% patients (6.9% non-gonococcal urethritis and 1.4% rectal chlamydia). Fifty (69%) patients attended for follow-up and only 8% of these did not complete treatment. Twenty-five (35%) patients attended for repeat serology at three months and 18 (25%) at six months. All of the patients followed up remained HIV-negative.

Implanon® failure in an HIV-positive woman on antiretroviral therapy resulting in two ectopic pregnancies.

Since its introduction in 1999, Implanon® remains one of the preferred contraceptive choices for many women as it offers a highly effective means of long-term contraception for three years that does not rely on adherence. Like all hormonal contraceptives, certain hepatic enzyme-inducing drugs may reduce its efficacy. We present an interesting case of an HIV-positive woman on antiretroviral therapy having tubal pregnancies on two separate occasions with Implanon in place.

A case of multidrug resistance in the central nervous system.

HIV-1 infection may persist in the central nervous system (CNS) despite antiretroviral therapy. We present a case of severe cognitive decline in a man with HIV-1 infection on a fully active regimen for five years. All infective causes were excluded. Despite fully suppressed virus in the blood, HIV RNA in the cerebrospinal fluid measured 3.52 log(10) RNA copies/mL and genotyping of this sample showed an extensive pattern of resistance. This suggested that either the antiretroviral agents were not adequately penetrating the CNS or the CNS had resistant virus as a result of adherence problems. This case highlights the possibility that drug-resistant mutations may develop in the CNS compartment while plasma virus remains suppressed.

Over-investigated and under-treated: children with febrile convulsion in a Malaysian district hospital.

INTRODUCTION: We conducted a retrospective audit on the inpatient assessment and care of children admitted with febrile convulsion to Hospital Batu Pahat, a district hospital in Malaysia, using the Malaysian national clinical practice guidelines and the American Academy of Paediatrics practice parameters on febrile convulsion as the reference standards. METHODS: The case notes of 100 consecutive children admitted in 2004 were analysed. The documentation of major clinical features, selection of investigations, the timeliness of antipyresis and frequency of parental education were evaluated. RESULTS: In general, the major clinical features that were relevant to the presenting problem were adequately documented, although fever was not mentioned as a presenting complaint in one quarter of the cases. On an average, about five investigations were ordered for every patient on admission. There was no major difference in the number of investigations conducted between children who were more severely ill and the rest of the patients. The majority of the investigations did not yield any useful diagnostic information. Only 38 percent of the children received antipyretics and 53 percent were tepid-sponged during fever, with 23 percent having received tepid-sponging without concurrently receiving antipyretics. No parental education on febrile convulsion was recorded in half of the cases. CONCLUSION: Excessive unjustified investigations, deficient antipyresis when required and inadequate communication with the family of children with febrile convulsion were observed. Awareness of such deficiencies from this audit should lead to regular staff education, monitoring and future audits in order to improve the quality of our clinical care.

Hepatic encephalopathy as an unusual late complication of transjugular intrahepatic portosystemic shunt insertion for non-cirrhotic portal hypertension caused by nodular regenerative hyperplasia in an HIV-positive patient on highly active antiretroviral therapy.

Transjugular intrahepatic portosystemic shunt (TIPS) is an artificially created conduit between the portal and systemic vascular system in the liver performed percutaneously via radiological guidance. It is used mainly in conditions causing portal hypertension and its resulting complications. It reduces portal pressure by diverting portal blood flow into the systemic circulation. Hepatic encephalopathy is the most common complication following TIPS insertion and tends to present fairly early. We describe a case of hepatic encephalopathy as an unusual late complication of TIPS insertion (first presenting six years after) for non-cirrhotic portal hypertension caused by nodular regenerative hyperplasia in an HIV-positive patient on highly active antiretroviral therapy.

Keratoconus associated with congenital stationary night blindness type 1.

A 35-year-old man presented with keratoconus; his best corrected visual acuities were -18.00/+10.00 ×180 (6/60) oculus dexter and -10.00/+8.00 ×5 (6/36) oculus sinister. Bilateral steep central corneal thinning, paracentral ectasia and Vogts striae were present. Normal fundi. Corneal topography disclosed 7.4 dioptres of irregular astigmatism in the central 3 mm with thinning (335 µm). Electroretinography (ERG) showed no response. There were no medical or environmental influences for his keratoconus. Occurrence of keratoconus and congenital stationary night blindness (CSNB) in the patient may represent a chance association, but keratoconus has not been previously linked with CSNB1 either as a chance or true association though both show genetic predisposition.

Community psycho-behavioural surveillance and related impact on outbreak control in Hong Kong and Singapore during the SARS epidemic.

1. The promotion of personal protective health practices must take into account background perceptions of risk and psychological responses in the community-at-large. 2. Population psycho-behavioural factors in Hong Kong and Singapore are shown to be an important potential vector for the transmission of an infectious agent. 3. Comparative psycho-behavioural surveillance and analysis can yield important insights into generic versus population-specific issues that could be used to inform, design and benchmark public health infection control measures.

Comparison of postoperative intraocular pressure in patients with Densiron-68 vs conventional silicone oil: a case-control study.

UNLABELLED: A solution of perfluorohexyloctane and silicone oil with a specific gravity of 1.06 g/cm(3) (Densiron-68) has similar properties as conventional silicone oil (SO) in terms of the shape of the bubble and its ability to act as an internal tamponade agent. We conducted a case-control study to compare the postoperative intraocular pressure (IOP) in patients treated with Densiron-68 with those treated with SO. METHODS: Seventy-one eyes of 71 patients and 57 eyes of 57 patients who had received Densiron-68 and SO, respectively, were included in our study. Both groups were found to have matched for their preoperative comorbidities (diabetes, glaucoma, phakic status, and refractive errors). IOP at first day, between seventh and fourteenth day, and at 4 week postoperatively was recorded. RESULTS: The mean IOP was higher in patients treated with Densiron-68 at day 1 and between seventh and fourteenth day postoperatively (P=0.05 and 0.01, respectively). By the 4th week, the IOP difference between the two groups was insignificant (P=0.17). The difference in the two groups could still be clinically significant and the raised IOP in Densiron-68 group was more difficult to treat in some cases.On day 1, nine eyes (12.7%) in the Densiron-68 group and two eyes (3.5%) in the SO group had IOP greater than 30 mmHg. At 4 weeks, IOP of more than 30 mmHg was seen in nine eyes (12.7%) in the Densiron-68-treated group and in one eye (1.8%) in the SO group. CONCLUSION: The use of Densiron-68 was associated with a higher IOP in the early postoperative period when compared with SO.