Early HIV infection is associated with reduced proportions of gamma delta T subsets as well as high creatinine and urea levels

Renal dysfunctions are major predictors of co-morbidities and mortality in HIV-infected individuals. Unconventional T cells have been shown to regulate kidney functions. However, there is dearth of information on the effect of HIV-associated nephropathies on γδ and DN T cells. It is also not clear whether γδ T cell perturbations observed during the early stages of HIV infection occur before immune activation. In this study, we investigated the relationship between creatinine and urea on the number of unconventional T cells in HIV-infected individuals at the early and chronic stages of infection. Persons in the chronic stage of infection were divided into treatment naïve and exposed groups. Treatment exposed individuals were further subdivided into groups with undetectable and detectable HIV-1RNA in their blood. Creatinine and urea levels were significantly higher among persons in the early HIV infection compared with the other groups. Proportions of γδ T, γδ + CD8, γδ + CD16 cells were also significantly reduced in the early stage of HIV infection (P < .01). Markers of immune activation, CD4 + HLA-DR and CD8 + HLA-DR, were also significantly reduced during early HIV infection (P < .01). Taken together, our findings suggest that high levels of renal markers as well as reduced proportions of gamma delta T cells are associated with the early stages of HIV infection. This event likely occurs before systemic immune activation reaches peak levels. This study provides evidence for the need for early HIV infection diagnosis and treatment.     

A Phase Ib Study of NUC-1031 in Combination with Cisplatin for the First-Line Treatment of Patients with Advanced Biliary Tract Cancer (ABC-08)

BackgroundCisplatin/gemcitabine is standard first‐line treatment for patients with advanced biliary tract cancer (ABC). NUC‐1031 (phosphoramidate transformation of gemcitabine) is designed to enhance efficacy by maximizing intratumoral active metabolites.MethodsPatients with untreated ABC, Eastern Cooperative Oncology Group performance status 0–1 received NUC‐1031 (625 or 725 mg/m²) and cisplatin (25 mg/m²) on days 1 and 8, every 21 days. Primary objectives were safety and maximum tolerated dose; secondary objectives were objective response rate (ORR), pharmacokinetics, progression‐free survival (PFS), and overall survival (OS).ResultsTwenty‐one patients (median age 61 years, n = 13 male; 17 cholangiocarcinoma, 2 ampullary, and 2 gallbladder cancer) received NUC‐1031 625 mg/m² (n = 8 and expansion n = 7; median six cycles) or 725 mg/m² (n = 6; median 7.5 cycles). Treatment was well tolerated; most common treatment‐emergent grade 3–4 adverse events occurring in more than one patient with 625 mg/m² NUC‐1031 were increased gamma‐glutamyl transferase (GGT), 40%; alanine aminotransferase, 20%; bilirubin, 13%; neutropenia, 27%; decreased white cell count, 20%; thrombocytopenia, 13%; nausea, 13%; diarrhea, 13%; fatigue, 13%; and thrombus, 20% and with 725 mg/m², increased GGT, 67%, and fatigue, 33%. NUC‐1031 725 mg/m² was selected as the recommended dose with cisplatin in ABC. ORR was 33% (one complete response, six partial responses), DCR was 76%, median PFS was 7.2 months (95% confidence interval [CI], 4.3–10.1), and median OS was 9.6 months (95% CI, 6.7–13.1). The median estimates of area under the plasma concentration–time curve from time 0 to last measurable time and maximum concentration were highest for NUC‐1031 (218–324 μg•h/mL and 309–889 μg/mL, respectively) and lowest for di‐fluoro‐deoxycytidine (0.47–1.56 μg•h/mL and 0.284–0.522 μg/mL, respectively).ConclusionThis is the first study reporting on the combination of NUC‐1031 with cisplatin in ABC and demonstrated a favorable safety profile; 725 mg/m² NUC‐1031 in combination with cisplatin is undergoing phase III trial evaluation in ABC. (ClinicalTrials.gov ID: {"type":"clinical-trial","attrs":{"text":"NCT02351765","term_id":"NCT02351765"}}NCT02351765; EudraCT ID: 2015‐000100‐26).Implications for PracticeThe prognosis for patients with advanced biliary tract cancer (ABC) is approximately 1 year, and new treatment options are required. The cisplatin/gemcitabine combination is standard first‐line treatment for patients with ABC. NUC‐1031 is a phosphoramidate transformation of gemcitabine and is designed to enhance efficacy by maximizing intratumoral active metabolites. This phase Ib study (ABC‐08) demonstrated a favorable safety profile of NUC‐1031 in combination with cisplatin for the first‐line treatment of patients with ABC, and 725 mg/m² NUC‐1031 was recommended in combination with cisplatin for phase III trial evaluation; the NuTide:121 global randomized study is currently enrolling.     

Mood, cognition and in vivo protein imaging: the emerging nexus in clinical neuroscience

INTRODUCTION: Disorders of mood and cognition overlap in the elderly and there is an emerging consensus that both groups of disorders share neurobiological substrates. METHODS: Salient peer reviewed articles focusing on late-life depression, structural neuroimaging and recent developments in positron emission tomography based in vivo protein imaging. RESULTS: Epidemiological and clinical evidence indicates that mood and cognition in the elderly are clinically inter-related and common neurobiological mechanisms may underlie both groups of disorders. Degenerative, vascular and related mechanisms like genetically programmed abnormal protein deposition may provide the underlying neurobiological links between these disorders. CONCLUSIONS: Modern neuroimaging approaches such as positron emission tomography (PET) based in vivo protein binding may help further elucidate common pathophysiological mechanisms and assist in the early identification of patients at risk for developing dementia over time. These developments have important mechanistic and public health significance in the elderly.     

Building research capacity for child and adolescent mental health in Africa

Background

Behavioural/emotional problems may be common in preschool children living in resource-poor settings, but assessment of these problems in preschool children from poor areas is challenging owing to lack of appropriate behavioural screening tools. The child behaviour checklist (CBCL) is widely known for its reliability in identifying behavioural/emotional problems in preschool children, but it has not been validated for use in sub-Saharan Africa.

Methods

With permission from developers of CBCL, we translated this tool into Ki-Swahili and adapted the items to make them culturally appropriate and contextually relevant and examined the psychometric properties of the CBCL, particularly reliability, validity and factorial structure in a Kenyan community preschool sample of 301 children. It was also re-administered after 2 weeks to 38 randomly selected respondents, for the purpose of evaluating retest reliability. To evaluate inter-informant reliability, the CBCL was administered to 46 respondents (17 alternative caretakers and 29 fathers) alongside the child’s mother. Generalised linear model was used to measure associations with behavioural/emotional scores. We used structural equation modelling to perform a confirmatory factor analysis to examine the seven-syndrome CBCL structure.

Results

During the first phase we found that most of the items could be adequately translated and easily understood by the participants. The inter-informant agreement for CBCL scores was excellent between the mothers and other caretakers [Pearson’s correlation coefficient (r) = 0.89, p < 0.001] and fathers (r = 0.81; p < 0.001). The test–retest reliability was acceptable (r = 0.76; p < 0.001). The scale internal consistency coefficients were excellent for total problems [Cronbach’s alpha (α) = 0.95] and between good and excellent for most CBCL sub-scales (α = 0.65–0.86). Behavioural/emotional scores were associated with pregnancy complications [adjusted beta coefficient (β) = 0.44 (95 % CI, 0.07–0.81)] and adverse perinatal events [β = 0.61 (95 % CI, 0.09–1.13)] suggesting discriminant validity of the CBCL. Most fit indices for the seven-syndrome CBCL structure were within acceptable range, being <0.09 for root mean squared error of approximation and >0.90 for Tucker–Lewis Index and Comparative Fit Index.

Conclusion

The CBCL has good psychometric properties and the seven-syndrome structure fits well with the Kenyan preschool children suggesting it can be used to assess behavioural/emotional problems in this rural area.

     

Online responses to the ending of the one-child policy in China: implications for preconception care

Aim: A critical analysis of online public postings in response to the news about the ending of China’s one-child policy was conducted. The specific study aims were to 1) identify the dominant public discourse in response to the news about the ending of the one-child policy and the beginning of the new two-child policy, and 2) explore implications for preconception care from the public discourse.

Material and methods: Data sources were 10 top-ranked, online news media sites in China, including one Hong Kong-based media site. Selected online sites announced the news about the ending of the one-child policy on 29 October 2015. Online postings associated with the first news release of each online media site before midnight of 29 October were collected and analyzed. Critical discourse analysis was used for data analysis.

Results: Three main discourse concepts were identified. The online postings referenced the concepts of cost, generation, and timing with regard to the ending of the one-child policy and the beginning of the new two-child policy. Each concept represents an aspect of the public’s view of preconception care, particularly interconception care, in China.

Discussion: These findings suggest that the change in the family planning policy may not result in a huge surge in the population in a short period of time, as some may opt not to have a second child. Nonetheless, there is an urgent need to incorporate interconception care into various health initiatives, as it is a time-sensitive choice for many couples to have a second child.     

Fingerprint profiling of polysaccharides from different parts of lotus root varieties

Thirty-nine polysaccharides isolated from different parts of 13 lotus root varieties were characterized with fingerprint and chemometrics analyses to explore their similarity and diversity. The physicochemical features of lotus root polysaccharides (LRPs) were found to be the following: LRPs contained mainly polysaccharides (5.94 kDa) and polysaccharide-protein complexes (11.57 kDa and 5.30 kDa); their carbohydrates were composed of mannose, rhamnose, glucuronic acid, galacturonic acid, glucose, galactose and arabinose approximately in the molar ratio of 0.19 : 0.14 : 0.08 : 0.17 : 6.49 : 1.00 : 0.16; and node LRPs possessed more binding proteins and uronic acids than both flesh and peel LRPs. Their fingerprints based on Fourier-transform infrared spectroscopy, pre-column derivatization high-performance liquid chromatography and high performance size-exclusion chromatography all exhibited relatively high similarities, contributing to the common figerprint models which could be utilized as references for the identification of LPRs. In addition, the fingerprint characteristics associated with the between-group variability of LRPs in the score plots derived from multivariate analytical models might indicate which variety or part of lotus root they were isolated from. Therefore, multi-fingerprinting techniques have the potential to be applied to the identification and quality control of LRPs.

Thirty-nine polysaccharides isolated from lotus roots were characterized with fingerprint and chemometrics analyses to explore their similarity and diversity.     

Open versus Laparoscopic Hiatal Hernia Repair

Background:

The literature reports the efficacy of the laparoscopic approach to paraesophageal hiatal hernia repair. However, its adoption as the preferred surgical approach and the risks associated with paraesophageal hiatal hernia repair have not been reviewed in a large database.

Method:

The Nationwide Inpatient Sample dataset was queried from 1998 to 2005 for patients who underwent repair of a complicated (the entire stomach moves into the chest cavity) versus uncomplicated (only the upper part of the stomach protrudes into the chest) paraesophageal hiatal hernia via the laparoscopic, open abdominal, or open thoracic approach. A multivariate analysis was performed controlling for demographics and comorbidities while looking for independent risk factors for mortality.

Results:

In total, 23,514 patients met the inclusion criteria. By surgical approach, 55% of patients underwent open abdominal, 35% laparoscopic, and 10% open thoracic repairs. Length of stay was significantly reduced for all patients after laparoscopic repair (P < .001). Age ≥60 years and nonwhite ethnicity were associated with significantly higher odds of death. Laparoscopic repair and obesity were associated with lower odds of death in the uncomplicated group.

Conclusion:

Laparoscopic repair of paraesophageal hiatal hernia is associated with a lower mortality in the uncomplicated group. However, older age and Hispanic ethnicity increased the odds of death.