Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ...ribavirin for treating patients with COVID-19.
This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688.
Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3–7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days IQR 5–11) than the control group (12 days 8–15; hazard ratio 4·37 95% CI 1·86–10·24, p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir–ritonavir because of biochemical hepatitis. No patients died during the study.
Early triple antiviral therapy was safe and superior to lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted.
The Shaw-Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine.
Social communicative precursors to autism spectrum disorder may influence how infants who are later diagnosed with autism spectrum disorder interact with their social partners and the responses they ...receive, thus bidirectionally influencing early social experience. This systematic review aimed to identify a developmental timeline for parent–infant interaction in the first 2 years of life in at-risk infants and in emergent autism spectrum disorder, and to examine any parent–infant interaction associations with later social-communicative outcomes. In total, 15 studies were identified investigating parent–infant interaction in infants at familial autism risk (i.e. with an older sibling with autism spectrum disorder). Starting from the latter part of the first year, infants at risk of autism spectrum disorder (and particularly infants with eventual autism spectrum disorder) showed parent–infant interaction differences from those with no eventual autism spectrum disorder, most notably in infant gesture use and dyadic qualities. While parental interactions did not differ by subsequent child autism spectrum disorder outcome, at-risk infants may receive different ‘compensatory’ socio-communicative inputs, and further work is needed to clarify their effects. Preliminary evidence links aspects of parent–infant interaction with later language outcomes. We discuss the potential role of parent–infant interaction in early parent-mediated intervention.
Epstein-Barr virus (EBV) is a herpesvirus associated with nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), and other malignancies. EBV is the first human virus found to express microRNAs ...(miRNAs), the functions of which remain largely unknown. We report on the regulation of a cellular protein named p53 up-regulated modulator of apoptosis (PUMA) by an EBV miRNA known as miR-BART5, which is abundantly expressed in NPC and EBV-GC cells. Modulation of PUMA expression by miR-BART5 and anti-miR-BART5 oligonucleotide was demonstrated in EBV-positive cells. In addition, PUMA was found to be significantly underexpressed in approximately 60% of human NPC tissues. Although expression of miR-BART5 rendered NPC and EBV-GC cells less sensitive to proapoptotic agents, apoptosis can be triggered by depleting miR-BART5 or inducing the expression of PUMA. Collectively, our findings suggest that EBV encodes an miRNA to facilitate the establishment of latent infection by promoting host cell survival.
To investigate the incidence of gastric cancer (GC) attributed to gastric intestinal metaplasia (IM), and validate the Operative Link on Gastric Intestinal Metaplasia (OLGIM) for targeted endoscopic ...surveillance in regions with low-intermediate incidence of GC.
A prospective, longitudinal and multicentre study was carried out in Singapore. The study participants comprised 2980 patients undergoing screening gastroscopy with standardised gastric mucosal sampling, from January 2004 and December 2010, with scheduled surveillance endoscopies at year 3 and 5. Participants were also matched against the National Registry of Diseases Office for missed diagnoses of early gastric neoplasia (EGN).
There were 21 participants diagnosed with EGN. IM was a significant risk factor for EGN (adjusted-HR 5.36; 95% CI 1.51 to 19.0; p<0.01). The age-adjusted EGN incidence rates for patients with and without IM were 133.9 and 12.5 per 100 000 person-years. Participants with OLGIM stages III-IV were at greatest risk (adjusted-HR 20.7; 95% CI 5.04 to 85.6; p<0.01). More than half of the EGNs (n=4/7) attributed to baseline OLGIM III-IV developed within 2 years (range: 12.7-44.8 months). Serum trefoil factor 3 distinguishes (Area Under the Receiver Operating Characteristics 0.749) patients with OLGIM III-IV if they are negative for
. Participants with OLGIM II were also at significant risk of EGN (adjusted-HR 7.34; 95% CI 1.60 to 33.7; p=0.02). A significant smoking history further increases the risk of EGN among patients with OLGIM stages II-IV.
We suggest a risk-stratified approach and recommend that high-risk patients (OLGIM III-IV) have endoscopic surveillance in 2 years, intermediate-risk patients (OLGIM II) in 5 years.
Background: Recent models of the early emergence of autism spectrum disorder (ASD) propose that infant intrinsic risk susceptibilities in behaviour may be amplified by interaction within the early ...social environment into an increasingly atypical developmental trajectory. This study examines whether 6‐ and 12‐month parent–infant interactions in at‐risk siblings differ from those with low‐risk and whether – in at‐risk siblings – such interactions predict later 3‐year classification of ASD or no ASD.
Method: Within the British Autism Study of Infant Siblings (BASIS), 6‐min videotaped episodes of parent–infant free play in infants at 6–10 months (45 at‐risk siblings and 47 low‐risk siblings) and 12–15 months (43 at‐risk siblings and 48 low‐risk siblings) in a laboratory setting were rated on the Manchester Assessment of Caregiver‐Infant Interaction (MACI), blind to participant information. Standard tests were administered for concurrent behavioural signs of ASD features and developmental level. Systematic consensus diagnostic classification of ASD was made at 3 years for the at‐risk siblings.
Results: Parent nondirectiveness and sensitive responsiveness differed in relation to ASD/risk status (at‐risk ASD, at‐risk no‐ASD and low‐risk) at both 6 and 12 months. At 6 months, infant liveliness was lower in the at‐risk groups; at 12 months, infant attentiveness to parent and positive affect were lower in the at‐risk group later diagnosed with ASD. Dyadic mutuality and intensity of engagement showed a group effect at 12 months. Dyadic mutuality, infant positive affect and infant attentiveness to parent at 12 months (but not 6 months) predicted 3‐year ASD outcome, whereas infant ASD‐related behavioural atypicality did not.
Conclusions: This is the first prospective evidence that early dyadic interaction between at‐risk infants and their parents is associated with later diagnostic outcome in ASD. Possible explanations for these findings and their theoretical implications are considered.
► We studied parent–infant interaction in six-month-old infants with a sibling with ASD. ► Play interactions were rated for global parent, infant and dyadic characteristics. ► At-risk sibs were less ...lively than controls, possibly reflecting a trait difference. ► Parents of at-risk sib infants tended to have a more directive interactive style. ► Research must explore if disrupted interaction may amplify infant social atypicality.
Recent models of the early emergence of autism spectrum disorder (ASD) propose an interaction between risk susceptibility and the infant's social environment, resulting in a progressively atypical developmental trajectory. The infant's early social environmental experience consists mostly of interaction with caregivers, yet there has been little systematic study of early parent–infant interaction in infants at risk of ASD. This study examined the global characteristics of parent–infant interaction in 6- to 10-month-old infants with an older sibling diagnosed with ASD (at-risk sibs), in comparison with a group of infants with no family history of ASD (low-risk sibs). As part of the British Autism Study of Infant Siblings (BASIS), 6-min videotaped unstructured play interactions of mother–infant dyads (45 at-risk sibs and 47 low-risk sibs) were rated on global aspects of parent–infant interaction, blind to participant information. Differences in global characteristics of interaction were observed in both infant and parent contributions in the at-risk group compared to low-risk controls. In analyses adjusted for age and developmental level, at-risk sib infants were less lively, and their parents showed higher directiveness, and lower sensitive responding (as a trend after adjustment). Level of infant liveliness was independent of other interactive behaviour. Consistent with reports in previous literature in older children with autism and in other neurodevelopmental disorders, our findings may suggest that infants at genetic risk are exposed to a more directive interactive style relatively early in infancy. We discuss possible explanations for these findings and implications for further developmental study and intervention.
Diabetes is a major cause of end stage renal disease (ESRD), yet the natural history of diabetic kidney disease is not well understood. We aimed to identify patterns of estimated GFR (eGFR) ...trajectory and to determine the clinical and genetic factors and their associations of these different patterns with all-cause mortality in patients with type 2 diabetes. Among 6330 patients with baseline eGFR >60 ml/min per 1.73 m2 in the Hong Kong Diabetes Register, a total of 456 patients (7.2%) developed Stage 5 chronic kidney disease or ESRD over a median follow-up of 13 years (incidence rate 5.6 per 1000 person-years). Joint latent class modeling was used to identify different patterns of eGFR trajectory. Four distinct and non-linear trajectories of eGFR were identified: slow decline (84.3% of patients), curvilinear decline (6.5%), progressive decline (6.1%) and accelerated decline (3.1%). Microalbuminuria and retinopathy were associated with accelerated eGFR decline, which was itself associated with all-cause mortality (odds ratio OR 6.9; 95% confidence interval CI: 5.6–8.4 for comparison with slow eGFR decline). Of 68 candidate genetic loci evaluated, the inclusion of five loci (rs11803049, rs911119, rs1933182, rs11123170, and rs889472) improved the prediction of eGFR trajectories (net reclassification improvement 0.232; 95% CI: 0.057-–0.406). Our study highlights substantial heterogeneity in the patterns of eGFR decline among patients with diabetic kidney disease, and identifies associated clinical and genetic factors that may help to identify those who are more likely to experience an accelerated decline in kidney function.
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•Non-alcoholic fatty liver disease has been linked to chronic kidney disease in observational studies.•In this cohort of 1,763 patients with type 2 diabetes, we show that liver ...fibrosis but not steatosis was associated with albuminuria.•The association remains consistent using different liver stiffness cut-offs and adjusting for other metabolic factors and medications.
Increasing evidence suggests that non-alcoholic fatty liver disease (NAFLD) may be an independent risk factor for chronic kidney disease (CKD). Given the high prevalence of NAFLD among patients with diabetes who are also at risk of CKD, we aimed to investigate the association between NAFLD and albuminuria, a marker commonly found in diabetic nephropathy.
This study included a cohort of Chinese patients with type 2 diabetes from the Hong Kong Diabetes Registry recruited between March 2013 and May 2014. Liver stiffness measurement (LSM), with probe-specific cut-offs, was used to detect advanced liver fibrosis. While controlled attenuation parameter (CAP) was used to assess liver steatosis using transient elastography.
A total of 1,763 Chinese patients with type 2 diabetes were recruited in this analysis. The mean (standard deviation) age and duration of diabetes were 60.7 (11.5) years and 10.8 (8.5) years, respectively. The prevalence of albuminuria was higher in diabetic patients with liver steatosis and those with advanced fibrosis (no NAFLD vs. liver steatosis vs. advanced fibrosis: 41.4% vs. 46.2% vs. 64.2%, p <0.001). After adjustment for potential confounders including glycated hemoglobin, hypertension and body mass index, advanced fibrosis, but not liver steatosis, was associated with increased risk of albuminuria (odds ratio OR 1.52; 95% confidence interval CI 1.02–2.28; p = 0.039) in patients with eGFR ≥60 ml/min/1.73 m2. The odds of albuminuria increased with greater severity of liver fibrosis in a dose dependent manner, with the highest odds observed in patients with LSM scores ≥11.5 kPa assessed by M probe or ≥11.0 kPa assessed by XL probe (adjusted OR 1.53; 95% CI 1.07–2.20; p = 0.021).
Advanced liver fibrosis, but not steatosis, is independently associated with albuminuria in Chinese patients with type 2 diabetes. Attention should be paid to liver fibrosis in patients with obesity and type 2 diabetes complicated with albuminuria.
In this study, we assessed the link between non-alcoholic fatty liver disease (NAFLD) and albuminuria in a cohort of 1,763 Chinese patients with type 2 diabetes. This study shows that advanced liver fibrosis, a severe form of NAFLD, was independently associated with increased risk of albuminuria. The risk of albuminuria increased with greater severity of liver fibrosis.
Abstract Background Maternal sensitivity to infant cues and developmental needs may be pivotal for social and cognitive development. Animal and recent human studies emphasise a major role for ...Oxytocin (OT) in mediating sensitive caregiving but no study has examined the relationship between OT and extreme variation in human maternal sensitivity. Methods : From 105 expectant mothers, 80 underwent blind-rating of maternal sensitivity at 4–6 months postpartum through free-play interaction with their infants. At 7–9 months postpartum, 30 mothers at extremes of maternal sensitivity: 15 ‘sensitive mothers’ (high sensitivity mothers – HSMs, mean=4.47; SD=0.74) and 15 ‘less sensitive mothers’ (low sensitivity mothers – LSMs, mean=2.13; SD=0.52) underwent plasma OT measurements before and after 10 min infant play. Results : Baseline and post-interaction plasma OT was higher in LSMs than HSMs F (1, 26)=8.42; p =0.01. HSMs showed a trend towards significant reduction in plasma OT t (14)=2.01; p =0.06 following play-interaction; no change was shown by LSMs t (13)=−0.14; p =0.89. Conclusion Higher baseline OT levels in healthy LSMs may imply greater stress responses to the demands of caring for an infant, or past deficiencies in own parenting relationship and act as a biomarker for poor parental sensitivity. OT may be acting to reduce stress and anxiety in LSMs consistent with studies of plasma OT and stress in women. By contrast, in HSMs, play interaction with their infants maybe relaxing as indicated by significant reduction in plasma OT from baseline. Ascertainment of mothers in well-defined sensitivity groups might facilitate examination of distinct coping strategies in parents and better understanding of variation in parental caregiving behaviour and its potential for modulation by OT. This article is part of a Special Issue entitled Oxytocin and Social Behav.
Synthesis of the diarylethene‐containing ligand L1 based on Suzuki cross‐coupling reaction between thienyl boronic acid and the dibromophenanthroline ligand is reported. On coordination to the ...rhenium(I) tricarbonyl complex system, the photochromism of L1 could be photosensitized and consequently extended from intraligand excitation at λ≤340 nm in the free ligand to metal‐to‐ligand charge‐transfer (MLCT) excitation at λ≤480 nm in the complex. The photochromic reactions were studied by 1H NMR, UV/Vis, and steady‐state emission spectroscopy. Photosensitization was further probed by ultrafast transient absorption and time‐resolved emission spectroscopy. The results provided direct evidence that the formation of the closed form by the MLCT‐sensitized photochromic process was derived from the 3MLCT excited state. This supports the photosensitization mechanism, which involves an intramolecular energy‐transfer process from the 3MLCT to the 3IL(L1) state that initiated the ring‐closure reaction. The photophysical and electrochemical properties of the complex were also investigated.
Photochromic reactions of diarylethene‐containing ligand L1 and its ReCl(CO)3 complex (see picture) were studied inter alia by ultrafast transient absorption and time‐resolved emission spectroscopy. The photochromism of L1 could be photosensitized and extended from intraligand (IL) excitation at λ≤340 nm in the free ligand to metal‐to‐ligand charge‐transfer (MLCT) excitation at λ≤480 nm in the complex. The results support the depicted mechanism, in which intramolecular energy‐transfer (ET) from the 3MLCT to the 3IL(L1) state initiates ring closure.
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