DSpace Collection:http://hdl.handle.net/10722/386282024-03-19T09:28:24Z2024-03-19T09:28:24ZRole of gut microbiota in the regulation of intestinal serotonin availabilityCai, Jieling蔡洁玲http://hdl.handle.net/10722/3415962024-03-18T09:56:16Z2023-01-01T00:00:00ZTitle: Role of gut microbiota in the regulation of intestinal serotonin availability
Authors: Cai, Jieling; 蔡洁玲
Abstract: Peripheral serotonin mainly produced from enterochromaffin cells plays an essential role in the regulation of gastrointestinal (GI) motility. However, excessive serotonin stimulation initiates different functional GI disorders. The effectiveness of serotonin receptor blockers in the amelioration of radiation therapy-induced emesis suggests the pathophysiological involvement of serotonin. Gut microbiota is closely linked with the health of host via working in partnership with the host digestive system to produce energy and microbial metabolites. Previous studies have demonstrated that radiation therapy-induced GI side effects are in part associated with the alterations of gut microbiota. Relationship between gut microbiota and peripheral serotonin has been proposed, yet the mechanism remains inconclusive. Here, we aim to investigate the role of gut microbiota in the regulation of intestinal serotonin availability. A mouse radiation model followed by fecal microbiota transplantation from donors fed a 3-week grain-based normal chow diet (NCD), synthetic low-fat diet (LFD) or high-fat diet (HFD) was used for in vivo investigation. As a result, the suppression of intestinal serotonin level by HFD-induced microbiome (HFM) was found to be attributed to an increase in butyrate production at ileum level in irradiated recipient mice. Treatment with butyrate in irradiated mouse ileal organoids increased the uptake of extracellular serotonin, and the process was visualized by real-time tracking of a fluorescent substrate for monoamine transporters. Silencing serotonin transporter (SERT) in the organoids abolished the effect of butyrate on serotonin uptake. However, in both in vivo and in vitro studies, there was no significant change in either mRNA abundance or protein expression of SERT in response to butyrate. Combined treatment with selective serotonin reuptake inhibitors and butyrate suggested butyrate acted as a positive allosteric modulator of SERT. The analysis of human gut microbiome revealed that butyrate production was associated with the interconversion between acetate and butyrate, and fecal contents of both acetate and butyrate which were strongly correlated were negatively associated with serum serotonin level. However, only fecal butyrate level was positively correlated with body mass index (BMI) in human. Our findings reveal that short-term HFD-associated gut microbiota decreased the serotonin level in the ileum through stimulating the production of butyrate. Furthermore, short-term HFD may be beneficial for alleviating GI symptoms by increasing butyrate to suppress local serotonin level and providing extra energy to cancer patients undergoing radiation.2023-01-01T00:00:00ZTo investigate the safety and effectiveness of antipsychotics in chronic and acute treatment : through observational studies and experimental study (randomised clinical trial)Lao, Shijian劳石坚http://hdl.handle.net/10722/3415802024-03-18T09:56:07Z2019-01-01T00:00:00ZTitle: To investigate the safety and effectiveness of antipsychotics in chronic and acute treatment : through observational studies and experimental study (randomised clinical trial)
Authors: Lao, Shijian; 劳石坚
Abstract: Antipsychotic is one of the most commonly used psychotropic drug class. As the utilisation of antipsychotics has been increasing, safety and effectiveness concerns on the use of antipsychotics have been highlighted. However, population-level evidence on the safety and effectiveness for chronic and acute treatment of antipsychotics in general mental patients and vulnerable patient groups is lacking. This thesis aims to investigate the safety and effectiveness of antipsychotics in chronic and acute treatments through observational studies and a randomised clinical trial.
The primary objectives of respective chapters in this thesis are to investigate: 1) the drug utilisation, the mortality risk in chronic treatment, and risk of neuroleptic malignant syndrome acutely after treatment initiation by multiple population-based observational study designs, and 2) the effectiveness and safety of short-acting injections in managing acute agitation in the emergency settings by a multicentre double-blinded randomised clinical trial. Clinical data from the Hong Kong Clinical Data Analysis and Reporting System, and data prospectively collected from patients recruited for the trial was used in this thesis. The results of these studies were then compared to the literature for discussion.
First, this thesis reports a cross-sectional descriptive utilisation study in Hong Kong. Antipsychotics have been increasingly prescribed in the general population, children, and older patients. There was an increase in second-generation antipsychotic prescribing. The prescription volume of first-generation antipsychotics haloperidol is notably higher in Hong Kong compared to overseas settings.
Secondly, this thesis reports an association between antipsychotics and mortality risk in long-term using a population-based cohort. We observed that haloperidol is associated with increased mortality risk in a long-term exposure period time over other antipsychotics.
Thirdly, a randomised clinical trial on the safety and effectiveness of intramuscular antipsychotics in managing acute agitation in the emergency setting is presented. The results of the interim analysis suggested the generally equivalent effectiveness between the novel choice of sedative olanzapine, and conventional sedatives haloperidol or midazolam.
The final part of the thesis presents a case-crossover study on the risk of the neuroleptic malignant syndrome in antipsychotic users in Hong Kong, through a case-crossover study using a population-based cohort. The initiation of antipsychotic medication, haloperidol and quetiapine were associated with an acutely increased risk of developing NMS, but not risperidone or olanzapine.
Findings of the thesis demonstrate a particularly high prevalence of haloperidol prescribing in Hong Kong despite the increasing use of second-generation antipsychotics. However, a consistently higher risk of premature mortality and neuroleptic malignant syndrome associated with haloperidol was observed. The interim results of randomised clinical trial suggested generally comparable effectiveness among olanzapine, midazolam, and haloperidol. Various pharmacoepidemiological methodologies using the healthcare databases provide access to high-level research evidence to broaden the understanding of antipsychotic safety and inform clinical practice of prescribing antipsychotic especially haloperidol. Future research direction is to combine with different databases/study sites for a more significant sample size to obtain extra robustness and strengthen generalisability of the findings.2019-01-01T00:00:00ZExamining the extra-glycaemic properties of SGLT2 inhibitors among type 2 diabetes patients using real-world clinical dataAu, Chun Ming區震銘http://hdl.handle.net/10722/3415722024-03-18T09:56:03Z2023-01-01T00:00:00ZTitle: Examining the extra-glycaemic properties of SGLT2 inhibitors among type 2 diabetes patients using real-world clinical data
Authors: Au, Chun Ming; 區震銘
Abstract: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a new class of glucose-lowering drugs. Multiple placebo-controlled cardiorenal outcomes trials and multinational observational studies have been conducted to study the extra-glycaemic properties of SGLT2i. SGLT2i were found to confer cardiovascular and renal benefits in patients with type 2 diabetes. Despite initial efforts, there is still much to learn about the comparative effectiveness of SGLT2i against other classes of glucose-lowering drugs in terms of cardiorenal benefits. Dipeptidyl peptidase 4 inhibitors (DPP4i) are of particular interest. Like SGLT2i, DPP4i are a recent class of glucose-lowering drugs that have been widely used as second or third-line antidiabetic medication. Regarding the comparative renal benefits of SGLT2i and DPP4i, besides composite renal outcomes, there have not been many large studies investigating specific renal endpoints, such as albuminuria and acute renal failure (ARF), and existing results were not consistent.
Interestingly, outside cardiorenal benefits, recent adverse events analyses and network meta-analysis of previous cardiorenal trials suggested additional benefits to the respiratory system. Although these studies were hypothesis-generating in nature, they started to attract interest in the real-world effectiveness of the observed respiratory benefits.
This thesis studied the associations of SGLT2i with renal and respiratory outcomes, using DPP4i as active comparator. Renal outcomes included end-stage renal disease (ESRD), albuminuria, ARF, and the change in estimated glomerular filtration rate (eGFR) decline, while respiratory outcomes included the incidence and mortality of pneumonia, and the incidence and exacerbations of obstructive airway disease (OAD). These are population-based retrospective cohort studies which collected electronic health data of patients with type 2 diabetes from the Hong Kong CDARS electronic health database. Since DPP4i are an older class of drugs than SGLT2i, many patients using SGLT2i in Hong Kong are previous or ongoing DPP4i users. Unlike previous studies, to account for the potential bias due to previous exposure to an active comparator, this thesis adopted the recent “prevalent new-user” design. A propensity score matching method was also adopted to balance the baseline characteristics of the study groups.
In this thesis, compared to DPP4i, for renal outcomes, SGLT2i were found to associate with a 81% reduced risk of ESRD, a 70% reduced risk of ARF, a 50% reduced risk of albuminuria, as well as a slower decline in eGFR. For respiratory outcomes, SGLT2i were found to associate with a 41% reduced risk of pneumonia, as well as a 35% reduced risk of incident OAD and a 46% reduced rate of OAD exacerbations.
These studies provided real-world evidence on the comparative benefits of SGLT2i over DPP4i, and filled the potential research gaps regarding extra renal and respiratory effects of SGLT2i. These results would have clinical significance in changing the use of SGLT2i among patients with type 2 diabetes. However, due to the observational nature of these studies, they are prone to residual or unmeasured confounding. Further pooled analyses of similar studies from different populations and subgroups are warranted.2023-01-01T00:00:00ZReal-world effectiveness beyond symptom control and safety of methylphenidate for attention deficit hyperactivity disorderGao, Le高樂http://hdl.handle.net/10722/3366442024-02-26T08:30:57Z2023-01-01T00:00:00ZTitle: Real-world effectiveness beyond symptom control and safety of methylphenidate for attention deficit hyperactivity disorder
Authors: Gao, Le; 高樂
Abstract: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 2–7% of children worldwide. However, despite ADHD being a multifactorial disease and many studies have explored it using either self-report in cohorts or medical information in electronic health records (EHRs), very little research has linked these data sources for a more comprehensive understanding of the long-term progression and treatment outcome of ADHD. Methylphenidate is the most commonly prescribed drug for ADHD in many countries including Hong Kong, with the usage rising over the past 20 years. Although methylphenidate has demonstrated acceptable effectiveness and safety in clinical trials, evidence is still lacking on how well it works beyond symptom control to prevent physical abuse and all-cause poisoning, or how safe it is in terms of drug poisoning and fracture risk in real-world settings.
Therefore, this thesis presents five objectives to fill the aforementioned research gaps: (1) to investigate the feasibility of linking cohorts with EHRs; (2) to examine the preventive effect of methylphenidate against physical abuse; (3) to assess the association between methylphenidate and all-cause poisoning; (4) to describe ADHD drug poisoning cases and explore its correlation with the prescription trend; and (5) to investigate the fracture risk mediated by methylphenidate.
The data used included EHRs, two cohorts – ‘Children of 1997’ birth cohort and the Chinese Early Development Instrument cohort, and poisoning records in Hong Kong. The findings indicated that (1) the use of date of birth and sex is feasible and highly accurate when linking cohorts with EHRs, with some discrepancies found in ADHD between reported symptoms from cohort and clinical information from EHRs; (2) the risk of physical abuse was observed to be higher 90 days before the commencement of methylphenidate, decreased to baseline level 90 days after treatment initiation, and continued to decline throughout the subsequent treatment period, suggesting that such treatment may be associated with a reduced risk of being physically abused; (3) the risk of all-cause poisoning was highest during the period around methylphenidate initiation and decreased in subsequent treatment period, showing that long-term methylphenidate use may be associated with a lower risk of all-cause poisoning; (4) despite there were a few ADHD drug poisoning incidents between 2009 and 2019 in Hong Kong and no significant correlation with the prescribing trend, the management and safe storage of ADHD medications should nevertheless be emphasised; (5) and there was a lower fracture risk associated with methylphenidate treatment compared to non-medicated individuals from the systematic review, and the within-individual comparison showed that the risk was lowered by 32–41% during the treated period versus the pre-treatment period, suggesting that the effectiveness on the protection against traumatic injuries may outweigh the potential fracture risk that may be mediated by methylphenidate.
This research provided a feasible linking method and a linked database for future studies and demonstrated that methylphenidate is effective in preventing physical abuse and all-cause poisoning, with fewer safety issues on drug poisoning and fracture, which may provide more evidence for the treatment choices in clinical practice.2023-01-01T00:00:00Z