Mixed effects modelling of excess mortality and COVID-19 lockdowns in Thailand.

Accurate mortality data are critical for understanding the impact of COVID-19 and learning lessons from crisis responses. But published statistics risk misrepresenting deaths due to limited testing, underreporting, and lack of subnational data, especially in developing countries. Thailand experienced four COVID-19 waves between January 2020 and December 2021, and used a color-coded, province-level system for lockdowns. To account for deaths directly and indirectly caused by COVID-19, this paper uses mixed effects modelling to estimate counterfactual deaths for 2020-2021 and construct a monthly time series of provincial excess mortality. A fixed effects negative binomial and mixed effects Poisson model both substantiate other studies' estimates of excess deaths using subnational data for the first time. Then, panel regression methods are used to characterize the correlations among restrictions, mobility, and excess mortality. The regressions show that mobility reductions modestly curbed mortality immediately upon imposition, suggesting that aversion of non-COVID deaths was a major aspect of the lockdowns' effect in Thailand. However, the estimates are imprecise. An auto-regressive distributed lag model suggests that the effect of lockdowns was through reduced mobility, but the effectiveness appears to have varied over the course of the pandemic.

Reducing single-use cutlery with green nudges: Evidence from China's food-delivery industry.

Rising consumer demand for online food delivery has increased the consumption of disposable cutlery, leading to plastic pollution worldwide. In this work, we investigate the impact of green nudges on single-use cutlery consumption in China. In collaboration with Alibaba's food-delivery platform, Eleme (which is similar to Uber Eats and DoorDash), we analyzed detailed customer-level data and found that the green nudges-changing the default to "no cutlery" and rewarding consumers with "green points"-increased the share of no-cutlery orders by 648%. The environmental benefits are sizable: If green nudges were applied to all of China, more than 21.75 billion sets of single-use cutlery could be saved annually, equivalent to preventing the generation of 3.26 million metric tons of plastic waste and saving 5.44 million trees.

Prognostic and Predictive Value of PIK3CA Mutations in Metastatic Colorectal Cancer.

BACKGROUND: Comprehensive genomic profiling is used to guide the management of metastatic colorectal cancer (mCRC); however, the role of PIK3CA mutations, present in up to 20% of mCRCs, is unclear. OBJECTIVE: This study aimed to evaluate the association of PIK3CA mutations with other common mutations in mCRC and determine the prognostic and predictive value of PIK3CA mutations. PATIENTS AND METHODS: A retrospective chart review was performed on patients in the Moffitt Clinical Genomic Database with mCRC. A meta-analysis was performed to further evaluate the predictive value of PIK3CA mutations to the response to anti-epidermal growth factor receptor (EGFR) therapy. RESULTS: Among 639 patients, PIK3CA was positively correlated with KRAS mutation (r = 0.11, p = 0.006) and negatively correlated with TP53 mutation (r = - 0.18, p ≤ 0.001) and ERBB2 amplification (r = - 0.08, p = 0.046). The median overall survival (OS) of patients with PIK3CA-mutant mCRC (n = 49) was 35.5 (95% confidence interval [CI] 18.7-48.1) months vs. 55.3 (95% CI 47.5-65.6) months for PIK3CA wild-type mCRC (n = 286) [p = 0.003]. This OS difference remained significant with exon 9 and exon 20 subset analyses. There was no significant difference in response rate between patients with PIK3CA wild-type (n = 97) versus mutant (n = 9) mCRC who received anti-EGFR therapy (43% vs. 56%, p = 0.61) and no significant difference in median progression-free survival (PFS) of 10.3 versus 7.2 months (p = 0.60). However, our meta-analysis of 12 studies, including ours, using a common effect model identified that PIK3CA mutations are associated with reduced response to anti-EGFR therapy, with a relative risk of 0.56 (95% CI 0.38-0.82). CONCLUSION: Our study identified PIK3CA mutations as a poor prognostic factor, and our meta-analysis identified PIK3CA mutations as predictive of decreased response to anti-EGFR therapy in patients with mCRC.

Copy Number Alterations as Novel Biomarkers and Therapeutic Targets in Colorectal Cancer.

In colorectal cancer, somatic mutations have played an important role as prognostic and predictive biomarkers, with some also functioning as therapeutic targets. Another genetic aberration that has shown significance in colorectal cancer is copy number alterations (CNAs). CNAs occur when a change to the DNA structure propagates gain/amplification or loss/deletion in sections of DNA, which can often lead to changes in protein expression. Multiple techniques have been developed to detect CNAs, including comparative genomic hybridization with microarray, low pass whole genome sequencing, and digital droplet PCR. In this review, we summarize key findings in the literature regarding the role of CNAs in the pathogenesis of colorectal cancer, from adenoma to carcinoma to distant metastasis, and discuss the roles of CNAs as prognostic and predictive biomarkers in colorectal cancer.

Phase 2 study of copanlisib in combination with gemcitabine and cisplatin in advanced biliary tract cancers.

BACKGROUND: Biliary tract cancer (BTC) has a poor prognosis despite treatment with first-line gemcitabine and cisplatin. In BTC, PI3K/AKT pathway activation has been shown to increase resistance to chemotherapy, which may be overcome with PI3K inhibition. This phase 2 study evaluated the safety and efficacy of copanlisib, a PI3K inhibitor, with gemcitabine and cisplatin in advanced BTCs. The role of PTEN expression in outcomes was also explored. METHODS: Patients with advanced/unresectable BTC received gemcitabine, cisplatin, and copanlisib as their first-line treatment. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were the response rate (RR), median overall survival (OS)/PFS, and safety profile. An assessment of PTEN expression by immunohistochemistry was also performed along with molecular profiling. RESULTS: Twenty-four patients received at least 1 dose of the study drug. The PFS rate at 6 months was 51%; the median OS was 13.7 months (95% CI, 6.8-18.0 months), and the median PFS was 6.2 months (95% CI, 2.9-10.1 months). Nineteen patients were evaluable for RR: 6 patients achieved a partial response (31.6%), and 11 (57.9%) had stable disease. The most common grade 3/4 adverse events were a decreased neutrophil count (45.83%), anemia (25%), increased lipase (25%), and hypertension (20.8%). Twenty patients had tissue evaluable for the PTEN status. The PFS for low (n = 9) and high PTEN expression (n = 11) was 8.5 and 4.6 months, respectively (P = .19). The median OS for low and high PTEN expression groups was 17.9 and 7.0 months, respectively (P = .19). CONCLUSIONS: The addition of copanlisib to gemcitabine and cisplatin does not improve PFS at 6 months. However, future studies using PTEN as a potential biomarker should be considered. LAY SUMMARY: The addition of copanlisib, a PI3K inhibitor, to standard chemotherapy for advanced biliary tract cancers was assessed for efficacy and safety. Twenty-four patients with advanced biliary tract cancer received treatment in this study. There was no difference in survival with the addition of copanlisib in comparison with standard chemotherapy. Copanlisib may be more effective and increase survival in patients with low PTEN expression levels. Further studies are needed to confirm this. No unexpected adverse events occurred.

Toxicities of systemic agents in squamous cell carcinoma of the head and neck (SCCHN); A new perspective in the era of immunotherapy.

Squamous cell carcinoma of the head and neck (SCCHN) is a difficult to treat malignancy and represents the seventh most common cancer worldwide. Systemic therapy has a critical role in the treatment of locally advanced and recurrent/metastatic disease. Cytotoxic chemotherapy has been primarily used along with radiation and surgery, with cisplatin being the standard of care choice of therapy. When contraindications to cisplatin exist, other agents such as carboplatin, taxanes, 5-fluorouracil, and cetuximab are used. Similarly, in the advanced or metastatic setting, platinum agents, taxanes and cetuximab have been predominantly utilized. With the recent approval of novel agents such as pembrolizumab and nivolumab, and their distinct toxicity profiles, an understanding of the potential sequelae of the different systemic agents is essential to the careful selection of agents in the advanced disease setting. Going forward, choosing novel agents will be weighed against traditional chemotherapy, and understanding the toxicities at stake is critical in this process. In addition to providing an overview of the toxicity profile of the different systemic agents, we also provide a perspective into the future of SCCHN treatment.

Acute respiratory symptoms in adults in general practice.

BACKGROUND: Community studies have shown that approximately 30% of patients with acute respiratory tract symptoms have no identifiable infective aetiology. This may not be applicable in general practice. OBJECTIVE: The purpose of this study was to determine the infective aetiology in patients who presented to primary care doctors with acute respiratory symptoms. METHODS: A prospective study was carried out in all nine primary care clinics belonging to the National Healthcare Group Polyclinics (NHGPs) in Singapore. The subjects comprised 594 consecutive patients (318 males, 276 females) aged > or = 21 years who presented with complaints of any one of cough, nasal or throat symptoms of <7 days duration. Data collection was through interview using structured questionnaire, physical examination, throat swabs for bacterial culture and nasal swabs for virus identification by immunofluorescence (IF) and polymerase chain reaction (PCR). Additional PCR was performed on a subsample of 100 patients. Patients were followed-up until resolution of symptoms. RESULTS: The aetiological diagnosis by infective agent is as follows: 150 patients (25.2%) had virus infections, of which 90.7% (136/150) were by rhinovirus. Fourteen patients (2.4%) had bacterial infections, of which 10 were due to group G streptococcus. Group A streptococcus was not detected. Nineteen patients with new pathogens were identified by further PCR. These included parainfluenza 4, human coronavirus OC43, adenovirus, enterovirus and Chlamydia pneumoniae. No pathogen could be identified in 49% of patients. There were no differences in clinical presentation and socio-demographic variables between patients who had viral infections and those in whom no pathogen could be identified. CONCLUSION: In about half of patients who presented at NHGPs, no pathogens could be identified even after PCR. A non-infective aetiology could be considered in these patients.