METHODS: We conducted a two-stage time-stratified case-crossover study to examine the association between temperature and under-five mortality, spanning the period from 2014 to 2018 across all six regions in Malaysia. In the first stage, we estimated region-specific temperature-mortality associations using a conditional Poisson regression and distributed lag nonlinear models. We used a multivariate meta-regression model to pool the region-specific estimates and examine the potential role of local characteristics in the association, which includes geographical information, demographics, socioeconomic status, long-term temperature metrics, and healthcare access by region.
RESULTS: Temperature in Malaysia ranged from 22 °C to 31 °C, with a mean of 27.6 °C. No clear seasonality was observed in under-five mortality. We found no strong evidence of the association between temperature and under-five mortality, with an "M-" shaped exposure-response curve. The minimum mortality temperature (MMT) was identified at 27.1 °C. Among several local characteristics, only education level and hospital bed rates reduced the residual heterogeneity in the association. However, effect modification by these variables were not significant.
CONCLUSION: This study suggests a null association between temperature and under-five mortality in Malaysia, which has a tropical climate. The "M-" shaped pattern suggests that under-fives may be vulnerable to temperature changes, even with a small temperature change in reference to the MMT. However, the weak risks with a large uncertainty at extreme temperatures remained inconclusive. Potential roles of education level and hospital bed rate were statistically inconclusive.
METHODS: siRNA was conjugated with a thermo-responsive copolymer that was synthesized by copolymerization of N-isopropylacrylamide (NIPAAm) and hydrophilic N,N-dimethylacrylamide (DMAA) to permit thermally controlled interaction between siRNA and an intracellular gene silencing-related protein by utilizing the coil-to-globule phase transition of the copolymer. The composition of the copolymer was fine-tuned to obtain lower critical solution temperature (LCST) around body temperature, and the phase transition behavior was evaluated. The cellular uptake and gene silencing efficiency of the copolymer-siRNA conjugates were then investigated in cultured cells.
RESULTS: The siRNA conjugated with the copolymer with LCST of 38.0°C exhibited ~ 11.5 nm of the hydrodynamic diameter at 37°C and ~ 9.8 nm of the diameter at 41°C, indicating the coil-globule transition above the LCST. In line with this LCST behavior, its cellular uptake and gene silencing efficiency were enhanced when the temperature was increased from 37°C to 41°C.
CONCLUSION: By fine-tuning the LCST behavior of the copolymer that was conjugated with siRNA, siRNA activity could be controlled in a thermo-responsive manner around the body temperature. This technique may offer a promising approach to induce therapeutic effects of siRNA selectively in the target site even in the in vivo conditions.