遠隔教育の実施と大学での教育に関する一考察 ―建学の精神を伝える授業のオンラインでの実施をもとに―

2019年末に端を発した新型コロナ感染症（COVID-19）の拡大によって、多くの大学は2020年度の新学期から遠隔教育の実施に踏み切った。本学においても遠隔教育の採用が決定され、ホスピタリティ概論も IT 機器を活用したオンラインでの実施となった。この中で大学教育の将来像に大きな影響を与えると考えられるオンライン授業の在り方を探る基礎調査を実施した。その結果、次のことが明らかになった。1）受講生の IT 環境の整備には、差がみられること、2）受講生の使用する機器は、パソコン、タブレット、スマートフォンに分かれること、3）オンライン授業に関しては、肯定する意見がある一方、改善を要望する意見も見られること、4）スマートフォンのみでの受講者とパソコンおよびタブレットでの受講者を比較分析した結果、画面の明瞭度や授業の進行、及び授業の理解などにおいて両者に差がみられ、スマートフォンのみでの受講者の方が有意に低い結果であったこと、5）遠隔授業に関する要望等の中には、遠隔教育の利点を述べている受講生の他に、授業以外の大学が持つ機能、つまり、友人獲得や相互啓発に関する不安も多くみられたこと。この結果等を踏まえ、オンライン授業のあり方、及び、将来社会における大学教育のあり方に関する提案を行った

B型肝炎病毒基因體變異在慢性B型肝炎急性發作的角色探討: 一前瞻性全長基因體研究(III)

慢性B 型肝炎急性發作的免疫致病機轉迄今尚未明瞭。病毒株變異或是宿主的免疫反應 改變導致病毒與宿主間的平衡狀態破壞，被認為是引發急性發作最重要的因素，但何者為重 仍有爭論。本研究欲以前瞻性研究及全長基因體分析來探討病毒株變異與慢性B 型肝炎急性 發作的相關性。縱使真正致病機轉仍未明，臨床觀察及動物實驗常發現血清ALT 值升高前會 出現病毒量驟升的現象，若能解開此病毒量驟升之謎，應對B 型肝炎急性發作的致病機轉有 進一步的了解。病毒日產量極高，其複製脢又欠缺校正錯誤的能力，因此極有機會出現病毒 變異株，藉著逃脫宿主免疫能力攻擊或是具有較好的複製能力，使病毒量驟升，進而引發B 型肝炎急性發作。之前許多相關研究並無法得到一致的結論，次基因体的研究策略及欠缺適 當的研究模式為主要因素；更重要的是其採樣進行病毒核酸序列分析的時間點多在急性發作 之中或後，因此無法推測這些病毒核酸變異是否真正引發急性發作，或僅是代表宿主免疫攻 擊後的產物。前瞻性研究及全長基因體分析當可回答此一重要問題。 第一年計劃中，我們已更廣泛地收集14 位自發性或是在醫療介入後發生B 型肝炎急性 發作的病患，我們首先定期分析血清ALT 值和HBV DNA 以釐清血清HBV DNA 和ALT 值 升高的相對應關係。結果相當一致地，在13 位(93%)病患ALT 值升高前都會有病毒量竄升的 現象。為探討病毒發生變異是否引發急性發作，我們特別在急性發作過程中的四個點收集血 清並進行HBV 全長基因体分析: 收錄病患時、血清病毒量增加到最高時、血清ALT 值達最 高時、和急性發作之後。每一病患在不同時間點得到的HBV 全長基因体分別與病患收錄時的 HBV 全長基因体比較並找出變異所在，之後我們與已知病毒免疫反應標的區氨基酸序列相對 比和利用體外短暫轉染法，來進一步探討這些變異可能代表的免疫學或病毒生物學方面的意 義。結果發現在病毒量竄升到最高點時，遑論是發生在急性發作之前或是與急性發作同時發 生，病毒基因體幾乎與病患收錄時的病毒基因體保持一致。在急性發作過程中，體內出現不 同主要病毒基因體的病患比例隨發作進展而逐漸增高：在血清ALT 值升到最高值時其比例為 36%；在急性發作之後，其比例則增高為50%。基因體出現的變異絕大多數是多重核甘酸點 變異或次基因體缺損。我們的結果顯示急性發作與病毒發生變異無關。(Liu CJ et al, Gastroenterology 2004) 就病毒長期演變的觀點來看，為探討急性發作後出現的病毒變異是否真會造成新的急性 發作，我們在第二年計劃中收錄連續發生急性發作的病患及其系列血清，增殖定序其HBV 全 長基因体並加以比對，以釐清此一問題。結果，我們同樣發現在每一次急性發作中臨床出現 肝炎活性之前，病毒基因體幾乎維持不變；而重複發生急性發作的患者在急性發作後會出現 病毒變異株，此病毒變異株與下一次急性發作中竄升的病毒株也不相同。另外，我們利用專 一於病毒變異株的PCR 方法證實下一次急性發作中竄升的病毒株已既存於病人收錄時的病毒 池中。我們的結果支持某些病毒株的任意活化是造成急性發作的機轉之一。最後，真正具致 病性的是肝細胞內的HBV ，而大部份研究僅探討血清中的病毒基因体。為釐清血清中的HBV 是否能代表肝細胞內的HBV ，我們也自相同病患在同一時間取得其肝及血清檢體，進一步比 較二者檢體中病毒基因体的異同。我們發現兩個來源的主要病毒全長基因體以及病毒物種類 似程度大致相同。此一發現意味著血清中的病毒株能代表真正具致病性的肝內病毒株。 第三年計劃中，我們已順利完成上述工作，並特別著重分析急性發作前宿主免疫狀態的 改變。另一方面，肝內及血清中的病毒株皆源自肝細胞核中的cccDNA 。本計畫同時也證實 自肝及血清得到的病毒株等同於cccDNA 。(Liu CJ et al, Hepatology 2004)我們經由此前瞻性全長病毒基因体研究，成功釐清病毒株發生變異並非造成急性發作的 重要因素，此一發現將對慢性B 型肝炎急性發作的免疫致病機轉有重要貢獻。The onset of acute exacerbation (AE) during the course of chronic hepatitis B is likely related to the break of balance between virus and host immune responses. Whether such a break of immune tolerance is triggered major by the changes of host immune status or by an alteration of HBV hepatitis B virus (HBV) genome still remains controversial. To address this issue, a prospective study from silent (asymptomatic) stage to acute exacerbation and a full-length sequencing strategy are needed. Although the underlying mechanism remains unknown, clinical observations and animal studies clearly show that an upsurge of viral load always precedes or sometimes coincides with AE in chronic hepatitis B. Thereby, a key to the understanding of these AEs seems to unravel the origin and identity of such a viral surge. To clarify these issues, in the first year, we have already collected the clinical and serological data from 14 patients who developed acute exacerbation of chronic hepatitis B spontaneously, after discontinuing lamivudine treatment, or during interferon treatment. We first regularly monitored the serum ALT levels and HBV DNA levels during the development of acute exacerbation. Our results consistently showed that serum viral load resurged before the maximal hepatitis activity in 13 (93%). We then performed full-length HBV genome sequencing from the serum samples obtained at 4 points: at enrollment, at the peak of serum viral load, at the peak of serum ALT level, and after acute exacerbation. We found that the viral genome at virologic peak remained almost identical to that at baseline in 12 (86%) of them. On the contrary, the viral genomes obtained after the development of hepatitis exacerbation are different from the corresponding one at baseline in 7 (50%). Our preliminary results suggested that the development of hepatitis B exacerbation was not related to the changes of HBV genome. Nevertheless, from a viral evolution point of view, we need to consider the origin of the HBV strains at baseline. Some viral strains may exist and remain inactive in the host for a long time before reactivation, as is the case of chemotherapy-induced AE. The other baseline viral strains, especially those from repeated spontaneous AE, may just represent survivors from previous episode of AE. These HBV survivors may either be new viral variants selected out from host immune surveillance in previous exacerbation, or they may remain the same strain as prior to preceding AE and again trigger the current episode of exacerbation. Our previous results suggested that the development of hepatitis B exacerbation was not related to the changes of HBV genome. Nevertheless, from a viral evolution point of view, we need to consider the origin of the HBV strains at baseline. Some viral strains may exist and remain inactive in the host for a long time before reactivation, as is the case of chemotherapy-induced AE. The other baseline viral strains, especially those from repeated spontaneous AE, may just represent survivors from previous episode of AE. These HBV survivors may either be new viral variants selected out from host immune surveillance in previous exacerbation, or they may remain the same strain as prior to preceding AE and again trigger the current episode of exacerbation. (Liu CJ et al, Gastroenterology 2003) AE of chronic hepatitis B is usually preceded by re-emergence or increase of HBV in the serum. To investigate their origin, in the second year, we compared the identity of the serum viral genome to that in the liver and in previous AE by full-length sequencing. The full-length viral genome and extent of quasispecies were obtained from serum and liver biopsy specimens at the same time from 9 subjects with hepatitis B exacerbation (group I). Composition of viral quasispecies was compared by the genetic diversity and the average number of nucleotide substitutions within and between different viral sources. Another two patients with repeated AEs (group II) were also enrolled and their serial serum ALT, HBV DNA levels and full-length sequences were determined. In all group I patients, serum viral genome was identical to that in the liver. The genetic diversity and the average number of nucleotide difference were also comparable between serum and liver tissue. In two group II patients, viral variant emerged after previous AE was not identical to that caused subsequent AE. Dominant viral strains for serial AEs in a single patient did not show a sequential evolution, but presented as a horizontal selection of a minor population from the original viral pool. The findings suggested that serum viral strain reflects the intrahepatic one in AE. Random reactivation of the original HBV pool, other than a sequential evolution of one strain, also contributes to the onset of repeated AE. In the third year, the above full-length genomic sequencing and comparison work has been finished. In addition, the serial serum samples have been collected and cytokines/chemokines including Th1 and Th2 cytokines immediately before the onset of hepatitis B exacerbation will be determined to see if certain antiviral host factors become defective before AE. Furthermore, since all serum and intrahepatic HBVs originate from the covalently closed circular DNA (cccDNA) within the nucleus of the infected hepatocyte. We have already compared the nucleotide sequences and genetic complexity among serum viral genome, intra-hepatic one and the cccDNA. (Liu CJ et al, Hepatology 2004) We have provided evidence to clarify whether alteration of viral genome or changes in host cytokine profiles is related to the trigger of AE. Future studies should focus on the host factors dysfunctional before AE and allow active replication of HBV