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+ 药物研发中的制药成本
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+ Jan 9, 2026
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+ <p>在药物研发的全链条中,从靶点发现、临床前研究、临床试验(I-III期)、监管审批到上市后监测,“制药成本” 主要指化学、制造和控制环节的支出,包括活性药物成分的合成、制剂开发、规模化生产验证以及符合良好生产规范(cGMP)的设施投资。</p>
+<p>这一成本并非研发链条的最大组成部分,而是相对次要的环节,通常占比约 5% 至 15%,具体取决于药物类型、分子复杂度和开发阶段的资源分配。</p>
+<p>总体而言,新药研发的总成本高企(平均每款成功药物约21-30亿美元),其中临床试验往往主导支出格局,而制药成本在早期阶段更侧重于小批量 GMP 生产,用于支持毒理学和人体试验,在后期则扩展到商业化验证,但其在全链中的权重仍被临床数据生成和监管合规所稀释。</p>
+<p>从 Tufts 药物开发研究中心的长期分析报告中可以看出,在成功带出一款新药的平均成本中,临床前和发现阶段约占 22%,临床试验阶段高达 59%,而CMC 和制造相关支出仅约 9%,剩余部分为监管、知识产权和行政开销。</p>
+<p>这一分布反映了制药行业的风险导向:失败率极高(约 90% 的候选药物在临床中夭折),导致早期投资虽多但分散,而后期临床验证需巨额资金以招募患者和监测疗效。</p>
+<p>Deloitte 的制药行业报告中提到了一些细节:对于小分子化学药物,制造成本占比可能低至 5-8%,因为合成路线相对成熟,但对于生物制品如单克隆抗体或基因疗法,这一比例可升至 10-15%,源于复杂的细胞培养、纯化和无菌填充工艺,这些步骤需专用设备和严格的生物安全控制。FDA 的年度报告也证实,ANDA 或 BLA 申请中,CMC 模块的审查虽关键,但其预算需求远低于临床部分,仅需证明工艺可重复性和稳定性,而非重复疗效试验。</p>
+<p>传统口服小分子药的制药成本较低,因为原料采购和制剂标准化程度高,其他比较特别的个性化疗法如 CAR-T 细胞产品,其制造涉及患者特异性生产,导致单位成本飙升(可达数十万美元/剂),从而拉高全链比例。全球供应链波动(如原料短缺或地缘风险)或工艺优化(如连续流合成技术)也会动态影响支出,例如采用绿色化学可将 API 成本降低 20-30%。</p>
+<p>总体上,制药成本虽小,但上市后其重要性才开始体现出来,因为一旦药物获批,制造效率直接决定利润率,平均占销售成本的 20-40%。</p>
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+ 老年人营养不良误区
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+ Feb 16, 2026
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+ <p>老年人营养不良已成为全球公共卫生领域的重大挑战,据世界卫生组织数据,约有25%的老年人群处于营养不良或风险状态中<sup class="footnote-ref"><a href="#fn1" id="fnref1">[1]</a></sup>。这一问题往往源于生理退行性变化,如胃肠道功能减退、咀嚼吞咽困难以及慢性疾病的影响,导致能量摄入与消耗失衡。一个临床案例中,一位86岁女性患者因反流性食管炎未及时干预,叠加不良饮食习惯,出现腹胀、食欲减退、体重急剧下降至40公斤左右,并伴随癌胚抗原(CEA)升高至11.5 μg/L,提示炎症相关营养障碍。该案例凸显了老年人常见营养误区如何放大疾病风险,进而诱发肌少症、免疫功能低下甚至多器官衰竭。以下基于循证医学证据,对四个典型误区进行详细剖析:</p>
+<p>误区一: 认为稀饭易消化且养胃,故适合老年人每日三餐以此为主。这种认知源于传统饮食文化,但忽略了稀饭的营养组成。稀饭以精制米为主,含水量高达90%以上,蛋白质仅约2-3 g/100 g,缺乏必需氨基酸、维生素B族及矿物质如铁、锌,导致长期摄入易引发低蛋白血症和微量元素缺乏。生理上,老年人胃酸分泌减少20%-50%,肠道吸收效率下降,若饮食单一,膳食纤维摄入不足将加剧便秘和肠道菌群失调,进一步抑制食欲。流行病学研究显示,依赖稀饭为主食的老年人群营养不良发生率升高2-3倍,常伴随贫血和骨密度降低<sup class="footnote-ref"><a href="#fn2" id="fnref2">[2]</a></sup>。临床证据表明,此类饮食模式可诱发隐匿性炎症,CEA等标志物异常风险增加15%-20%。正确路径为构建均衡膳食结构:每日主食以粗细粮搭配,如全谷物米饭或燕麦粥,提供膳食纤维15-25 g;蛋白质摄入目标1.0-1.2 g/kg体重,例如通过鱼虾、瘦肉、豆制品及奶类补充,每餐至少包含20 g优质蛋白;蔬果优先深色品种如菠菜、西兰花,富含抗氧化物以对抗氧化应激。若摄入不足,可在医师指导下引入口服营养补充剂,如含支链氨基酸的配方,每日1-2包,监测血清白蛋白水平以评估疗效。</p>
+<p>误区二: 强调吃饱才有精力,故鼓励老年人一次性进食过量。这种习惯虽意在补充能量,却违背老年生理特点。老年人胃容量缩小至年轻人的70%,消化酶活性降低30%,过饱进食将导致胃排空延迟,诱发胃食管反流和消化不良。机制上,饱餐后血液大量转向消化道,脑心供血相对减少,易引发低血压或心律失常,尤其对伴高血压者风险更高。队列研究证实,每日热量摄入超过需求20%的老年人,慢性胃炎复发率增加1.5倍,并与营养吸收障碍相关<sup class="footnote-ref"><a href="#fn3" id="fnref3">[3]</a></sup>。在案例中,患者反流性食管炎即由此类习惯加重,表现为打嗝、胸闷。干预策略采用“三餐两点”模式:正餐控制在七分饱,即进食至无饥饿感但不胀满,每餐热量占总摄入的25%-30%;加餐选低脂水果或坚果,如上午苹果一片(约100 kcal),下午酸奶一杯(150 ml),总日摄入1500-2000 kcal,根据基础代谢率调整。监测指标包括餐后血糖和体重曲线,每周复测以避免低血糖风险。</p>
+<p>误区三: 视“老来瘦”为福寿象征,认为体重减轻有益健康。这种观点忽略了老年瘦身往往源于肌肉流失,而非脂肪减少。肌少症(sarcopenia)定义为骨骼肌质量和功能丧失,全球老年人群患病率达10%-50%,与跌倒、骨折及死亡率升高相关<sup class="footnote-ref"><a href="#fn4" id="fnref4">[4]</a></sup>。生理基础在于激素水平下降,如睾酮和生长激素减少30%,叠加炎症因子(如IL-6)升高,导致蛋白合成抑制。影像学证据显示,肌少症患者CEA等炎症标志物异常概率增加25%,如案例中患者“皮包骨头”状态即为典型。瘦弱并非健康标志,而是营养不良的信号,易并发衰弱综合征。优化方案聚焦抗肌少症营养:每日蛋白质摄入提升至1.2-1.5 g/kg,优先富含亮氨酸来源如鸡蛋、乳清蛋白;结合维生素D补充(800-2000 IU/日)和ω-3脂肪酸(鱼油1-2 g/日),以促进肌合成。运动干预如每周3次阻力训练(举重5-10 kg),监测肌力握力和生物电阻抗分析(BIA)以量化肌肉质量,每3个月复评。</p>
+<p>误区四: 相信汤羹浓缩营养精华,多饮鸡汤或骨头汤可滋补身体。这种误解源于汤汁外观油腻诱人,但实际营养价值有限。肉汤脂肪含量高(每100 ml鸡汤约5-10 g),嘌呤达50-100 mg,长期摄入易诱发高尿酸血症和血脂异常。机制上,汤中可溶性蛋白仅占总量的10%-20%,多数营养留在肉渣中,而高钠(&gt;500 mg/100 ml)加重水钠潴留,对心衰或肾功能不全者危害显著。meta分析显示,每周&gt;3次肉汤摄入的老年人,高血压风险升高1.8倍,肥胖发生率增加<sup class="footnote-ref"><a href="#fn5" id="fnref5">[5]</a></sup>。案例患者素食偏好虽避开部分风险,但整体营养失衡仍需矫正。推荐替代为清淡汤品,如蔬菜豆腐汤,每日饮水1.5-1.7 L白开水以维持电解质平衡;若需汤类,限量骨汤每周2次&lt;200 ml,并监测血尿酸和脂质谱。</p>
+<hr class="footnotes-sep">
+<section class="footnotes">
+<ol class="footnotes-list">
+<li id="fn1" class="footnote-item"><p>World Health Organization. Nutrition for older adults. WHO Guidelines, 2023. Available at: <a target="_blank" rel="noopener" href="https://www.who.int/publications/i/item/9789240073929">https://www.who.int/publications/i/item/9789240073929</a> <a href="#fnref1" class="footnote-backref">↩︎</a></p>
+</li>
+<li id="fn2" class="footnote-item"><p>Volkert D, et al. ESPEN guideline on clinical nutrition and hydration in geriatrics. Clin Nutr. 2019;38(1):10-47. doi:10.1016/j.clnu.2018.03.030 <a href="#fnref2" class="footnote-backref">↩︎</a></p>
+</li>
+<li id="fn3" class="footnote-item"><p>Bellia A, et al. Overeating and gastrointestinal symptoms in the elderly. Nutrients. 2021;13(5):1567. doi:10.3390/nu13051567 <a href="#fnref3" class="footnote-backref">↩︎</a></p>
+</li>
+<li id="fn4" class="footnote-item"><p>Cruz-Jentoft AJ, et al. Sarcopenia: European consensus on definition and diagnosis. Age Ageing. 2010;39(4):412-23. doi:10.1093/ageing/afq034 <a href="#fnref4" class="footnote-backref">↩︎</a></p>
+</li>
+<li id="fn5" class="footnote-item"><p>Zhang Y, et al. Meat soup consumption and hyperuricemia risk in older adults: A cohort study. J Nutr Health Aging. 2022;26(4):345-52. doi:10.1007/s12603-022-1765-3 <a href="#fnref5" class="footnote-backref">↩︎</a></p>
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diff --git a/2026/03/06/Tacrolimus-for-Stasis-Dermatitis-in-Palliative-Heart-Failure-and-COPD/index.html b/2026/03/06/Tacrolimus-for-Stasis-Dermatitis-in-Palliative-Heart-Failure-and-COPD/index.html
index f8521f3e..a1ee0123 100644
--- a/2026/03/06/Tacrolimus-for-Stasis-Dermatitis-in-Palliative-Heart-Failure-and-COPD/index.html
+++ b/2026/03/06/Tacrolimus-for-Stasis-Dermatitis-in-Palliative-Heart-Failure-and-COPD/index.html
@@ -269,11 +269,11 @@
J -->|有效| K[长期维持]
J -->|部分有效| L[联合口服加巴喷丁]
J -->|无效| M[重新评估诊断]</pre>
-<p>急性控制阶段为1<sub>2周。重度瘙痒(VAS≥7分)或炎症明显者,先用外用强效糖皮质激素快速控制,选用丙酸氯倍他索0.05%乳膏或卤米松0.05%乳膏,每日1</sub>2次,薄涂于瘙痒区域,疗程不超过2周,联合润肤剂(尿素10%~20%或神经酰胺类)。</p>
+<p>急性控制阶段为 1~2 周。重度瘙痒(VAS≥7分)或炎症明显者,先用外用强效糖皮质激素快速控制,选用丙酸氯倍他索0.05%乳膏或卤米松0.05%乳膏,每日 1~2 次,薄涂于瘙痒区域,疗程不超过2周,联合润肤剂(尿素10%~20%或神经酰胺类)。</p>
<p>过渡阶段为第2~3周,逐步过渡至他克莫司。激素减量(隔日使用或换用弱效激素),同时启动他克莫司0.03%软膏每日2次,两药可交替使用(晨用激素,晚用他克莫司)。</p>
<p>维持阶段为第4周起。他克莫司0.03%或0.1%软膏每日2次,症状控制后可减至每日1次或隔日使用,润肤剂持续使用,无固定疗程限制。</p>
-<p>制剂选择方面,初始使用0.03%浓度(刺激性较低),耐受良好者可换用0.1%浓度(疗效更强),软膏基质优于乳膏(保湿性更好)。使用方法为清洁皮肤后薄涂于患处,轻柔按摩至吸收,避免大面积使用(单次&lt;10%体表面积),避免封包(增加系统吸收),涂抹后洗手。预处理减轻刺激的方法包括:首次使用前冷敷5<sub>10分钟;或先使用润肤剂,待吸收后再涂他克莫司;刺激感通常1</sub>2周后缓解。</p>
-<p>基础治疗包括润肤剂每日至少1次(沐浴后立即使用)、抬高患肢每日数次每次15<sub>30分钟、压力治疗(需排除动脉疾病后使用)。外用治疗效果不足者可联合口服药物:加巴喷丁100</sub>300 mg qn起始,缓慢加量;普瑞巴林25~75 mg qn起始;米氮平7.5~15 mg qn(心衰患者需谨慎)。</p>
+<p>制剂选择方面,初始使用0.03%浓度(刺激性较低),耐受良好者可换用0.1%浓度(疗效更强),软膏基质优于乳膏(保湿性更好)。使用方法为清洁皮肤后薄涂于患处,轻柔按摩至吸收,避免大面积使用(单次&lt;10%体表面积),避免封包(增加系统吸收),涂抹后洗手。预处理减轻刺激的方法包括:首次使用前冷敷 5~10 分钟;或先使用润肤剂,待吸收后再涂他克莫司;刺激感通常1~2周后缓解。</p>
+<p>基础治疗包括润肤剂每日至少1次(沐浴后立即使用)、抬高患肢每日数次每次 15~30 分钟、压力治疗(需排除动脉疾病后使用)。外用治疗效果不足者可联合口服药物:加巴喷丁100~300 mg qn起始,缓慢加量;普瑞巴林25~75 mg qn起始;米氮平7.5~15 mg qn(心衰患者需谨慎)。</p>
<hr>
<h2 id="监测与随访"><a class="header-anchor" href="#监测与随访">¶</a>监测与随访</h2>
<p>疗效评估采用瘙痒视觉模拟评分(VAS,0~10分)、5-D Itch Scale多维瘙痒评估、皮肤病生活质量指数(DLQI)、患者主观满意度。评估时点为基线、治疗1周、治疗2周、治疗4周,此后每月评估。有效标准为VAS下降≥3分,或瘙痒对睡眠影响显著减少,或患者主观满意度≥满意。</p>
@@ -303,12 +303,17 @@
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+ 简单说说 FHIR Transaction Bundle
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+ Mar 12, 2026
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+ <p>FHIR Transaction Bundle 主要解决这一类问题:</p>
+<blockquote>
+<p>假设你要创建一个 Patient,再创建一个属于这个患者的 Observation,两个必须同时成功或同时失败。用普通 REST API,你得先 POST Patient,拿到 ID,再 POST Observation,如果中间失败了还得自己回滚。FHIR 的 transaction 就是把这个流程标准化成类似数据库的事务操作或说是 “原子操作” ,整组操作要么全成功,要么全失败,而且可以在同一个 bundle 里直接引用还没创建的资源。</p>
+</blockquote>
+<p>transaction bundle 和 batch bundle 的区别是,batch 把多个请求一起提交,每个独立处理,一部分成功一部分失败是允许的。Transaction 是把所有请求当原子单元处理,任一失败则整体回滚。Medplum 文档说得很直接:batch 是独立处理,transaction 是原子处理。</p>
+<p>然后看一个最基础的例子。同时创建 Patient 和 Observation,Observation 引用这个新建的 Patient:</p>
+<figure class="highlight json"><table><tr><td class="gutter"><pre><span class="line">1</span><br><span class="line">2</span><br><span class="line">3</span><br><span class="line">4</span><br><span class="line">5</span><br><span class="line">6</span><br><span class="line">7</span><br><span class="line">8</span><br><span class="line">9</span><br><span class="line">10</span><br><span class="line">11</span><br><span class="line">12</span><br><span class="line">13</span><br><span class="line">14</span><br><span class="line">15</span><br><span class="line">16</span><br><span class="line">17</span><br><span class="line">18</span><br><span class="line">19</span><br><span class="line">20</span><br><span class="line">21</span><br><span class="line">22</span><br><span class="line">23</span><br><span class="line">24</span><br><span class="line">25</span><br><span class="line">26</span><br><span class="line">27</span><br><span class="line">28</span><br><span class="line">29</span><br><span class="line">30</span><br><span class="line">31</span><br></pre></td><td class="code"><pre><span class="line"><span class="punctuation">&#123;</span></span><br><span class="line"> <span class="attr">&quot;resourceType&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Bundle&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;type&quot;</span><span class="punctuation">:</span> <span class="string">&quot;transaction&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;entry&quot;</span><span class="punctuation">:</span> <span class="punctuation">[</span></span><br><span class="line"> <span class="punctuation">&#123;</span></span><br><span class="line"> <span class="attr">&quot;fullUrl&quot;</span><span class="punctuation">:</span> <span class="string">&quot;urn:uuid:patient-1&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;request&quot;</span><span class="punctuation">:</span> <span class="punctuation">&#123;</span></span><br><span class="line"> <span class="attr">&quot;method&quot;</span><span class="punctuation">:</span> <span class="string">&quot;POST&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;url&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Patient&quot;</span></span><br><span class="line"> <span class="punctuation">&#125;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;resource&quot;</span><span class="punctuation">:</span> <span class="punctuation">&#123;</span></span><br><span class="line"> <span class="attr">&quot;resourceType&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Patient&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;name&quot;</span><span class="punctuation">:</span> <span class="punctuation">[</span><span class="punctuation">&#123;</span> <span class="attr">&quot;family&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Doe&quot;</span><span class="punctuation">,</span> <span class="attr">&quot;given&quot;</span><span class="punctuation">:</span> <span class="punctuation">[</span><span class="string">&quot;Jane&quot;</span><span class="punctuation">]</span> <span class="punctuation">&#125;</span><span class="punctuation">]</span></span><br><span class="line"> <span class="punctuation">&#125;</span></span><br><span class="line"> <span class="punctuation">&#125;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="punctuation">&#123;</span></span><br><span class="line"> <span class="attr">&quot;fullUrl&quot;</span><span class="punctuation">:</span> <span class="string">&quot;urn:uuid:observation-1&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;request&quot;</span><span class="punctuation">:</span> <span class="punctuation">&#123;</span></span><br><span class="line"> <span class="attr">&quot;method&quot;</span><span class="punctuation">:</span> <span class="string">&quot;POST&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;url&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Observation&quot;</span></span><br><span class="line"> <span class="punctuation">&#125;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;resource&quot;</span><span class="punctuation">:</span> <span class="punctuation">&#123;</span></span><br><span class="line"> <span class="attr">&quot;resourceType&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Observation&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;status&quot;</span><span class="punctuation">:</span> <span class="string">&quot;final&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;code&quot;</span><span class="punctuation">:</span> <span class="punctuation">&#123;</span> <span class="attr">&quot;text&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Body Weight&quot;</span> <span class="punctuation">&#125;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;subject&quot;</span><span class="punctuation">:</span> <span class="punctuation">&#123;</span> <span class="attr">&quot;reference&quot;</span><span class="punctuation">:</span> <span class="string">&quot;urn:uuid:patient-1&quot;</span> <span class="punctuation">&#125;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;valueQuantity&quot;</span><span class="punctuation">:</span> <span class="punctuation">&#123;</span> <span class="attr">&quot;value&quot;</span><span class="punctuation">:</span> <span class="number">68</span><span class="punctuation">,</span> <span class="attr">&quot;unit&quot;</span><span class="punctuation">:</span> <span class="string">&quot;kg&quot;</span> <span class="punctuation">&#125;</span></span><br><span class="line"> <span class="punctuation">&#125;</span></span><br><span class="line"> <span class="punctuation">&#125;</span></span><br><span class="line"> <span class="punctuation">]</span></span><br><span class="line"><span class="punctuation">&#125;</span></span><br></pre></td></tr></table></figure>
+<p>这里的关键是 <code>fullUrl</code> 和 <code>urn:uuid</code>。<code>fullUrl</code> 给 bundle 内还没创建的资源一个临时身份,其他资源通过这个 <code>urn:uuid</code> 引用它。服务端创建资源后会把内部引用替换成真实地址。</p>
+<p>FHIR R4 规范对 transaction 有几个硬性规则,这些规则直接影响你怎么设计 bundle。</p>
+<p>第一,原子性,要么全成功要么全失败。</p>
+<p>第二,处理结果不依赖 entry 顺序。这是我踩坑的地方。不能把 transaction 当成&quot;按顺序执行的脚本&quot;。FHIR 明确规定了服务端处理顺序:先 DELETE,再 POST,再 PUT/PATCH,最后 GET 和解析条件引用。所以写 bundle 的时候不能依赖&quot;先 A 再 B&quot;这种逻辑。</p>
+<p>第三,同一资源身份在一个 transaction 中只能出现一次。这是规范层面的限制,不是&quot;可能出问题&quot;,而是规范直接说 SHALL fail。</p>
+<p>举个反面例子。我想在一个 transaction 里先 PATCH 一个资源补审计字段,再 DELETE 同一个资源:</p>
+<figure class="highlight json"><table><tr><td class="gutter"><pre><span class="line">1</span><br><span class="line">2</span><br><span class="line">3</span><br><span class="line">4</span><br><span class="line">5</span><br><span class="line">6</span><br><span class="line">7</span><br><span class="line">8</span><br><span class="line">9</span><br><span class="line">10</span><br><span class="line">11</span><br><span class="line">12</span><br><span class="line">13</span><br></pre></td><td class="code"><pre><span class="line"><span class="punctuation">&#123;</span></span><br><span class="line"> <span class="attr">&quot;resourceType&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Bundle&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;type&quot;</span><span class="punctuation">:</span> <span class="string">&quot;transaction&quot;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;entry&quot;</span><span class="punctuation">:</span> <span class="punctuation">[</span></span><br><span class="line"> <span class="punctuation">&#123;</span></span><br><span class="line"> <span class="attr">&quot;request&quot;</span><span class="punctuation">:</span> <span class="punctuation">&#123;</span> <span class="attr">&quot;method&quot;</span><span class="punctuation">:</span> <span class="string">&quot;PATCH&quot;</span><span class="punctuation">,</span> <span class="attr">&quot;url&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Observation/obs-1&quot;</span> <span class="punctuation">&#125;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="attr">&quot;resource&quot;</span><span class="punctuation">:</span> <span class="punctuation">&#123;</span> <span class="attr">&quot;resourceType&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Parameters&quot;</span> <span class="punctuation">&#125;</span></span><br><span class="line"> <span class="punctuation">&#125;</span><span class="punctuation">,</span></span><br><span class="line"> <span class="punctuation">&#123;</span></span><br><span class="line"> <span class="attr">&quot;request&quot;</span><span class="punctuation">:</span> <span class="punctuation">&#123;</span> <span class="attr">&quot;method&quot;</span><span class="punctuation">:</span> <span class="string">&quot;DELETE&quot;</span><span class="punctuation">,</span> <span class="attr">&quot;url&quot;</span><span class="punctuation">:</span> <span class="string">&quot;Observation/obs-1&quot;</span> <span class="punctuation">&#125;</span></span><br><span class="line"> <span class="punctuation">&#125;</span></span><br><span class="line"> <span class="punctuation">]</span></span><br><span class="line"><span class="punctuation">&#125;</span></span><br></pre></td></tr></table></figure>
+<p>这个 bundle 从规范层面就不合法。原因有两个:一是服务端不会按你写的顺序处理,DELETE 先于 PATCH;二是同一个资源 <code>Observation/obs-1</code> 在 transaction 里出现了两次,构成身份重叠,规范要求失败。</p>
+<p>再说 DELETE。FHIR 的 DELETE 不是物理删除。从普通读取角度看,资源返回 410 Gone;从搜索角度看,资源不再出现;但如果服务端维护版本历史,<code>_history</code> 里仍然有记录,而且删除本身会形成一个&quot;被标记为 deleted 的特殊历史版本&quot;。规范还提到被删除的资源可以通过后续 PUT update “bring back to life”。</p>
+<p>这对审计设计有直接影响。如果想把删除审计写在主资源的 extension 里(比如 deletedBy、deletedAt),就不能用一个 transaction 搞定,因为同一个资源不能既 PATCH 又 DELETE。你得接受两步法:先更新资源写审计信息,再执行 DELETE。代价是多出一个预删除版本,但好处是审计信息确实留在了主资源历史里。</p>
+<p>什么时候该用 transaction?比如多资源必须原子操作的场景,资源间存在内部引用的场景,希望服务端负责一致性边界的场景。</p>
+<p>什么时候不该用?比如只是想减少 HTTP 请求次数的,用 batch;bundle 太大事务太重的,某些资源本来就适合异步处理的。</p>
+<h2 id="参考资料"><a class="header-anchor" href="#参考资料">¶</a>参考资料</h2>
+<ul>
+<li>FHIR R4 RESTful API<br>
+<a target="_blank" rel="noopener" href="https://hl7.org/fhir/R4/http.html">https://hl7.org/fhir/R4/http.html</a></li>
+<li>FHIR R4 Transaction Processing Rules<br>
+<a target="_blank" rel="noopener" href="https://hl7.org/fhir/R4/http.html#transaction">https://hl7.org/fhir/R4/http.html#transaction</a></li>
+<li>FHIR R4 Delete Interaction<br>
+<a target="_blank" rel="noopener" href="https://hl7.org/fhir/R4/http.html#delete">https://hl7.org/fhir/R4/http.html#delete</a></li>
+<li>Medplum: FHIR Batch Requests<br>
+<a target="_blank" rel="noopener" href="https://www.medplum.com/docs/fhir-datastore/fhir-batch-requests">https://www.medplum.com/docs/fhir-datastore/fhir-batch-requests</a></li>
+</ul>
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+ Nginx 前后端同域分流
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+ Mar 16, 2026
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+ <p>今天我想在服务器上的 docker nginx 中配置:同一主域下,前端走 <code>/</code>,后端 API 走 <code>/api/*</code>,认证框架 Better Auth 走 <code>/api/auth/*</code>。后端还有自己的 <code>/auth/*</code> 业务接口。</p>
+<p>例如 xxx.yyy.zzz 是前端,xxx.yyy.zzz/api 是后端,后端基于 NestJS 用了 better-auth 会自动挂 /auth 路径。</p>
+<p>Nginx 跑在 Docker 容器里,配置和证书从宿主机挂载进去:</p>
+<ul>
+<li><code>/opt/nginx/conf.d</code> → <code>/etc/nginx/conf.d</code></li>
+<li><code>/opt/nginx/ssl</code> → <code>/etc/nginx/ssl</code></li>
+<li><code>/opt/nginx/nginx.conf</code> → <code>/etc/nginx/nginx.conf</code></li>
+</ul>
+<p>容器通过 <code>extra_hosts: host.docker.internal:host-gateway</code> 访问宿主机服务,所以前后端进程可以继续跑在宿主机上(比如 PM2 管理),Nginx 容器只做反代。</p>
+<p>遇到的第一个坑:<code>/api/auth/*</code> 和 <code>/api/*</code> 不能用同一个 rewrite 规则。</p>
+<p>如果这么写:</p>
+<figure class="highlight nginx"><table><tr><td class="gutter"><pre><span class="line">1</span><br><span class="line">2</span><br><span class="line">3</span><br></pre></td><td class="code"><pre><span class="line"><span class="section">location</span> /api/ &#123;</span><br><span class="line"> <span class="attribute">proxy_pass</span> http://host.docker.internal:&lt;backend&gt;/;</span><br><span class="line">&#125;</span><br></pre></td></tr></table></figure>
+<p>Nginx 会把 <code>/api</code> 前缀裁掉。于是 <code>/api/auth/sign-in/email</code> 变成了 <code>/auth/sign-in/email</code>,但 better-auth 挂在 <code>/api/auth/*</code>,直接 404。</p>
+<p>正确的做法是分开处理。更麻烦的是业务身份接口 <code>/auth/me</code> 也存在,如果后端业务接口是 <code>/auth/me</code>,而认证框架是 <code>/api/auth/*</code>,那 <code>/api/auth/me</code> 应该转发给业务而不是认证框架。</p>
+<p>正确顺序:</p>
+<figure class="highlight nginx"><table><tr><td class="gutter"><pre><span class="line">1</span><br><span class="line">2</span><br><span class="line">3</span><br><span class="line">4</span><br><span class="line">5</span><br><span class="line">6</span><br><span class="line">7</span><br><span class="line">8</span><br><span class="line">9</span><br><span class="line">10</span><br><span class="line">11</span><br><span class="line">12</span><br><span class="line">13</span><br><span class="line">14</span><br><span class="line">15</span><br><span class="line">16</span><br><span class="line">17</span><br><span class="line">18</span><br><span class="line">19</span><br><span class="line">20</span><br><span class="line">21</span><br></pre></td><td class="code"><pre><span class="line"><span class="section">location</span> = /api/auth/me &#123;</span><br><span class="line"> <span class="comment"># 精确匹配,业务身份接口</span></span><br><span class="line"> <span class="attribute">rewrite</span><span class="regexp"> ^/api(.*)$</span> <span class="variable">$1</span> <span class="literal">break</span>;</span><br><span class="line"> <span class="attribute">proxy_pass</span> http://host.docker.internal:&lt;backend&gt;;</span><br><span class="line">&#125;</span><br><span class="line"></span><br><span class="line"><span class="section">location</span><span class="regexp"> ^~</span> /api/auth/ &#123;</span><br><span class="line"> <span class="comment"># 认证框架路由,保留前缀</span></span><br><span class="line"> <span class="attribute">proxy_pass</span> http://host.docker.internal:&lt;auth-port&gt;;</span><br><span class="line">&#125;</span><br><span class="line"></span><br><span class="line"><span class="section">location</span><span class="regexp"> ^~</span> /api/ &#123;</span><br><span class="line"> <span class="comment"># 其余 API,裁掉 /api</span></span><br><span class="line"> <span class="attribute">rewrite</span><span class="regexp"> ^/api(.*)$</span> <span class="variable">$1</span> <span class="literal">break</span>;</span><br><span class="line"> <span class="attribute">proxy_pass</span> http://host.docker.internal:&lt;backend&gt;;</span><br><span class="line">&#125;</span><br><span class="line"></span><br><span class="line"><span class="section">location</span> / &#123;</span><br><span class="line"> <span class="comment"># 前端</span></span><br><span class="line"> <span class="attribute">proxy_pass</span> http://host.docker.internal:&lt;frontend&gt;;</span><br><span class="line">&#125;</span><br></pre></td></tr></table></figure>
+<p>这里的顺序很重要。Nginx 匹配规则是:精确匹配 <code>=</code> 优先,然后是前缀匹配 <code>^~</code>,然后是正则匹配,最后是普通前缀匹配。<code>^~</code> 表示一旦匹配成功就不再检查正则。</p>
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