Herpes Zoster

The ZOster ecoNomic Analysis (ZONA) model (Fig. 5) was developed in MS Excel. It is a static multi-cohort Markov model. Cohorts are split into 5 age groups for people aged 50+ years (i.e., 50–59, 60–64, 65–69, 70–79, 80+). If the “50+ years combined” option is selected, the model assumes that all of the subjects in the 50–59, 60–64, 65–69, 70–79 and 80+ age cohorts are vaccinated, as in a one-off ‘catch-up’ campaign, at an age of 50, 60, 65, 70 and 80 y respectively. The model follows all subjects within a cohort over their remaining life-time from the year of vaccination with annual cycle lengths. As such all subjects remain in their initial cohort and all subsequent events are counted in that cohort only. Three different HZ vaccination strategies are compared; no vaccination (control), vaccination with ZVL, and vaccination with HZ/su. Within each vaccine arm/strategy, individuals can be fully compliant with the vaccine dosing schedule, partially compliant or not vaccinated at all, depending on the corresponding vaccine coverage and compliance rates assumed. An overview of the model structure is presented in Fig. 5. Transition probabilities between the health states HZ, natural death, HZ related deaths, recover, recurrent HZ,.. occur using an annual time step. PHN and NON-PHN complications are health states which occur within a HZ episode and as such occur within this annual time step. Probabilities of moving between health states are derived from Germany specific literature and are age-group specific.
Figure 5.

Schematic overview of Markov structure – ZONA model. HZ: herpes zoster; PHN: postherpetic neuralgia.

In this analysis 3 age cohorts were considered, i.e., 50–59, 60–69 and 70+ years, i.e., combining results from the 60–64 and 65–69 cohorts and the 70–79 and 80+ cohorts, respectively, for presentation purposes. The age cohorts were selected to capture age-dependent differences in disease incidence, complications, outcomes, costs and potential public health decision making.

RUPEE provides two modes, fast and top-aligned. Each operating mode builds on the results provided by the min-hashing and LSH system described above. When a structure search is executed in either mode, a number of concurrent tasks are executed corresponding to the 33 bands used for LSH. These concurrent tasks identify candidate matches based on a single band match; for each candidate match, we estimate the Jaccard similarity using the min-hashes. In this way, RUPEE quickly compares the query structure to every structure in the database, which in the case of ECOD is greater than 600,000 protein domains.
In fast mode, the top 8000 matches from the min-hashing and LSH initial filtering are obtained. For each match, we adjust the Jaccard similarity to account for matched shingles that are out of sequence order. For this adjustment, we calculate the exact denominator in the definition of Jaccard similarity from the original shingle sequences of the structures. As for the numerator, instead of using the total number of matched shingles, we use the length of the longest common subsequence (LCS) of the shingle sequences for each match. This LCS adjustment to the Jaccard similarity enforces the constraint that all valid shingles matches must appear in order along the length of each structure. The final step of fast mode is to sort the matches based on the adjusted Jaccard similarity scores and return the results.
Top-aligned is an additional step following fast mode that uses TM-align to identify the best pairwise alignments among the 8000 matches returned from fast mode. First, we execute TM-align on the 8000 matches obtained from fast mode using a reduced number of dynamic programming iterations in the TM-align algorithm. We sort these initial alignments by the sort criterion entered by the user, either RMSD or TM-score, and obtain the top 400 matches. Finally, we execute TM-align using the default number of dynamic programming iterations on the top 400 matches and return the sorted results based on the sort criterion.
The filter sizes of 8000 and 400 have been chosen based on quality of results and speed. We have found that increasing the size of either of these filters results in only marginal improvements in the quality of results. Given that performing pairwise alignments is the most time-consuming aspect of the RUPEE structure search, the marginal improvements gained from larger filter sizes have to be balanced against the number of pairwise alignments performed.
Top-aligned is a simple step following fast mode that establishes RUPEE fast mode as an effective filtering method that contains in its top 8000 results enough good matches to compete with the best available structure searches.

The need for written consent from patients was waived because we ensured all the information and treatment records of the patients were kept anonymous by all researchers involved. Patients diagnosed with ZRN (course of disease < 1 month) with a clear history of zoster and hospitalized at the Guangdong Provincial Shenzhen People's Hospital (Ethics No. LL-KY-2022144-01) from May 2019 to December 2021 were included in this study. The inclusion criteria were: (1) patients diagnosed with ZRN with a clear history of zoster; (2) patients aged between 50 to 75 years; (3) patients with pain located in the T3-T12 spinal nerve distribution area; (4) patients with visual analogous scale (VAS) score ≥ 5, and; (5) ZRN patients only received medication 1 week prior to the study. The exclusion criteria were: (1) patients with a history of cancer, infection in the spinal canal or diabetes; (2) patients with systemic immune disease, impaired cardiac and pulmonary function or respiratory tract infection; (3) patients with presence of intercostal neuralgia but not caused by HZ, and; (4) patients with pain located beyond T3-T12 spinal nerve distribution area. In all, 90 patients were randomly allocated to group A, group B and group C, with 30 ones in each group.

Zona pellucidae from blastocysts were removed with 0.5% pronase (Sigma P8811) and embryos were plated onto confluent feeder layers of mouse embryonic fibroblasts (mEF) and cultured for 6 days at 37 °C, 3% CO₂, 5% O₂ and 92% N₂ in ESC derivation medium. The medium consisted of DMEM/F12 (Gibco 11320-033) with 0.1 mM nonessential amino acids (Gibco 11140-050), 1mM L-glutamine (Gibco 21051-024), 0.1 mM β-mercaptoethanol (Sigma M6250), 5 ng/ml basic fibroblast growth factor (bFGF, Sigma F-0291), 10 µM ROCK inhibitor (Sigma SCM075), 10% fetal bovine serum (FBS, Hyclone Thermo Scientific SH30071.03) and 10% knockout serum replacement (KSR, Gibco 10828-028). ESC colonies were manually dissociated and replated onto fresh mEFs for further propagation and analyses. FBS and ROCK inhibitor were omitted after the first passage of ESCs and KSR was increased to 20%. All ESC lines have been authenticated by short tandem repeat (STR) genotyping, confirming their origin from the gamete donors from this study. ESC lines are available to researchers upon OHSU IRB approval and signed OHSU MTA.

A tailored craniotomy with the aid of neuronavigation is performed. After durotomy and exposure of the brain, a corticectomy around the most superficial part of the tumor is performed. A sort of perilesional plane around the contrast-enhancing part of the tumor is found through the tractionof the tumor away from the normal appearing brain using dedicated spatulas (see Fig. 1).Fig. 1

Shows the identification of a perilesional plane through traction with dedicated dissection spatulas. A and B show a case of a left parietal GB

In this way, the white matter is gradually and circumferentially suctioned until the bottom of the tumor is reached. This circumferential movement allows the surgeon to perform the hemostasis during the surgical resection progressively;it also delineates a separation plane in the white matter (or at the level of the arachnoid sulci when they form a part of the dissection planes) that can be protected placing a cottonoid pattie over another in a “shingles on the roof” fashion while the circumferential dissection is progressing. The use of neuronavigation and intraoperative ultrasound (iOUS) reduces the risk of losing a correct trajectory around the tumor; in this way, this is circumnavigated (see Fig. 2).Fig. 2

Shows the circumnavigation of a case of a right fronto-opercular GB: AT2-weighted preoperative MRI; B,C T1-weighted with gadolinium pre-operative brain MRI. D–F A dissection plane is found and delimited with cottonoid patties

After the bottom is reached, a cottonoid pattie is placed over the normal appearing white matter. When the tumor has been circumnavigated, it can be detached from the bottom of the surgical cavity and removed enbloc with a film of normal-appearing white matter attached to the contrast-enhancing tumor. When the volume of the tumor mass does not allow the surgeon to spatulate the white matter, it can be centrally debulked, like in meningioma surgery, to permit tractions (see Supplemental Fig. 1). Hemostasis is easily performed with gentle retraction of the patties and coagulating the strips of white matter attached to them. An online intraoperative video is available in the supplementary materials. After resection is considered completed by the primary surgeon and checked with an iOUS, biopsy samples are randomly collected with dedicated forceps from the walls of the surgical cavity that are not considered in relation to eloquent areas (see Fig. 3). No surgical adjuncts are used in order to avoid false negative results.Fig. 3

This figure shows a case of a right temporal GB operated with the perilesional dissection technique. In this picture it is possible to understand how US and MRI can look like similar pictures