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Supplementary Material 3
|
39754224_p29
|
39754224
|
Electronic supplementary material
| 1.265481 |
biomedical
|
Other
|
[
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0.0031711191404610872,
0.1747591644525528
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[
0.11604286730289459,
0.8754331469535828,
0.0065435729920864105,
0.001980437431484461
] |
en
| 0.999994 |
Previous research has indicated that cannabinoid metabolism and patient responses can exhibit variability, even when comparable doses and formulations are administered . Factors influencing variability include high lipophilicity of cannabinoids, the impact of food on absorption, and tendency to accumulate in adipose tissue, and being highly protein bound . Another potential explanation is genetic polymorphisms in genes responsible for cannabinoid metabolism . For example, subsets of the population who have genetic variants or atypical phenotypes for CYP3A4, CYP2C9, and/or CYP2C19 genes may metabolize tetrahydrocannabinol (THC) and cannabidiol (CBD) differently than the general population (Table 1 ) (PHARMGKB n.d. ). A third possibility is that interactions between cannabinoids and prescription medications via the CYP450 pathways . Currently known CYP450 pathways influencing THC metabolism are CYP2C9, CYP3A4, and CYP3A5, and CBD metabolism are CYP2C19, CYP3A4, and CYP3A5 . Given the increasing nationwide use of THC and CBD, knowledge of genetic polymorphisms and medication use that could potentially alter cannabinoid metabolism at least in a subset of patients may enable safer patient care .
|
39754268_p0
|
39754268
|
Introduction
| 4.222341 |
biomedical
|
Study
|
[
0.9994887113571167,
0.0003222474188078195,
0.00018895375251304358
] |
[
0.928960382938385,
0.0013873588759452105,
0.06933590769767761,
0.0003163630317430943
] |
en
| 0.999996 |
Table 1 Phenotype of genes encoding CYP450 enzymes, their function, and hypothesized effect on THC and CBD metabolism (PHARMGKB n.d. ). Phenotype Function* Hypothesized effect on THC/CBD metabolism Poor metabolizer Greatly reduced to no function of the CYP enzyme Decreased metabolism of THC or CBD Intermediate metabolizer Moderately reduced function of the CYP enzyme Decreased metabolism of THC or CBD Intermediate to normal metabolizer Mildly reduced function of the CYP enzyme Decreased metabolism of THC or CBD Rapid metabolizer Moderately increased function of the CYP enzyme Increased metabolism of THC or CBD Ultrarapid metabolizer Greatly increased function of the CYP enzyme Increased metabolism of THC or CBD Abbreviations : CBD cannabidiol, THC tetrahydrocannabinol *Applies to CYP2C9, CYP2C19, and CYP3A4 but not CYP3A5. In the case of CYP3A5, intermediate and normal metabolizer phenotypes results in increased function and metabolism of the CYP enzyme
|
39754268_p1
|
39754268
|
Introduction
| 4.190214 |
biomedical
|
Study
|
[
0.9995859265327454,
0.0002820936497300863,
0.00013199013483244926
] |
[
0.9903025031089783,
0.007545839063823223,
0.0019153853645548224,
0.00023621476429980248
] |
en
| 0.999997 |
Our current understanding of the impact of atypical genetic variants and medications on THC and CBD metabolism is constrained by the scarcity of published literature. To date, only three published studies have reported the changes that atypical variants can have on THC and CBD levels or response . The first study investigated the impact of the CYP2C9 *2 and *3 alleles, which are known to reduce CYP2C9 function . In this study, oral THC was administered to 43 individuals, and the area under the curve (AUC) for THC was measured . Individuals who were CYP2C9-poor metabolizers (*3/*3 genotype) exhibited a 70% increase in AUC for THC compared to normal metabolizers . Additionally, CYP2C9-intermediate and -poor metabolizers (i.e., carriers of the *3 allele) showed a trend toward increased sedation with THC compared to normal metabolizers . The second study evaluated the impact of CYP2C9 *2 and *3 alleles on THC metabolism, reporting higher THC levels in patients who were carriers of these alleles . The third study associated genetic variations in CYP2C9 and CYP3A4 with negative effects of THC and cannabis use disorder, with sex-specific differences . However, research in this area is incomplete; the effects of variants within CYP2C19, and CYP3A5 genes that affect cannabinoid metabolism have not been described in clinical settings.
|
39754268_p2
|
39754268
|
Introduction
| 4.16207 |
biomedical
|
Study
|
[
0.9995113611221313,
0.0002954035298898816,
0.00019330019131302834
] |
[
0.9867026805877686,
0.00033323292154818773,
0.01280131470412016,
0.00016283248260151595
] |
en
| 0.999999 |
Similarly, there is only one in vivo study on the effect of medications on cannabinoid levels. In this phase I study, the impact of rifampicin (a strong inducer of CYP3A4) and ketoconazole (a strong inhibitor of CYP3A4) on the pharmacokinetics of THC and CBD was evaluated in healthy volunteers . The authors reported that CYP3A4 inhibitors and inducers significantly increased and decreased, respectively, the levels of both THC and CBD . Although there is limited clinical data at this point, we cannot ignore the possibility of varied THC or CBD metabolism in different patients due to atypical variants or use of medications than what is currently published.
|
39754268_p3
|
39754268
|
Introduction
| 4.065315 |
biomedical
|
Study
|
[
0.9994444251060486,
0.00040492630796507,
0.0001505618420196697
] |
[
0.9987290501594543,
0.0007217302918434143,
0.00045150192454457283,
0.0000977354429778643
] |
en
| 0.999997 |
In this context, this study aims to describe the presence of atypical pharmacogenomic profiles, the use of medications metabolized via CYP450 pathways in conjunction with THC and CBD, and to hypothesize their potential impact on THC and CBD metabolism in a nonselected sample of patients reporting oral cannabis use.
|
39754268_p4
|
39754268
|
Introduction
| 4.085313 |
biomedical
|
Study
|
[
0.99933260679245,
0.0004700037825386971,
0.00019740361312869936
] |
[
0.9994186162948608,
0.0002880152314901352,
0.00021266320254653692,
0.0000806765237939544
] |
en
| 0.999998 |
We conducted a retrospective chart review on a cohort of unselected patients who had previously completed pharmacogenomic testing and reported cannabis use to their medical provider in a clinical encounter.
|
39754268_p5
|
39754268
|
Study design
| 2.960321 |
biomedical
|
Study
|
[
0.9817166924476624,
0.017499154433608055,
0.0007841716287657619
] |
[
0.9894804954528809,
0.005261640530079603,
0.002645090688019991,
0.002612704411149025
] |
en
| 0.999996 |
For this study, we utilized data from the Mayo-Baylor RIGHT 10 K Study, which includes a cohort of over 10,000 patients who had previously undergone pharmacogenomic testing, specifically targeted oligonucleotide-capture sequencing of 77 pharmacogenes previously described . The results of these 77 pharmacogenes were integrated into the electronic medical records (EMR) to facilitate the incorporation of pharmacogenomic data into clinical practice and to provide practice-based alerts . Inclusion criteria included (1) research authorization, (2) adult (age 18 and older), and (3) documentation of oral cannabis use, as defined as “oral” or “by mouth” route of administration. Patients were excluded if cannabis use was only documented in clinical encounters that occurred outside of Mayo Clinic.
|
39754268_p6
|
39754268
|
Patients
| 4.123449 |
biomedical
|
Study
|
[
0.9988345503807068,
0.0009072786779142916,
0.00025813558022491634
] |
[
0.9992851614952087,
0.00038051276351325214,
0.00022867841471452266,
0.00010563253454165533
] |
en
| 0.999999 |
With electronic data search tools, we used the search terms CBD, THC, and cannabis to identify patients within this cohort who had oral cannabis use mentioned in their EMR. Clinical notes were manually reviewed to confirm use of cannabis and determine the date on which cannabis use was first documented in the EMR. Given the limited documentation on the exact composition of the cannabis products, we assumed all products had both CBD and THC. Demographics data, including age, sex, race, ethnicity, level of education, nicotine, and alcohol use were electronically and manually abstracted. Medication lists closest to the date of cannabis documentation were manually abstracted and pharmacogenomic phenotypes for CYP2C9, CYP2C19, CYP3A4, and CYP3A5 for each participant were electronically abstracted from their EMR.
|
39754268_p7
|
39754268
|
Data collection
| 4.068613 |
biomedical
|
Study
|
[
0.9983586668968201,
0.0013905097730457783,
0.0002507861063349992
] |
[
0.9992586970329285,
0.00037238624645397067,
0.00024253252195194364,
0.00012642150977626443
] |
en
| 1 |
Two pharmacists (JW and LH) with clinical expertise in pharmacogenomics reviewed medications in each participant to determine clinically relevant cannabis-drug interactions, as defined by involvement of strong or moderate inducers or inhibitors, that could potentially alter the metabolism of THC and CBD based on CYP450 metabolism pathways from UpToDate ( n.d. ). Based on the information provided in UpToDate, only strong or moderate inhibitors and inducers for CYP2C9, CYP2C19, CYP3A4, and CYP3A5 were deemed to be clinically relevant for the purposes of this study (UpToDate n.d. ). Medications metabolized by CYP2C9, CYP3A4, and CYP3A5 were identified as potential THC-drug interactions. Similarly, medications metabolized by CYP2C19, CYP3A4, and CYP3A5 were identified as potential CBD-drug interactions. A list of strong and moderate inhibitors and inducers found in this sample are listed in column 2 of Tables 3 and 4 . These phenotypes include intermediate to normal ( CYP2C9 , CYP2C19 , CYP3A4 , and CYP3A5 ), intermediate ( CYP2C9 , CYP2C19 , CYP3A4 , and CYP3A5 ), poor ( CYP2C9 , CYP2C19 , and CYP3A4 ), rapid ( CYP2C19 ), ultrarapid ( CYP2C19 ), and normal ( CYP3A5 ) metabolizers. Following this they hypothesized how the medications or atypical variants could influence the metabolism of THC and CBD, respectively, in each of the 71 patients.
|
39754268_p8
|
39754268
|
Study processes
| 4.141235 |
biomedical
|
Study
|
[
0.9990999698638916,
0.0007200862746685743,
0.00017993937944993377
] |
[
0.9990941286087036,
0.00041504125692881644,
0.00038857312756590545,
0.00010222582932328805
] |
en
| 0.999998 |
A search for cannabis use within the RIGHT 10 K cohort (10,077 patients) on April 16, 2021, identified 164 individuals of which oral cannabis use was confirmed in 71 individuals, which was our sample. The average age of our sample was 68.5 years, was predominantly women (73.2%), of Caucasian race (94.4%), and non-Hispanic ethnicity (95.8%) (Table 2 ). On average, patients were on 8.1 medications not including vitamins or supplements. Of the 71 patients, 10 had no atypical variants; 31 had atypical variants in CYP2C9 ; 37 had atypical variants in CYP2C19 ; 6 had atypical variants in CYP3A4 ; and 15 had atypical variants in CYP3A5 (Table 3 ). The phenotype and genotype for each gene is listed in Table 3 . Of the 71 patients, 5 were taking medications that could interact with THC, and 8 were taking medications that could interact with CBD. Table 2 Demographic and clinical characteristics ( N = 71) Variable No. (%) Gender Male 19 (26.8) Female 52 (73.2) Age of cannabis documentation (average) 68.5 Race Caucasian 67 (94.4) African American 1 (1.4) Other 3 (4.2) Ethnicity Hispanic 2 (2.8) Non-Hispanic 68 (95.8) Unknown 1 (1.4) Alcohol use Current 49 (69.0) Former 7 (9.9) Never 15 (21.1) Smoking status Current 7 (9.9) Former 29 (40.8) Never 35 (49.3) Education level High school or less 6 (8.5) Some college 25 (35.2) Bachelor’s degree 16 (22.5) Advanced degree 22 (31.0) No information 2 (2.8) Table 3 Distribution of CYP450 metabolism phenotypes in the sample Gene, Phenotype, and genotype Number CYP2C9 Poor metabolizer activity score 0 0 Poor metabolizer activity score 0.5 1 *2/*3 1 Intermediate metabolizer activity score 1.0 12 *1/*3 12 Intermediate metabolizer activity score 1.5 18 *1/*2 18 Normal metabolizer 40 *1/*1 40 CYP2C19 Poor metabolizer 1 *2/*2 1 Intermediate metabolizer 15 *1/*2 15 Intermediate to normal metabolizer 7 *2/*17 7 Normal metabolizer 34 *1/*1 34 Rapid metabolizer 12 *1/*17 12 Ultrarapid metabolizer 2 *17/*17 2 CYP3A4 Intermediate to normal metabolizer 6 *1/*22 5 *1/novel allele with heterozygous c.200A>G, p.Lys67Arg 1 Normal metabolizer 65 *1/*1 65 CYP3A5 Poor metabolizer 56 *3/*3 55 *3/*3 with a heterozygous c.1111A>G, p.Ile371Val 1 Intermediate metabolizer 15 *1/*3 15
|
39754268_p9
|
39754268
|
Results
| 4.16349 |
biomedical
|
Study
|
[
0.9990999698638916,
0.0006425908068194985,
0.00025749424821697176
] |
[
0.999407172203064,
0.0002909576578531414,
0.00021410029148682952,
0.00008782956138020381
] |
en
| 0.999996 |
Among the 71 patients, 4 had potential for both medication and gene interactions, 38 had potential for interactions involving single or combination genes only, 1 had potential for medication only interactions, and 28 had no relevant interactions with THC (Table 4 ). Information on inducers and inhibitors, atypical variants, and the hypothesized impact on THC metabolism for each patient is in Table 4 . Table 4 Hypothesized influence on THC metabolism Participant Medications: Inhibitors/Inducers Atypical variants Hypothesized influence on THC metabolism 1 Fluconazole strong inhibition of CYP3A4 and weak inhibition of CYP2C9 CYP2C9 IM In this patient, two CYP pathways for THC metabolism could be downregulated by fluconazole. This patient, due to their CYP2C9 IM phenotype, has a genetic predisposition to reduced THC metabolism. 2,3 Diltiazem moderate inhibition of CYP3A4 CYP3A5 IM In these two patients, one of the CYP pathways for THC metabolism could be downregulated by diltiazem. These two patients, due to their CYP3A5 IM phenotype, have a genetic predisposition to increased THC metabolism. 4 Carbamazepine strong CYP3A4 induction CYP2C9 IM-NM In this patient, one of the CYP pathways for THC metabolism could be upregulated by carbamazepine. This patient, due to their CYP2C9 IM-NM phenotype, has a genetic predisposition to reduced THC metabolism. 5 CYP2C9 PM This patient, due to their CYP2C9 PM phenotype, has a genetic predisposition to reduced THC metabolism. 6–15 CYP2C9 IM These patients, due to their CYP2C9 IM phenotype, have a genetic predisposition to reduced THC metabolism. 16–19 CYP3A4 IM-NM These patients, due to their CYP3A4 IM-NM phenotype, have a genetic predisposition to reduced THC metabolism. 20 CYP2C9 IM-NM, CYP3A4 IM-NM, and CYP3A5 IM This patient, due to their complex gene profile (CYP2C9 IM-NM, CYP3A4 IM-NM, and CYP3A5 IM), may have a genetic predisposition to altered THC metabolism. The net genetic impact on the metabolism is currently unknown. 21 CYP2C9 IM and CYP3A5 IM This patient, due to their complex gene profile (CYP2C9 IM, and CYP3A5 IM), may have a genetic predisposition to altered THC metabolism. The net genetic impact on the metabolism is currently unknown. 22–34 CYP2C9 IM-NM These patients, due to their CYP2C9 IM-NM phenotype, have a genetic predisposition to reduced THC metabolism. 35 CYP2C9 IM-NM and CYP3A4 IM-NM This patient, due to their CYP2C9 IM-NM and CYP3A4 IM-NM phenotype, has a genetic predisposition to reduced THC metabolism. 36–42 CYP3A5 IM These patients, due to their CYP3A5 IM phenotype, have a genetic predisposition to increased THC metabolism. 43 Diltiazem moderate inhibition of CYP3A4 In this patient, one of the CYP pathways for THC metabolism could be downregulated by diltiazem. 44–71 N/A These patients had no medication or gene interactions that could alter THC metabolism. Abbreviations: IM intermediate metabolizer, IM-NM intermediate-to-normal metabolizer, N/A not applicable, PM poor metabolizer, RM rapid metabolizer, THC tetrahydrocannabinol, UM ultrarapid metabolizer
|
39754268_p10
|
39754268
|
Hypothesized influence on THC metabolism
| 4.287216 |
biomedical
|
Study
|
[
0.9974537491798401,
0.0022906148806214333,
0.00025562173686921597
] |
[
0.9982129335403442,
0.0007907033432275057,
0.0006534862914122641,
0.0003428473137319088
] |
en
| 0.999995 |
Among the 71 patients, 4 had potential for both medication and gene interactions, 36 had potential for interactions involving single or combination genes only, 4 had potential for medication only interactions, and 27 had no relevant interactions with CBD (Table 5 ). Information on inducers and inhibitors, atypical variants, and their hypothesized impact on CBD metabolism for each patient is in Table 5 . Table 5 Hypothesized influence on CBD metabolism Participant Medications: Inhibitors/Inducers Atypical variants Hypothesized influence on CBD metabolism 1 Fluoxetine moderate CYP2C19 inhibition CYP2C19 PM In this patient, one CYP pathway for CBD metabolism could be downregulated by fluoxetine. This patient, due to their CYP2C19 PM phenotype, has a genetic predisposition to reduced CBD metabolism. 2 Diltiazem moderate inhibition of CYP3A4 CYP3A5 IM In this patient, one CYP pathway for CBD metabolism could be downregulated by diltiazem. This patient, due to their CYP3A5 IM phenotype, has a genetic predisposition to increased CBD metabolism. 3 Fluoxetine moderate inhibition of CYP2C19 CYP3A5 IM In this patient, one CYP pathway for CBD metabolism could be downregulated by fluoxetine. This patient, due to their CYP3A5 IM phenotype, has a genetic predisposition to increased CBD metabolism. 4 Diltiazem moderate inhibition of CYP3A4 CYP2C19 RM CYP3A5 IM In this patient, one CYP pathway for CBD metabolism could be downregulated by diltiazem. This patient, due to their CYP2C19 RM and CYP3A5 IM phenotype, has a genetic predisposition to increased CBD metabolism. 5,6 CYP2C19 UM These patients, due to their CYP2C19 UM phenotype, have a genetic predisposition to increased CBD metabolism. 7–9 CYP2C19 RM and CYP3A5 IM These patients, due to their CYP2C19 RM and CYP3A5 IM phenotype, have a genetic predisposition to increased CBD metabolism. 10–16 CYP2C19 RM These patients, due to their CYP2C19 RM phenotype, have a genetic predisposition to increased CBD metabolism. 17–20 CYP3A5 IM These patients, due to their CYP3A5 IM phenotype, have a genetic predisposition to increased CBD metabolism. 21–32 CYP2C19 IM These patients, due to their CYP2C19 IM phenotype, have a genetic predisposition to reduced CBD metabolism. 33 CYP2C19 IM and CYP3A4 IM-NM This patient, due to their CYP2C19 IM and CYP3A4 IM-NM phenotype, has a genetic predisposition to reduced CBD metabolism. 34,35 CYP2C19 IM-NM These patients, due to their CYP2C19 IM-NM phenotype, have a genetic predisposition to reduced CBD metabolism. 36,37 CYP2C19 IM-NM and CYP3A4 IM-NM These patients, due to their CYP2C19 IM and CYP3A4 IM-NM phenotype, have a genetic predisposition to reduced CBD metabolism. 38,39 CYP3A4 IM-NM These patients, due to their CYP3A4 IM-NM phenotype, have a genetic predisposition to reduced CBD metabolism. 40 Carbamazepine strong induction of CYP3A4 In this patient, one CYP pathway for CBD metabolism could be upregulated by carbamazepine. 41 Fluconazole strong inhibition of CYP2C19 and CYP3A4 In this patient, one CYP pathway for CBD metabolism could be downregulated by fluconazole. 42 Diltiazem moderate inhibition of CYP3A4 In this patient, one CYP pathway for CBD metabolism could be downregulated by diltiazem. 43 Fluoxetine moderate inhibition of CYP2C19 In this patient, one CYP pathway for CBD metabolism could be downregulated by fluoxetine. 44–71 N/A These patients had no medication or gene interactions that could alter CBD metabolism. Abbreviations: CBD cannabidiol, IM intermediate metabolizer, IM-NM intermediate to normal metabolizer, N/A not applicable, PM poor metabolizer, RM rapid metabolizer, UM ultrarapid metabolizer
|
39754268_p11
|
39754268
|
Hypothesized influence on CBD metabolism
| 4.282193 |
biomedical
|
Study
|
[
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0.0024919486604630947,
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[
0.9980721473693848,
0.0008422996615990996,
0.0007811326649971306,
0.0003044538607355207
] |
en
| 0.999996 |
The results of our study highlight the spectrum of potential alterations in THC and CBD metabolism that may arise due to atypical genetic variants and medications and is the first study to report this range of possibilities. Given the limited literature, assessing the clinical significance of these interactions is challenging. However, until more evidence emerges, clinicians should remain aware of their potential impact on patients’ responses to THC and CBD.
|
39754268_p12
|
39754268
|
Discussion
| 4.014297 |
biomedical
|
Study
|
[
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0.00031934629078023136,
0.00014224591723177582
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[
0.9982767105102539,
0.0006123081548139453,
0.0010039386106655002,
0.00010708015179261565
] |
en
| 0.999995 |
From a pharmacogenomic perspective, although atypical variants may influence cannabinoid metabolism, the greatest clinical value may reside in identifying patients with extreme phenotypes. These individuals potentially exhibit a higher likelihood of altering THC or CBD metabolism, which may impact therapeutic outcomes. This includes poor metabolizers of CYP2C9, CYP2C19, or CYP3A4, normal metabolizers of CYP3A5, and ultrarapid metabolizers of CYP2C19. In our sample that was predominantly Caucasian, only three of the 71 patients were poor metabolizers for CYP2C9 (1.4%) or CYP2C19 (2.8%), consistent with the prevalence of CYP2C9 and CYP2C19 poor metabolizers within Caucasian populations (1% and 2%-5%, respectively) . Our sample did not contain any patients with extreme CYP3A4 nor CYP3A5 phenotypes, which is not surprising because it is rare in the Caucasian population. This suggests that only a small percentage of patients in a Caucasian sample may experience notable baseline alterations in THC or CBD metabolism. Although we observed several other atypical variants ( n = 42), we believe that over 90% of these are unlikely to have clinical significance. The overall distribution of atypical variants in our sample is consistent with previous studies, which report atypical variants for CYP2C9 and CYP2C19 phenotypes ranging from 37 to 39% and 54–60%, respectively, in populations of Caucasian ancestry . However, these results cannot be generalized to non-Caucasian samples, and future prospective studies evaluating whether THC and CBD metabolism varies in diverse populations may be of value.
|
39754268_p13
|
39754268
|
Discussion
| 4.165133 |
biomedical
|
Study
|
[
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0.0005466028233058751,
0.000153001252328977
] |
[
0.9989443421363831,
0.00037590941064991057,
0.0005669593228958547,
0.00011278143210802227
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en
| 0.999997 |
The results of our study suggest that CYP pathways for THC and CBD metabolism may be influenced by medications. This may be particularly relevant for medications that are moderate to strong inhibitors or inducers of CYP2C9, CYP2C19, and CYP3A4, as they can have a higher likelihood to alter cannabis metabolism. According to the FDA, moderate inhibitors increase the AUC by 2-fold up to 5-fold, while strong inhibitors increase the AUC by more than 5-fold . In this context, relevant inhibitors and inducers in our sample included fluconazole, diltiazem, fluoxetine (inhibitors), and carbamazepine (inducer). While these medications were specific to our sample, other medications could also potentially influence cannabinoid metabolism. Currently, there is no comprehensive resource or tool that lists all these medications. However, commonly prescribed medications that may be relevant in this context include moderate to strong inhibitors of CYP2C9, CYP2C19, and CYP3A4 such as omeprazole, azithromycin, verapamil, fluvoxamine, sulfamethoxazole/trimethoprim, and nirmatrelvir-ritonavir. A detailed list of these medications is beyond the scope of this paper.
|
39754268_p14
|
39754268
|
Discussion
| 4.12286 |
biomedical
|
Study
|
[
0.9995484948158264,
0.00023900957603473216,
0.0002124328020727262
] |
[
0.9992235898971558,
0.00017866745474748313,
0.0005404414841905236,
0.00005735666854889132
] |
en
| 0.999998 |
Based on the current data, it is premature to recommend pharmacogenomic testing for all patients who use cannabis. Since pharmacogenomic testing has become more common, it may be beneficial to ask patients if they have undergone such testing and to incorporate these results into their medication evaluations. For patients who have not had pharmacogenomic testing, it may be worth considering if they experience unexpected serious adverse effects. As a medical community, we are still working to understand the complexities of appropriate cannabis use. Currently, there is a lack of clinical guidelines to predict adverse effects of cannabis resulting from its metabolism. Until such information is available, awareness of atypical cannabinoid metabolism resulting from atypical variants and medications, and consultation with a clinician such as a pharmacist with expertise can help guide clinical care.
|
39754268_p15
|
39754268
|
Discussion
| 3.895495 |
biomedical
|
Other
|
[
0.977580189704895,
0.020935067906975746,
0.0014847290003672242
] |
[
0.01556310523301363,
0.8914250135421753,
0.08935633301734924,
0.003655552864074707
] |
en
| 0.999995 |
One of the strengths of our study is that it is the first to report atypical variants of CYP2C9, CYP2C19, CYP3A4, and CYP3A5 phenotypes identified through sequencing in a clinical sample of cannabis users. Sequencing can detect rare variants that genotyping might miss, providing a more comprehensive view. Previous studies that used genotyping to examine CYP2C9 and THC interactions only evaluated CYP2C9 *2 and *3 variants and could have missed important alleles that resulted in false-normal interpretation of the CYP2C9 phenotype . In contrast, our study that interrogated all variants in the CYP2C9 gene reassured us that the CYP2C9 phenotype interpretation was comprehensive. Another strength of our study is the concurrent reporting of both atypical variants and medications that influence cannabis metabolism in a clinical sample.
|
39754268_p16
|
39754268
|
Strengths and limitations
| 4.108372 |
biomedical
|
Study
|
[
0.9994686245918274,
0.0003058790462091565,
0.00022554882161784917
] |
[
0.999528169631958,
0.00018154727877117693,
0.00023028498981148005,
0.00005999533459544182
] |
en
| 0.999997 |
Our study had several limitations. First, we used a convenience sample that required documentation of cannabis use in EMR, which might have led to missing patients who used cannabis but did not report it, or providers who did not document cannabis use reported by patients, and self-reporting bias. Second, details related to cannabis use, such as dosing, formulation, and frequency, were often poorly documented, leading us to assume all documented cannabis contained both THC and CBD, which might not have been accurate. Third, determining if patients were using cannabis and interacting medications simultaneously from retrospective chart reviews was challenging. We assumed continuous cannabis use for our hypothesis, but intermittent use might not produce as prominent of an effect in terms of cannabis accumulation. These limitations highlight the current challenge of how cannabis is documented in medical records. Fourth, there is a complex bidirectional relationship between cannabis and medications. Since our primary aim was to evaluate the effect of medications on cannabinoid metabolism, we intentionally focused on this aspect of the interaction. We acknowledge that cannabis can affect medications levels, however, this was not incorporated in the analysis of our study since this was not our primary aim. Fifth, we acknowledge there are other pathway for cannabinoid-drug-gene interactions such as uridine glucuronosyltransferase (UGT) enzymes. However, the pharmacogenomic testing that was done as part of the RIGHT10K did not report UGT genes in the electronic medical records. Therefore, no information regarding UGT enzymes was available for this sample. We acknowledge that this may be a limitation. Sixth, patients with certain ancestries, particularly South Asian, may have a higher risk of atypical phenotypes affecting THC and CBD metabolism . Since our convenience sample was predominantly Caucasian, our results may not be generalizable to other ancestries. Finally, our sample included mostly older patients. It is known that the expression and activity of CYP450 enzymes vary with age, which can influence medications metabolism and should be considered . Despite these limitations, our study adds important information to the current scant body of literature and may be beneficial as a hypothesis to support future clinical studies evaluating these questions.
|
39754268_p17
|
39754268
|
Strengths and limitations
| 4.15833 |
biomedical
|
Study
|
[
0.9992227554321289,
0.0005601083394140005,
0.00021711121371481568
] |
[
0.9991951584815979,
0.00022917479509487748,
0.00047727019409649074,
0.00009841186692938209
] |
en
| 0.999998 |
There’s an increasing demand for minimally invasive and aesthetically pleasing tooth restorations, this explains the increasing popularity of partial-coverage ceramic restorations, as they offer a conservative approach to restore destructed tooth structure while achieving both cosmetic and functional demands .
|
PMC11699763_p0
|
PMC11699763
|
Background
| 2.110834 |
biomedical
|
Other
|
[
0.9732850790023804,
0.0055269841104745865,
0.02118792198598385
] |
[
0.002931544790044427,
0.9935355186462402,
0.0028831902891397476,
0.000649736903142184
] |
en
| 0.999996 |
Adhesive dentistry introduced innovative restoration designs, resulting in a greater adoption of partial-coverage ceramic restorations. Overlay restorations have become a prevalent treatment option for posterior teeth with coronal damage. either due to caries or non-caries issues as abfraction [ 3 – 6 ].
|
PMC11699763_p1
|
PMC11699763
|
Background
| 2.687406 |
biomedical
|
Other
|
[
0.9922494888305664,
0.0016949988203123212,
0.0060555231757462025
] |
[
0.03152021765708923,
0.9436009526252747,
0.023936571553349495,
0.0009421558352187276
] |
en
| 0.999996 |
Ceramic restorations merge between excellent biocompatibility and optimal optical and material properties, satisfying both patient and clinical demands [ 7 – 9 ], which is indicated for veneers, inlays, onlays, crowns, and FPDs [ 7 – 11 ].
|
PMC11699763_p2
|
PMC11699763
|
Background
| 3.171433 |
biomedical
|
Other
|
[
0.9945659637451172,
0.0012824320001527667,
0.004151530098170042
] |
[
0.03227481245994568,
0.8722204566001892,
0.09469709545373917,
0.0008077193051576614
] |
en
| 0.999996 |
Glass-ceramics, including lithium disilicate and zirconia-reinforced lithium silicate, are aesthetically appealing restorative materials fabricated with computer-aided design (CAD) computer-aided manufacturing (CAM) technologies. They were designed to replace metal-alloy frameworks, providing benefits in optical, physical, and biological properties .
|
PMC11699763_p3
|
PMC11699763
|
Background
| 3.117071 |
biomedical
|
Other
|
[
0.9855141639709473,
0.0014456026256084442,
0.013040237128734589
] |
[
0.02413938008248806,
0.9689541459083557,
0.006423700135201216,
0.0004827937518712133
] |
en
| 0.999996 |
The durability of ceramic restorations primarily depends on the quality of bonding and the proper application technique. Cementation enhances fracture resistance by filling the irregularities on the etched fitting surface of the restoration, thereby enhancing bonding strength and preventing crack propagation especially the glass ceramics .
|
PMC11699763_p4
|
PMC11699763
|
Background
| 3.239819 |
biomedical
|
Other
|
[
0.9734237790107727,
0.002613659482449293,
0.023962469771504402
] |
[
0.023910004645586014,
0.9723605513572693,
0.0034537091851234436,
0.0002757827169261873
] |
en
| 0.999997 |
Maintaining fracture resistance is essential for ensuring the effectiveness of ceramic restorations. It is influenced by preparation design, ceramic material properties, restoration thickness, cementation technique, functional load, and internal ceramic defects . Preparation designs, including cavity depth, width of the isthmus, the degree of taper, and the internal line angles, can influence fracture resistance. Additionally, the aging of the ceramic restoration/tooth complex may affect the failure rate .
|
PMC11699763_p5
|
PMC11699763
|
Background
| 3.797612 |
biomedical
|
Study
|
[
0.9856875538825989,
0.0008417390054091811,
0.013470688834786415
] |
[
0.5164128541946411,
0.40677085518836975,
0.07633992284536362,
0.0004764089244417846
] |
en
| 0.999997 |
The marginal fit of restoration is a critical element that affects the longevity of overlay restorations. Poor adaptation can create gaps between the restoration and tooth, leading to microleakage, plaque buildup, and potential recurrence of decay .
|
PMC11699763_p6
|
PMC11699763
|
Background
| 3.204665 |
biomedical
|
Other
|
[
0.9920119643211365,
0.004799641668796539,
0.0031883122865110636
] |
[
0.025759581476449966,
0.96792072057724,
0.005427994765341282,
0.000891695381142199
] |
en
| 0.999998 |
It’s worth mentioning that only a limited number of studies have investigated the impact of the design of preparation on the characteristics of overlay restorations, with most of these focusing mainly on the fracture resistance of the restorations [ 1 , 3 , 19 – 22 ]. Most of the previous pertinent research has assessed inlays and/or onlays that provide partial cusp coverage .
|
PMC11699763_p7
|
PMC11699763
|
Background
| 3.083853 |
biomedical
|
Study
|
[
0.9871931672096252,
0.0008709667599759996,
0.01193583756685257
] |
[
0.8071704506874084,
0.024563336744904518,
0.16774658858776093,
0.000519563618581742
] |
en
| 0.999999 |
An information gap exists concerning the impact of preparation configuration on the marginal fit of ceramic overlays. Therefore, this research aimed to examine the marginal gap and fracture resistance of Advanced Zirconia-reinforced Lithium disilicate (ALD) overlays with various preparation designs. The null hypothesis for this study stated that there is no significant difference in marginal fit (before or after thermal aging) or fracture resistance among the studied groups.
|
PMC11699763_p8
|
PMC11699763
|
Background
| 3.942938 |
biomedical
|
Study
|
[
0.9903934597969055,
0.001088125049136579,
0.008518446236848831
] |
[
0.9994087219238281,
0.00036727797123603523,
0.00016833117115311325,
0.00005561210127780214
] |
en
| 0.999998 |
The study followed an in-vitro, parallel-controlled design, in which three parallel groups’ marginal fit and fracture resistance were evaluated. It was conducted in the laboratory of the Conservative Dentistry Department at the Faculty of Dentistry, Alexandria University, Egypt.
|
PMC11699763_p9
|
PMC11699763
|
Study design and sample size
| 2.637491 |
biomedical
|
Study
|
[
0.995474636554718,
0.0030726606491953135,
0.001452696043998003
] |
[
0.9958160519599915,
0.003544089151546359,
0.00023802330542821437,
0.00040180247742682695
] |
en
| 0.999995 |
The sample size was estimated assuming a 5% alpha error and 80% study power. Based on the difference between independent means of previous study , the minimum sample size was calculated to be 7 samples per group, increased to 9 samples to make up for processing errors. Total sample = number per group x number of groups = 9 × 3 = 27 samples.
|
PMC11699763_p10
|
PMC11699763
|
Study design and sample size
| 3.57839 |
biomedical
|
Study
|
[
0.9990886449813843,
0.00029345977236516774,
0.0006178351468406618
] |
[
0.9929314851760864,
0.0066997758112847805,
0.00026455530314706266,
0.00010416028089821339
] |
en
| 0.999997 |
The sample size was calculated by G*Power 3.1.9.7.
|
PMC11699763_p11
|
PMC11699763
|
Study design and sample size
| 2.288027 |
biomedical
|
Study
|
[
0.9931347370147705,
0.0008072560885921121,
0.006057917606085539
] |
[
0.8942570686340332,
0.10422447323799133,
0.0009323189151473343,
0.0005860524252057076
] |
en
| 0.999997 |
Three second mandibular molars typodont teeth (Columbia Dentoform Corporation, USA), were prepared using the following designs :
|
PMC11699763_p12
|
PMC11699763
|
Specimen preparation
| 2.286871 |
biomedical
|
Other
|
[
0.9914053678512573,
0.003790926653891802,
0.004803749732673168
] |
[
0.31842344999313354,
0.6757051348686218,
0.0009841379942372441,
0.00488731125369668
] |
en
| 0.999998 |
Group (O) a traditional overlay preparation with anatomical occlusal reduction 1.5 mm. Group (OS) an overlay preparation with anatomical occlusal reduction 1.5 mm and 1.0 mm shoulder finish line circumferentially. Group (OG) an overlay with anatomical occlusal reduction 1.5 mm and central groove preparation with a pulpal depth of 1.0 mm and a width of 2.0 mm.
|
PMC11699763_p13
|
PMC11699763
|
Specimen preparation
| 3.036726 |
biomedical
|
Study
|
[
0.8982594609260559,
0.09783301502466202,
0.003907515201717615
] |
[
0.5394124388694763,
0.4524082839488983,
0.0014132544165477157,
0.006766028236597776
] |
en
| 0.999994 |
The typodont teeth that had been prepared were subjected to scanning using an extraoral scanner (InEos X5; Dentsply Sirona, USA), to design three dies corresponding to the tooth preparations. Print out of twenty-seven dies made from 3D printing resin (Model Resin, Formlabs, Somerville, MA), which possess a comparable modulus of elasticity to dentin (modulus = 10 GPa). A laboratory printer (FormLab 2, Formlabs) was used . Each resin die was subsequently embedded in a copper metallic mold filled with auto-polymerizing acrylic resin (Acrostone, Egypt), exposing only the crown and 2 mm apical to the cementoenamel junction, simulating the bone level.
|
PMC11699763_p14
|
PMC11699763
|
Specimen preparation
| 4.092004 |
biomedical
|
Study
|
[
0.9987939596176147,
0.0006364824948832393,
0.0005694327992387116
] |
[
0.9981512427330017,
0.0015265195397660136,
0.00020934331405442208,
0.00011292901035631076
] |
en
| 0.999997 |
A computer-aided design (CAD) digital software (inLab CAD SW 22.0.0; Dentsply Sirona) was used to design the restorations with a standardized morphology [Fig. 1 ] . Twenty-seven overlays were fabricated using CAM technology (inLab MCXL, Dentsply Sirona) using Advanced Zirconia-reinforced lithium disilicate CAD/CAM blocks (Dentsply Sirona, Tessera ™).
|
PMC11699763_p15
|
PMC11699763
|
Design and fabrication of overlay restorations
| 4.023042 |
biomedical
|
Study
|
[
0.9964756369590759,
0.0027451496571302414,
0.0007792029646225274
] |
[
0.9777286648750305,
0.020941004157066345,
0.0004429916152730584,
0.000887334521394223
] |
en
| 0.999996 |
Fig. 1 Shows the restoration design created using CAD technology on three distinct preparation designs: ( A ) group O, ( B ) group OS, and ( C ) group OG
|
PMC11699763_p16
|
PMC11699763
|
Design and fabrication of overlay restorations
| 2.376602 |
biomedical
|
Study
|
[
0.9891605973243713,
0.0026439607609063387,
0.008195425383746624
] |
[
0.7027058601379395,
0.29389697313308716,
0.0016238447278738022,
0.0017733210697770119
] |
en
| 0.999997 |
Twenty-seven specimens were grouped according to the overlay design into three groups, nine for each. Overlay ceramic restorations were glazed and sintered based on the manufacturer’s guidelines.
|
PMC11699763_p17
|
PMC11699763
|
Grouping of specimens
| 2.755105 |
biomedical
|
Study
|
[
0.9907279014587402,
0.0028688227757811546,
0.006403186358511448
] |
[
0.980945348739624,
0.018154794350266457,
0.0003719785891007632,
0.0005278679891489446
] |
en
| 0.999997 |
A 9.5% hydrofluoric acid (Porcelain Etch ® , Bisco, USA) was applied on the dry intaglio surface of the restorations for 20 s, rinsed with a copious amount of water for 60 s, and air dried. Silane (Porcelain Primer; Bisco, Schaumburg, IL, USA) was applied on the etched restorations surface and air dried after 60 s. The overlays were then cemented to the prepared dies with a dual-cure resin cement following the manufacturer’s instructions (BisCem; Bisco, Schaumburg, IL, USA). Cement was auto-mixed and applied on both the intaglio surface of the restoration, and the prepared die surface, each restoration loaded with cement was gently seated on its corresponding prepared die, initially with finger pressure followed by application of a constant static load of 200 g , by a specially designed device to ensure seating of the restoration for 60 s before photopolymerization. Then specimens were tack-cured for 2 s and excess cement was eliminated using scalpel, subsequently, a light curing procedure was applied for 20 s on each surface. Finally, the tooth-restoration interface was polished with polishing disks. The specimens were stored in water at room temperature before being tested.
|
PMC11699763_p18
|
PMC11699763
|
Cementation of the specimens
| 4.102154 |
biomedical
|
Study
|
[
0.9912838935852051,
0.007892832159996033,
0.000823283800855279
] |
[
0.9346891641616821,
0.06194274127483368,
0.0018072212114930153,
0.001560973934829235
] |
en
| 0.999998 |
Evaluation of marginal fit was conducted following the methodology outlined by Holmes et al., The fit accuracy of the overlays on their corresponding prepared teeth was measured twice before and after the thermal aging procedure. Six measurements were taken for each: mesiobuccal, midbuccal, distobuccal, mesiolingual, midlingual, and distolingual. The measurements were performed at a magnification of X20 and X110 using a stereomicroscope connected to a digital camera [ Fig. 2 ] . The measurements were determined, and a mean value was calculated and performed by a single-blind examiner for each overlay.
|
PMC11699763_p19
|
PMC11699763
|
Marginal fit evaluation before thermal aging
| 4.100506 |
biomedical
|
Study
|
[
0.998700737953186,
0.0007954210741445422,
0.0005038678064011037
] |
[
0.9993346333503723,
0.0002979640557896346,
0.0002981874567922205,
0.00006921877502463758
] |
en
| 0.999996 |
Fig. 2 Marginal fit measurements before thermal aging for the three groups: ( A ) Group O, ( B ) Group OG, and ( C ) Group OS. Group OS ( C ) shows the least marginal gap before thermal aging
|
PMC11699763_p20
|
PMC11699763
|
Marginal fit evaluation before thermal aging
| 2.688949 |
biomedical
|
Study
|
[
0.9851322770118713,
0.0014897887594997883,
0.013377944007515907
] |
[
0.9688225388526917,
0.030446283519268036,
0.0004491833969950676,
0.00028199946973472834
] |
en
| 0.999997 |
Thermal aging was performed with a custom-built device for a total of 5000 cycles representing a 6-month clinical service, between 5 and 55 degrees Celsius in water baths with dwell times of 15 Sects. .
|
PMC11699763_p21
|
PMC11699763
|
Thermal aging
| 3.158254 |
biomedical
|
Study
|
[
0.9964062571525574,
0.0009507492650300264,
0.0026429924182593822
] |
[
0.9477946162223816,
0.05101631581783295,
0.000696148257702589,
0.0004929195274598897
] |
en
| 0.999998 |
Following thermal aging, the measurements were assessed using a stereomicroscope at the same magnification and predefined measurement points [Fig. 3 ]. The collected data were then analyzed statistically after processing.
|
PMC11699763_p22
|
PMC11699763
|
Marginal fit evaluation after thermal aging
| 2.895587 |
biomedical
|
Study
|
[
0.9959945678710938,
0.0005566916079260409,
0.0034487382508814335
] |
[
0.9969382286071777,
0.0026590379420667887,
0.00026140999398194253,
0.00014123518485575914
] |
en
| 0.999999 |
Fig. 3 Marginal fit measurements after thermal aging for the three groups: ( A ) Group O, ( B ) Group OG, and ( C ) Group OS. The marginal gap increased after thermal aging in all three groups following the same pattern as before thermal aging where the maximum marginal discrepancy was noted in ( A ) group O
|
PMC11699763_p23
|
PMC11699763
|
Marginal fit evaluation after thermal aging
| 2.989691 |
biomedical
|
Study
|
[
0.9920641779899597,
0.0014940279070287943,
0.006441754754632711
] |
[
0.9934064149856567,
0.006132614333182573,
0.0002875078353099525,
0.00017338951874990016
] |
en
| 0.999998 |
A universal testing machine (5ST, Tinius oslen, England) was used to evaluate the fracture resistance of the specimens. A stylus with a 6 mm diameter custom-made stainless-steel ball was used to apply the load on the central fossa on the occlusal surface of the overlay along the long axis. A rubber sheet was placed under the sphere indenter to serve as a cushion and distribute forces evenly at the occlusal surface. The crosshead speed was 1 mm/min until fracture [Fig. 4 ]. The software program (version 10.2.4.0; Horizon) automatically recorded the maximum loads for each specimen in newtons (N). The failure mode for each specimen was classified according to the structures involved in the fracture according to Burke’s classification (Table 1 ) .
|
PMC11699763_p24
|
PMC11699763
|
fracture resistance test
| 4.134008 |
biomedical
|
Study
|
[
0.9983335137367249,
0.0004907249240204692,
0.00117587111890316
] |
[
0.9995468258857727,
0.0002489050093572587,
0.00016055823653005064,
0.00004373431147541851
] |
en
| 0.999995 |
Fig. 4 Schematic representation of the fracture resistance test setup. A universal testing machine (5ST, Tinius Olsen, England) applied load using a custom-made 6 mm diameter stainless-steel ball on the central fossa of the overlay along the long axis. A rubber sheet was placed beneath the sphere indenter to cushion and evenly distribute forces across the occlusal surface. The load was applied at a crosshead speed of 1 mm/min until fracture occurred
|
PMC11699763_p25
|
PMC11699763
|
fracture resistance test
| 3.989981 |
biomedical
|
Study
|
[
0.9972936511039734,
0.0007905864040367305,
0.001915738801471889
] |
[
0.9916953444480896,
0.007779308129101992,
0.00035390869015827775,
0.00017135888629127294
] |
en
| 0.999998 |
Table 1 illustrates Burke’s classification of failure modes Mode of failure I Slight crack or fracture in restoration II Under 50% of the restoration lost III Fracture of the restoration extending through the midline IV Over 50% of the restoration lost V Serious fracture of the tooth structure and\or restoration
|
PMC11699763_p26
|
PMC11699763
|
fracture resistance test
| 2.804772 |
biomedical
|
Other
|
[
0.9095779657363892,
0.0018111754907295108,
0.08861085772514343
] |
[
0.48998382687568665,
0.5071672201156616,
0.0023147310130298138,
0.0005341293872334063
] |
en
| 0.999998 |
Normality was checked using Shapiro Wilk test and Q-Q plots. Marginal fit and fracture resistance were not normally distributed thus both were presented mainly using median, minimum, maximum in addition to mean and standard deviation. The Kruskal Wallis test was used to analyze data between groups, followed by Dunn’s post hoc test with Bonferroni correction. Differences in marginal fit before and after thermal aging were analyzed using Wilcoxon Sign Rank test. All tests were two-tailed, with the significance level established at a p-value of ≤ 0.05. Data was analyzed using IBM SPSS, version 23 for Windows, Armonk, NY, USA.
|
PMC11699763_p27
|
PMC11699763
|
Statistical analysis
| 3.889974 |
biomedical
|
Study
|
[
0.9990550875663757,
0.00020306587975937873,
0.0007419101893901825
] |
[
0.9985785484313965,
0.00114947569090873,
0.00021840701811015606,
0.00005350921492208727
] |
en
| 0.999996 |
For marginal gap, the greatest mean marginal gap prior to thermal aging was observed in group O with a median gap value of 76.97 μm followed by group OG with a median gap value of 52.94 μm and the group OS with a median gap value of 35.57 μm. The marginal gap significantly increased after thermal aging in all three groups ( p < 0.05) following the same pattern as before thermal aging where the maximum marginal discrepancy was noted in group O with a median gap 114.84 μm succeeded by group OG with a median gap value 103.01 μm and the minimum marginal gap was noted in group OS with a median gap value 93.50 μm [Fig. 5 ].
|
PMC11699763_p28
|
PMC11699763
|
Marginal gap before and after thermal aging
| 4.13325 |
biomedical
|
Study
|
[
0.9981626868247986,
0.0007116273627616465,
0.0011257031001150608
] |
[
0.9995021820068359,
0.00023373009753413498,
0.00021927698981016874,
0.00004489655475481413
] |
en
| 0.999995 |
Fig. 5 Waterfall Chart showing comparison of marginal fit results of the three studied groups before and after thermal aging. With a significantly increased marginal gap after thermal aging in all three groups following the same pattern as before the thermal aging
|
PMC11699763_p29
|
PMC11699763
|
Marginal gap before and after thermal aging
| 2.952009 |
biomedical
|
Study
|
[
0.9910577535629272,
0.0011350683635100722,
0.007807138375937939
] |
[
0.9897339940071106,
0.00978014338761568,
0.00031522143399342895,
0.0001706271868897602
] |
en
| 0.999999 |
For fracture resistance, the O group had the highest median fracture load value 1809.08 N followed by Os group with median 1632.77 N. The OG group had the lowest median fracture load values of 1379.63 N [Fig. 6 ].
|
PMC11699763_p30
|
PMC11699763
|
Fracture resistance
| 3.740708 |
biomedical
|
Study
|
[
0.9973675608634949,
0.00038302523898892105,
0.002249395940452814
] |
[
0.9993476271629333,
0.000485172524349764,
0.00012275666813366115,
0.00004453870496945456
] |
en
| 0.999994 |
Fig. 6 Waterfall chart showing a comparison of fracture resistance of the three studied groups. Group O had the highest median fracture load value of 1809.08 N, followed by Group OS, with a median fracture load value of 1632.77 N. The OG Group had the lowest median fracture load value, 1379.63 N
|
PMC11699763_p31
|
PMC11699763
|
Fracture resistance
| 3.264052 |
biomedical
|
Study
|
[
0.9942458271980286,
0.0005933932261541486,
0.005160731263458729
] |
[
0.9983330368995667,
0.0014782714424654841,
0.0001237263932125643,
0.00006496393325505778
] |
en
| 0.999998 |
Among the fracture modes , there is no statistically significant difference between the three studied groups ( p = 0.027). In the (O) group ( n = 9), 3/9 (33.3%) had mode II of fracture, 2/9 (22.2%) had mode III of fracture, and 4/9 (44.4%) had mode V of fracture. In group (OS) ( n = 9), 3/9 (33.3%) had mode II of fracture, 1/9 (11.1%) had mode III of fracture, and 5/9 (55.6%) had mode V of fracture. In group (OG) ( n = 9), 1/9 (11.1%) had mode II of fracture, 3/9 (33.3%) had mode III of fracture, and 5/9 (55.6%) had mode V of fracture, [ Figs. 7 and 8 , and 9 ] indicates the frequency of various modes of failure within the groups.
|
PMC11699763_p32
|
PMC11699763
|
Modes of failure
| 4.034276 |
biomedical
|
Study
|
[
0.9976422190666199,
0.0014734938740730286,
0.0008841891540214419
] |
[
0.9994057416915894,
0.0003789248294197023,
0.00012729382433462888,
0.00008812063606455922
] |
en
| 0.999997 |
Fig. 7 Chart showing a comparison of modes of fracture with no statistically significant difference between the three studied groups ( p = 0.027)
|
PMC11699763_p33
|
PMC11699763
|
Modes of failure
| 2.590276 |
biomedical
|
Study
|
[
0.9954030513763428,
0.0020293144043534994,
0.002567542949691415
] |
[
0.978396475315094,
0.02022133767604828,
0.0008746220264583826,
0.000507491989992559
] |
en
| 0.999998 |
Fig. 8 Illustrates the fracture mode observed in this study; as ( A ) mode II: less than half of the restoration lost. ( B ) mode III: Fracture of the restoration extending through the midline; half of the restoration lost. ( C ) mode V: Serious fracture of the tooth structure and restoration
|
PMC11699763_p34
|
PMC11699763
|
Modes of failure
| 2.465959 |
biomedical
|
Study
|
[
0.9736534953117371,
0.002631130628287792,
0.023715373128652573
] |
[
0.7744802236557007,
0.2236400842666626,
0.0006469027721323073,
0.0012327753938734531
] |
en
| 0.999999 |
Fig. 9 Presents the fracture modes from the occlusal view: ( A ) mode III: Fracture of the restoration extending through the midline and ( B ) mode V: Serious fracture of the tooth structure and restoration
|
PMC11699763_p35
|
PMC11699763
|
Modes of failure
| 2.116313 |
biomedical
|
Other
|
[
0.8966803550720215,
0.004069203045219183,
0.09925048053264618
] |
[
0.19117505848407745,
0.8065282702445984,
0.0009559016907587647,
0.001340784365311265
] |
en
| 0.999997 |
This research sought to evaluate and compare the marginal fit and fracture resistance of three different overlay designs using advanced zirconia-reinforced lithium disilicate CAD/CAM material. Both null hypotheses were rejected, as the preparation designs used significantly affected fracture resistance and marginal fit of studied groups. This outcome is consistent with prior research findings that demonstrated a substantial influence of preparation design on the marginal fit and the fracture resistance of restorations . In this study, the marginal fit and fracture resistance of the advanced zirconia-reinforced lithium disilicate (ALD) CAD/ CAM material for three different overlay preparation designs on molars were compared.
|
PMC11699763_p36
|
PMC11699763
|
Discussion
| 4.10555 |
biomedical
|
Study
|
[
0.9970408082008362,
0.001001358381472528,
0.0019578244537115097
] |
[
0.9994770884513855,
0.0002769908751361072,
0.00018856397946365178,
0.00005736624007113278
] |
en
| 0.999998 |
This study selected advanced zirconia-reinforced lithium disilicate (ALD) over other materials, such as 5Y-Zirconia and novel fully crystallized lithium disilicate, due to its superior combination of mechanical strength and aesthetic properties. While 5Y-Z offers enhanced translucency, its reduced fracture toughness and absence of transformation toughening make it more prone to failure under stress. ALD, by contrast, provides a favorable balance between strength and translucency, making it particularly suitable for posterior restorations. Moreover, novel fully crystallized lithium disilicate materials were not fully stabilized or commercially available when the study was initiated. ALD also simplifies bonding protocols by eliminating the need for sandblasting, which can compromise surface integrity, thereby ensuring both durability and efficiency . Diligent efforts were made to replicate the clinical intraoral environment in this study. A single scanner system was used to standardize the intraoral scanning process, minimizing variations and ensuring more accurate results. Each preparation design was duplicated to produce standardized dies using 3D printing resin (Model Resin, Formlabs, Somerville, MA) possessing an elasticity modulus similar to that of dentin , for evaluation of ceramic overlays’ marginal adaptation and fracture resistance. The stimulation of the clinical environment was also taken into account in various aspects of the research, including tooth preparation, impression creation, procedure for fabrication, and cementation of restorations.
|
PMC11699763_p37
|
PMC11699763
|
Discussion
| 4.143203 |
biomedical
|
Study
|
[
0.998375654220581,
0.0005739009357057512,
0.0010503941448405385
] |
[
0.9994242191314697,
0.00023002750822342932,
0.0003002763551194221,
0.00004550270386971533
] |
en
| 0.999997 |
In this research, 3D-printed resin dies (Model Resin, Formlabs) were chosen over natural teeth due to their ability to provide consistent geometry across all specimens, eliminating variations in size and preparation design inherent to natural teeth. This approach also minimizes the challenges and variability associated with collecting, storing, hand-prepping, and handling natural teeth. Resin dies have a tensile strength of 61.0 MPa, which falls within the range of dentin tensile strength (44.4–97.8 MPa), making them a suitable substitute . Studies have demonstrated that crowns cemented to resin die yield fracture strength results comparable to those cemented on natural teeth. For instance, one study concluded that resin dies closely mimic the fracture behavior of crowns on dentin. Furthermore, another study reported that zirconia crowns fractured on resin dies exhibited similar strength values to those fractured on enamel dies . They did not replicate the natural tooth structure for cement adhesion. However, adhesion was not a primary focus of our research.
|
PMC11699763_p38
|
PMC11699763
|
Discussion
| 4.129056 |
biomedical
|
Study
|
[
0.99896240234375,
0.00028275803197175264,
0.0007548531866632402
] |
[
0.9995243549346924,
0.00020996222156099975,
0.00022996589541435242,
0.00003568429747247137
] |
en
| 0.999995 |
Based on Holmes et al., the term “marginal gap” denotes the vertical gap between the cervical edge of restoration and the prepared tooth surface. In simpler terms, the marginal gap pertains to the surface area of the cement, which is subjected to the oral environment and is susceptible to degradation . In this study the marginal gap was evaluated using the direct-view technique using a stereomicroscope. Some earlier research has also utilized this method .
|
PMC11699763_p39
|
PMC11699763
|
Discussion
| 3.560139 |
biomedical
|
Study
|
[
0.9974448680877686,
0.00029108478338457644,
0.0022640300448983908
] |
[
0.9947744011878967,
0.003861934645101428,
0.001271448447369039,
0.0000922173130675219
] |
en
| 0.999996 |
The marginal fit was evaluated in this study before and after thermal aging. The findings indicated that the marginal gap for all groups was below 120 μm before and after thermal aging, falling within the range considered clinically acceptable as determined by the Consensus among most authors suggests . Comparing data on marginal adaptation from various studies poses challenges and potential inaccuracies due to several factors, including variations in preparation design, measurement techniques, the number and location of measurement points, the type of resin cement employed, and the method used to fabricate the restoration. Advanced 4- or 5-axis milling machines, which can enhance the fit between the prepared tooth structure and the restoration’s intaglio surface, also contribute to these variations. However, the precision and reliability of the outcomes improve when more measurement points are included and consistently assessed at the same locations across samples. This approach reduces variability, ensuring that the results accurately reflect the restoration’s adaptation quality. Our study adopted this approach to ensure accurate and reliable results. Therefore, carefully considering these variations is essential when making in vitro comparisons of data . In this research, the restorations were adhered under 200 g applied weight to standardize the pressure applied . However, to ensure consistency in the cementation procedure, all restorations were placed by the same operator. Based on the findings of this research, group OS revealed the minimal marginal gap after cementation with a median gap value of 35.57 μm, succeeded by group OG with a median gap value of 52.94 μm and group O with a median gap value of 76.97 μm.
|
PMC11699763_p40
|
PMC11699763
|
Discussion
| 4.128232 |
biomedical
|
Study
|
[
0.9985803365707397,
0.0010910523124039173,
0.00032867389381863177
] |
[
0.9990761280059814,
0.0003033129614777863,
0.0005183111061342061,
0.00010216931696049869
] |
en
| 0.999999 |
Therefore, the preparation design of group OS (overlay preparation with 1.5 mm anatomical reduction of the occlusal surface and 1.0 mm circumferential shoulder finish line) has more retentive form and more defined margins, resulting in a reduction of the marginal gap size. These results aligned with the findings of Yang et al., who assessed how tooth preparation design influences the marginal adaptation of composite resin CAD-CAM Onlays by comparing two different preparation designs. They noted that the conventional design, which provided more excellent retention, resulted in greater adaptation. However, this result contradicted the findings of Falahchai et al., and Kim et al., Who determined that preparation designs lacking retention would offer superior adaptation to those with retention features. The variation can be ascribed to the different materials employed for restoration fabrication, variations in preparation designs, cementation techniques, and distinct techniques for gap measurement.
|
PMC11699763_p41
|
PMC11699763
|
Discussion
| 4.028285 |
biomedical
|
Study
|
[
0.9989315867424011,
0.0004451422137208283,
0.0006232607993297279
] |
[
0.9939703941345215,
0.00028654845664277673,
0.0056645008735358715,
0.00007852715498302132
] |
en
| 0.999997 |
In this research, there was a reduction in marginal fit (increase in micro gap) in all groups after exposure to thermal aging compared to the initial measurements. This observation aligned with the outcomes reported in earlier studies . They reported that the thermal aging affected all groups’ marginal fit and showed decreasing marginal adaptation. This finding was in agreement with the outcomes obtained in the current study. In group O, the statistical significance of the change in marginal gaps was noticeably lower compared to group OG and group OS. This may be due to the nature of 3D printing resin material; the temperature variations cause the resin to undergo expansion and contraction, particularly in thin margins .
|
PMC11699763_p42
|
PMC11699763
|
Discussion
| 4.081201 |
biomedical
|
Study
|
[
0.9986404776573181,
0.0005384032847359776,
0.0008211207459680736
] |
[
0.9995598196983337,
0.00016326074546668679,
0.00023333111312240362,
0.00004359633385320194
] |
en
| 0.999997 |
In the current study, the fracture resistance was evaluated for all groups after thermal aging. The force required to cause a fracture in the group (O) was 1809.08 N. However, it was 1632.77 N for group (OS). The lower value was recorded in group (OG) 1379.63 N. Studies showed that the occlusal forces generated during chewing and biting usually reach approximately 100 N, with a maximum bite force in habitual occlusion of up to 320 N . These values are considerably lower than the fracture resistance observed in our results, suggesting that partial restorations can comfortably endure occlusal forces without risk of failure. The durability of all-ceramic restorations is impacted by various factors, such as the ceramic material’s microstructure and fatigue, fabrication methods, preparation design, and bonding technique . The results of this study showed that group O (teeth with 1.5 mm anatomical occlusal reduction that received occlusal veneers) and group OS (teeth with 1.5 mm anatomical occlusal reduction and 1.0 mm circumferential shoulder finish line preparation) exhibited the highest fracture resistance of the studied groups under the imposed forces , This observation was consistent with the results obtained from Clausen et al., Who evaluated occlusal overlays and the influencing of ceramic material and preparation design. They reported that all-ceramic full coverage restorations bonded exclusively to enamel exhibited a tendency towards increased fracture resistance compared to those bonded to dentin with a finishing line located in enamel. Falahchai et al. revealed that teeth with less extensive restorations and sound marginal ridges demonstrated a lower incidence of fractures, reporting that increasing the reduction of tooth structure in the central area, such as with a mesio-occluso-distal preparation, leads to compromising the strength of the remaining tooth structure. Alternatively, the intracoronal extension of an overlay may produce a wedging effect. Hence, this clarifies why the fracture resistance outcomes of group (OS) exceeded those of group (OG) (characterized by anatomical occlusal reduction with a central groove), where both the central portion of the tooth and marginal ridges were eliminated. Also, preparation designs that emphasize retention have complex shapes with sharp inner edges, making them more prone to developing predetermined weak points. These geometric changes can lead to localized stress concentrations . This finding aligned with Channarong et al. , Who evaluated the resistance of bonded ceramic overlay restorations to fractures as influenced by different preparation designs. They found that the more natural tooth structure that remains, the more favorable the long-term prognosis for that tooth. Therefore, the conservation of natural tooth structure is crucial for the overall lifespan of the tooth. Also, they demonstrated that overlay restorations utilizing the adhesive system could reinforce defective teeth to a fracture resistance level similar to that of intact teeth. In contrast, the margin type and axial wall length did not affect the final fracture resistance. However, these results contradicted Alberto et al.‘s findings . They reported that the fracture resistance of the full-coverage crown restorations was notably greater than that of the occlusal-cover restorations. Also reported that the effect of the amount of the preparation that was 2.0 mm and 1.5 mm thick needed significantly more fatigue cycles to fail (17 − 15 times fatigue cycles) compared to crowns with a thickness of 1.0 mm. Also, the study has shown that self-adhesive resin cement exhibits weaker mechanical and bonding properties compared to conventional resin-luting cement . However, previous research has demonstrated that a 1 mm thin layer of lithium disilicate ceramic bonded to enamel exhibits a lower risk of fracture compared to bulker restorations (1.5–2 mm as recommended) bonded to dentin, primarily because of reduced mechanical complications . This confirms that other factors like ceramic thickness and type, type of cementation, tooth architecture, and study design can influence fracture resistance in addition to preparation design. Previous research indicated that any loss of tooth structure, whether caused by caries or cavity preparation, reduces the fracture resistance of restorations. The literature suggests that more conservative preparation designs with lower retention features tend to enhance fracture resistance . Building on the previous findings, this explains the results observed in our study. Group O, which featured the most conservative preparation design with no retentive form, demonstrated the highest fracture resistance. In contrast, Group OG, which included a central groove and internal angles, showed increased stress concentration in these areas, leading to reduced fracture resistance.
|
PMC11699763_p43
|
PMC11699763
|
Discussion
| 4.219965 |
biomedical
|
Study
|
[
0.9989780187606812,
0.000511227990500629,
0.0005107588949613273
] |
[
0.9990785121917725,
0.00018014651141129434,
0.0006697654607705772,
0.00007152024045353755
] |
en
| 0.999998 |
According to the study’s results, various preparation designs exhibited distinct. frequencies of modes of failure. Nevertheless, these differences were not significant. More than half of the restoration fractures noted in this study involved damage to both the die and the restorative material. This observation is consistent with the results documented in previous studies by Johnson et al., And Alberto et al., .
|
PMC11699763_p44
|
PMC11699763
|
Discussion
| 3.270719 |
biomedical
|
Study
|
[
0.9947659969329834,
0.0006376056117005646,
0.004596333019435406
] |
[
0.9986826777458191,
0.0007340278825722635,
0.0005128327757120132,
0.00007034884038148448
] |
en
| 0.999997 |
This study had several limitations. These limitations include that it was conducted in vitro, differing from a clinical setting where factors such as saliva and restricted access for the scanner inside the oral cavity would affect the precision of scanning prepared teeth. The internal adaptability was not evaluated in the study and faced challenges in accurately simulating a clinical setting.
|
PMC11699763_p45
|
PMC11699763
|
Discussion
| 2.650472 |
biomedical
|
Study
|
[
0.9981544613838196,
0.0007190207834355533,
0.0011264246422797441
] |
[
0.9969664216041565,
0.002499002730473876,
0.00032925832783803344,
0.00020538599346764386
] |
en
| 0.999999 |
According to the results of this research:
|
PMC11699763_p46
|
PMC11699763
|
Conclusions
| 1.454425 |
biomedical
|
Other
|
[
0.6318063735961914,
0.002230460988357663,
0.3659631907939911
] |
[
0.2275983840227127,
0.7651280760765076,
0.0058509353548288345,
0.0014225952327251434
] |
en
| 0.999997 |
All tested groups showed marginal fit results within clinically acceptable parameters. All preparation designs utilized in this study for creating overlay restorations from ALD ceramics demonstrated acceptable fracture resistance. Higher fracture resistance was shown with intact marginal ridges and less extensive preparations. Modification of tooth preparation significantly impacted the magnitude of the fracture resistance and the marginal gap observed around ALD overlays. Thermal aging affected the marginal gaps of the three groups following the same pattern as before thermal aging.
|
PMC11699763_p47
|
PMC11699763
|
Conclusions
| 4.086622 |
biomedical
|
Study
|
[
0.9983079433441162,
0.0007945504039525986,
0.0008975821547210217
] |
[
0.9994377493858337,
0.00023208430502563715,
0.0002751197898760438,
0.00005507835157914087
] |
en
| 0.999995 |
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an acquired multi-system disease characterized by persistent fatigue and exertional intolerance with a disproportionate worsening after physical or cognitive exertion referred to as post-exertional malaise (PEM). Furthermore, it is accompanied by a variety of other symptoms that are related to immunological, cognitive, and autonomic dysfunction.
|
PMC11699797_p0
|
PMC11699797
|
Introduction
| 3.926058 |
biomedical
|
Other
|
[
0.9984034895896912,
0.0012358070816844702,
0.0003606955287978053
] |
[
0.08394426852464676,
0.535676121711731,
0.3750360608100891,
0.005343515891581774
] |
en
| 0.999995 |
The worldwide prevalence was estimated at 0.89% in a pre-pandemic meta-analysis, though estimates vary according to the case definitions used. 1 While there is evidence for a genetic predisposition to ME/CFS, 2 it is most often triggered by viral infections. 3 Since the COVID-19 pandemic, SARS-CoV-2 has become the leading viral trigger for ME/CFS. 4 Given the high incidence of COVID-19, the prevalence of ME/CFS is expected to strongly increase.
|
PMC11699797_p1
|
PMC11699797
|
Introduction
| 3.628614 |
biomedical
|
Study
|
[
0.9993913173675537,
0.00025582389207556844,
0.0003528306551743299
] |
[
0.4838787317276001,
0.06432997435331345,
0.45062634348869324,
0.0011649916414171457
] |
en
| 0.999996 |
The diagnosis of ME/CFS is based on established diagnostic criteria, with the most frequently used being the Canadian Consensus Criteria (CCC) and the Institute of Medicine (IOM) criteria. These require the presence of key symptoms including lingering fatigue, PEM, unrefreshing sleep, cognitive impairment, and/or orthostatic intolerance. 5 ME/CFS diagnosis relies so far on these clinical criteria, although most patients present with objective clinical findings including diminished handgrip strength or autonomic dysfunction. 4
|
PMC11699797_p2
|
PMC11699797
|
Introduction
| 3.831017 |
biomedical
|
Review
|
[
0.9951393604278564,
0.003989851102232933,
0.0008707562228664756
] |
[
0.027677778154611588,
0.1294601410627365,
0.8403354287147522,
0.002526695840060711
] |
en
| 0.999997 |
The pathophysiological mechanism of ME/CFS is not yet known, but numerous studies suggest dysregulation of the immune system. Elevated antibodies were found in ME/CFS patients in several studies, most frequently against adrenergic and muscarinic receptors. 6 , 7 Elevated β1 and β2 adrenergic receptor autoantibodies (β1/β2 AR-AB) and M3/M4 acetylcholine receptor autoantibodies (M3/M4 AChR-AB) are likely to modulate the autonomic nervous system function and vasoregulation. 7 , 8
|
PMC11699797_p3
|
PMC11699797
|
Introduction
| 4.111707 |
biomedical
|
Study
|
[
0.9997549653053284,
0.00011816468759207055,
0.00012697062629740685
] |
[
0.9911310076713562,
0.0009441022993996739,
0.007799188606441021,
0.0001256699179066345
] |
en
| 0.999995 |
Levels of these autoantibodies were found to be associated with symptom severity and structural alterations in the central nervous system in both post-COVID syndrome (PCS) and ME/CFS. 9 , 10 , 11 , 12 , 13 The β2 AR-AB was the best marker for distinguishing PCS from recovered patients, and levels of β2 AR-AB were associated with both fatigue and vasomotor symptoms in PCS-ME/CFS patients. 10 , 14 Apart from elevated autoantibodies a chronic activation of inflammatory pathways and an alteration in memory B-cells were shown. 15 , 16
|
PMC11699797_p4
|
PMC11699797
|
Introduction
| 4.114207 |
biomedical
|
Study
|
[
0.999665379524231,
0.0001850252301665023,
0.0001495035830885172
] |
[
0.9940798282623291,
0.00032314914278686047,
0.0054859016090631485,
0.00011117015674244612
] |
en
| 0.999998 |
The goal of immunoadsorption (IA) is to improve the clinical condition of patients with autoantibody-mediated diseases by selectively removing immunoglobulins from circulation via extracorporeal adsorption from their plasma. 17 , 18 Unlike plasmapheresis, IA employs a high-affinity column that specifically binds and eliminates immunoglobulins including autoantibodies and immune complexes, leaving other plasma components behind. 18
|
PMC11699797_p5
|
PMC11699797
|
Introduction
| 3.959991 |
biomedical
|
Other
|
[
0.9984331727027893,
0.0011869905283674598,
0.00037981904461048543
] |
[
0.252191960811615,
0.6587595343589783,
0.08669722080230713,
0.002351326635107398
] |
en
| 0.999996 |
Given the previous evidence for a potential role of autoantibodies in PCS and ME/CFS and the effectiveness of IA in postinfectious ME/CFS, we here aimed to evaluate the effectiveness of IA treatment specifically in post-COVID ME/CFS patients. 19 , 20 Effectiveness was measured by assessing patient-reported outcomes and hand grip strength. We hypothesized that IA would lead to clinical improvement in ME/CFS patients four weeks after treatment, with an additional beneficial effect from repeat IA in responders with relapse.
|
PMC11699797_p6
|
PMC11699797
|
Introduction
| 4.11081 |
biomedical
|
Study
|
[
0.9955490827560425,
0.0041641914285719395,
0.00028670154279097915
] |
[
0.996938943862915,
0.0021278630010783672,
0.0006154718575999141,
0.0003176805912517011
] |
en
| 0.999996 |
This prospective cohort study, conducted at the outpatient department for immunodeficiencies at the Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, recruited patients between October 2022 and October 2023. Patients received IA treatment and follow-up visits for 12 months. Responders to the first cycle of IA were offered a second cycle. An interim report of the first 10 patients was published in October 2023. 21 This study was being conducted within the National Clinical Studies Group (NKSG), a clinical trial and translational research platform focused on developing therapies for PCS and ME/CFS, funded by the German Ministry of Education and Research (BMBF). 22
|
PMC11699797_p7
|
PMC11699797
|
Study design
| 3.730855 |
biomedical
|
Study
|
[
0.9715566039085388,
0.02754555456340313,
0.0008977878023870289
] |
[
0.9709675312042236,
0.026995211839675903,
0.0005175182595849037,
0.0015197310131043196
] |
en
| 0.999998 |
Patients were diagnosed and recruited at the outpatient department for immunodeficiencies at the Institute of Medical Immunology at the Charité - Universitätsmedizin Berlin. The diagnosis of ME/CFS was based on the modified Canadian Consensus Criteria (CCC) and a minimum of 14 h of PEM. 23 , 24 Inclusion criteria encompassed elevated β2 AR-AB at the time of screening and SARS-CoV-2 infection at the time of disease onset. All patients had to provide proof of SARS-CoV-2 infection by positive PCR, antigen test, or serology (SARS-CoV-2 nucleocapsid protein antibodies).
|
PMC11699797_p8
|
PMC11699797
|
Patients
| 3.995517 |
biomedical
|
Study
|
[
0.9951818585395813,
0.0045919641852378845,
0.00022606411948800087
] |
[
0.995922327041626,
0.003069056663662195,
0.0004280047432985157,
0.0005805737455375493
] |
en
| 0.999996 |
Patients were excluded from this study if they had relevant comorbidities, 25 pre-existing fatigue, evidence of organ dysfunction, or acute or chronic infections such as HIV or hepatitis. Additionally, patients who were unable to leave their homes due to the severity of their illness were also excluded.
|
PMC11699797_p9
|
PMC11699797
|
Patients
| 2.577512 |
biomedical
|
Study
|
[
0.9691125154495239,
0.029055573046207428,
0.0018318920629099011
] |
[
0.9748977422714233,
0.022203756496310234,
0.0010233334032818675,
0.0018751686438918114
] |
en
| 0.999997 |
All patients signed informed consent before study inclusion. The Ethics Committee of the Charité - Universitätsmedizin Berlin approved this study in accordance with the 1964 Declaration of Helsinki and its later amendments .
|
PMC11699797_p10
|
PMC11699797
|
Patients
| 1.191431 |
biomedical
|
Other
|
[
0.9683017134666443,
0.012578700669109821,
0.01911957748234272
] |
[
0.028316408395767212,
0.9674527645111084,
0.0007842120248824358,
0.003446615766733885
] |
en
| 0.999997 |
Five sessions of IA were administered at the Department of Nephrology at Charité - Universitätsmedizin Berlin. IA treatment was conducted in an outpatient setting over a ten-day period, with sessions spaced no more than two days apart. The TheraSorb® – Ig omni 5 adsorber (Miltenyi Biotech B.V. & Co. KG, Bergisch Gladbach, Germany) was used for removal of human lambda and kappa chains containing immunoglobulins IgG (subclasses IgG1-IgG4), IgA, IgM, IgE, and immune complexes as well as free lambda and kappa light chains from the plasma.
|
PMC11699797_p11
|
PMC11699797
|
Procedures
| 3.767353 |
biomedical
|
Study
|
[
0.9879012107849121,
0.011686135083436966,
0.00041269027860835195
] |
[
0.6936930418014526,
0.2945393919944763,
0.0017526898300275207,
0.010014846920967102
] |
en
| 0.999997 |
To ascertain the efficacy of IA, total serum immunoglobulin levels were assessed via immunoturbidimetry before, during, and after treatment. Antibodies against β1, β2, M3, and M4 receptors were determined using ELISA technology by CellTrend GmbH, Luckenwalde, Germany, both before and after treatment. Intra- and inter-assay coefficients of variation for the ELISAs provided by CellTrend were: b1 AR-AB 9.6%/12.0%, b2 AR-AB 4.2%/3.8%, M3 AchR-AB 5.9%/10.1%, and M4 AchR-AB 7.3%/12.5%. Pre- and post-treatment samples were analyzed in the same assay run. The upper normal levels of autoantibodies were determined based on validation studies of a healthy control group and defined as being larger than the 90th percentile of a healthy control group (>14U/l for β2 AR-AB).
|
PMC11699797_p12
|
PMC11699797
|
Procedures
| 4.125963 |
biomedical
|
Study
|
[
0.9993141889572144,
0.000505987205542624,
0.000179874652530998
] |
[
0.9992252588272095,
0.0003281179815530777,
0.00035905136610381305,
0.00008754415466682985
] |
en
| 0.999998 |
For patient-reported outcomes, questionnaires were filled out before, during, and after the treatment in monthly intervals and validated by physicians. Patients’ health-related quality of life was assessed using the 36-Item Short-Form Survey (SF-36), with scores ranging from 0 to 100, with 100 indicating no limitations. 26 Response to IA treatment was defined as a minimum increase in the SF-36 physical functioning domain (SF-36 PF) of 10 points from baseline to four weeks post IA, indicating a clinically relevant improvement. 27 Fatigue was evaluated using the Fatigue Severity Scale (FSS), ranging from 9 to 63, with a total score of 36 or more suggesting relevant fatigue. 28 Additionally, disease-related disability was scored according to the Bell score, rating the restriction in daily functioning on a scale from 0 to 100, with 100 indicating no restriction. 29 PEM was evaluated using the DePaul Symptom Questionnaire (PEM-DSQ), ranging from 0 to 20 for both severity and frequency, PEM duration was assessed ranging from 0 to 6, with higher values indicating higher PEM severity. 24 Further cardinal symptoms of both PCS and ME/CFS, including fatigue, muscle pain, immunological symptoms, and cognitive impairment, were scored on a numeric rating scale (NRS) from 1 to 10, with 10 indicating maximum symptom severity (not formally validated). Autonomic dysfunction was evaluated according to the Composite Autonomic Symptom Score (COMPASS31), ranging from 0 to 100, with 100 indicating maximum autonomic dysfunction. 30
|
PMC11699797_p13
|
PMC11699797
|
Procedures
| 4.223548 |
biomedical
|
Study
|
[
0.9954713582992554,
0.004232116509228945,
0.00029655126854777336
] |
[
0.9963616728782654,
0.0015697549097239971,
0.0017443085089325905,
0.00032419682247564197
] |
en
| 0.999998 |
Handgrip strength (HGS) of the dominant hand was measured using a digital hand dynamometer (EH101, Deyard, Shenzhen, China) in two separate sessions. Rest time between sessions was 60 min, in which no strenuous physical activity took place. Before starting the measurement, patients were shown two separate demonstrations of how the dynamometer should be used. Patients sat in an upright position facing a standard table during measurements of HGS. The forearm of the dominant hand was placed on the table in full supination holding the dynamometer. Under supervision and verbal motivation, the handle was pulled 10 times with maximum force for three seconds, followed by a five-second relaxation phase. The dynamometer displayed the highest value reached within these three seconds (measurement in kg), this single value was then recorded. The attempt with the highest reading out of ten repetitions was recorded as the maximum strength (Fmax), and the average strength (Fmean) of each session was calculated. 31
|
PMC11699797_p14
|
PMC11699797
|
Procedures
| 4.134043 |
biomedical
|
Study
|
[
0.9961814880371094,
0.0035340168979018927,
0.0002844806876964867
] |
[
0.9974218606948853,
0.0017112087225541472,
0.0004898995975963771,
0.0003771033661905676
] |
en
| 0.999998 |
Further, the Reactive hyperemia index (RHI), which is a measure for endothelial function, was assessed using a peripheral arterial tonometry device . The technology measures the pulsatile volume changes in the vascular beds of the finger using optical sensors. The subjects were in supine position for a minimum of 15 min before measurements, in a quiet, temperature-controlled room. Occlusion of the brachial artery was performed on the nondominant upper arm using a standard blood pressure cuff. The occlusion pressure was at least 60 mmHg above the systolic blood pressure. Upon release of the cuff, the resulting surge in blood flow causes vessel dilation. Each recording consisted of five minutes of baseline measurement, five minutes of occlusion measurement, and five minutes post-occlusion measurement. The post-occlusion dilation relative to pre-occlusion levels is calculated as the RHI. Endothelial dysfunction was defined as an RHI ≤ 1.67 based on previous cohort studies. 32
|
PMC11699797_p15
|
PMC11699797
|
Procedures
| 4.124345 |
biomedical
|
Study
|
[
0.9993601441383362,
0.0004759597941301763,
0.00016395763668697327
] |
[
0.9991100430488586,
0.00034672697074711323,
0.00044244443415664136,
0.00010072572331409901
] |
en
| 0.999997 |
Study data were collected and managed using the REDCap electronic data capture tools hosted at the Charité - Universitätsmedizin Berlin. 33 , 34
|
PMC11699797_p16
|
PMC11699797
|
Procedures
| 1.507173 |
biomedical
|
Study
|
[
0.9830827713012695,
0.002625375287607312,
0.014291906729340553
] |
[
0.6479333639144897,
0.34817278385162354,
0.002180699026212096,
0.0017131527420133352
] |
en
| 0.999996 |
Statistical analyses were conducted using R version 4.3.0 and RStudio version 2023.03.1. A linear mixed-effects model (LMM) was employed to assess changes in multiple outcome variables across different time points. The analysis was performed using the lmer function from the lme4 package (version 1.1-35.5), and ggplot2 (version 3.5.0) was utilized for data visualization. For each outcome variable, the LMM included time as a fixed effect and patient number as a random effect to account for within-patient correlation. The mixed model was fitted using restricted maximum likelihood (REML), and statistical significance was evaluated using t-tests with p -values approximated through Satterthwaite's method for degrees of freedom, implemented via the lmerTest package (version 3.1-3). Missing data were accounted for by using all available observations in the model, allowing for the estimation of fixed and random effects without listwise deletion, assuming data are missing at random.
|
PMC11699797_p17
|
PMC11699797
|
Statistical analysis
| 4.117046 |
biomedical
|
Study
|
[
0.9994174242019653,
0.00033341627568006516,
0.00024912803201004863
] |
[
0.9989062547683716,
0.0005734089063480496,
0.0004402822523843497,
0.00008015008643269539
] |
en
| 0.999998 |
For comparisons between groups the non-parametric Whitney-U test was used. Correlation analysis was performed using the nonparametric Spearman coefficient. A two-tailed p -value of <0.05 was considered to provide evidence of a statistically significant result.
|
PMC11699797_p18
|
PMC11699797
|
Statistical analysis
| 3.528713 |
biomedical
|
Study
|
[
0.9991284012794495,
0.0002839562948793173,
0.0005876421346329153
] |
[
0.9594087600708008,
0.038961973041296005,
0.0013536419719457626,
0.0002755201421678066
] |
en
| 0.999999 |
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
|
PMC11699797_p19
|
PMC11699797
|
Role of the funding source
| 0.978864 |
other
|
Other
|
[
0.06100447475910187,
0.0020385771058499813,
0.9369570016860962
] |
[
0.0030792111065238714,
0.9962848424911499,
0.00035098165972158313,
0.0002849063603207469
] |
en
| 0.999995 |
The β2 AR-AB levels of 402 patients, who met the CCC for post-infectious ME/CFS, were measured between June 2022 and March 2023. Out of these 402 patients, 189 (47%) had elevated β2 AR-AB levels. From this group, patients who planned IA treatment and fulfilled inclusion criteria were offered to participate in this trial and 23 were recruited for the study between September 2022 and October 2023. Three patients withdrew their consent to participate prior to the treatment due to concerns about the burden of study participation. 20 patients completed a six-month follow-up resulting in an 87% retention rate, suggesting that the protocol was generally acceptable to those who proceeded with the treatment.
|
PMC11699797_p20
|
PMC11699797
|
Results
| 3.869976 |
biomedical
|
Study
|
[
0.7545285224914551,
0.24121077358722687,
0.00426067179068923
] |
[
0.5374614596366882,
0.4499852955341339,
0.002224960830062628,
0.0103283217176795
] |
en
| 0.999998 |
The five IA treatment sessions were completed for all patients within a 10-day period in an outpatient setting. Sessions lasted between 4.5 and 9 h and were followed by a minimum of one day and a maximum of two days of rest. In five out of 20 patients, a Shaldon's catheter was required for vascular access; for the other patients peripheral venous puncture was sufficient. One patient experienced a thrombosis of the internal jugular vein as a side effect of the catheter. Otherwise, no severe side effects of IA treatment were reported.
|
PMC11699797_p21
|
PMC11699797
|
Results
| 3.599096 |
clinical
|
Study
|
[
0.391704797744751,
0.6061025857925415,
0.0021926178596913815
] |
[
0.7283121943473816,
0.16623328626155853,
0.004736384842544794,
0.10071811825037003
] |
en
| 0.999997 |
The treatment was generally reported as physically exhausting and frequently triggered PEM. To mitigate this, we aimed to minimize external stressors, ensured proper oral hydration, and offered lorazepam for up to three days as supportive therapy.
|
PMC11699797_p22
|
PMC11699797
|
Results
| 1.795682 |
clinical
|
Other
|
[
0.23960508406162262,
0.7541846632957458,
0.006210244260728359
] |
[
0.030207863077521324,
0.6614927053451538,
0.0031942243222147226,
0.30510520935058594
] |
en
| 0.999996 |
The median disease duration was 22 months (IQR: 15–31) at the time of inclusion. Seven patients were male and 13 were female with a median age of 40 (IQR: 36–51). All patients had a severe degree of disability with a median Bell score of 30 (range 20–40), corresponding to reduction of the functional state to 50% and being usually housebound. Individual patient characteristics are displayed in Table 1 . Table 1 Cohort characteristics and response to treatment as assessed by the SF36 PF. Patient Gender (M/F) Age (years) Time since COVID-19 (months) SF36 PF pre IA SF36 PF post IA (M1) ΔSF36 PF Responder to IA (yes/no) 1 F 36 39 15 70 55 Yes 2 M 41 25 25 70 45 Yes 3 F 56 15 25 65 40 Yes 4 F 37 21 45 85 40 Yes 5 F 52 23 45 80 35 Yes 6 M 59 31 35 65 30 Yes 7 F 51 38 15 35 20 Yes 8 F 31 19 40 60 20 Yes 9 F 59 32 20 35 15 Yes 10 F 50 31 15 30 15 Yes 11 F 36 10 15 25 10 Yes 12 M 36 9 40 50 10 Yes 13 M 46 32 20 30 10 Yes 14 M 57 14 50 60 10 Yes 15 M 33 23 25 30 5 No 16 F 36 15 25 30 5 No 17 F 44 14 5 5 0 No 18 M 33 39 60 60 0 No 19 F 37 15 30 25 −5 No 20 F 39 19 50 45 −5 No F: female; IA: immunoadsorption; M: male; M1: month 1 post immunoadsorption; SF36 PF: Short Form-36 physical functioning.
|
PMC11699797_p23
|
PMC11699797
|
Results
| 4.062853 |
biomedical
|
Study
|
[
0.970312774181366,
0.029216479510068893,
0.0004708107153419405
] |
[
0.9902218580245972,
0.006010659970343113,
0.0008047279552556574,
0.002962730824947357
] |
en
| 0.999994 |
There was a positive correlation between the immune score, which depicts the severity of the lymph node pain, throat pain, and flu-like symptoms, and the levels of antibodies against β1 AR ( r = 0.53, p = 0.017), β2 AR ( r = 0.46, p = 0.040), M3 AChR ( r = 0.60, p = 0.006), and M4 AChR ( r = 0.60, p = 0.006) at baseline. Otherwise, no significant correlation was found between the autoantibody levels and the clinical presentation.
|
PMC11699797_p24
|
PMC11699797
|
Results
| 4.063676 |
biomedical
|
Study
|
[
0.9995039701461792,
0.0003009490901604295,
0.0001950211590155959
] |
[
0.9994645714759827,
0.00018759109661914408,
0.00028657607617788017,
0.00006130913970991969
] |
en
| 0.999997 |
There was a mean increase in the SF-36 PF of 17.75 points ( CI : 13.41–26.16, p < 0.001) four weeks post IA. The corresponding Cohen's d was calculated as 1.19, indicating a large effect size. There were, however, four patients with an increase of 10 points, which is considered as a clinically meaningful but small effect. 27 As seen in Fig. 1 , though the SF-36 PF scores tended to decrease between three and six months post IA, at month six post IA a significant mean improvement of 12.81 points ( CI : 4.99–20.61, p = 0.002) remained. Fourteen out of 20 patients (70%) responded to the treatment as defined by an increase of at least 10 points in the SF-36 PF four weeks post IA suggesting a clinically meaningful improvement. Seven patients were non-responders according to this definition; however, two of these showed a delayed response at month 2. Fig. 1 Course of the mean 36-Item Short-Form Survey physical functioning domain (SF36 PF) over the study period. The duration of IA therapy is indicated by the green bar. A higher score indicates less restriction in physical functioning. Error bars represent 95% confidence intervals. Data were analyzed using a linear mixed-effects model fitted by restricted maximum likelihood (REML), with t-tests computed using Satterthwaite's method for degrees of freedom with significance levels indicated as ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001. From top to bottom, the panels display the trajectories of the SF36 PF for: a) the whole cohort ( n = 20), b) responders to the treatment defined by a ≥ ten-point increase in the SF36 PF at month 1 post IA ( n = 14), and c) non-responders to the treatment defined by a ≤ ten-point increase in the SF36 PF at month 1 post IA ( n = 7).
|
PMC11699797_p25
|
PMC11699797
|
Results
| 4.166182 |
biomedical
|
Study
|
[
0.9971204996109009,
0.0025395683478564024,
0.0003399105044081807
] |
[
0.9987671375274658,
0.0006108488305471838,
0.0004224258882459253,
0.00019956688629463315
] |
en
| 0.999997 |
There was no significant difference in age, symptom severity, disease duration, or level of β2 AR-AB between responders and non-responders. However, among female patients, responders had a significantly higher maximum HGS at baseline ( Mdn = 23.5 kg, IQR: 17.7–25.5 kg) compared to non-responders ( Mdn = 9.8 kg, IQR: 8.53–11.05 kg) ( z = −2.62, p = 0.006, r = 0.73).
|
PMC11699797_p26
|
PMC11699797
|
Results
| 4.103904 |
biomedical
|
Study
|
[
0.998970627784729,
0.0008058228413574398,
0.00022348591301124543
] |
[
0.9992934465408325,
0.0003511318936944008,
0.0002640446473378688,
0.00009124755160883069
] |
en
| 0.999997 |
Serum IgG, IgA, and IgM levels were collected from all patients at baseline, before each treatment, and after treatment. Compared to baseline, IgG, IgA, and IgM were significantly decreased during IA treatment ( p < 0.001) with a mean IgG reduction of 8.66 g/l ( CI : 8.06–9.26 g/l) (79%, CI : 73–84%), mean IgA reduction of 1.3 g/l ( CI : 1.2–1.51 g/l) (68%, CI : 63–78%), and mean IgM reduction of 1.1 g/l ( CI : 0.84–1.34 d/l) (76%, CI : 58–93%) at day five of the treatment. Fig. 2 a–c shows the course of immunoglobulin levels over time. β2 AR-AB decreased in parallel with the immunoglobulins with a mean reduction of 26.57 U/l ( CI : 20.11–33.02 U/l) (77%, CI : 58–95%). Fig. 2 Course of immunoglobulin and autoantibody levels over the study period ( n = 20), the duration of IA therapy is indicated by the green bar. Error bars represent 95% confidence intervals. Data were analyzed using a linear mixed-effects model fitted by restricted maximum likelihood (REML), with t-tests computed using Satterthwaite's method for degrees of freedom with significance levels indicated as ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001. From left to right, the panels display the trajectories of: a) immunoglobulin G (IgG), b) immunoglobulin A (IgA), c) immunoglobulin M (IgM), d) β1 adrenergic receptor autoantibodies (β1 AR-AB), e) β2 adrenergic receptor autoantibodies (β2 AR-AB), f) M3 acetylcholine receptor autoantibodies (M3 AchR-AB), and g) M4 acetylcholine receptor autoantibodies (M4 AchR-AB).
|
PMC11699797_p27
|
PMC11699797
|
Results
| 4.167166 |
biomedical
|
Study
|
[
0.9990924596786499,
0.0006756474613212049,
0.00023189815692603588
] |
[
0.9993392825126648,
0.0002739901829045266,
0.0002907867019530386,
0.00009586192027200013
] |
en
| 0.999998 |
Patients reported improvements in several key clinical symptoms at four weeks post IA. There were significant improvements in fatigue, as measured by the SF-36 energy/fatigue domain, and in pain, as measured by the SF-36 pain domain, following IA treatment. These improvements remained significant through month six. The maximal change was observed two months after IA, with a mean increase of 19 points ( CI : 11.61–26.39, p < 0.001) and 22.63 points ( CI : 13.28–31.96, p < 0.001) from baseline, respectively, as shown in Fig. 3 . Fig. 3 Clinical symptom progression over the study period ( n = 20). The duration of IA therapy is indicated by the green bar. Error bars represent 95% confidence intervals. Data were analyzed using a linear mixed-effects model fitted by restricted maximum likelihood (REML), with t-tests computed using Satterthwaite's method for degrees of freedom with significance levels indicated as ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001. From left to right, the panels display the trajectories of: a) 36-Item Short-Form Survey energy/fatigue domain (SF36 energy/fatigue), where a higher score indicates less fatigue, b) 36-Item Short-Form Survey pain domain (SF36 pain), where a higher score indicates less pain, c) post-exertional malaise (PEM) as assessed by the DePaul Symptom Questionnaire (DSQ-PEM), higher scores indicate more severe PEM, and d) Composite Autonomic Symptom Score (COMPASS31), where a higher score indicates more autonomic symptoms.
|
PMC11699797_p28
|
PMC11699797
|
Results
| 4.189101 |
biomedical
|
Study
|
[
0.9977774024009705,
0.001925236196257174,
0.00029734597774222493
] |
[
0.9987921118736267,
0.0005538722616620362,
0.0004864027432631701,
0.0001676584070082754
] |
en
| 0.999995 |
Furthermore, patients reported a lasting improvement in autonomic symptoms, as shown in Fig. 3 d. Improvements were most noticeable in the orthostatic, secretomotor, and gastrointestinal domains of the COMPASS31, which are shown in Figure S4 in the Supplement , as well as in the total score with a mean decrease of 12.23 points ( CI : 19.06–5.4, p = 0.001) at month one.
|
PMC11699797_p29
|
PMC11699797
|
Results
| 4.144843 |
biomedical
|
Study
|
[
0.9973512887954712,
0.0023761403281241655,
0.0002726589736994356
] |
[
0.998488187789917,
0.0007268941262736917,
0.0005869643646292388,
0.0001980144443223253
] |
en
| 0.999995 |
All patients experienced severe PEM lasting at least 14 h, as specified by the inclusion criteria. Both frequency and severity of post-exertional symptoms significantly decreased after IA according to the DSQ-PEM. The total score is shown in Fig. 3 c, remaining significantly decreased through month six.
|
PMC11699797_p30
|
PMC11699797
|
Results
| 3.405431 |
biomedical
|
Study
|
[
0.987441897392273,
0.011655731126666069,
0.0009023947059176862
] |
[
0.9953811168670654,
0.0033917624969035387,
0.0004454428271856159,
0.0007817232399247587
] |
en
| 0.999997 |
Additionally, there was a significant mean decrease of 4.9 points ( CI : 1.34–8.46, p = 0.009) in fatigue as assessed by the FSS at month one after IA as shown in Figure S3 in the Supplement . According to the symptom scores (NRS 1–10), there were also improvements in muscle pain, immunological as well as cognitive symptoms, that remained significant through month 6 with their maximum decrease between months two and three after IA as shown in Figure S1 in the Supplement .
|
PMC11699797_p31
|
PMC11699797
|
Results
| 4.115742 |
biomedical
|
Study
|
[
0.9985870122909546,
0.0011852503521367908,
0.00022771675139665604
] |
[
0.998783528804779,
0.0006311057368293405,
0.000453937886049971,
0.00013140258670318872
] |
en
| 0.999997 |
The improvement in the degree of disability according to the Bell score post IA reached statistical significance only at months two, four, five, and six, with a maximum mean increase of 5.18 points ( CI : 1.24–9.12, p = 0.013) at month two post IA as shown in Figure S2 in the Supplement .
|
PMC11699797_p32
|
PMC11699797
|
Results
| 4.078932 |
biomedical
|
Study
|
[
0.9987836480140686,
0.0009023537277244031,
0.0003139916225336492
] |
[
0.9991446733474731,
0.0004483311786316335,
0.0003138889151159674,
0.00009316507203038782
] |
en
| 0.999997 |
Subsets and Splits
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The query retrieves a limited set of clinical case documents with a high educational score, providing a basic filtered view of the dataset.