1.Cost-effectiveness of Fractional Flow Reserve Versus Intravascular Ultrasound to Guide Percutaneous Coronary Intervention: Results From the FLAVOUR Study
Doyeon HWANG ; Hea-Lim KIM ; Jane KO ; HyunJin CHOI ; Hanna JEONG ; Sun-ae JANG ; Xinyang HU ; Jeehoon KANG ; Jinlong ZHANG ; Jun JIANG ; Joo-Yong HAHN ; Chang-Wook NAM ; Joon-Hyung DOH ; Bong-Ki LEE ; Weon KIM ; Jinyu HUANG ; Fan JIANG ; Hao ZHOU ; Peng CHEN ; Lijiang TANG ; Wenbing JIANG ; Xiaomin CHEN ; Wenming HE ; Sung Gyun AHN ; Ung KIM ; You-Jeong KI ; Eun-Seok SHIN ; Hyo-Soo KIM ; Seung-Jea TAHK ; JianAn WANG ; Tae-Jin LEE ; Bon-Kwon KOO ;
Korean Circulation Journal 2025;55(1):34-46
Background and Objectives:
The Fractional Flow Reserve and Intravascular UltrasoundGuided Intervention Strategy for Clinical Outcomes in Patients with Intermediate Stenosis (FLAVOUR) trial demonstrated non-inferiority of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) compared with intravascular ultrasound (IVUS)-guided PCI. We sought to investigate the cost-effectiveness of FFR-guided PCI compared to IVUS-guided PCI in Korea.
Methods:
A 2-part cost-effectiveness model, composed of a short-term decision tree model and a long-term Markov model, was developed for patients who underwent PCI to treat intermediate stenosis (40% to 70% stenosis by visual estimation on coronary angiography).The lifetime healthcare costs and quality-adjusted life-years (QALYs) were estimated from the healthcare system perspective. Transition probabilities were mainly referred from the FLAVOUR trial, and healthcare costs were mainly obtained through analysis of Korean National Health Insurance claims data. Health utilities were mainly obtained from the Seattle Angina Questionnaire responses of FLAVOUR trial participants mapped to EQ-5D.
Results:
From the Korean healthcare system perspective, the base-case analysis showed that FFR-guided PCI was 2,451 U.S. dollar lower in lifetime healthcare costs and 0.178 higher in QALYs compared to IVUS-guided PCI. FFR-guided PCI remained more likely to be cost-effective over a wide range of willingness-to-pay thresholds in the probabilistic sensitivity analysis.
Conclusions
Based on the results from the FLAVOUR trial, FFR-guided PCI is projected to decrease lifetime healthcare costs and increase QALYs compared with IVUS-guided PCI in intermediate coronary lesion, and it is a dominant strategy in Korea.
2.Association of Age, Sex and Education With Access to the Intravenous Thrombolysis for Acute Ischemic Stroke
Yoona KO ; Beom Joon KIM ; Youngran KIM ; Jong-Moo PARK ; Kyusik KANG ; Jae Guk KIM ; Jae-Kwan CHA ; Tai Hwan PARK ; Kyungbok LEE ; Jun LEE ; Keun-Sik HONG ; Byung-Chul LEE ; Kyung-Ho YU ; Dong-Eog KIM ; Joon-Tae KIM ; Jay Chol CHOI ; Jee Hyun KWON ; Wook-Joo KIM ; Kyu Sun YUM ; Sung-Il SOHN ; Hyungjong PARK ; Sang-Hwa LEE ; Kwang-Yeol PARK ; Chi Kyung KIM ; Sung Hyuk HEO ; Moon-Ku HAN ; Anjail Z. SHARRIEF ; Sunil A. SHETH ; Hee-Joon BAE ;
Journal of Korean Medical Science 2025;40(13):e49-
Background:
Barriers to treatment with intravenous thrombolysis (IVT) for patients with acute ischemic stroke (AIS) in South Korea remain incompletely characterized. We analyze a nationwide prospective cohort to determine patient-level features associated with delayed presentation and non-treatment of potential IVT-eligible patients.
Methods:
We identified consecutive patients with AIS from 01/2011 to 08/2023 from a multicenter and prospective acute stroke registry in Korea. Patients were defined as IVT candidates if they presented within 4.5 hours from the last known well, had no lab evidence of coagulopathy, and had National Institute of Health Stroke Scale (NIHSS) ≥ 4. Multivariable generalized linear mixed regression models were used to investigate the associations between their characteristics and the IVT candidates or the use of IVT among the candidates.
Results:
Among 84,103 AIS patients, 41.0% were female, with a mean age of 69 ± 13 years and presentation NIHSS of 4 [interquartile range, 1–8]. Out of these patients, 13,757 (16.4%) were eligible for IVT, of whom 8,179 (59.5%) received IVT. Female sex (adjusted risk ratio [RR], 0.90; 95% confidence interval [CI], 0.86–0.94) and lower years of education (adjusted RR, 0.90; 95% CI, 0.84–0.97 for 0–3 years, compared to ≥ 13 years) were associated with a decreased likelihood of presenting as eligible for IVT after AIS; meanwhile, young age (adjusted RR, 1.12; 95% CI, 1.01–1.24 for ≤ 44 years, compared to 75–84 years) was associated with an increased likelihood of being an IVT candidate. Among those who were eligible for IVT, only age was significantly associated with the use of IVT (adjusted RR, 1.09; 95% CI, 1.03–1.16 for age 65–74 and adjusted RR, 0.83; 95% CI, 0.76–0.90 for ≥ 85 years, respectively).
Conclusion
Most patients with AIS present outside IVT eligibility in South Korea, and only 60% of eligible patients were ultimately treated. We identified increased age, female sex and lower education as key features on which to focus interventions for improving IVT utilization.
3.Group B Streptococcus Detection Rate and Clindamycin Resistance Among Reproductive-Age Women in Korea During 2003–2022
Areum SHIN ; Doo Ri KIM ; Ji-Hee SUNG ; Jinyoung YANG ; Suk-Joo CHOI ; Cheong-Rae ROH ; Tae Yeul KIM ; Hee Jae HUH ; Nam Yong LEE ; Soo-young OH ; Yae-Jean KIM
Journal of Korean Medical Science 2025;40(15):e29-
Background:
Group B Streptococcus (GBS) is one of the leading causes of neonatal earlyonset sepsis, resulting in high mortality and significant comorbidity. Intrapartum penicillin prophylaxis is recommended for pregnant women with GBS colonization to prevent vertical transmission. For pregnant women at high risk of anaphylaxis to penicillin, clindamycin is recommended only if the susceptibility of GBS isolates has been identified. We retrospectively examined the GBS detection rate and clindamycin resistance among Korean women of reproductive age over the last 20 years.
Methods:
Microbiologic studies using vaginal, vaginal–rectal or vaginal–perianal swabs from female patients 15–49 years of age during 2003–2022 were reviewed. Annual GBS detection rates and clindamycin resistance rates were calculated. The study period was divided into two periods (period 1, 2003–2015; period 2, 2016–2022) based on the introduction of universal culture-based GBS screening in our center in 2016. GBS detection rates and clindamycin resistance rates were compared between the periods using χ2 tests.
Results:
A total of 14,571 women were tested 16,879 times and GBS was isolated in 1,054 tests (6.2%), with 423 clindamycin-resistant isolates (40.1%). The GBS detection rate increased from 3.4% (301/8,869) in period 1 to 9.4% (2,753/8,010) in period 2 (P < 0.001). Even during period 1, the GBS detection rate was higher in 2009–2015 compared to 2003–2008 (P < 0.001). Clindamycin resistance rates have remained at similar levels since 2009, which were 39.5% (199/301) in period 1 and 40.2% (303/753) in period 2 (P = 0.833).
Conclusion
This study demonstrated that GBS detection rates in Korean women of reproductive age significantly increased almost three times during the twenty years of the study period, with a persistently high clindamycin resistance rate of up to 40%.
4.Radiation-Induced Meningiomas Have an Aggressive Clinical Course:Genetic Signature Is Limited to NF2Alterations, and Epigenetic Signature Is H3K27me3 Loss
Tae-Kyun KIM ; Jong Seok LEE ; Ji Hoon PHI ; Seung Ah CHOI ; Joo Whan KIM ; Chul-Kee PARK ; Hongseok YUN ; Young-Soo PARK ; Sung-Hye PARK ; Seung-Ki KIM
Journal of Korean Medical Science 2025;40(18):e62-
Background:
While the clinical course of radiation-induced meningioma (RIM) is considered to be more aggressive than that of sporadic meningioma (SM), the genetic predisposition for RIM is not established well. The present study aimed to analyze the clinical and genetic characteristics of RIMs to increase understanding of the tumorigenesis and prognosis of RIMs. Methods: We investigated a database of 24 patients who met the RIM criteria between January 2000 and April 2023. Genetic analysis through next-generation sequencing with a targeted gene panel was performed on 10 RIM samples. Clinical, radiological, and pathological parameters were evaluated with genetic analyses.
Results:
The median ages for receiving radiotherapy (RT) and RIM diagnosis were 8.0 and 27.5 years, respectively, with an interval of 17.5 years between RT and RIM diagnosis. RIMs tended to develop in non-skull bases and multifocal locations. Most primary pathologies included germ cell tumors and medulloblastoma. The tumor growth rate was 3.83 cm 3 per year, and the median doubling time was 0.8 years. All patients underwent surgical resection of RIMs. The histological grade of RIMs was World Health Organization grade 1 (64%) or 2 (36%). RIMs showed higher incidences in young-age (63%), high-dose (75%), and extendedfield (79%) RT groups. The recurrence rate was 21%. Genetic analysis revealed NF2 one copy loss in 90% of the patients, with truncating NF2 mutations and additional copy number aberrations in grade 2 RIMs. TERT promoter mutation and CDKN2A/B deletion were not identified. Notably, loss of H3K27me3 was identified in 26% of RIMs. H3K27me3 loss was associated with a higher prevalence of grade 2 RIMs (67%) and high recurrence rates (33%).
Conclusion
The study reveals a higher prevalence of high-grade tumors among RIMs with more rapid growth and higher recurrences than SMs. Genetically, RIMs are primarily associated with NF-2 alterations with chromosomal abnormalities in grade 2 tumors, along with a higher proportion of H3K27me3 loss.
5.Efficacy of Anti-Adhesive Substitute and Step-by-Step Techniques in Decompressive Craniectomy and Subsequent Cranioplasty
You-Sub KIM ; Jae-Woong KIM ; Sung-Pil JOO ; Tae-Sun KIM
Journal of Korean Neurosurgical Society 2025;68(3):360-368
Objective:
: Dural substitutes have been widely used in decompressive craniectomy to prevent adhesion, and have significantly reduced blood loss and operation time. However, there are only limited studies providing information regarding detailed techniques and the specific operation time that is associated with good prognoses. In this study, we evaluate the effectiveness of using a dural substitute as an anti-adhesive material during cranioplasty, focusing on technical details and operation time from incision to bone closure.
Methods:
: A retrospectively reviewed total of 66 patients were included who underwent a craniectomy and subsequent cranioplasty caused by either a severe traumatic brain injury (n=35) or malignant infarction (n=31). The patients were divided into two groups depending on whether Neuro-Patch was used or not (31 in the Neuro-Patch group, 35 in the non-Neuro-Patch group). Propensity score matching was used to minimize the differences. Associated morbidities as well as operation time, and blood loss were analyzed and compared between the two groups.
Results:
: To prevent adhesion, Neuro-Patch was placed as an onlay, enough to cover the surrounding skull at least 1 cm beyond the bone edges. A small piece was also placed over the temporalis muscle during the craniectomy. A step-by-step dissection was performed to minimize retraction-related injury during the subsequent cranioplasty. The mean estimated blood loss was significantly lower in the Neuro-Patch group (54.6±34.9 vs. 149.0±70.8 mL, p<0.001) and the mean time from incision to bone closure in the Neuro-Patch group was 40.8±14.3 minutes, which was significantly lower than in the non-Neuro-Patch group (91.5±38.2 minutes) as well. For each analysis of complications, the differences were not significant, however, the overall complication rate was significantly lower in the Neuro-Patch group (9.7%) than in the non-Neuro-Patch group (42.9%).
Conclusion
: Neuro-Patch can be used safely and effectively as an anti-adhesive substitute during cranioplasty. To improve clinical outcomes as well as intraoperative parameters including the time from incision to bone closure, planned placement of Neuro-Patch during craniectomy and the step-by-step dissection during cranioplasty is important.
6.Association of Age, Sex and Education With Access to the Intravenous Thrombolysis for Acute Ischemic Stroke
Yoona KO ; Beom Joon KIM ; Youngran KIM ; Jong-Moo PARK ; Kyusik KANG ; Jae Guk KIM ; Jae-Kwan CHA ; Tai Hwan PARK ; Kyungbok LEE ; Jun LEE ; Keun-Sik HONG ; Byung-Chul LEE ; Kyung-Ho YU ; Dong-Eog KIM ; Joon-Tae KIM ; Jay Chol CHOI ; Jee Hyun KWON ; Wook-Joo KIM ; Kyu Sun YUM ; Sung-Il SOHN ; Hyungjong PARK ; Sang-Hwa LEE ; Kwang-Yeol PARK ; Chi Kyung KIM ; Sung Hyuk HEO ; Moon-Ku HAN ; Anjail Z. SHARRIEF ; Sunil A. SHETH ; Hee-Joon BAE ;
Journal of Korean Medical Science 2025;40(13):e49-
Background:
Barriers to treatment with intravenous thrombolysis (IVT) for patients with acute ischemic stroke (AIS) in South Korea remain incompletely characterized. We analyze a nationwide prospective cohort to determine patient-level features associated with delayed presentation and non-treatment of potential IVT-eligible patients.
Methods:
We identified consecutive patients with AIS from 01/2011 to 08/2023 from a multicenter and prospective acute stroke registry in Korea. Patients were defined as IVT candidates if they presented within 4.5 hours from the last known well, had no lab evidence of coagulopathy, and had National Institute of Health Stroke Scale (NIHSS) ≥ 4. Multivariable generalized linear mixed regression models were used to investigate the associations between their characteristics and the IVT candidates or the use of IVT among the candidates.
Results:
Among 84,103 AIS patients, 41.0% were female, with a mean age of 69 ± 13 years and presentation NIHSS of 4 [interquartile range, 1–8]. Out of these patients, 13,757 (16.4%) were eligible for IVT, of whom 8,179 (59.5%) received IVT. Female sex (adjusted risk ratio [RR], 0.90; 95% confidence interval [CI], 0.86–0.94) and lower years of education (adjusted RR, 0.90; 95% CI, 0.84–0.97 for 0–3 years, compared to ≥ 13 years) were associated with a decreased likelihood of presenting as eligible for IVT after AIS; meanwhile, young age (adjusted RR, 1.12; 95% CI, 1.01–1.24 for ≤ 44 years, compared to 75–84 years) was associated with an increased likelihood of being an IVT candidate. Among those who were eligible for IVT, only age was significantly associated with the use of IVT (adjusted RR, 1.09; 95% CI, 1.03–1.16 for age 65–74 and adjusted RR, 0.83; 95% CI, 0.76–0.90 for ≥ 85 years, respectively).
Conclusion
Most patients with AIS present outside IVT eligibility in South Korea, and only 60% of eligible patients were ultimately treated. We identified increased age, female sex and lower education as key features on which to focus interventions for improving IVT utilization.
7.Group B Streptococcus Detection Rate and Clindamycin Resistance Among Reproductive-Age Women in Korea During 2003–2022
Areum SHIN ; Doo Ri KIM ; Ji-Hee SUNG ; Jinyoung YANG ; Suk-Joo CHOI ; Cheong-Rae ROH ; Tae Yeul KIM ; Hee Jae HUH ; Nam Yong LEE ; Soo-young OH ; Yae-Jean KIM
Journal of Korean Medical Science 2025;40(15):e29-
Background:
Group B Streptococcus (GBS) is one of the leading causes of neonatal earlyonset sepsis, resulting in high mortality and significant comorbidity. Intrapartum penicillin prophylaxis is recommended for pregnant women with GBS colonization to prevent vertical transmission. For pregnant women at high risk of anaphylaxis to penicillin, clindamycin is recommended only if the susceptibility of GBS isolates has been identified. We retrospectively examined the GBS detection rate and clindamycin resistance among Korean women of reproductive age over the last 20 years.
Methods:
Microbiologic studies using vaginal, vaginal–rectal or vaginal–perianal swabs from female patients 15–49 years of age during 2003–2022 were reviewed. Annual GBS detection rates and clindamycin resistance rates were calculated. The study period was divided into two periods (period 1, 2003–2015; period 2, 2016–2022) based on the introduction of universal culture-based GBS screening in our center in 2016. GBS detection rates and clindamycin resistance rates were compared between the periods using χ2 tests.
Results:
A total of 14,571 women were tested 16,879 times and GBS was isolated in 1,054 tests (6.2%), with 423 clindamycin-resistant isolates (40.1%). The GBS detection rate increased from 3.4% (301/8,869) in period 1 to 9.4% (2,753/8,010) in period 2 (P < 0.001). Even during period 1, the GBS detection rate was higher in 2009–2015 compared to 2003–2008 (P < 0.001). Clindamycin resistance rates have remained at similar levels since 2009, which were 39.5% (199/301) in period 1 and 40.2% (303/753) in period 2 (P = 0.833).
Conclusion
This study demonstrated that GBS detection rates in Korean women of reproductive age significantly increased almost three times during the twenty years of the study period, with a persistently high clindamycin resistance rate of up to 40%.
8.Radiation-Induced Meningiomas Have an Aggressive Clinical Course:Genetic Signature Is Limited to NF2Alterations, and Epigenetic Signature Is H3K27me3 Loss
Tae-Kyun KIM ; Jong Seok LEE ; Ji Hoon PHI ; Seung Ah CHOI ; Joo Whan KIM ; Chul-Kee PARK ; Hongseok YUN ; Young-Soo PARK ; Sung-Hye PARK ; Seung-Ki KIM
Journal of Korean Medical Science 2025;40(18):e62-
Background:
While the clinical course of radiation-induced meningioma (RIM) is considered to be more aggressive than that of sporadic meningioma (SM), the genetic predisposition for RIM is not established well. The present study aimed to analyze the clinical and genetic characteristics of RIMs to increase understanding of the tumorigenesis and prognosis of RIMs. Methods: We investigated a database of 24 patients who met the RIM criteria between January 2000 and April 2023. Genetic analysis through next-generation sequencing with a targeted gene panel was performed on 10 RIM samples. Clinical, radiological, and pathological parameters were evaluated with genetic analyses.
Results:
The median ages for receiving radiotherapy (RT) and RIM diagnosis were 8.0 and 27.5 years, respectively, with an interval of 17.5 years between RT and RIM diagnosis. RIMs tended to develop in non-skull bases and multifocal locations. Most primary pathologies included germ cell tumors and medulloblastoma. The tumor growth rate was 3.83 cm 3 per year, and the median doubling time was 0.8 years. All patients underwent surgical resection of RIMs. The histological grade of RIMs was World Health Organization grade 1 (64%) or 2 (36%). RIMs showed higher incidences in young-age (63%), high-dose (75%), and extendedfield (79%) RT groups. The recurrence rate was 21%. Genetic analysis revealed NF2 one copy loss in 90% of the patients, with truncating NF2 mutations and additional copy number aberrations in grade 2 RIMs. TERT promoter mutation and CDKN2A/B deletion were not identified. Notably, loss of H3K27me3 was identified in 26% of RIMs. H3K27me3 loss was associated with a higher prevalence of grade 2 RIMs (67%) and high recurrence rates (33%).
Conclusion
The study reveals a higher prevalence of high-grade tumors among RIMs with more rapid growth and higher recurrences than SMs. Genetically, RIMs are primarily associated with NF-2 alterations with chromosomal abnormalities in grade 2 tumors, along with a higher proportion of H3K27me3 loss.
9.Efficacy of Anti-Adhesive Substitute and Step-by-Step Techniques in Decompressive Craniectomy and Subsequent Cranioplasty
You-Sub KIM ; Jae-Woong KIM ; Sung-Pil JOO ; Tae-Sun KIM
Journal of Korean Neurosurgical Society 2025;68(3):360-368
Objective:
: Dural substitutes have been widely used in decompressive craniectomy to prevent adhesion, and have significantly reduced blood loss and operation time. However, there are only limited studies providing information regarding detailed techniques and the specific operation time that is associated with good prognoses. In this study, we evaluate the effectiveness of using a dural substitute as an anti-adhesive material during cranioplasty, focusing on technical details and operation time from incision to bone closure.
Methods:
: A retrospectively reviewed total of 66 patients were included who underwent a craniectomy and subsequent cranioplasty caused by either a severe traumatic brain injury (n=35) or malignant infarction (n=31). The patients were divided into two groups depending on whether Neuro-Patch was used or not (31 in the Neuro-Patch group, 35 in the non-Neuro-Patch group). Propensity score matching was used to minimize the differences. Associated morbidities as well as operation time, and blood loss were analyzed and compared between the two groups.
Results:
: To prevent adhesion, Neuro-Patch was placed as an onlay, enough to cover the surrounding skull at least 1 cm beyond the bone edges. A small piece was also placed over the temporalis muscle during the craniectomy. A step-by-step dissection was performed to minimize retraction-related injury during the subsequent cranioplasty. The mean estimated blood loss was significantly lower in the Neuro-Patch group (54.6±34.9 vs. 149.0±70.8 mL, p<0.001) and the mean time from incision to bone closure in the Neuro-Patch group was 40.8±14.3 minutes, which was significantly lower than in the non-Neuro-Patch group (91.5±38.2 minutes) as well. For each analysis of complications, the differences were not significant, however, the overall complication rate was significantly lower in the Neuro-Patch group (9.7%) than in the non-Neuro-Patch group (42.9%).
Conclusion
: Neuro-Patch can be used safely and effectively as an anti-adhesive substitute during cranioplasty. To improve clinical outcomes as well as intraoperative parameters including the time from incision to bone closure, planned placement of Neuro-Patch during craniectomy and the step-by-step dissection during cranioplasty is important.
10.Impact of HER2-Low Status on Pathologic Complete Response and Survival Outcome Among Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy
Young Joo LEE ; Tae-Kyung YOO ; Sae Byul LEE ; Il Yong CHUNG ; Hee Jeong KIM ; Beom Seok KO ; Jong Won LEE ; Byung Ho SON ; Sei Hyun AHN ; Hyehyun JEONG ; Jae Ho JUNG ; Jin-Hee AHN ; Kyung Hae JUNG ; Sung-Bae KIM ; Hee Jin LEE ; Gyungyub GONG ; Jisun KIM
Journal of Breast Cancer 2025;28(1):11-22
Purpose:
This study analyzed the pathological complete response (pCR) rates, long-term outcomes, and biological features of human epidermal growth factor receptor 2 (HER2)-zero, HER2-low, and HER2-positive breast cancer patients undergoing neoadjuvant treatment.
Methods:
This single-center study included 1,667 patients who underwent neoadjuvant chemotherapy from 2008 to 2014. Patients were categorized by HER2 status, and their clinicopathological characteristics, chemotherapy responses, and recurrence-free survival (RFS) rates were analyzed.
Results:
Patients with HER2-low tumors were more likely to be older (p = 0.081), have a lower histological grade (p < 0.001), and have hormone receptor (HorR)-positive tumors (p < 0.001). The HER2-positive group exhibited the highest pCR rate (23.3%), followed by the HER2-zero (15.5%) and HER2-low (10.9%) groups. However, the pCR rate did not differ between HER2-low and HER2-zero tumors in the HorR-positive or HorR-negative subgroups.The 5-year RFS rates increased in the following order: HER2-low, HER2-positive, and HER2-zero (80.0%, 77.5%, and 74.5%, respectively) (log-rank test p = 0.017). A significant survival difference between patients with HER2-low and HER2-zero tumors was only identified in HorR-negative tumors (5-year RFS for HER2-low, 74.5% vs. HER2-zero, 66.0%; log-rank test p-value = 0.04). Multivariate survival analysis revealed that achieving a pCR was the most significant factor associated with improved survival (hazard ratio [HR], 4.279; p < 0.001).Compared with HER2-zero, the HRs for HER2-low and HER2-positive tumors were 0.787 (p = 0.042) and 0.728 (p = 0.005), respectively. After excluding patients who received HER2-targeted therapy, patients with HER2-low tumors exhibited better RFS than those with HER2-zero (HR 0.784, p = 0.04), whereas those with HER2-positive tumors exhibited no significant difference compared with those with HER2-low tumors (HR, 0.975; p = 0.953).
Conclusion
Patients with HER2-low tumors had no significant difference in pCR rate compared to HER2-zero but showed better survival, especially in HorR-negative tumors.Further investigation into biological differences is warranted.

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