First birth following assisted sperm fusion insemination using sperm bound to zona pellucida.

PURPOSE: To report a live birth after transfer of a vitrified-warmed blastocyst produced by assisted sperm fusion insemination (ASFI). METHODS: Oocyte retrieval and in vitro fertilization (IVF) were performed on a 37-year-old woman. Six hours after IVF, an oocyte exhibited a single polar body and so was defined as an unfertilized oocyte. A motile sperm was collected from the zona pellucida of the unfertilized oocyte by an injection needle. The motile sperm was pressed onto the membrane of the unfertilized oocyte. RESULTS: Two oocytes were matured and subjected to IVF. One of the 2 oocytes exhibited only one polar body and was defined as an unfertilized oocyte at 6 h after IVF; this oocyte then was subjected to ASFI. Two pronuclei were observed on the next day and cultured to the blastocyst stage. This embryo achieved blastocyst status and was vitrified on day 5. The resulting vitrified-warmed blastocyst was transferred, resulting in pregnancy and subsequent delivery of a healthy boy. CONCLUSION: This report describes the first case of a successful birth following transfer of a vitrified-warmed blastocyst produced by ASFI.

Efficient Light-Harvesting Antennae Resulting from the Dense Organization of Dyes into DNA Junctions through d-Threoninol.

Herein we report the construction of efficient light-harvesting antennae by hybridization of DNA oligonucleotides containing high densities of fluorophores into DNA junctions through d-threoninol. Six pyrene donors could be incorporated into each arm without self-quenching. A perylene acceptor was located at the center of the junction. Antenna effects of a duplex and three- to eight-way junctions were systematically compared. Six- and eight-way junctions had the highest antenna effects, and their effective absorption coefficients were 8.5 times higher than that of perylene. Interestingly, even-numbered junctions had higher efficiencies than odd-numbered junctions. Nondenaturing gel analyses and fluorescence lifetime measurements demonstrated that the strong odd-even effects were derived from differences in the stability of junctions. The results presented will guide the design of efficient artificial photosynthetic systems.

Concentration-dependent photophysical switching in mixed self-assembled monolayers of pentacene and perylenediimide on gold nanoclusters.

Photophysical control and switching on organic-inorganic hybrid interfaces are of great interest in diverse fundamental and applicative research areas. 6,13-Bis(triisopropylsilylethynyl)pentacene (TP) is well-known to exhibit efficient singlet fission (SF) for generation of high-yield triplet excited states in aggregated forms, whereas perylenediimide (PDI) ensembles show the characteristic excimer formation. Additionally, a combination of pentacene (electron donor: D) and PDI (electron acceptor: A) is expected to undergo an efficient photoinduced electron transfer (PET), and absorption of two chromophores combined covers the entire visible region. Therefore, the concentration-dependent mixed self-assembled monolayers (SAMs) composed of two chromophores enable us to control and switch the photophysical processes on a surface. In this work, a series of mixed SAMs composed of TP and PDI units on gold nanoclusters (GNCs) were newly synthesized by changing the relative molecular concentration ratios. Structural control of mixed SAMs on a gold surface based on the concentration ratios was successfully achieved. Time-resolved femtosecond and nanosecond transient absorption measurements clearly demonstrate photophysical control and switching of the above competitive reactions such as SF, electron transfer (ET) and excimer formation. The maximum quantum yields of triplet states (ΦT = ∼170%) and electron transfer (ΦET = ∼95%) were quantitatively evaluated by changing the concentration ratios. The rate constants of SF and excimer processes are largely dependent on the concentration ratios, whereas the rate constants of ET processes approximately remain constant. These findings are also discussed based on the statistical framework of the assembly of chromophores on the gold surface.

Effects of cyclophosphamide administration on the in vitro fertilization of mice.

PURPOSE: To evaluate the oocyte fertilization ability and embryo growth after cyclophosphamide (CPA) treatment in mice. METHODS: Mice were treated with CPA at different doses (0-800 mg/kg body weight). The oocytes then were retrieved and evaluated for their in vitro fertilization efficiency. RESULTS: The average number of metaphase II (MII) oocytes significantly decreased by ≥400 mg/kg CPA administration. The fertilization rate also decreased in the group that was treated with ≥400 mg/kg CPA. However, after fertilization, the embryos demonstrated normal growth ability. Two weeks after CPA administration, the number of mice from which the oocytes could be retrieved markedly decreased, but the fertilization rate and development of morphological features in the embryos were similar to those of the controls. One month after CPA administration, the number of mice from which the oocytes could be retrieved, fertilization rate, and development of the morphological features in the embryos were similar to those of the controls. CONCLUSION: The number of oocytes decreased as the CPA administration level increased; however, the oocytes' potential for fertilization and development to the blastocyst stage was not significantly affected. One month after CPA administration, the number of oocytes and the potential for development into blastocysts were recovered.

Bilateral tubal pregnancies after a single-embryo transfer.

Case: To present an extremely rare case of bilateral tubal pregnancies following a single-embryo transfer in a woman with a 4 year history of infertility prior to seeking assisted reproductive technology. Outcome: A pregnancy resulted from the transfer of an embryo that had been thawed from a frozen blastocyst during a hormone replacement cycle. An ultrasound that was performed at 5 weeks and 5 days of gestation revealed a gestational sac, embryo, and heartbeat in the right fallopian tube and similar signs of a gestational sac in the left fallopian tube. A laparoscopy revealed clear signs of an ectopic pregnancy in the ampulla of the right fallopian tube. Signs of swelling also were seen in the ampulla of the left fallopian tube. As the possibility of bilateral tubal pregnancies could not be ruled out, both fallopian tubes were removed. Pathological tests revealed chorionic villi and trophoblasts in both the left and right fallopian tubes. Conclusion: All previously reported cases of bilateral tubal pregnancies have been a result of multiple ovulations or multiple-embryo transfer and no case of bilateral tubal pregnancies after a single-embryo transfer has ever been reported. No genetic testing was performed; thus, it cannot be definitively stated that the divided chorionic villi and trophoblasts came from only one embryo.

Controllable Electronic Structures and Photoinduced Processes of Bay-Linked Perylenediimide Dimers and a Ferrocene-Linked Triad.

A series of perylene-3,4,9,10-bis(dicarboximide) (PDI) dimers linked through the bay regions was systematically synthesized to examine the electronic structures and photophysical properties in dependence on the distance and orientation between the two PDI units. The spectroscopic and electrochemical measurements suggested that the coupling value of a directly linked PDI dimer (PDI)2 is much larger than those of para- and meta-phenylene-bridged PDI dimers p-(PDI)2 and m-(PDI)2 . The width of Davydov splitting was quantitatively evaluated to compare the coupling values between the two PDI units in these dimers by absorption spectroscopy in frozen 2-methyl-THF. Excimer formation of PDI dimers induced the strong fluorescence quenching and large red-shifts. Femtosecond transient absorption revealed a broad absorption derived from an excimer in the range from about 600 nm to the near-IR region. The rate constants of formation and decay of the excimer are strongly dependent on the coupling values. Time-resolved measurements on ferrocene-linked p-(PDI)2 revealed a competition between the photoinduced processes of electron transfer and excimer formation in PhCN, which is in sharp contrast with the sole electron-transfer process in toluene.

Synthetic Control of the Excited-State Dynamics and Circularly Polarized Luminescence of Fluorescent "Push-Pull" Tetrathia[9]helicenes.

A series of fluorescent "push-pull" tetrathia[9]helicenes based on quinoxaline (acceptor) fused with tetrathia[9]helicene (donor) derivatives was synthesized for control of the excited-state dynamics and circularly polarized luminescence (CPL) properties. In this work, introduction of a quinoxaline onto the tetrathia[9]helicene skeleton induced the "push-pull" character, which was enhanced by further introduction of an electron-releasing Me2 N group or an electron-withdrawing NC group onto the quinoxaline unit (denoted as Me2 N-QTTH and NC-QTTH, respectively). These trends were successfully discussed in terms of by electrochemical measurements and density functional theory (DFT) calculations. As a consequence, significant enhancements in the fluorescence quantum yields (ΦFL ) were achieved. In particular, the maximum ΦFL of Me2 N-QTTH was 0.43 in benzene (NC-QTTH: ΦFL =0.30), which is more than 20 times larger than that of a pristine tetrathia[9]helicene (denoted as TTH; ΦFL =0.02). These enhancements were also explained by kinetic discussion of the excited-state dynamics such as fluorescence and intersystem crossing (ISC) pathways. Such significant enhancements of the ΦFL values thus enabled us to show the excellent CPL properties. The value of anisotropy factor gCPL (normalized difference in emission of right-handed and left-handed circularly polarized light) was estimated to be 3.0 × 10(-3) for NC-QTTH.

Protonation-induced red-coloured circularly polarized luminescence of [5]carbohelicene fused by benzimidazole.

Benzimidazole-fused [5]carbohelicene ([5]HeliBI) was newly synthesized to examine the spectroscopic and chiroptical properties. The reversible protonation and deprotonation processes of [5]HeliBI were successfully investigated using (1)H NMR, absorption and fluorescence spectral measurements. We also confirmed the circularly polarized luminescence of protonated [5]HeliBI (H(+)-[5]HeliBI). This is the first observation of red-coloured CPL of a helicene derivative.

Control of local structures and photophysical properties of zinc porphyrin-based supramolecular assemblies structurally organized by regioselective ligand coordination.

Nano- and micro-sized molecular assemblies of zinc porphyrins [5,10,15,20-tetrakis(4-carboxyphenyl)porphyrinato-zinc(II) (ZnTCPP)] utilizing bridging nitrogen ligands such as diazabicycro[2.2.2]octane (DABCO) were prepared to demonstrate the regioselective coordination by two different synthetic strategies such as (I) the solvothermal method and (II) the colloidal metal organic framework (MOF) method. The initial organization process is a planar checkerboard patterned formation (2D platform) of zinc porphyrins organized by paddlewheel secondary building units (PSBUs) between carboxylate and zinc ions. Then, DABCO moieties are decorated on zinc atoms in the metal centres of the porphyrin rings (m-cPDC) in the solvothermal method, whereas the metal centres in the porphyrin rings (n-uPDC) remain uncoordinated in the colloidal MOF method. These internal structural changes between m-cPDC and n-uPDC are in sharp contrast with the corresponding reference systems using ZnTCPP and a 4,4'-bipyridine (BPY) ligand (i.e., m-cPBC and n-cPBC). Concretely, the metal centres of zinc porphyrins in n-uPDC were unsaturated and uncoordinated with the DABCO ligands, which was confirmed by XRD and steady-state spectroscopic measurements. These different coordination features have great effect on the spectroscopic and photophysical properties. For example, the average fluorescence lifetime of m-cPDC is much smaller than that of n-uPDC because of the acceleration of nonradiative processes, which are highly related with the coordination of DABCO to the Zn(II) centre of the ZnTCPP unit. Finally, fluorescence quenching experiments via photoinduced electron transfer (PET) utilizing an electron acceptor: benzoquinone (BQ) were performed. The apparent association constant (Kapp) of n-uPDC is larger than that of m-cPDC. This suggested that the unsaturated ZnTCPP units embedded in n-uPDC easily accommodate guest molecules as compared to the other systems.

Long-Lived Triplet Excited States of Bent-Shaped Pentacene Dimers by Intramolecular Singlet Fission.

Intramolecular singlet fission (ISF) is a promising photophysical process to construct more efficient light energy conversion systems as one excited singlet state converts into two excited triplet states. Herein we synthesized and evaluated bent-shaped pentacene dimers as a prototype of ISF to reveal intrinsic characters of triplet states (e.g., lifetimes of triplet excited states). In this study, meta-phenylene-bridged TIPS-pentacene dimer (PcD-3Ph) and 2,2'-bipheynyl bridged TIPS-pentacene dimer (PcD-Biph) were newly synthesized as bent-shaped dimers. In the steady-state spectroscopy, absorption and emission bands of these dimers were fully characterized, suggesting the appropriate degree of electronic coupling between pentacene moieties in these dimers. In addition, the electrochemical measurements were also performed to check the electronic interaction between two pentacene moieties. Whereas the successive two oxidation peaks owing to the delocalization were observed in a directly linked-pentacene dimer (PcD) by a single bond, the cyclic voltammograms in PcD-Biph and PcD-3Ph implied the weaker interaction compared to that of p-phenylene-bridged TIPS-pentacene dimer (PcD-4Ph) and PcD. The femtosecond and nanosecond transient absorption spectra clearly revealed the slower ISF process in bent-shaped pentacene dimers (PcD-Biph and PcD-3Ph), more notably, the slower relaxation of the excited triplet states in PcD-Biph and PcD-3Ph. Namely, the quantum yields of triplet states (ΦT) by ISF approximately remain constant (ca. 180-200%) in all dimer systems, whereas the lifetimes of the triplet excited states became much longer (up to 360 ns) in PcD-Biph as compared to PcD-4Ph (15 ns). Additionally, the lifetimes of the corresponding triplet states in PcD-Biph and PcD-3Ph were sufficiently affected by solvent viscosity. In particular, the lifetimes of PcD-Biph triplet state in THF/paraffin (1.0 µs) increased up to approximately three times as compared to that in THF (360 ns), whereas those of PcD-4Ph were quite similar in both solvent.

Randomized trial of low-dose peginterferon α-2b plus low and escalating doses of ribavirin in older patients with chronic hepatitis C with high viral load genotype 1.

Elderly patients with chronic hepatitis C cannot tolerate standard combination therapy of peginterferon and ribavirin, which remains the backbone of therapy in many countries, including Japan. The efficacy and safety of low-dose peginterferon α-2b in combination with low and escalating doses of ribavirin in older patients with high viral load genotype 1 were investigated in this randomized controlled trial. Thirty-two patients (age ≥ 60 years) were randomized into standard (group 1) or low (group 2) doses of peginterferon α-2b in combination with low and escalating doses of ribavirin. Patients were evaluated for safety and efficacy of treatment. There was a higher virological response rate in group 1 than in group 2. However, the response in men was higher than in women in the early treatment phase and 24 weeks after treatment (P = 0.008). There was no significant difference between the two groups in the virological response rate in men and women. Completion of therapy was higher in group 2 than in group 1 (31% vs. 13%, P = 0.200). Dose modification of ribavirin was less frequent in group 2 than in group 1 (69% vs. 88%, P = 0.200). These data suggest that combination therapy with low-dose peginterferon plus low and escalating doses of ribavirin may be safer in older patients than that with standard dose peginterferon, without impairing the treatment response.

Randomized trial of peginterferon alpha-2b plus low and escalating dose of ribavirin in patients with chronic hepatitis C with high viral load genotype 1.

It has been reported that elderly patients with chronic hepatitis C infection cannot tolerate standard combination therapy. In this randomized, controlled trial, the efficacy and safety of peginterferon alpha-2b plus a low and escalating dose of ribavirin in chronic hepatitis C patients with high viral load genotype 1 were investigated. Sixty-two patients were randomized into combination therapy with standard ribavirin dosing (group 1) or low and escalating ribavirin dosing (group 2). Patients were evaluated for safety and efficacy of treatment. There was no significant difference in the prevalence of virological response between the groups throughout the treatment as well as 24 weeks after treatment. However, the response in patients ≥60 years of age was higher in group 1 than in group 2 at early treatment phase (P = 0.015). The prevalence of completion of therapy in patients ≥60 years of age tended to be higher in group 2 than in group 1 (50% vs. 0%, P = 0.055). There was no significant difference in dose modification of peginterferon alpha-2b between the groups. However, dose modification of ribavirin was significantly more frequent in group 1 than in group 2 (60% vs. 24%, P = 0.005). These data suggest that combination therapy with low and escalating dosing of ribavirin may be safer in elderly patients than that with standard dosing of ribavirin without impairing the treatment response.

Hetero-Selective DNA-Like Duplex Stabilized by Donor-Acceptor Interactions.

We report on the characterization of a novel hetero-selective DNA-like duplex of pyrene and anthraquinone pseudo base pairs. The pyrene/anthraquinone pairs showed excellent selectivity in hetero-recognition and even trimers were found to form a hetero-duplex. Pyrene and anthraquinone moieties were tethered on acyclic D-threoninol linkers and linked to adjacent residues by using standard phosphoramidite chemistry. When pyrene and anthraquinone were incorporated at pairing positions in complementary strands of natural DNA oligonucleotides, the duplex was stabilized significantly. Moreover, a pyrene hexamer and an anthraquinone hexamer formed a stable artificial hetero-duplex without the assistance of natural base pairs. The pyrene/anthraquinone pair was so stable that even trimers formed a hetero-duplex under conditions in which natural DNA strands of three residues do not.

Effectiveness of extending treatment duration in therapy with pegylated interferon and ribavirin for genotype 2 hepatitis C virus infection.

The effectiveness of extending treatment duration as response guided therapy was previously reported for chronic hepatitis C (CHC) genotype 1, but is still controversial for genotype 2. The present study is a retrospective cohort study to investigate the effectiveness of extending treatment duration in therapy with pegylated interferon and ribavirin for patients with CHC genotype 2 by focusing on the timing at which patients obtained undetectable HCV RNA. A total of 306 patients who obtained undetectable HCV RNA by week 24 of treatment and completed 24 weeks of treatment were enrolled. Rapid virological response (RVR) to standard therapy was achieved by 122 patients (51%), and 89% of them obtained sustained virological response (SVR), while 69% of non-RVR patients achieved SVR. Non-RVR patients with undetectable HCV RNA at week 8, and insufficient adherence＜80% pegylated interferon and ribavirin during the first 24 weeks, significantly improved their SVR rate by extended therapy. Among patients receiving extended therapy, drug adherences did not differ between SVR and non-SVR patients, indicating that extending treatment duration might compensate for insufficient antiviral effects due to insufficient drug adherences. This finding might be useful in creating a guideline for extending treatment duration for patients with CHC genotype 2.

In vitro fertilization embryo development from caffeine-treated murine sperm.

Purpose: To evaluate the effect of long-term caffeine administration on murine sperm and subsequent in vitro fertilization (IVF). Methods: Male mice were injected with various doses (0, 0.2 and 1.0 mg/mouse/day) of caffeine for 1 month. After sperm collection, the IVF rate and embryo development to the blastocyst stage were evaluated. Results: The mean body weight significantly decreased in the 1.0 mg/day treatment group compared to the control group (P < 0.01). Testicular weight and histological features did not differ, and total blood testosterone was no different in spite of the difference between 0.2 and 1.0 mg/day of caffeine. The IVF rate differed significantly between the control group [100/105 (95.2 %)] and 0.2 mg/day group [106/121 (87.6 %)] (P < 0.05). Furthermore, blastocyst formation was significantly and dose-dependently lower with higher caffeine levels: control group: 85/100 (85.0 %); 0.2 mg/day group: 84/106 (79.2 %) (P < 0.05); 1.0 mg/day group: 64/102 (62.7 %) (P < 0.001). Conclusions: Caffeine treatment affected body weight of male mice. However, testicular weight, histological features and total blood testosterone concentration were not statistically different. In addition, following IVF using sperm from these mice, blastocyst formation decreased in a dose-dependent manner. These findings suggest that embryo development from oocytes fertilized with sperm from caffeine-administered male mice is negatively affected.

Formation of one-dimensional helical columns and excimerlike excited states by racemic quinoxaline-fused [7]carbohelicenes in the crystal.

A series of quinoxaline-fused [7]carbohelicenes (HeQu derivatives) was designed and synthesized to evaluate their structural and photophysical properties in the crystal state. The quinoxaline units were expected to enhance the light-emitting properties and to control the packing structures in the crystal. The electrochemical and spectroscopic properties and excited-state dynamics of these compounds were investigated in detail. The first oxidation potentials of HeQu derivatives are approximately the same as that of unsubstituted reference [7]carbohelicene (Heli), whereas their first reduction potentials are shifted to the positive by about 0.7 V. The steady-state absorption, fluorescence, and circular dichroism spectra also became redshifted compared to those of Heli. The molecular orbitals and energy levels of the HOMO and LUMO states, calculated by DFT methods, support these trends. Moreover, the absolute fluorescence quantum yields of HeQu derivatives are about four times larger than that of Heli. The structural properties of the aggregated states were analyzed by single-crystal analysis. Introduction of appropriate substituents (i.e., 4-methoxyphenyl) in the HeQu unit enabled the construction of one-dimensional helical columns of racemic HeQu derivatives in the crystal state. Helix formation is based on intracolumn π-stacking between two neighboring [7]carbohelicenes and intercolumn CH⋅⋅⋅N interaction between a nitrogen atom of a quinoxaline unit and a hydrogen atom of a helicene unit. The time-resolved fluorescence spectra of single crystals clearly showed an excimerlike delocalized excited state owing to the short distance between neighboring [7]carbohelicene units.

Systematic control of the excited-state dynamics and carrier-transport properties of functionalized benzo[ghi]perylene and coronene derivatives.

A series of benzo[ghi]perylene (Bp) and coronene (Cor) derivatives substituted with electron-withdrawing methoxycarbonyl (COOMe) or electron-donating methoxyl (MeO) groups was synthesized. The electrochemical, spectroscopic, and photophysical properties of these compounds were investigated by cyclic voltammetry, steady-state and time-resolved spectroscopy, and quantum-yield measurements. Introduction of suitable substituents onto the aromatic rings enabled control of electrochemical and spectroscopic behavior. Examination of excited-state dynamics revealed that fluorescence quantum yields increased with increasing number of COOMe groups in both Bp and Cor derivatives, consistent with the findings of DFT calculations. Single-crystal analysis allowed the performance of field-effect transistors containing single crystals of the derivatives to be rationalized.

Photoinduced electron transfer of zinc porphyrin-oligo(thienylenevinylene)-fullerene[60] triads; thienylenevinylenes as efficient molecular wires.

Two novel donor-bridge-acceptor arrays (ZnP-nTV-C60) with zinc porphyrin (ZnP) and fullerene (C60), covalently connected by oligo(thienylenevinylene) (nTV) molecular wires (n = 3 and 8; ), have been prepared in a multistep convergent manner. The influence of the nTV-length on the electrochemical and electronic properties of the ZnP-nTV-C60 triads has been revealed. Interestingly, an efficient photoinduced electron transfer process occurs in both triads with formation of intermediate radical-ion pairs (namely, ZnP˙(+)-nTV-C60˙(-) and ZnP-nTV˙(+)-C60˙(-)) as confirmed by the nanosecond transient absorption measurements in the visible and NIR regions. In polar and nonpolar solvents, the rate constants of charge-separation processes (kCS) via(1)ZnP*-nTV-C60 were found to decrease from ca. 1.2 × 10(10) s(-1) for n = 3 (RDA = 20 Å) to (5-7) × 10(9) s(-1) for n = 8 (RDA = 60 Å) on the basis of fluorescence lifetime measurements of the ZnP moiety. From these data, together with those previously obtained ones for n = 4 in the related ZnP-nTV-C60 systems, a low attenuation coefficient was evaluated for the nTV molecular wires.

Enzyme stability in polymer hydrogel-enzyme hybrid nanocarrier containing phosphorylcholine group.

Enzymes are biological catalysts with good biocompatibility and high efficiency and have been widely used in many fields, such as wastewater treatment, biosensors, and the medical industry. However, their inherently low stability under conditions of practical use limits further applications. Zwitterionic polymers possessing a pair of oppositely charged groups in their repeating units can increase protein stability because of their good biocompatibility and high water content. In this study, zwitterionic copolymer nanogels comprising poly(2-methacryloyloxyethyl phosphorylcholine (MPC)-co-methacrylic acid-N-hydroxy succinimide ester (MNHS)) (PMS) were synthesized via reversible addition-fragmentation chain-transfer polymerization (RAFT). ß-Galactosidase (ß-gal) was post-modified within zwitterionic polymer nanogels with a covalently-bound spacer and the activity was compared with that of directly immobilized ß-gal and free ß-gal. Compared with direct immobilization, covalent immobilization with a spacer could reduce the structural change of ß-gal, as confirmed by the circular dichroism spectra. Although the activity of ß-gal decreased after immobilization, the hybrids of the ß-gal immobilized nanogels, termed hybrid nanogel-enzymes, demonstrated superior stability compared to the free enzymes. The hybrid nanogel-enzymes maintained their function against inactivation by organic solvents and proteinases owing to their high water content, anti-biofouling properties, and limited mass transfer. They can also withstand protein aggregation at high temperatures and maintain their activity. Compared to direct immobilization, immobilization with a spacer resulted in a dramatic increase in the enzyme activity and a slight decrease in the stability. These results indicate that polymer nanogels containing phosphorylcholine units are promising materials for enzyme immobilization, expanding the scope of enzyme applications.

Investigation of real-world heparin resistance and anticoagulation management prior to cardiopulmonary bypass: report from a nationwide survey by the Japanese Association for Thoracic Surgery heparin resistance working group.

OBJECTIVE: Heparin resistance is often encountered during cardiopulmonary bypass. Heparin dose and activated clotting time target values for the initiation of cardiopulmonary bypass are not yet universally standardized; further no consensus exists on the management of heparin resistance. This study aimed to investigate the current real-world practice on heparin management and anticoagulant treatment for heparin resistance in Japan. METHODS: A questionnaire survey was conducted at medical institutions nationwide with which The Japanese Society of Extra-Corporeal Technology in Medicine members are affiliated, targeting surgical cases with cardiopulmonary bypass performed from January 2019 through December 2019. RESULTS: Among 69% (230/332) of the participating institutions, the criterion for heparin resistance was defined as "the target activated clotting time value not reached even with an additional dose of heparin administration". Cases of heparin resistance were reported in 89.8% (202/225) of the responded institutions. Of note, 75% (106/141) of the responded institutions reported heparin resistance associated with antithrombin activity ≥ 80%. Antithrombin concentrate was used in 38.4% (238/619 responses) or third dose of heparin in 37.8% (234/619 responses) for advanced heparin resistance treatment. Antithrombin concentrate was found to be effective in resolving heparin resistance in patients having normal, as well as lower antithrombin activity. CONCLUSION: Heparin resistance has occurred in many cardiovascular centers, even among patients with normal antithrombin activities. Interestingly, the administration of antithrombin concentrate resolved heparin resistance, regardless of the baseline antithrombin activity value.