Development and validation of a novel overhead method for anteroposterior radiographs of fractured rat femurs.

We aimed to establish a new method of obtaining femur anteroposterior radiographs from live rats. We used five adult male Sprague-Dawley rats and created a femoral fracture model with an 8 mm segmental fragment. After the surgery, we obtained two femoral anteroposterior radiographs, a novel overhead method, and a traditional craniocaudal view. We obtained the overhead method three times, craniocaudal view once, and anteroposterior radiograph of the isolated femoral bone after euthanasia. We compared the overhead method and craniocaudal view with an isolated femoral anteroposterior view. We used a two-sample t-test and intraclass correlation coefficient (ICC) to estimate the intra-observer reliability. The overhead method had significantly smaller differences than the craniocaudal view for nail length (1.53 ± 1.26 vs. 11.4 ± 3.45, p < 0.001, ICC 0.96) and neck shaft angle (5.82 ± 3.8 vs. 37.8 ± 5.7, p < 0.001, ICC 0.96). No significant differences existed for intertrochanteric length/femoral head diameter (0.23 ± 0.13 vs. 0.23 ± 0.13, p = 0.96, ICC 0.98) or lateral condyle/medial condyle width (0.15 ± 0.16 vs. 0.13 ± 0.08, p = 0.82, ICC 0.99). A fragment displacement was within 0.11 mm (2.4%). The overhead method was closer to the isolated femoral anteroposterior view and had higher reliability.

Development and validation of prediction scores for the outcome associated with persistent inflammation, immunosuppression, and catabolism syndrome among patients with trauma.

Background: Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has impacted on long-term prognosis of patients with trauma. We aimed to identify patients with trauma at risk of PICS-related complications early in the intensive care unit (ICU) course. Methods: A single-center retrospective cohort study was conducted. All consecutive patients with trauma who had stayed in the ICU for >7 days were included in the study. We developed the prediction score for the incidence of PICS-related outcomes in the derivation cohort for the initial period and then evaluated in the validation cohort for the subsequent period. Other outcomes were also assessed using the score. Results: In total, 170 and 133 patients were included in the derivation and validation cohorts, respectively. The prediction score comprised the variables indicating PICS presence, including a maximum value of C-reactive protein >15 mg/dL, minimum value of albumin <2.5 g/dL, and an episode of nosocomial infection for the first 7 days after admission. A score of 1 was assigned to each variable. The area under the receiver operating characteristic curve of the score to predict PICS incidence was 0.74 (95% CI 0.66 to 0.81) and 0.72 (95% CI 0.64 to 0.81) in the derivation and validation cohorts, respectively. The higher score was also significantly associated with a higher Sequential Organ Failure Assessment score at day 14, a longer duration of mechanical ventilation, a longer length of stay in ICU, and experienced multiple episodes of infection. Similar results were obtained in the validation cohort. Conclusions: Our scoring system could predict the outcomes associated with PICS among patients with trauma. Because the score comprised the parameters measured for the first 7 days during the ICU course, it could contribute to identifying patients at a high risk of unfavorable outcome earlier. Level of evidence: Multivariate prediction models; level IV.

Oncologic outcomes after laparoscopic versus open multivisceral resection for local advanced colorectal cancer: A meta-analysis.

Laparoscopic (lap) colectomies for advanced colorectal cancer (CRC) often require resection of other organs. We systematically reviewed currently available literature on lap multi-visceral resection for CRC, with regard to short- and long-term oncological outcomes, and compared them with open procedures. We performed a systematic literature search in MEDLINE, EMBASE, Google Scholar and PubMed from inception to November 30, 2020. The aim of this study was to synthesize short-term and oncological outcomes associated with laparoscopic versus open surgery. Pooled proportions and risk ratios (RRs) were calculated using an inverse variance method. We included six observational cohort studies published between 2012 and 2020 (lap procedures: n = 262; open procedures: n = 273). Collectively, they indicated that postoperative complications were significantly more common after open surgeries than lap surgeries (RR: 0.53; 95% confidence interval [CI]: 0.39-0.72; P < 0.00001), but the two approaches did not significantly differ in positive resection margins (RR: 0.75; 95% CI: 0.38-1.50; P = 0.42), local recurrence (RR: 0.66; 95% CI: 0.28-1.62; P = 0.37), or (based on two evaluable studies) 5-year OS (RR: 0.70; 95% CI: 0.46-1.04; P = 0.08) or 5-year DFS (RR: 0.86; 95% CI: 0.67-1.11) for T4b disease. In conclusion, laparoscopic and open multi-visceral resections for advanced CRC have comparable oncologic outcomes. Although a randomized study would be ideal for further research, no such studies are currently available.

A case of sigmoid colon volvulus with transanal ileus tube placement and Sharon's operation performed safely.

Although endoscopic repair is often performed for sigmoid colon volvulus without intestinal necrosis, surgery is the common choice of treatment due to recurrence. With no established treatment, Hartmann's operation or sigmoid colon resection is often performed. We report a case of a 65-year-old man with transanal ileus tube placement before surgery for sigmoid colon volvulus to prevent recurrence and achieve intestinal decompression followed by Sharon's operation to achieve one-stage anastomosis. The patient showed good postoperative course, with no recurrence 3 months after surgery. This report discusses the usefulness of the transanal ileus tube and Sharon's operation for sigmoid colon volvulus without intestinal necrosis along with a review of the literature.

Effectiveness of a doctor dispatch system activated by an advanced automatic collision notification from a single-vehicle accident: A case report.

A 79-year-old woman collided with a cliff in a passenger automobile. The fire department acknowledged an automated collision notification from the D-Call Net (DCN) at 1 min after the accident and called for doctors by helicopter ("Doctor-Heli" [DH] in Japan) 9 min after the injury. The DH reached the victim 28 min after the injury, and examinations revealed pain in the right side of her chest, tachypnea, and a weak radial artery pulse (indicating shock). The DH arrived at the hospital 49 min after the injury. A thoracic drainage was performed for right-sided tension pneumothorax. She recovered from the shock, but was diagnosed with flail chest and placed on a respirator. She was extubated on postoperative day 6 and transferred to a rehabilitation hospital on postoperative day 57. Due to the DCN, the patient received treatment 15 min earlier than the time taken by the conventional system. Emergency response task forces must develop strategies for connecting DCN warnings to a rapid medical response.

A case of severe hemorrhagic shock caused by traumatic avulsion of uterine fibroid.

Case presentation: A 40-year-old woman was injured in a motor vehicle accident. Physician-staffed helicopter emergency medical service (HEMS) was dispatched, and after the HEMS physician performed thoracostomy and tracheal intubation to relieve the tension pneumothorax and hemorrhagic shock, her carotid artery became unpalpable. The physician then decided to perform prehospital resuscitative thoracotomy. Immediately after arriving at the hospital, an emergency laparotomy was performed. Intraoperative findings showed that a huge uterine fibroid had been avulsed from the uterine wall, and we performed temporary hemostasis by extraction of the avulsed tumor and application of packing to the pelvic cavity. She was transferred to a rehabilitation hospital 42 days after the operation. Conclusion: The injury mechanism in this case was considered a "submarine effect." This was an extremely rare case in which the acute care surgeon and a gynecologist collaboratively employed a damage control strategy to deal with impending cardiac arrest.

Initial entry via the left upper quadrant with an optical trocar in laparoscopic bariatric surgery.

INTRODUCTION: Laparoscopic bariatric surgery (BS) is not readily performed in Japan. To facilitate safe initial access to the abdominal cavity, we insert an optical viewing trocar at a unique site in the left upper quadrant (LUQ). Herein, we describe the technique, its advantages, and outcomes. MATERIALS AND SURGICAL TECHNIQUE: Briefly, the optical trocar is inserted just below the left subcostal margin, 8 cm from the midline. On insertion, layers of the abdominal wall are visualized on the monitor. Depending on the angle of insertion, five, seven, or eight layers are seen. DISCUSSION: In assessing our initial entry technique, used in 21 obese patients undergoing laparoscopic sleeve gastrectomy, we found median insertion time to be 25 seconds. There were no related complications. In nearly all (20/21) patients, the abdominal wall was visualized as seven layers: subcutaneous fat, anterior rectus sheath, rectus abdominis muscle, posterior rectus sheath, transverse abdominis muscle, transversalis fascia, and peritoneum. Understanding the layers of the abdominal wall visualized during optical trocar insertion in the LUQ will provide for safe and rapid initial entry in patients undergoing laparoscopic BS and can further the widespread acceptance of laparoscopic BS.

Influence of new coronavirus pandemic on behavior and awareness of young nurses and nursing students in Japan.

BACKGROUND: Although mental health disorders of health care workers in the coronavirus disease 2019 (COVID-19) pandemic have been focused, little is known about the psychological impact on nurses and the influence on their behavior and awareness, such as professionalism and views on life and death, in Japan where there are fewer cases of infection and deaths than in other countries. Moreover, the influence of the pandemic on nursing students is still unclear. METHODS: An online questionnaire survey was conducted among nurses and nursing students. Feelings during the state of emergency (at the peak of the pandemic) in Japan, changes in behavior and awareness after the rise of COVID-19, and the associated factors influencing these changes were analyzed, comparing nurses with nursing students. RESULTS: Significantly increased scores of anxiety/fear (p < .005) and voluntary restraint (p < .005) and significantly decreased score of motivation (p < .005) were observed during the state of emergency in both nurses and students. Scores of experience of discrimination (p < .005) and consideration of premature retirement (p < .01) were significantly increased in nurses. Moreover, preventive behavior (p < .005), lifestyle (p < .005), anxiety about nursing (p < .005) and views on life and death (p < .005) significantly changed after the rise of COVID-19 in both nurses and students. Only nurses reported significant damage to their professionalism (p < .01). Anxiety/fear and/or voluntary restraint and/or decreased motivation during the state of emergency were major factors associated with these changes. Also, the type of hospital, experience of care of infected patients and sex affected some of the changes. Voluntary restraint (p = .008), increased preventive behavior (p = .021) and decreased motivation (p = .005) were more marked in nurses than in students, while change in views on life and death was greater in students than in nurses (p = .002). CONCLUSION: The COVID-19 pandemic has had a psychological impact on nurses and nursing students, associated with changes in behavior and awareness even in Japan. Of note, the COVID-19 pandemic has affected nurses' professionalism and views on life and death. This study demonstrates the importance of having a coping strategy for anxiety and damaged professionalism in nurses, and education on life and death in nursing students.

Successful one-stage laparoscopic procedure for de Garengeot hernia: a totally extraperitoneal repair-first approach.

The de Garengeot hernia is a femoral hernia in which the appendix migrates into the hernia sac. It is usually diagnosed intraoperatively due to its rarity and lack of clinical presentation typical to acute appendicitis. Although most cases need emergency operation due to incarceration, no standard procedure exists. We report the case of a 49-year-old woman who was diagnosed with a de Garangeot hernia preoperatively by contrast-enhanced computed tomography. She underwent one-stage laparoscopic surgery via a totally extraperitoneal approach followed by laparoscopic appendectomy. She recovered uneventfully and was discharged on postoperative Day 3. Generally, hernioplasty and appendectomy are required for the de Garengeot hernia treatment. Avoiding a peritoneal incision around the herniation and performing a mesh repair prior to appendectomy is expected to carry a lower infectious risk than other laparoscopic procedures. With accurate diagnosis, this procedure could be a useful modality for de Garengeot hernia.

Suppression of liver transplant rejection by anti-donor MHC antibodies via depletion of donor immunogenic dendritic cells.

BACKGROUND: We previously found two distinct passenger dendritic cell (DC) subsets in the rat liver that played a central role in the liver transplant rejection. In addition, a tolerance-inducing protocol, donor-specific transfusion (DST), triggered systemic polytopical production of depleting alloantibodies to donor class I MHC (MHCI) antigen (DST-antibodies). METHODS: We examined the role of DST-antibodies in the trafficking of graft DC subsets and the alloresponses in a rat model. We also examined an anti-donor class II MHC (MHCII) antibody that recognizes donor DCs more selectively. RESULTS: Preoperative transfer of DST-antibodies or DST pretreatment eliminated all passenger leukocytes, including both DC subsets and depleted the sessile DCs in the graft to ~20% of control. The CD172a+CD11b/c+ immunogenic subset was almost abolished. The intrahost direct or semi-direct allorecognition pathway was successfully blocked, leading to a significant suppression of the CD8+ T-cell response in the recipient lymphoid organs and the graft with delayed graft rejection. Anti-donor MHCII antibody had similar effects without temporary graft damage. Although DST pretreatment had a priming effect on the proliferative response of recipient regulatory T cells, DST-primed sera and the anti-donor MHCII antibody did not. CONCLUSION: DST-antibodies and anti-donor MHCII antibodies could suppress the CD8+ T-cell-mediated liver transplant rejection by depleting donor immunogenic DCs, blocking the direct or semi-direct pathways of allorecognition. Donor MHCII-specific antibodies may be applicable as a selective suppressant of anti-donor immunity for clinical liver transplantation without the cellular damage of donor MHCII- graft cells and recipient cells.

Laparoscopic transabdominal preperitoneal hernioplasty for recurrent obturator hernia: A case report.

Reports of recurrence after obturator hernia repair are few. We describe the case of an 89-year-old woman who presented to us with a thrice recurrent obturator hernia. She had undergone open non-mesh repair twice and then laparoscopic non-mesh repair. She was readmitted to our hospital 6 months after the laparoscopic repair. Manual reduction was successful, paving the way for elective transabdominal preperitoneal repair. During the endoscopic repair, surgical mesh was placed extraperitoneally over the hernia defect and then fixed to Cooper's ligament with absorbable tacks. The patient was discharged on postoperative day 2 without complications. In the 2 months that have passed since the surgery there has been no sign of recurrence, but the patient will be carefully followed up. Repair of a recurrent obturator hernia is technically challenging; however, the transabdominal preperitoneal approach seems to be reliable and safe.

Primary extraskeletal osteosarcoma of the mesentery: A case report.

INTRODUCTION: Extraskeletal osteosarcoma is a rare malignant soft tissue tumor without attachment to the bone. To the best of our knowledge, we present here the first report of a primary extraskeletal osteosarcoma of the mesentery in Japan. CASE PRESENTATION: A 46-year-old female underwent a health examination, with no complaint. Following an ultrasonography a solid mass was detected in the abdominal cavity. Computed tomography showed a 38 × 25 mm heterogeneously enhancing mass. The latter was characterized by the presence of mottled calcifications and a cystic portion. The tumor was resected with a single incisional laparoscopic curative resection. Histopathological examination revealed the presence of a primary extraskeletal osteosarcoma arising from the mesentery. Postoperative course was uneventful. The patient did not receive chemotherapy during follow-up. She was recurrence free 10 months post-surgery. DISCUSSION: Patients with extraskeletal osteosarcoma generally have a poor prognosis. A tumor size <5 cm represents an important prognostic factor. Unexpectedly, our case was detected by ultrasonography at an early stage. This is the first report of a single incisional laparoscopic resection. CONCLUSION: A primary extraskeletal osteosarcoma of the mesentery is an extremely rare occurrence. Its diagnosis should be taken into consideration also when a soft tissue mass of the mesentery is found.

Taxonomic re-examination of "Chloromonas nivalis (Volvocales, Chlorophyceae) zygotes" from Japan and description of C. muramotoi sp. nov.

Recent molecular data has strongly suggested that field-collected cysts of snow algae that are morphologically identifiable as the zygotes of Chloromonas nivalis are composed of multiple species. Motile vegetative cells, however, have not been directly obtained from these cysts because of the difficulties involved in inducing their germination. Recently, our comparative molecular analyses, using both field-collected and cultured materials, demonstrated that one Japanese lineage of "C. nivalis zygotes" belongs to C. miwae. Herein, we examined another Japanese lineage of field-collected "C. nivalis zygotes" and a new strain originating from Japan. Our molecular data demonstrated that these two different life cycle stages are conspecific, and that they represent a new species that we herein describe as C. muramotoi sp. nov., based on the vegetative and asexual morphological characteristics of the strain. Multigene phylogenetic analyses showed that this new species was sister to C. miwae. Scanning electron microscopy demonstrated that the cysts of C. muramotoi are different from those of C. miwae, based on the arrangement of the flanges developing on the cell wall.

Electronic and Thermoelectric Properties of Layered Oxychalcogenides (BiO)Cu Ch ( Ch = S, Se, Te).

We study the new details of electronic and thermoelectric properties of polycrystalline layered oxychalcogenide systems of (BiO)Cu Ch ( Ch = Se, Te) prepared by using a solid-state reaction. The systems were characterized by using photoemission (PE) spectroscopy and four-probe temperature-dependent electrical resistivity ρ( T). PE spectra are explained by calculating the electronic properties using the generalized-gradient approximation method. PE spectra and ρ( T) show that (BiO)CuSe system is a semiconductor, while (BiO)CuTe system exhibits the metallic behavior that induces the high thermoelectric performance. The calculation of electronic properties of (BiO)Cu Ch ( Ch = S, Se, Te) confirms that the metallic behavior of (BiO)CuTe system is mainly induced by Te 5p states at Fermi energy level, while the indirect bandgaps of 0.68 and 0.40 eV are obtained for (BiO)CuS and (BiO)CuSe systems, respectively. It is also shown that the local symmetry distortion at Cu site strongly stimulates Cu 3d-t2g to be partially hybridized with Ch p orbitals. This study presents the essential properties of the inorganic systems for novel functional device applications.

Delayed Expression of Circulating TGF-ß1 and BMP-2 Levels in Human Nonunion Long Bone Fracture Healing.

BACKGROUND: The healing process of bone fracture requires a well-controlled multistage and sequential order beginning immediately after the injury. However, complications leading to nonunion exist, creating serious problems and costs for patients. Transforming growth factor-beta 1 (TGF-ß1) and bone morphogenic protein 2 (BMP-2) are two major growth factors involved in human bone fracture healing by promoting various stages of bone ossification. In this study, we aimed to determine the role of these factors during the fracture healing of human long bones and assess their impacts on nonunion condition. MATERIALS AND METHODS: We performed a comprehensive analysis of plasma TGF-ß1 and BMP-2 levels in blood samples from 10 patients with proved nonunion and 10 matched patients with normal union following a predetermined time schedule. The concentrations of TGF-ß1 and BMP-2 were measured at each time point using a solid-phase ELISA. RESULTS: TGF-ß1 and BMP-2 levels were detectable in all patients. For all patients, a maximal peak for TGF-ß1 was found at 3-week. In normal union group, TGF-ß1 showed a maximal peak at 2-week while nonunion group had a delayed maximal peak at 3-week. Plasma levels of BMP-2 for all patients and for normal union group reached a maximal peak at 1-week, but nonunion group showed a delayed maximal peak at 2-week. In general, plasma TGF-ß1 or BMP-2 level was not significantly different between normal union and nonunion groups. CONCLUSION: The expression levels of TGF-ß1 and BMP-2 appeared to be delayed in nonunion patients which could play an important role in developing an early marker of fracture union condition and facilitate improved patient's management.

Impact of urgent resuscitative surgery for life-threatening torso trauma.

PURPOSE: This study investigated the advantages of performing urgent resuscitative surgery (URS) in the emergency department (ED); namely, our URS policy, to avoid a delay in hemorrhage control for patients with severe torso trauma and unstable vital signs. METHODS: We divided 264 eligible cases into a URS group (n = 97) and a non-URS group (n = 167) to compare, retrospectively, the observed survival rate with the predicted survival using the Trauma and Injury Severity Score (TRISS). RESULTS: While the revised trauma score and the injury severity score were significantly lower in the URS group than in the non-URS group, the observed survival rate was significantly higher than the predicted rate in the URS (48.5 vs. 40.2%; p = 0.038). URS group patients with a systolic blood pressure (SBP) <90 mmHg and a Glasgow coma scale (GCS) score of ≥9 had significantly higher observed survival rates than predicted survival rates (0.433 vs. 0.309, p = 0.008), (0.795 vs. 0.681, p = 0.004). The implementation of damage control surgery (DCS) was found to be a significant predictor of survival (OR 5.23, 95% CI 0.113-0.526, p < 0.010). CONCLUSION: The best indications for the URS policy are an SBP <90 mmHg, a GCS ≥9 on ED arrival, and/or the need for DCS. By implementing our URS policy, satisfactory survival of patients requiring immediate hemostatic surgery was achieved.

Spontaneously ruptured hepatic cyst treated with laparoscopic deroofing and cystobiliary communication closure: A case report.

The rupture of a nonparasitic hepatic cyst with biliary communication is rare. We report the case of a patient with a hepatic cyst with biliary communication that spontaneously ruptured and was successfully treated by laparoscopic deroofing and closure of the communication. A 61-year-old woman presented at our hospital with a chief complaint of right upper abdominal pain. Enhanced abdominal CT showed a collapsed hepatic cyst and fluid collection. Drip infusion CT cholangiography showed contrast medium pooling in the collapsed cyst. Therefore, hepatic cyst rupture with biliary communication was diagnosed, and laparoscopic deroofing and closure of the communication were performed. The postoperative course was uneventful, and the patient was discharged on postoperative day 6. In cases of hepatic cyst rupture, even in the presence of biliary communication, laparoscopic deroofing and closure of the communication should be recommended as the first-choice treatment.

Dispatch of Helicopter Emergency Medical Services Via Advanced Automatic Collision Notification.

BACKGROUND: Advanced automatic collision notification (AACN) is a system for predicting occupant injury from collision information. If the helicopter emergency medical services (HEMS) physician can be alerted by AACN, it may be possible to reduce the time to patient contact. OBJECTIVE: The purpose of this study was to validate the feasibility of early HEMS dispatch via AACN. METHODS: A full-scale validation study was conducted. A car equipped with AACN was made to collide with a wall. Immediately after the collision, the HEMS was alerted directly by the operation center, which received the information from AACN. Elapsed times were recorded and compared with those inferred from the normal, real-world HEMS emergency request process. RESULTS: AACN information was sent to the operation center only 7 s after the collision; the HEMS was dispatched after 3 min. The helicopter landed at the temporary helipad 18 min later. Finally, medical intervention was started 21 min after the collision. Without AACN, it was estimated that the HEMS would be requested 14 min after the collision by fire department personnel. The start of treatment was estimated to be at 32 min, which was 11 min later than that associated with the use of AACN. CONCLUSIONS: The dispatch of the HEMS using the AACN can shorten the start time of treatment for patients in motor vehicle collisions. This study demonstrated that it is feasible to automatically alert and activate the HEMS via AACN.

The Pedicled Omental Flap Technique for Treating Extensive Defects or Soft-Tissue Infection of the Pelvic Area: A Report of 2 Cases.

Severe trauma injuries, such as open pelvic fractures and degloving injuries, have recently become salvageable. However, extensive soft-tissue defects often remain and can lead to disuse atrophy of the extremities, prolonged hospital stays, and numerous other problems. Such injuries can be easily and effectively treated by a general trauma surgeon performing the pedicled omental flap technique. We report on 2 highly diverse and complicated cases of soft-tissue defect that were both successfully treated with this technique. One case was an extensive right-sided defect of the pelvic soft-tissue in a 20-year-old woman. The other case was in a 55-year-old man who underwent emergency artificial vessel replacement surgery for a femoral artery tear with severe damage to the surrounding muscle. Although the surgery was successful, a methicillin-resistant Staphylococcus aureus infection developed around the artificial vessel 10 days after surgery. In both cases, the pedicled omental flap technique was successfully performed and yielded epithelization without serious infection and with the infection subsiding with wound-area healing. To our knowledge, the pedicled omental flap technique has rarely been used to treat severe trauma, and our results suggest its usefulness for both preventing infection in large wounds and healing infected wounds.

Approaches to Quality Risk Management When Using Single-Use Systems in the Manufacture of Biologics.

Biologics manufacturing technology has made great progress in the last decade. One of the most promising new technologies is the single-use system, which has improved the efficiency of biologics manufacturing processes. To ensure safety of biologics when employing such single-use systems in the manufacturing process, various issues need to be considered including possible extractables/leachables and particles arising from the components used in single-use systems. Japanese pharmaceutical manufacturers, together with single-use suppliers, members of the academia and regulatory authorities have discussed the risks of using single-use systems and established control strategies for the quality assurance of biologics. In this study, we describe approaches for quality risk management when employing single-use systems in the manufacturing of biologics. We consider the potential impact of impurities related to single-use components on drug safety and the potential impact of the single-use system on other critical quality attributes as well as the stable supply of biologics. We also suggest a risk-mitigating strategy combining multiple control methods which includes the selection of appropriate single-use components, their inspections upon receipt and before releasing for use and qualification of single-use systems. Communication between suppliers of single-use systems and the users, as well as change controls in the facilities both of suppliers and users, are also important in risk-mitigating strategies. Implementing these control strategies can mitigate the risks attributed to the use of single-use systems. This study will be useful in promoting the development of biologics as well as in ensuring their safety, quality and stable supply.