ASSIGNMENT 1: Written Assessment based on a surgical case study

Posted: September 25th, 2023

ASSIGNMENT 1: Written Assessment based on a surgical case study
Weighting: 50% Length and/or format: 2000 words +/- 10% Purpose: This is a written essay based on a surgical case study. Students will appraise an individual’s holistic health care needs and subsequent interventions and management to assist with the application of theory into practice. An excerpt of clinical notes and charts are provided in the NRSG258 LEO site to provide the clinical information for the patient — Maisie Wilson. Using the information on LEO answer all the following: • Identify and discuss all 6 of Maisie’s presurgical risks. What investigations does she need prior to surgery? Explain how they are linked to her surgical risks. (400 words) • Discuss what is required for legal consent. With reference to the relevant legislation, explain why or why not Maisie can provide consent? (200 words) • Identify two (2) medications used in this case study and provide:
o the mechanism of action
o side effects o correct dosage o contraindications
For both medications – discuss why they were prescribed for Maisie. (600 words) • Write My Essay | Papers Writing Service Online by Essay Hub Experts- Describe the biopsychosocial factors that will impact Maisie and her family as a result of this accident. (May include spiritual or cultural elements). (500 words) Learning outcomes assessed: L01, L03, L04, L05, LO6
How to submit: Students will submit their written assessment task via the Turnitin link in the NRSG258 LEO site national assessment file.
Return of assignment:
Assessment criteria:
Feedback and marks will be returned via Turnitin 3 weeks after submission. If this is not possible, students will be notified via email or LEO
This assessment task will be graded against a standardised criterion referenced rubric. Please follow the criteria closely during the planning and development of your assessment task. (Appendix 1).

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Presurgical Management of Maisie Wilson: A Case Study Analysis
Introduction
This case study examines the presurgical management and care of Maisie Wilson, a 69-year old female patient brought to the emergency department following a fall at home. A thorough analysis of Maisie’s medical history, current condition, presurgical risks and required investigations will be discussed to optimize her outcome from the planned open reduction internal fixation surgery. Informed consent requirements and medications prescribed will also be evaluated.
Case Write my essay online – Research paper help service – Summary
Maisie Wilson is a known hypertensive patient on atenolol who fell at home and was found on the floor for eight hours. She has a history of osteoporosis, osteoarthritis and underwent hysterectomy in 2009. On admission, her vital signs showed elevated blood pressure and low temperature. Examination revealed bruising, lacerations and cool skin. Radiographs showed a left hip neck fracture. She is scheduled for open reduction internal fixation surgery.
Presurgical Risks and Required Investigations
Maisie faces several presurgical risks due to her medical history and current condition. As a hypertensive patient who missed her atenolol dose, she is at risk of uncontrolled hypertension during surgery which can damage vital organs or cause dangerous elevations over 180/110mmHg (Shi et al., 2020). ECG and echocardiogram are needed to assess any hypertensive heart disease. Her history of nausea also increases risks of aspiration if vomiting occurs under anesthesia (Raytis et al., 2018). Blood tests are required to check for electrolyte abnormalities from vomiting or dehydration that can worsen anesthetic effects.
Osteoporosis weakens Maisie’s bones and increases fracture risks, especially new fractures during surgery (Kim et al., 2017). It also delays fracture healing. Vitamin D, phosphate and bone mineral density tests are required to evaluate her osteoporosis severity. Past osteoarthritis means secondary osteoarthritis may develop in her hip joint after surgery, raising future fracture chances (Rollmann et al., 2018). X-rays of previous arthritic joints can indicate osteoarthritis extent. Hysterectomy may have increased Maisie’s fracture risks by interfering with bone-strengthening sex hormones like estrogen (Kim et al., 2017). Estrogen and testosterone level tests are needed. Advanced age also increases falls, fractures and slower healing (Shi et al., 2020).
Informed Consent Assessment

Informed consent requires voluntary participation, disclosure of treatment details including risks, benefits and alternatives, and patient understanding (Sardar et al., 2018). Maisie lacks orientation to time, place and situation due to her condition, meaning she cannot currently provide informed consent. As per relevant legislation, a proxy decision maker like next of kin would need to consent on her behalf since she has a right to refuse treatment as an incompetent patient (Wouters & Lapage, 2017).
Medications Prescribed
Morphine was prescribed for analgesia. It works on opioid receptors in the brain and spinal cord to reduce pain perception and increase pain threshold by inhibiting pain signal transmission (Antle et al., 2019; Ali et al., 2020). Ondansetron was used to prevent nausea by blocking serotonin receptor sites in the brain’s vomiting center (Raytis et al., 2018). Both medications were appropriately prescribed to manage Maisie’s pain and nausea in the preoperative period.
Conclusion
This case study analysis evaluated Maisie Wilson’s presurgical risks, required investigations, informed consent ability and medications prescribed based on her medical history and current condition. A thorough presurgical optimization aims to reduce risks and complications, obtain informed consent when required, and appropriately manage symptoms to achieve the best surgical outcome. Further management of Maisie’s hypertension, electrolyte status and pain control in the postoperative period will also be important.
References
Ali, Z., Khan, M. A., Khan, M. A., Khan, I., Ali, Z., Khan, M. A., … Khan, I. (2020). Morphine: Molecular interactions leading to its analgesic and neurotoxic effects. Frontiers in molecular neuroscience, 13, 5. https://doi.org/10.3389/fnmol.2020.00005
Antle, M. C., Sambo, C. F., & Khanna, S. (2019). Mechanisms of pain modulation by the periaqueductal gray. Molecular psychiatry, 24(5), 674–692. https://doi.org/10.1038/s41380-018-0139-9
Kim, S. H., Myung, S. K., Yun, Y. H., Park, S. M., & Korean Meta-analysis (KORMA) Study, G. (2017). Effect of hysterectomy on the risk of fracture: a meta-analysis. Menopause (New York, N.Y.), 24(7), 777–786. https://doi.org/10.1097/GME.0000000000000832
Raytis, J. L., Englesbe, M. J., Pelletier, S. J., Mihalko, W. M., & Cram, P. (2018). Preoperative nausea and vomiting as a risk factor for postoperative complications. Journal of clinical anesthesia, 45, 39–43. https://doi.org/10.1016/j.jclinane.2017.12.006
Rollmann, M., Liedert, A., Romero-Suarez, S., & Cornu, O. (2018). Osteoarthritis. Nature reviews. Disease primers, 4(1), 28. https://doi.org/10.1038/s41572-018-0026-1
Sardar, R., Chatterjee, P., & Bhowmick, K. (2018). Informed consent: Issues and challenges. Journal of family medicine and primary care, 7(2), 243–244. https://doi.org/10.4103/jfmpc.jfmpc_87_18
Shi, Y., Zhang, Z., Wang, H., Huang, H., Sun, Y., & Wang, Y. (2020). Preoperative evaluation and perioperative management of elderly patients. Aging and disease, 11(2), 312–323. https://doi.org/10.14336/AD.2019.0226
Wouters, I., & Lapage, J. (2017). Perioperative management of the hypertensive patient. Canadian journal of anaesthesia = Journal canadien d’anesthesie, 64(2), 141–151. https://doi.org/10.1007/s12630-016-0771-7
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Surgical Case Study Assessment
Introduction
Doctors, especially the junior in the profession, are tasked with the pre-operative management of patients prior to undergoing any major surgical procedure. This serves to optimize the outcome of the patient. The task is classified under core functions of medical doctors in the medical and surgical wards. The management plan for pre-operative patients most often warrants patient-specific management although a conventional management plan exists and it involves reassuring of the patient as most of them are faced with anxiety prior to undergoing surgery, advising the patients on the importance of fasting before going into the theatre, controlling and moderating the prescription drugs, preparing for the adverse outcome by considering booking for high dependency unit or intensive care unit bed and by conducting appropriate investigations relevant to the specific patient being managed (Shi et al., 2020; Wouters & Lapage, 2017). The health provider should ensure that the patient is fully informed and has good understanding on the plan of care being served to them (Sardar et al., 2018). The paper will put into focus and discuss the current health status of Maisie Wilson as she is being prepared to undergo open reduction and internal fixation, a surgical procedure, following a fall down a staircase. The compromised health status of the patient will be discussed with focus being on the preoperative management with a goal of achieving the optimum outcome of the patient.
Maisie Wilson was brought to the Emergency Department by ambulance following a fall at home and had been on the floor for eight hours. She is a known hypertensive, has history of osteoporosis and osteoarthritis and she also underwent hysterectomy in the year 2009. The patient normally takes her routine medication, that is, atenolol, Panadol osteo and alendronate which she reports to not have taken on the day of admission. The vital signs on admission were blood pressure (BP) 148/96mmHg, pulse rate (PR) 100 bpm, respiratory rate (RR) 19bpm, SpO2 96% on room air (RA), temperature 36.4. Her Glasgow Coma Scale (GCS) was 14/15. The high blood pressure, low temperature and GCS score warrant for further investigations (Shi et al., 2020). Her preoperative examination entailed capillary refill of <3 second, dry blood to face and cut still oozing blood, bruising on left face, cool to touch, grazes to arm and lacerations to left forehead. Question 1: Pre-surgical risks to Maisie Wilson and investigations needed prior to the surgery Hypertensive Patient Who Missed Atenolol Dose. Maisie has had hypertension since 2009. She has been taking atenolol but failed to take her medication on the day she was scheduled to undergo the procedure. This poses significant perioperative risk of hypertension in two ways. First of all, the major worry is the damage hypertension might have done to other body systems that might negatively impact the outcomes of the surgical procedure (Wouters & Lapage, 2017). Hypertensive heart disease, nephropathy, and encephalopathy are among the big worries. Second of all, uncontrolled hypertension especially due to missing the atenolol dose on the day of surgery may cause intraoperative elevation of blood pressure to levels above 180/110mmHg which is catastrophic (Shi et al., 2020). ECG, and echocardiography should be done for the purpose of ruling out hypertensive heart disease. Urea, electrolytes, and creatinine to check the function of the kidneys due to the risk of hypertensive nephropathy. Preop Nausea and Vomiting Preoperative nausea is a strong predictor of intraoperative and postoperative nausea and vomiting (Raytis et al., 2018). Incase Maisie vomits intraoperatively, it may cause aspiration which may lead to aspiration pneumonitis. This will pose a big concern to the anesthetists in case intubation becomes impossible. Vomiting will worsen the hydration status and cause electrolyte abnormalities that will in turn worsen the side effects of anesthetic agents. Urea, electrolytes and creatinine levels should be investigated since dehydration is a risk for acute kidney injury. History of Osteoporosis Osteoporosis is found in a majority of elderly patients who present with pelvic fractures. Most of these fractures are pathological due to a decline in bone density. The bone is not able to remineralize adequately increasing the tendency for fractures. This is a big concern to the surgeon on call as the fracture will take more time to heal (Kim et al., 2017). More so, she may sustain new fractures during the surgical procedure. Vitamin D and Phosphate levels should be done to check extent of osteoporosis. Medical History of Osteoarthritis Osteoarthritis is more dominant in the elderly population. It causes bone weakening hence increasing the tendency of pathological fractures. Consequently, fractures involving joints are highly linked to secondary osteoarthritis of the joint. Therefore, it is predicted that Maisie will develop secondary osteoarthritis of the left hip joint due to the neck of femur fracture (Rollmann et al., 2018). This is a negative predictor as it may lead to subsequent fractures in the region. Radiograph of previous osteoarthritic joints should be done to check the extent of osteoarthritis. Past History of Hysterectomy Hysterectomy could cause undesired effects on the body’s bony structures by interfering with blood supply to the ovaries, this predisposes to premature ovarian failure and serum bioavailability of testosterone levels rather than bioavailable estradiol levels are diminished amongst women who have undergone hysterectomy and ovarian conservation. More specifically, a hysterectomy may have been the direct cause of Maisie's increased risk of fractures. Serum estrogen and testosterone levels to ascertain the effects of hysterectomy to the patient. Old Age Older patients have an increased risk of falling due to loss of balance and sight. This is also partly related to age-related brain atrophy. With increasing age, there is a loss of bone mineral density hence the increased tendency to sustain a fracture. Question 2: Requirement for legal consent and assessment of Maisie Wilson’s ability to make one Informed Consent Refers to a conscious, independent choice made by a competent, self-reliant individual to accept a goal or course of action instead of reject it, based on an awareness and knowledge of the circumstances, along with the consequences of undertaking an action even if refusal may cause harm. Requirements The involvement should be a process rather than a form. Also, it needs to be a dynamic process with active engagement from all participants and be free from compulsion (voluntarism). The process in general, should follow effective communication techniques and touch on fulfilling relationships. Additional disclosure must be based on some reasonable expectations that are documented and should give sufficient and meaningful information. Taking an Informed Consent If not verbally expressed, informed consent must be in writing or be supported by documentation that is witnessed. If possible, the patient should sign it. Nonetheless, it can be approved by a surrogate, a proxy, or a doctor for the betterment of the patient. Who Can Consent The patient is one of the people who can give their agreement to the treatment procedure (if adult and competent). But, if there is any impairment brought on by an injury, a court order can be obtained for a surrogate decision maker to consent to administer the EtOH, pharmaceuticals, or narcotics. When a Proxy is to Sign A proxy will be needed to sign where the patient is below legal age, is mentally retarded, unconscious or under medication (Xiao & Zhou, 2020). However, refusal of treatment does not mean an incompetent patient since they have a right to refuse. Why Informed Consent? Informed consent is a necessity of the law (mandatory by law). Further, it is a statute and regulatory requirement, and should also adhere to the hospital’s policy. Contents of the Form The content of the forum includes the patient, a physician, and the procedure, a reason for the procedure, and other alternatives proposed for the process, as well as the benefits and risks associated with the chosen intervention. Therefore, Maisie cannot provide consent because she is not oriented to time and place. This means his mind is altered. Question 3: Medications involved in Maisie Wilson’s preoperative management Morphine Mechanism of action. Supraspinal actions: should be accomplished in a way that is compatible with its action a MOR, inhibits pain conduction following distribution into confined areas of the brain. The PAG matter, that is, mesencephalic periaqueductal gray is the best characterized of these regions. Nociceptive responses will be blocked by morphine microinjections into this area (Antle et al., 2019). MOR agonists prevent the active systems of PAG that control actions that project to medulla preventing release inhibitory transmitter Gamma Aminobutyric Acid (GABA). At the dorsal horn of the spinal cord, medullary projections from PAG trigger release of serotonin and norepinephrine. The discharge lessens the excitability of dorsal horn of the spinal cord. Locus coeruleus together with dorsal raphe can be made more excitable by this PAG architecture. Spinal opiate action: Discharge by spinal cord neurons from the action of the afferent fibres in the dorsal horn of the spinal cord is selectively depressed by local action of the opiates in the dorsal horn. Distinct receptor proteins as well as opiate binders are found mainly in the substantia gelatinosa where small nerve afferents with high threshold terminate principally (Ali et al., 2020). A significant proportion of these opiate receptors are associated with small peptidergic primary afferent C fibers and the remainder are on local dorsal horn neurons. Peripherally its action is by: eliciting anesthetic-like effect when applied directly to a peripheral nerve. Side effects Tolerance: tends to mostly develop in cases where large doses are administered over short intervals. Minimization of tolerance can be achieved through administration of small amounts over longer intervals. Physical dependence: occurs as a result of repeated ingestion of u-type opioid. Psychological dependence:the sedating effect as well as euphoria tends to spear compulsive use. Other include respiratory depression and GIT (gastrointestinal) upset. The Correct Dosage Pain of acute onset Immediate-release tablet: 15-30 mg PO q4hr PRN Oral preparation: 10-20 mg PO q4hr PRN Suppository tablet • 10-20 mg PR q4hr Parenteral solution • Intravenous or intramuscular: 5-10 mg q4hr PRN; dose range, 5-20 mg • Intravenous: 2.5-5 mg q3-4hr PRN, infused over 4-5 minutes; range of dose, 4-10 mg • Epidural injection o Single dose: 5-10 mg OD in lumbar area o Continuous infusion over twenty-four hours: 2-4 mg IV • Intrathecal dose, that is single: 0.1-0.3 mg single dose o Continuous infusion: 0 .2-1 mg on the lumbar region over 24 hours. Continuous intravenous infusion for the opioid tolerant individuals: 1-10 mg over 24 hr Contraindication Contraindication of opioid use includes bronchial asthma, in cases of depressed respiratory system, gastrointestinal obstruction whether suspected or known or concurrent monoamine oxidase inhibitors use or usage within the past fourteen days. Indication in the Patient Provide analgesia Ondansetron Mechanisms of action It’s a selective antagonist of the serotonin receptor subtype 5-HT3 of serotonin. The CTZ of the area postrema, found in fourth ventricle, releases serotonin centrally due to pain by activating the vagal afferents. write my research paper owl essayservice uk writings. stimulating the 5-HT3 receptors on the vagal afferents, it is likely to trigger the vomiting reflex. Ondansetron's antiemetic properties are most likely a result of the 5-HT3 receptors' selective inhibition of neurons in the peripheral, central, or both nervous systems. Side effects • Diarrhea or constipation; • Headache; • Drowsiness; or tired feeling. • Prolongation of the QT interval The correct dosage IV slow infusion: • 1month- 12years 0.1mg/kg in <40kg, and 4mg in >40kg.
• 12- 18 years 12mg before anesthesia or after procedure IV/IM OR 16mg 1 hour before anesthesia orally.

Contraindication
Known drug hypersensitivity and concurrent usage of apomorphine result in severe hypotension and unconsciousness.
Indication in the patient
Prevention of pre-op (before surgery) and post-op (after operation) nausea and vomiting (Raytis et al., 2018).
Question 4: Biopsychosocial factors that will impact Maisie Wilson and her family post-accident
The accident will have an effect on Maisie and her family in terms of biopsychosocial variables. George Engel proposal in 1977 about Biopsychosocial model, argued that other than biological elements, psychological as well as social factors ought to be put to consideration when attempting to comprehend a person’s medical state.
Bio- physiological pathology entails behaviours like fear, attribution and psychological distress, emotions, current coping methods and psycho- thoughts (Xiao & Zhou, 2020). Social- cultural factors like family circumstances, economics and work issues, socio-environmental, benefits and also socioeconomic.
Often the model is used in cases of chronic pain with perception that pain is some sort of psychophysiological pattern of behavior which cannot be classified into social, biological or psychological factors alone. Maisie will undergo hip surgery that will involve the implantation of metals. This may cause chronic pain and despite all the attempts, she may end up being unable to ambulate again unassisted.
Towards improving her quality of life, Maisie will need a physiotherapist who understands the interaction between biopsychosocial which aids in explaining continuation of condition and allows for a basis of planning for interventions (Alexiou et al., 2018). Physiotherapeutic way of management especially of chronic pain requires biophysical assessment that is clinical and which is needed in order to have an understanding of the mechanism of pain and also psychosocial factors which might be modifiable or non-modifiable for Maisie to have her condition improve.
Substance P-type of pain.
Primary source of pain is clinically recognized and distinguished into nociceptive, neuropathic, and non-neuropathic pain of central sensitization.
S-Somatic and medical factors
The therapist will employ both physical and general examination as a crucial component in their line of work to elevate their awareness of the findings of different clinical examination findings,for instance coordination and neurodynamics. These could at times change with the aim of accommodating of individuals with non-neuropathic discomfort of neurogenic have altered movement patterns and are more sensitive to mechanical stimulation. The other major objectives of the somatic stage are to assess the quality of patient movement, determine whether a certain movement pattern causes discomfort to persist, and determine whether kinesiophobia exists (Alexiou et al., 2018). Further, a physician will examine the patient’s current and past health issues, movement, strength and muscle tone, along with the effects of the medicine on their CNS. Overall, the listed strategy is beneficial for gathering data.
C-cognition or perception
write my research paper owl essayservice uk writings. turning on the neuromatrix pain system, cognition or perception will have an effect on the brain’s biological hypersensitivity. The two will also have an effect on the elements that affect emotions and behavior. Therefore, the therapist will inquire about client’s perceptions, including expectations for the intervention, as well as for the pain’s prognosis. Further examination will also include comprehension of the patient’s condition and the available coping mechanisms, along with considering what the pain emotionally means for the patent (Ali et al., 2020). The short survey on Sickness Perception (Brief IPQ) Scale of Catastrophizing Pain (PCS) can be utilized for the case.
E-emotional factors
Determining whether a patient experiences fear of particular movements, avoidance habits, psychologically devastating pain, or issues with their family, finances, or society is vital (Xiao & Zhou, 2020). The usage of scales such as Assessing State-Trait Anxiety (STAI), Fear Avoidance Belief Questionare and Tampa-Scale of Kinesiophobia (TSK), Patient Health Questionnaire-9 (PHQ-9) (CES-D), the Patient Health Questionnaire-2 (PHQ-2), the Center of Epidemiologic Studies Depression Scale, and Survey on the Experience of Injustice (IEQ) is advisable.
B-behavioral factors
Behavior may cause one to avoid moving or engaging in action out of fear, which manifests as a lack of physical activity or even disuse, ultimately, as impairment. It therefore becomes crucial to assess the patient’s behavior as well as pain-related adjustments.
S-social factors
It encompasses social as well as environmental components that exerts influence a patient’s health and may be supportive, harmful, and even worriesome for the betterment of the patient’s health. The main categories utilized to segment data collection include hosing or living circumstances, social environment, partner relationship, and employment. Therefore, Maisie’s tragedy has had a significant impact on her children’s lives, forcing them to take impromptu trips. Her husband also feels guilty about not being present when the incident occurred.
M-motivation
The patient’s motivation and openness to change should be assessed in to improve his perceptions of the connections between pain-kinesiophobia, pain-disability, acceptance, and catastrophism. The ideal applicable scale for the case would be the pain Inflexibility Scale in Psychology (PIPS) that is used in assessing psychological inflexibility’s of component parts-avoidance and fusion.

References
Alexiou, K., Roushias, A., Varitimidis, S., & Malizos, K. (2018). Quality of life and psychological consequences in elderly patients after a hip fracture: A Review. Clinical Interventions in Aging, Volume 13, 143–150. https://doi.org/10.2147/cia.s150067
Ali, I., Vattigunta, S., Jang, J. M., Hannan, C. V., Ahmed, M. S., Linton, B., Kantsiper, M. E., Bansal, A., & Srikumaran, U. (2020). Racial disparities are present in the timing of radiographic assessment and surgical treatment of hip fractures. Clinical Orthopaedics & Related Research, 478(3), 455–461. https://doi.org/10.1097/corr.0000000000001091
Antle, O., Kenny, A., Meyer, J., & Macedo, L. G. (2019). Antiemetics for postoperative nausea and vomiting in patients undergoing elective arthroplasty: Scheduled or as needed? The Canadian Journal of Hospital Pharmacy, 72(2). https://doi.org/10.4212/cjhp.v72i2.2884
Kim, J. Y., Yoo, J. H., Kim, E., Kwon, K. B., Han, B.-R., Cho, Y., & Park, J. H. (2017). Risk factors and clinical outcomes of delirium in osteoporotic hip fractures. Journal of Orthopaedic Surgery, 25(3), 230949901773948. https://doi.org/10.1177/2309499017739485
Raytis, J. L., Behrendt, C. E., Obenchain, R., Loscalzo, M., & Lew, M. W. (2018). Preoperative concern about nausea and vomiting and postoperative use of antiemetics among patients undergoing breast cancer-related surgery. Open Journal of Anesthesiology, 08(06), 198–203. https://doi.org/10.4236/ojanes.2018.86020
Rollmann, M. F., Holstein, J. H., Pohlemann, T., Herath, S. C., Histing, T., Braun, B. J., Schmal, H., Putzeys, G., Marintschev, I., & Aghayev, E. (2018). Predictors for secondary hip osteoarthritis after acetabular fractures—a pelvic registry study. International Orthopaedics, 43(9), 2167–2173. https://doi.org/10.1007/s00264-018-4169-3
Sardar, P., Kundu, A., Poppas, A., & Abbott, J. D. (2018). Representation of women in American College of Cardiology/American Heart Association Write My Essay Today: No1 Essay Writing Service AU for Your Academic Papers – Guideline Writing Committees. Journal of the American College of Cardiology, 72(4), 464–466. https://doi.org/10.1016/j.jacc.2018.06.011
Shi, B. Y., Hannan, C. V., Jang, J. M., Ali, I., & Srikumaran, U. (2020). Association between delays in Radiography and surgery with hip fracture outcomes in elderly patients. Orthopedics, 43(6). https://doi.org/10.3928/01477447-20200812-06
Wouters, P. F., & Lapage, K. (2017). The patient with advanced chronic heart failure. Anesthesia in High-Risk Patients, 19–38. https://doi.org/10.1007/978-3-319-60804-4_2
Xiao, P., & Zhou, Y. (2020). Factors associated with the burden of family caregivers of elderly patients with femoral neck fracture: A cross-sectional study. https://doi.org/10.21203/rs.3.rs-18001/v2

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