Development of an artificial intelligence model for predicting the likelihood of human embryo euploidy based on blastocyst images from multiple imaging systems during IVF.

STUDY QUESTION: Can an artificial intelligence (AI) model predict human embryo ploidy status using static images captured by optical light microscopy? SUMMARY ANSWER: Results demonstrated predictive accuracy for embryo euploidy and showed a significant correlation between AI score and euploidy rate, based on assessment of images of blastocysts at Day 5 after IVF. WHAT IS KNOWN ALREADY: Euploid embryos displaying the normal human chromosomal complement of 46 chromosomes are preferentially selected for transfer over aneuploid embryos (abnormal complement), as they are associated with improved clinical outcomes. Currently, evaluation of embryo genetic status is most commonly performed by preimplantation genetic testing for aneuploidy (PGT-A), which involves embryo biopsy and genetic testing. The potential for embryo damage during biopsy, and the non-uniform nature of aneuploid cells in mosaic embryos, has prompted investigation of additional, non-invasive, whole embryo methods for evaluation of embryo genetic status. STUDY DESIGN, SIZE, DURATION: A total of 15 192 blastocyst-stage embryo images with associated clinical outcomes were provided by 10 different IVF clinics in the USA, India, Spain and Malaysia. The majority of data were retrospective, with two additional prospectively collected blind datasets provided by IVF clinics using the genetics AI model in clinical practice. Of these images, a total of 5050 images of embryos on Day 5 of in vitro culture were used for the development of the AI model. These Day 5 images were provided for 2438 consecutively treated women who had undergone IVF procedures in the USA between 2011 and 2020. The remaining images were used for evaluation of performance in different settings, or otherwise excluded for not matching the inclusion criteria. PARTICIPANTS/MATERIALS, SETTING, METHODS: The genetics AI model was trained using static 2-dimensional optical light microscope images of Day 5 blastocysts with linked genetic metadata obtained from PGT-A. The endpoint was ploidy status (euploid or aneuploid) based on PGT-A results. Predictive accuracy was determined by evaluating sensitivity (correct prediction of euploid), specificity (correct prediction of aneuploid) and overall accuracy. The Matthew correlation coefficient and receiver-operating characteristic curves and precision-recall curves (including AUC values), were also determined. Performance was also evaluated using correlation analyses and simulated cohort studies to evaluate ranking ability for euploid enrichment. MAIN RESULTS AND THE ROLE OF CHANCE: Overall accuracy for the prediction of euploidy on a blind test dataset was 65.3%, with a sensitivity of 74.6%. When the blind test dataset was cleansed of poor quality and mislabeled images, overall accuracy increased to 77.4%. This performance may be relevant to clinical situations where confounding factors, such as variability in PGT-A testing, have been accounted for. There was a significant positive correlation between AI score and the proportion of euploid embryos, with very high scoring embryos (9.0-10.0) twice as likely to be euploid than the lowest-scoring embryos (0.0-2.4). When using the genetics AI model to rank embryos in a cohort, the probability of the top-ranked embryo being euploid was 82.4%, which was 26.4% more effective than using random ranking, and ∼13-19% more effective than using the Gardner score. The probability increased to 97.0% when considering the likelihood of one of the top two ranked embryos being euploid, and the probability of both top two ranked embryos being euploid was 66.4%. Additional analyses showed that the AI model generalized well to different patient demographics and could also be used for the evaluation of Day 6 embryos and for images taken using multiple time-lapse systems. Results suggested that the AI model could potentially be used to differentiate mosaic embryos based on the level of mosaicism. LIMITATIONS, REASONS FOR CAUTION: While the current investigation was performed using both retrospectively and prospectively collected data, it will be important to continue to evaluate real-world use of the genetics AI model. The endpoint described was euploidy based on the clinical outcome of PGT-A results only, so predictive accuracy for genetic status in utero or at birth was not evaluated. Rebiopsy studies of embryos using a range of PGT-A methods indicated a degree of variability in PGT-A results, which must be considered when interpreting the performance of the AI model. WIDER IMPLICATIONS OF THE FINDINGS: These findings collectively support the use of this genetics AI model for the evaluation of embryo ploidy status in a clinical setting. Results can be used to aid in prioritizing and enriching for embryos that are likely to be euploid for multiple clinical purposes, including selection for transfer in the absence of alternative genetic testing methods, selection for cryopreservation for future use or selection for further confirmatory PGT-A testing, as required. STUDY FUNDING/COMPETING INTEREST(S): Life Whisperer Diagnostics is a wholly owned subsidiary of the parent company, Presagen Holdings Pty Ltd. Funding for the study was provided by Presagen with grant funding received from the South Australian Government: Research, Commercialisation, and Startup Fund (RCSF). 'In kind' support and embryology expertise to guide algorithm development were provided by Ovation Fertility. 'In kind' support in terms of computational resources provided through the Amazon Web Services (AWS) Activate Program. J.M.M.H., D.P. and M.P. are co-owners of Life Whisperer and Presagen. S.M.D., M.A.D. and T.V.N. are employees or former employees of Life Whisperer. S.M.D, J.M.M.H, M.A.D, T.V.N., D.P. and M.P. are listed as inventors of patents relating to this work, and also have stock options in the parent company Presagen. M.V. sits on the advisory board for the global distributor of the technology described in this study and also received support for attending meetings. TRIAL REGISTRATION NUMBER: N/A.

Gender differences in clinical and angiographic findings of patients with Takayasu arteritis.

OBJECTIVES: Because Takayasu arteritis (TA) predominantly affects females, few data regarding gender differences have been reported. The aim of the present study is to describe clinical features and angiographic findings of patients with TA according to gender. METHODS: According to the 1990 American College of Rheumatology criteria, 294 patients were diagnosed with TA between September 1994 and April 2014 at a single tertiary hospital. We reviewed clinical, laboratory, and radiologic data at the time of diagnosis. RESULTS: Among the 294 patients studied, 257 (87.4%) were female (male:female ratio=1:6.9). Female patients had a higher tendency to exhibit blood pressure differences between arms (p=0.595) and a weak pulse at the brachial artery (p=0.063). In male patients, we observed higher serum creatinine levels (p=0.038) and hypertension more frequently (p=0.061) than in females. Females exhibited more common lesions in the thoracic aorta and its branches, while males had more frequent lesions in the abdominal aorta and its branches. An analysis of angiographic classification according to the International TA Conference in Tokyo 1994 classification revealed that male patients had a higher incidence of type IV and females showed a higher incidence of types I, IIa, and IIb. CONCLUSIONS: Female patients with TA have more frequent involvement of the thoracic aorta and its branches, whereas involvement of the abdominal aorta and its branches is more common in males. Considering these gender-specific differences, adjustment of diagnostic criteria for TA according to gender may be necessary.

Sharing a microbe with man's best friend: A case of canine streptococcal infection in a diabetic patient.

We report a case of a diabetic patient with an infected leg wound leading to septicemia and abscess formation in the contra-lateral leg due to Streptococcus canis. This organism belongs to the Lancefield group G and is more commonly found in dogs. It is often mistaken for Streptococcus dysgalactiae which is a human strain of streptococci. Infections in humans are not common and usually involve infected wounds or ulcers and the surrounding soft tissue. In most reported cases, patients had close contact with domestic dogs and a pre-existing wound as a portal of entry. Our patient recovered after surgical debridement and drainage of abscess together with antibiotics. This organism is sensitive to common antibiotics like penicillin, amoxycillin, cephalosporins and erythromycin. The incidence of infections due to Streptococcus canis may be under-reported as laboratories may just report an isolate as group G streptococcus. Susceptible patients with wounds or ulcers should be counselled on proper wound care and advised to avoid or minimise contact with the family dog.

Achieving treat to target in gout: a clinical practice improvement project.

OBJECTIVE: Gout care is suboptimal because of lack of translation of knowledge into real-world practice, despite evidence-based guidelines. We have developed processes to ensure systematic care for gout patients and determined the predictors for achievement of a target serum uric acid (SUA) concentration of < 360 µmol/L in a prospective cohort of Asian gout patients requiring allopurinol therapy. METHODS: A 1-year clinical practice improvement project was undertaken using evidence-based guidelines and quality planning tools. Interventions included comprehensive patient education, enhanced telephone access, reappointments and refills, upward titration of allopurinol with no limitation specified by renal function, and increased frequency of visits until the target SUA concentration was achieved. The primary outcome was the time to achieve an SUA level of <360 µmol/L. RESULTS: We recruited 126 gout patients. The median time to achieving the target SUA concentration was 36.9 weeks [95% confidence interval (CI) 29.3-44.4]. Based on survival analysis, the proportion of patients achieving the target was 8.1% (95% CI 3.2-13.0), 40.6% (95% CI 31.4-50.8), and 72.0% (95% CI 61.2-82.8) at 3, 6, and 12 months, respectively. On average, our patients who achieved the target were seen once every 2 months and achieved the target after a mean of 2.5 (SD = 1.1) visits. Frequency of follow-up visits and older patients not taking aspirin were independent predictors associated with achieving the target outcome, regardless of renal function. CONCLUSIONS: Optimization of control of SUA is achievable, even in the setting of renal impairment, by redesigning and implementing processes involving changes in physician prescribing habits, enhanced nursing interventions, and patient empowerment and education.

An analysis of the pull-out strength of 6 suture loop configurations in flexor tendons.

PURPOSE: New, stronger suture materials have been introduced for flexor tendon surgery. The advantage of these materials can be lost if the suture loop pulls out from the tendon. The aim of this study was to compare the ability of various locking loops to grip the tendon. METHODS: We inserted 4 different standard and 2 experimental locking loops with 200-µm nitinol wire into human cadaveric flexor digitorum profundus tendons. The standard loops were: group 1, cruciate; group 2, Pennington modified Kessler; group 3, cross-stitch; and group 4, Lim-Tsai. The experimental loops were: group 5, a composition of Pennington modified Kessler with a cross-stitch loop; and group 6, a locking Kessler type of loop with a superficial transverse component. We loaded the loops until failure. We recorded the pull-out strength and stiffness and documented failure mechanisms during the pull-out test. RESULTS: The cruciate loop had the weakest holding capacity, 20 N, which was significantly less than in groups 2 to 6. The cross-stitch loop, Lim-Tsai loop, and modified Kessler loop performed similarly (36 N, 37 N, and 39 N, respectively). The experimental loops had the highest pull-out strength (group 5, 59 N; and group 6, 60 N, both significantly greater than groups 1 to 4). The mode of failure was pull-out for all of the standard loops and 7 of the experimental loops. Of 20 experimental loops, 13 failed by suture rupture. CONCLUSIONS: The 2 experimental loop configurations demonstrated higher pull-out strength and may have advantages when used with newer and stronger suture materials. The number of the locking components in the loops and the way the tension is transmitted to the tendon fibrils explain the results. CLINICAL RELEVANCE: The loops presented in this study and that grip the tendon better may be useful with new materials that have high tensile strength.

Nickel-titanium wire in circumferential suture of a flexor tendon repair: a comparison to polypropylene.

PURPOSE: Nickel-titanium (NiTi) has been proposed as an alternative material for flexor tendon core suture. To our knowledge, its suitability as a circumferential suture of flexor tendon repair has not been investigated before. The purpose of this ex vivo study was to investigate the biomechanical properties of NiTi circumferential repairs and to compare them with commonly used polypropylene. METHODS: Forty porcine flexor tendons were cut and repaired by simple running or interlocking mattress technique using 100 microm NiTi wire or 6-0 polypropylene. RESULTS: The NiTi circumferential repairs showed superior stiffness, gap resistance, and load to failure when compared to polypropylene repairs with both techniques. CONCLUSIONS: Nickel-titanium wire seems to be a potential material for circumferential repair of flexor tendons.

Effects of meaningful weight loss beyond symptomatic relief in adults with knee osteoarthritis and obesity: a systematic review and meta-analysis.

Existing clinical guidelines recommend weight loss for adults with knee osteoarthritis and obesity, but the supporting evidence to date remains inadequate. There is also no pooled data on physical function and quality of life. This study aims to examine the efficacy of weight loss on pain, self-reported disability, physical function and quality of life in adults with knee osteoarthritis and obesity. A systematic database search (from 1990 to June 2017) was conducted, and seven studies were eligible for inclusion. The meta-analyses demonstrated that a 5% to 10% weight loss significantly improved pain (effect size 0.33, 95% confidence intervals 0.17 to 0.48), self-reported disability (effect size 0.42, 95% confidence intervals 0.25 to 0.59) and quality of life (physical) (effect size 0.39, 95% confidence intervals 0.24 to 0.54). The results were based on adults with mean body mass index 33.6 to 36.4 kg m-2 and mild to moderate knee osteoarthritis. Results for physical function were inconclusive due to the lack of eligible studies and incomprehensive outcome measures used.

Common bacterial infections of the hand.

Infections of the hand are commonly encountered in general practice. Delay in diagnosis increases the risk of tissue loss and functional impairment. Staphyloccocal infections are most common, but polymicrobial infections are often seen in immunocompromised patients. In this pictorial essay, important and common conditions are illustrated to demonstrate key points and pitfalls in diagnosis and management.

The prevalence of absence of the palmaris longus--a study in a Chinese population and a review of the literature.

Most standard textbooks of hand surgery quote the prevalence of absence of palmaris longus at around 15%. However, this figure varies considerably in reports from different ethnic groups. We studied 329 Chinese men and women and found palmaris longus to be absent unilaterally in 3.3%, and bilaterally in 1.2%, with an overall prevalence of absence of 4.6%. There was no significant difference in its absence with regard to the body side or the sex. Our literature review revealed a low prevalence of absence in Asian, Black and Native American populations and a much higher prevalence of absence in Caucasian populations. It is clear that a standard prevalence of absence of the palmaris longus cannot be applied to all populations.

Does the absence of the palmaris longus affect grip and pinch strength?

The palmaris longus tendon is the most frequently harvested tendon for reconstructive plastic and hand surgical procedures. A question patients often ask is whether loss of the palmaris longus will result in any functional deficit. In order to answer this question, the presence or absence of the palmaris longus muscle was clinically determined in 418 normal Asian subjects. All subjects also had their grip and pinch strengths measured. No statistically significant difference was seen in the grip or pinch strength measurements between subjects who had a palmaris longus tendon and those who did not. This study demonstrates that absence of the palmaris longus is not associated with a decrease of grip or pinch strength.

Exhaled nitric oxide in cystic fibrosis patients with allergic bronchopulmonary aspergillosis.

Exhaled nitric oxide (NO) is thought to be a marker of asthmatic inflammation. Levels in cystic fibrosis (CF) are generally low. This study aimed to measure exhaled NO in CF patients at high risk of developing ABPA and patients at low risk. We studied nine patients at high risk of developing ABPA and 36 at low risk. The two groups were similar in age and spirometry. All patients in the high-risk group were taking oral or inhaled glucocorticoids, compared to 56% in the low-risk group (P=0.02). The exhaled NO levels were lower in the high-risk group than in the low-risk group (2.0 vs. 3.6 ppb), mean difference (95% CI) 1.6 (-3.6 to 0.4) ppb, P=0.001. On subgroup analysis of patients on oral glucocorticoids, the exhaled NO levels were significantly lower in patients with a high risk of developing ABPA (n=7) than patients with a low risk (n=8) (P=0.011). The number of patients who were on inhaled, but not oral glucocorticoids was too small to analyse usefully. Exhaled NO levels were lower in CF patients with a high risk of developing ABPA and on glucocorticoids. This may be because oral glucocorticoids exert a greater effect on exhaled NO than inhaled glucocorticoids. Alternatively, inducible nitric oxide synthase may be down-regulated by Aspergillus toxin.

The long head of the triceps brachii as a free functioning muscle transfer.

This anatomic study investigates the possibility of using the long head of the triceps brachii muscle as a free functioning muscle transfer for the upper limb. It has been reported that the long head is not difficult to harvest and that its loss does not create significant donor-site morbidity. The muscle was studied in 23 fresh frozen upper limbs. The long head in all 23 specimens had a constant and proximal vascular pedicle from the profunda brachii artery and vein. The mean pedicle was long (4 cm) and had large-caliber vessels (diameter, 3-mm artery and 4-mm vein). Angiograms were carried out in five specimens and dye perfusion studies in six specimens. A single branch from the radial nerve of at least 7 cm in length innervated the muscle. Muscle architecture was studied in 12 specimens and revealed that the long head of the triceps is better suited for forearm reconstruction than either the gracilis or the latissimus dorsi muscles. The mean physiologic cross-sectional area (8.36 cm(2)) and fiber length (10.8 cm on the superficial surface and 8.2 cm on the deep surface) of the long head match more closely those of the flexor digitorum profundus and the extensor digitorum communis, the muscles most commonly replaced.

Independent function in a tendon transfer of the split flexor carpi ulnaris.

This case demonstrates the efficacy of the split flexor carpi ulnaris transfer to restore thumb and finger extension. The humeral and ulnar compartments retained their viability and their function. In addition, they were able to work independently, and the patient has secured two separate functions from one muscle. The versatility and simplicity of this technique give it advantages over more complex reconstructive procedures.

Split flexor carpi radialis muscle.

A detailed anatomic and intramuscular neural staining study in 22 human and 5 monkey upper limbs revealed that the flexor carpi radialis can be raised on its proximal neurovascular pedicle and that the muscle can be split along its tendon into two independently functioning neuromuscular compartments, each with its own nerve and blood supply. A study of the muscle architecture in the human specimens found the radial compartment to have significantly longer fiber length and a larger physiologic cross-sectional area than the ulnar compartment. Independence of function of each compartment was demonstrated in electrical stimulation studies in six monkeys (Macaca fascicularis), but no significant difference was noted in the peak isometric load between the two compartments (p = 0.68) in the monkey. The extra functioning muscle units become important in local transfers for restoring function in multiple nerve palsies as in Hansen's disease, severe traumatic loss of muscle in crush injuries and compartment syndromes, and after wide resection in infective and neoplastic conditions in the forearm and hand.

The neuromuscular compartments of the flexor carpi ulnaris.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Report on the vascular supply and innervation pattern of the flexor carpi ulnaris. 2. Describe the muscle architecture of the flexor carpi ulnaris, including the physiological cross-sectional area and fiber length. 3. State the uses of the flexor carpi ulnaris both for resurfacing defects in the vicinity of the elbow and in local functional tendon transfers. 4. Understand the principles of splitting skeletal muscles based on neurovascular supply to enhance its utilization in reconstructive procedures. The aim of this study was to describe the intramuscular innervation and vascular supply of the human flexor carpi ulnaris, with confirmation of findings by a similar study in the primate. Two distinct intramuscular nerve branches running parallel to each other, on either side of a central tendon, from the proximal quarter of the muscle belly to its insertion were found. The muscle could then be split into a humeral and an ulnar compartment, each with its own primary nerve branch. Perfusion studies confirmed the adequacy of circulation to the two compartments. In the primate flexor carpi ulnaris, electrical stimulation of the respective branches revealed independent contraction of each compartment. This study provides useful information for enabling the local transfer of the muscle as a whole, both for resurfacing in the vicinity of the elbow and for functional tendon transfers. It will also enable the transfer of the muscle as one or two separate compartments (for resurfacing, in tendon transfers for muscle paralysis, congenital defects, and muscle defects resulting from trauma, and after resections for neoplasm and infection).

Traumatic posterior fossa extradural haematomas (PFEDH).

OBJECTIVES: While posterior fossa extradural haematomas (PFEDH) may lead to rapid neurological deterioration and death because of brainstem compression, prompt treatment often leads to a good outcome. The non-specific clinical signs and the rarity of this lesion in craniocerebral trauma adds to the difficulty in diagnosis. The aim of this study was to identify features which could lead to an early diagnosis. METHODS: Seventeen patients with posterior fossa extradural haematomas were operated on over 4 1/2 years, accounting for 7.5% of the 226 surgically operated extradural haematomas in the Department of Neurosurgery, Tan Tock Seng Hospital, Singapore. Four patients were excluded from this study due to non-availability of the case records. The remaining 13 patients formed the study group in this retrospective analysis. RESULTS: The majority of cases (77%) presented acutely within 24 hours. The mechanism of injury varied from a fall in 7 cases, a road traffic accident in 4 cases and assault in 2. Nine patients had evidence of external injury to the occiput, 8 patients had skull fractures, and diastasis of the lambdoid suture was seen in 2 cases. Presence of aerocele was noted in the CT scan of 4 cases. All 9 cases admitted with a high GCS score of more than 8 had a very good outcome. CONCLUSION: An early CT scan head is recommended if a combination of the following features is present: occipital soft tissue injury, drowsiness, occipital fracture or diastasis of the lambdoid suture.

HLA and antibiotic allergic skin eruption.

Chinese patients with cutaneous eruption due to antibiotics were found to be positively associated with HLA-BW46 (RR = 2.5; 95% confidence limit 1.2-4.9) and negatively associated with HLA-B40 (RR = 0.46; 95% confidence limit 0.22-0.98). The association with HLA-BW46 was even higher in patients with ampicillin sensitivity (RR = 3.5; 95% confidence limit 1.4-9.0).

Culture-negative hand abscesses in immunocompetent individuals.

Gonococcal infection is a common sexually-transmitted infection in the older male population in our local setting. It is caused by Neisseria gonorrhoeae, and results in fever, dysuria and a foul-smelling discharge from the external urethral meatus. Occasionally, it may also present with disseminated gonococcal infection - dermatitis, septic arthritis and even meningitis or endocarditis. We present two unusual cases, where the primary presentation was that of multiple subcutaneous hand and wrist abscesses. This illustrates the need for competent history-taking, especially in culture-negative patients. We also recommend the use of gonococcal polymerase chain reaction tests in patients who demonstrate negative routine cultures, or in lieu of gonococcal culture when the diagnosis is equivocal or urgently required.