Alzheimer's Disease: A Review of Pathology, Current Treatments, and the Potential Therapeutic Effect of Decreasing Oxidative Stress by Combined Vitamin D and l-Cysteine Supplementation.

Significance: Excess oxidative stress and neuroinflammation are risk factors in the onset and progression of Alzheimer's disease (AD) and its association with amyloid-ß plaque accumulation. Oxidative stress impairs acetylcholine (ACH) and N-methyl-d-aspartate receptor signaling in brain areas that function in memory and learning. Glutathione (GSH) antioxidant depletion positively correlates with the cognitive decline in AD subjects. Treatments that upregulate GSH and ACH levels, which simultaneously decrease oxidative stress and inflammation, may be beneficial for AD. Recent Advances: Some clinical trials have shown a benefit of monotherapy with vitamin D (VD), whose deficiency is linked to AD or with l-cysteine (LC), a precursor of GSH biosynthesis, in reducing mild cognitive impairment. Animal studies have shown a simultaneous decrease in ACH esterase (AChE) and increase in GSH; combined supplementation with VD and LC results in a greater decrease in oxidative stress and inflammation, and increase in GSH levels compared with monotherapy with VD or LC. Therefore, cosupplementation with VD and LC has the potential of increasing GSH, downregulation of oxidative stress, and decreased inflammation and AChE levels. Future Directions: Clinical trials are needed to determine whether safe low-cost dietary supplements, using combined VD+LC, have the potential to alleviate elevated AChE, oxidative stress, and inflammation levels, thereby halting the onset of AD. Goal of Review: The goal of this review is to highlight the pathological hallmarks and current Food and Drug Administration-approved treatments for AD, and discuss the potential therapeutic effect that cosupplementation with VD+LC could manifest by increasing GSH levels in patients. Antioxid. Redox Signal. 40, 663-678.

Clinical and Radiological Outcome of Osteoscopic-Assisted Treatment of Enchondroma in Hand with Artificial Bone Substitute or Bone Graft: A 7-Year Case Series and Literature Review.

Background: This study aims to look at the intermediate-term clinical, functional and radiological outcomes of patients with enchondroma in hand treated with osteoscopic-assisted curettage and artificial bone substitute or bone graft. The addition of osteoscopy allows direct visualisation of the bone cavity during and after curettage of tumour tissue without the need of creating a large opening in the bone cortex. This could lead to better clearance of tumour tissue and lower risk of iatrogenic fracture. Methods: A total of 11 patients who received surgery from December 2013 to November 2020 were retrospectively reviewed. All cases had histological diagnosis of enchondroma. Patients with a follow-up period of less than 3 months were excluded. The mean duration of follow-up was 20.9 months. For the clinical outcome, we measured the total active motion (TAM) and graded with Belsky score grip strength. For the functional outcome, the Quick Disabilities of the Arm, Shoulder and Hand Questionnaire (QuickDASH) score was used. For the radiological outcome, we evaluated the X-ray for bone cavity filling defect, new bone formation according to the system proposed by Tordai. Results: The mean TAM of patients was 257º. A total of 60% patients had Belsky score grading excellent, 40% patients had Belsky score grading good. The mean percentage of grip strength compared with the contralateral side was 86.2%. The mean QuickDASH score was 7.7. For the wound aesthetic rating by patients, 81.8% patients reported as excellent. For the radiological outcome, the postoperative X-ray of all patients showed bone filling defect less than 3 mm. The mean time to complete bone consolidation was 3.8 months. None of the patients showed any radiological signs of recurrence. Conclusions: Our study showed that patients with enchondromas in hand treated with this minimally invasive method demonstrated good functional and radiological outcome. Its application may also be extended into treating other benign bone lesions in hand. Level of Evidence: Level IV (Therapeutic).

Is It Possible to Perform Fifth Carpometacarpal Joint Arthroscopy? Cadaveric Study on Its Feasibility, Safety, and Potential Hazards in Portal Creation.

Background Fifth carpometacarpal joint (CMCJ) fracture dislocation is a relatively rare injury and most will require operative treatment because of its unstable nature. Improper reduction and fixation lead to joint surface destruction, pain, and reduced grasping power. Intra-articular fragment reduction is often obscured by dorsally displaced ulnar fragment. Therefore, fifth CMCJ arthroscopy can be advantageous in assisting intra-articular fragment reduction. However, there is no detailed description of the portal landmarks or portals' relationship with adjacent important structures in the literature. Purposes To explore the feasibility and safety of fifth CMCJ arthroscopy, locations of the portals are examined in cadaveric hand specimens. Their proximity to important anatomical structures such as dorsal cutaneous branch of ulnar nerve (DCBUN), ring finger and little finger extensor digitorum communis (EDC), and extensor digiti minimi (EDM) is measured. Methods Fifth CMCJ arthroscopy is performed on 11 cadaveric hand specimens by specialist-level surgeon. The portals are marked and portal positions are further confirmed under the fluoroscopy. Then the cadaveric specimens were undergone anatomical dissection by specialist-level surgeon. During dissection, the spatial relationship between the portal positions and DCBUN, EDC to ring finger and little finger, and EDM is identified. The distance between the portals and the above important structures was measured in millimeters. Results DCBUN was consistently found between fourth metacarpohamate (4-MH) and fifth metacarpohamate (5-MH) portals, with it being closer to the latter (mean distance, 2.03 mm; range, 0-4.43 mm; standard deviation [SD], 1.09 mm). The closest tendon for 4-MH portal is ring finger EDC (mean distance, 2.65 mm; range, 0-5.89 mm; SD, 1.78 mm), while 5-MH portal and accessory portal were closest to EDC (mean distance, 1.88 mm; range, 0-3.69 mm; SD, 1.25 mm) and EDM (mean distance, 7.79 mm; range, 6.63-10.72 mm; SD, 1.49 mm), respectively. During the process of specimen dissection, we found no damage to the above structures after portal introduction. Conclusion The above findings support the use of fifth CMCJ arthroscopy, which can be used for assisted reduction in fifth metacarpal base fracture dislocation and hamate body fracture. Gentle soft tissue spreading technique during portal creation prevents injury to the important structure surrounding the portals. Level of evidence This is a Level V study.

Next-Generation Cancer Magnetic Resonance Imaging With Tumor-Targeted Alkylphosphocholine Metal Analogs.

OBJECTIVES: In an effort to exploit the elevated need for phospholipids displayed by cancer cells relative to normal cells, we have developed tumor-targeted alkylphosphocholines (APCs) as broad-spectrum cancer imaging and therapy agents. Radioactive APC analogs have exhibited selective uptake and prolonged tumor retention in over 50 cancer types in preclinical models, as well as over 15 cancer types in over a dozen clinical trials. To push the structural limits of this platform, we recently added a chelating moiety capable of binding gadolinium and many other metals for cancer-targeted magnetic resonance imaging (MRI), positron emission tomography imaging, and targeted radionuclide therapy. The aim of this work was to synthesize, characterize, and validate the tumor selectivity of a new broad-spectrum, tumor-targeted, macrocyclic MRI chelate, Gd-NM600, in xenograft and orthotopic tumor models. A secondary aim was to identify and track the in vivo chemical speciation and spatial localization of this new chelate Gd-NM600 in order to assess its Gd deposition properties. MATERIALS AND METHODS: T1 relaxivities of Gd-NM600 were characterized in water and plasma at 1.5 T and 3.0 T. Tumor uptake and subcellular localization studies were performed using transmission electron microscopy. We imaged 8 different preclinical models of human cancer over time and compared the T1-weighted imaging results to that of a commercial macrocyclic Gd chelate, Gd-DOTA. Finally, matrix-assisted laser desorption and ionization-mass spectrometry imaging was used to characterize and map the tissue distribution of the chemical species of Gd-NM600. RESULTS: Gd-NM600 exhibits high T1 relaxivity (approximately 16.4 s-1/mM at 1.5 T), excellent tumor uptake (3.95 %ID/g at 48 hours), prolonged tumor retention (7 days), and MRI conspicuity. Moreover, minimal tumor uptake saturability of Gd-NM600 was observed. Broad-spectrum tumor-specific uptake was demonstrated in 8 different human cancer models. Cancer cell uptake of Gd-NM600 via endosomal internalization and processing was revealed with transmission electron microscopy. Importantly, tissue mass spectrometry imaging successfully interrogated the spatial localization and chemical speciation of Gd compounds and also identified breakdown products of Gd species. CONCLUSIONS: We have introduced a new macrocyclic cancer-targeted Gd chelate that achieves broad-spectrum tumor uptake and prolonged retention. Furthermore, we have demonstrated in vivo stability of Gd-NM600 by ultrahigh resolution MS tissue imaging. A tumor-targeted contrast agent coupled with the enhanced imaging resolution of MRI relative to positron emission tomography may transform oncologic imaging.

Reliability of Cell-Free DNA and Targeted NGS in Predicting Chromosomal Abnormalities of Patients With Myeloid Neoplasms.

Introduction: Cytogenetic analysis is important for stratifying patients with various neoplasms. We explored the use of targeted next generation sequencing (NGS) in detecting chromosomal structural abnormalities or copy number variations (CNVs) in patients with myeloid neoplasms. Methods: Plasma cell-free DNA (cfDNA) from 2821 myeloid or lymphoid neoplasm patients were collected. cfDNA was sequenced using a 275 gene panel. CNVkit software was used for analyzing and visualizing CNVs. Cytogenetic data from corresponding bone marrow (BM) samples was available on 89 myeloid samples. Results: Of the 2821 samples, 1539 (54.5%) showed evidence of mutations consistent with the presence of neoplastic clones in circulation. Of these 1539 samples, 906 (59%) showed abnormalities associated with myeloid neoplasms and 633 (41%) with lymphoid neoplasms. Chromosomal structural abnormalities in cfDNA were detected in 146 (16%) myeloid samples and 76 (12%) lymphoid samples. Upon comparison of the myeloid samples with 89 BM patients, NGS testing was able to reliably detect chromosomal gain or loss, except for fusion abnormalities. When cytogenetic abnormalities were classified according to prognostic classes, there was a complete (100%) concordance between cfDNA NGS data and cytogenetic data. Conclusions: This data shows that liquid biopsy using targeted NGS is reliable in detecting chromosomal structural abnormalities in myeloid neoplasms. In specific circumstances, targeted NGS may be reliable and efficient to provide adequate information without the need for BM biopsy considering broad mutation profiling can be obtained through adequate sequencing within the same test. Overall, this study supports the use of liquid biopsy for early diagnosis and monitoring of patients with myeloid neoplasms.

PNPT1, MYO15A, PTPRQ, and SLC12A2-associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India.

The study was conducted between 2018 and 2020. From a cohort of 113 hearing impaired (HI), five non-DFNB12 probands identified with heterozygous CDH23 variants were subjected to exome analysis. This resolved the etiology of hearing loss (HL) in four South Indian assortative mating families. Six variants, including three novel ones, were identified in four genes: PNPT1 p.(Ala46Gly) and p.(Asn540Ser), MYO15A p.(Leu1485Pro) and p.(Tyr1891Ter), PTPRQ p.(Gln1336Ter), and SLC12A2 p.(Pro988Ser). Compound heterozygous PNPT1 variants were associated with DFNB70 causing prelingual profound sensorineural hearing loss (SNHL), vestibular dysfunction, and unilateral progressive vision loss in one family. In the second family, MYO15A variants in the myosin motor domain, including a novel variant, causing DFNB3, were found to be associated with prelingual profound SNHL. A novel PTPRQ variant was associated with postlingual progressive sensorineural/mixed HL and vestibular dysfunction in the third family with DFNB84A. In the fourth family, the SLC12A2 novel variant was found to segregate with severe-to-profound HL causing DFNA78, across three generations. Our results suggest a high level of allelic, genotypic, and phenotypic heterogeneity of HL in these families. This study is the first to report the association of PNPT1, PTPRQ, and SLC12A2 variants with HL in the Indian population.

Comparing Outcomes between Arthroscopic-Assisted Reduction and Fluoroscopic Reduction in AO Type C Distal Radius Fracture Treatment.

Background Distal radius fracture is one of the most common injuries. Poor functional result with restricted wrist motion can be developed when there is intra-articular fibrous tissue development arising from articular step-off and gapping. Objectives The aim of this study is to compare the functional and radiological outcome between arthroscopic-assisted reduction and fluoroscopic reduction in treating unstable intra-articular distal radius fracture. Methods We retrospectively analyzed 12 patients with intraarticular AO type C distal radius fracture treated with arthroscopic-assisted fracture reduction and internal fixation and compared them with another group of 12 patients in which fracture reduction is assessed by fluoroscopy alone (15 males and 9 females, mean age 57.3, range 27-73). The two cohorts were analyzed for differences in radiological parameters including articular stepping and gapping, palmar tilt, radial inclination, ulnar variance as well as functional outcome in range of motion, grip strength, modified mayo wrist score, and Quick Disabilities of the Arm, Shoulder, and Hand (DASH) score at an average of 12.5 months (range 5-26) after surgery. Results Arthroscopic-assisted fracture reduction group has statistically better restoration of articular stepping and gapping, volar tilt and ulnar variance. Range of motion, grip strength, modified mayo wrist score and Quick DASH score also had statistically significant improvement in arthroscopic group. Conclusion Our study showed arthroscopic-assisted technique can precisely restore radiological parameters in highly comminuted distal radius fracture with good functional outcome. Also, associated intra-articular soft tissue injury can be detected and treated simultaneously. Level of Evidence This is a level III, retrospective cohort study.

Anatase Titanium Dioxide Imparts Photoluminescent Properties to PA2200 Commercial 3D Printing Material to Generate Complex Optical Imaging Phantoms.

Selective laser sintering (SLS) is a prominent 3D printing modality that typically uses a polyamide (PA) powder as the substrate. One commercially available SLS material is known as PA2200, which is comprised of nylon 12 and titanium dioxide (TiO2) and is widely used to generate 3D-printed parts. Here, we report a unique optical photoluminescence (PL) characteristic of native, white PA2200, in which it yields a persistent, phosphorescence-type emission. An analysis of luminescence imaging data with emission measurements demonstrated that the anatase phase of the titanium dioxide additive is the source of the persistent PL properties. This characteristic of PA2200 enables advanced optical imaging applications, as demonstrated by luminescence imaging of an anatomical rat skeleton and a novel Derenzo-type phantom on a commercial image station. In summary, the light emission properties of PA2200 induced by the presence of anatase titanium dioxide open the door to a vast new array of complex optical applications, including the generation of imaging phantoms for training, calibration, and quality control.

Hand Surgery in Hong Kong.

Hand surgery in Hong Kong was borne out of necessity. It has been changing with the social, economic, and political situations. The spectrum of hand surgeries evolves with time, from infection-related hand surgeries to microsurgical or non-microsurgical operations on the huge volume of industrial hand injuries, to a wider variety of reconstructions on rheumatological, congenital upper limbs, traumatic, neurological diseases, etc, to minimally invasive surgeries on hand, wrist, and elbow. Hand surgery was deeply-rooted in orthopaedics in Hong Kong and is inseparable from microsurgeries, which have built a strong foundation for any kind of its future development.

Low incidence of GIPC3 variants among the prelingual hearing impaired from southern India.

The broad spectrum of causal variants in the newly discovered GIPC3 gene is well reflected in worldwide studies. Except for one missense variant, none of the reported variants had reoccurred, thus reflecting the intragenic heterogeneity. We screened all the six coding exons of GIPC3 gene in a large cohort of 177 unrelated prelingual hearing impaired after excluding the common GJB2, GJB6 nuclear and A1555G mitochondrial variants. We observed a single homozygous pathogenic frameshift variant c.685dupG (p.A229GfsX10), accounting for a low incidence (0.56%) of GIPC3 variants in south Indian population. GIPC3 being a rare gene as a causative for deafness, the allelic spectra perhaps became much more diverse from population to population, thus resulting in a minimal recurrence of the variants in our study, that were reported by authors from other parts of the globe.

Genetic analysis of SLC26A4 gene (pendrin) related deafness among a cohort of assortative mating families from southern India.

PURPOSE: Assortative mating (AM) or preferential mating is known to influence the genetic architecture of the hearing-impaired (HI) population. AM is now seen as a universal phenomenon with individuals seeking partners based on quantitative, qualitative, and behavioral phenotypes. However, the molecular genetic dynamics of AM among the HI tested in real time are limited to the DFNB1 locus. METHODS: A total of 113 HI partners from 82 South Indian families (52 deaf marrying deaf and 30 deaf marrying normal), previously excluded for DFNB1 (GJB2/6) etiology, were screened for SLC26A4 gene (DFNB4) variants. RESULTS: A spectrum of seven pathogenic variants viz., p.S90L, p.V239D, p.V359E, p.Gly389Trpfs*79 (novel), p.T410M, p.N457K and p.K715N were identified. The pathogenic allele frequency of SLC26A4 variants identified in this study was 3.98% (9/226). CONCLUSION: We recommend a preliminary screening of mutational hotspots for future investigations to rapidly test for its recurrence among South Indian HI population. This will be the first study to comprehensively account for the incidence of SLC26A4 gene variants and the real-time dynamics of DFNB4 variants among this type of a HI cohort.

In Silico Docking of Alkylphosphocholine Analogs to Human Serum Albumin Predicts Partitioning and Pharmacokinetics.

Alkylphosphocholine (APC) analogs are a novel class of broad-spectrum tumor-targeting agents that can be used for both diagnosis and treatment of cancer. The potential for clinical translation for APC analogs will strongly depend on their pharmacokinetic (PK) profiles. The aim of this work was to understand how the chemical structures of various APC analogs impact binding and PK. To achieve this aim, we performed in silico docking analysis, in vitro and in vivo partitioning experiments, and in vivo PK studies. Our results have identified 7 potential high-affinity binding sites of these compounds on human serum albumin (HSA) and suggest that the size of the functional group directly influences the albumin binding, partitioning, and PK. Namely, the bulkier the functional groups, the weaker the agent binds to albumin, the more the agent partitions onto lipoproteins, and the less time the agent spends in circulation. The results of these experiments provide novel molecular insights into the binding, partitioning, and PK of this class of compounds and similar molecules as well as suggest pharmacological strategies to alter their PK profiles. Importantly, our methodology may provide a way to design better drugs by better characterizing the PK profile for lead compound optimization.

Role of DFNB1 mutations in hereditary hearing loss among assortative mating hearing impaired families from South India.

BACKGROUND: DFNB1, the first locus to have been associated with deafness, has two major genes GJB2 & GJB6, whose mutations have played vital role in hearing impairment across many ethnicities in the world. In our present study we have focused on the role of these mutations in assortative mating hearing impaired families from south India. METHODS: One hundred and six assortatively mating hearing impaired (HI) families of south Indian origin comprising of two subsets: 60 deaf marrying deaf (DXD) families and 46 deaf marrying normal hearing (DXN) families were recruited for this study. In the 60 DXD families, 335 members comprising of 118 HI mates, 63 other HI members and 154 normal hearing members and in the 46 DXN families, 281 members comprising of 46 HI and their 43 normal hearing partners, 50 other HI members and 142 normal hearing family members, participated in the molecular study. One hundred and sixty five (165) healthy normal hearing volunteers were recruited as controls for this study. All the participating members were screened for variants in GJB2 and GJB6 genes and the outcome of gene mutations were compared in the subsequent generation in begetting deaf offspring. RESULTS: The DFNB1 allele frequencies for DXD mates and their offspring were 36.98 and 38.67%, respectively and for the DXN mates and their offspring were 22.84 and 24.38%, respectively. There was a 4.6% increase in the subsequent generation in the DXD families, while a 6.75% increase in the DXN families, which demonstrates the role of assortative mating along with consanguinity in the increase of DFNB1 mutations in consecutive generations. Four novel variants, p.E42D (in GJB2 gene), p.Q57R, p.E101Q, p.R104H (in GJB6 gene) were also identified in this study. CONCLUSION: This is the first study from an Indian subcontinent reporting novel variants in the coding region of GJB6 gene. This is perhaps the first study in the world to test real-time, the hypothesis proposed by Nance et al. in 2000 (intense phenotypic assortative mating mechanism can double the frequency of the commonest forms of recessive deafness [DFNB1]) in assortative mating HI parental generation and their offspring.

Recurrence of reported CDH23 mutations causing DFNB12 in a special cohort of South Indian hearing impaired assortative mating families - an evaluation.

Mutations in CDH23 are known to cause autosomal-recessive nonsyndromic hearing loss (DFNB12). Until now, there was only one study describing its frequency in Indian population. We screened for CDH23 mutations to identify prevalent and recurring mutations among South Indian assortative mating hearing-impaired individuals who were identified as non-DFNB1 (GJB2 and GJB6). Whole-exome sequencing was performed in individuals found to be heterozygous for CDH23 to determine whether there was a second pathogenic allele. In our study, 19 variants including 6 pathogenic missense mutations were identified. The allelic frequency of pathogenic mutations accounts to 4.7% in our cohort, which is higher than that reported previously; three mutations (c.429+4G>A, c.2968G>A, and c.5660C>T) reported in the previous Indian study were found to recur. DFNB12 was found to be the etiology in 3.4% of our cohort, with missense mutation c.2968G>A (p.Asp990Asn) being the most prevalent (2.6%). These results suggest a need to investigate the possibility for higher proportion of CDH23 mutations in the South Indian hearing-impaired population.

Wrist Arthroscopy Under Portal Site Local Anesthesia Without Tourniquet and Sedation.

We had developed the technique of portal site local anaesthesia (PSLA) for wrist arthroscopy. Two percent lidocaine with 1:200,000 epinephrine is injected through a 25G needle to various portal sites. The radiocarpal joint is then distended with saline injection and portal is created with transverse superficial skin incision followed by dilation with curved hemostat. The patient is neither sedated, nor under general or regional anaesthesia. Tourniquet is not routinely used. PSLA can achieve satisfactory comfort level in 88% of our 111 patients without any complication. In well-selected patients, it is a safe and comfortable procedure.

Rare compound heterozygosity involving dominant and recessive mutations of GJB2 gene in an assortative mating hearing impaired Indian family.

Connexin 26 (Cx-26), a gap junction protein coded by GJB2 gene, plays a very important role in recycling of potassium ions, one of the vital steps in the mechanotransduction process of hearing. Mutations in the GJB2 gene have been associated with both autosomal recessive as well as dominant nonsyndromic hearing loss. As Cx-26 is linked with skin homeostasis, mutations in this gene are sometimes associated with syndromic forms of hearing loss showing skin anomalies. We report here a non consanguineous assortatively mating hearing impaired family with one of the hearing impaired partners, their hearing impaired sibling and hearing impaired offspring showing compound heterozygosity in the GJB2 gene, involving a dominant mutation p.R184Q and two recessive mutations p.Q124X and c.IVS 1+1G>A in a unique triallelic combination. To the best of our knowledge, this is the first report from India on p.R184Q mutation in the GJB2 gene associated with rare compound heterozygosity showing nonsyndromic presentation.

Arthroscopic synovectomy for rheumatoid wrists and elbows.

PURPOSE: To evaluate the treatment outcome of wrist and elbow arthroscopic synovectomy for patients with rheumatoid arthritis. METHODS: 3 men and 18 women aged 27 to 71 (mean, 54) years underwent arthroscopic synovectomy for rheumatoid arthritis of the wrist (n=12) and elbow (n=13). All patients had received multiple medications including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and steroids, as well as physiotherapy and splintage for 6 months, but the joint pain and disability persisted. The median duration of rheumatoid arthritis was 89 (range, 24-156) and 108 (range, 36-360) months for the wrist and elbow joints, respectively. According to the Larsen grading, the radiographic stages of the wrists and elbows were classified as grade 1 (n=4+4), grade 2 (n=4+5), and grade 3 (n=4+4). Visual analogue scale for pain, the wrist and elbow flexion-extension arcs, grip strength, key pinch strength, inflammatory markers, disability and symptoms were compared pre- and post-operatively. RESULTS: The median follow-up period was 30 (range, 18-78) and 34 (range, 18-78) months for wrists and elbows, respectively. There was significant improvement in pain, joint motion, inflammatory markers, and disability score. All patients were satisfied with the surgery. There was no neurovascular or wound complication. No patient was taking longterm pain-control drugs. One patient underwent a second arthroscopic synovectomy after 15 months owing to exacerbation of arthritis. CONCLUSION: Arthroscopic synovectomy is recommended for patients with rheumatoid arthritis who fail conservative treatment.

Ethical considerations in CT angiography.

The rapid development and clinical deployment of CT angiography raises several important issues, including assurance of professional competence and technical quality, self-referral, the relative role of radiologists and cardiologists, appropriateness and proper indications, the detection and disposition of unexpected or incidental findings and the concern for the rapidly increasing costs of health care and imaging. These questions are properly addressed within the framework of medical ethics, including principles of beneficence, autonomy and justice.