1. General Principles & Basic Science MCQs

Mutations of PHEX are responsible for X-linked hypophosphatemic rickets. Mutations of CLCN7 and TC1RG1 cause osteopetrosis. COLIA1 or COLIA2 mutations cause osteogenesis imperfecta (OI) which has literally hundreds of genotypes causing a more limited number of phenotypes as described by Silence. GNAS1 is the gene mutation of fibrous dysplasia that results in an activating mutation of the GSalpha1 protein. TGF-BR2 or FBN1 cause Marfan syndrome.

The paper cited is an excellent review in detail about confidence intervals including the mathematical equations.The p value is the probability that the chance selection of patients might suggest a difference in treatment that was not real. Only with a small p value are we willing to believe that the observed difference in treatment is very likely real and not simply due to chance.The confidence interval provides a measure of the magnitude of the possible difference between two groups of patients, regardless of whether or not the p value was small. This makes the confidence interval more informative than the p value when different treatments are compared. This is much beyond the scope of this review.

Based on the description of the infection and the history of close contact, the clinical scenario is most consistent with community-acquired MRSA (CA-MRSA). It is important to distinguish CA-MRSA and hospital-acquired MRSA (HA-MRSA) as the two display different sensitivities to antibiotics. Antibiotic selection is based on sensitivity and severity of infection. Because this infection is superficial and withoutany signs of systemic illness, an oral antibiotic regimen is appropriate. When culture results reveal resistance to erythromycin, then a D-zone test should be performed to check for inducible clindamycin resistance. The D-zone test is performed by plating the sample on an agar and placing antibiotic disks made of clindamycin and erythromycin on the agar. A zone of inhibition in the shape of the letter D is seen with an inducible strain. If the D-zone test is positive, then clindamycin should not be used because the strain of MRSA can become resistant to the treatment. Therefore, because of the positive D-zone test, the antibiotic should be changed to oral doxycycline. IV antibiotics are not indicated for this infection. Oral rifampin should never be used as a single agent as resistance rapidly develops.

There is no difference between daily showers with soap, water and dry dressings, and solutions comprising (1) saline and chlorhexidine, or (2) saline and hydrogen peroxide.The risks of external fixation include cellulitis, pin-track drainage, osteomyelitis and pin loosening. The rate of complications is about 20%. Chlorhexidine gluconate has broad spectrum activity against gram-positive and negative bacteria by disrupting cell membranes. It is not affected by blood and has low skin irritancy. Studies show that simple pin-site care (showers, dry dressings) maintains a low infection rate.Egol et al. performed a randomized trial examining external fixation pin tracts about the wrist. They compared (1) weekly dry dressings, (2) daily pin care with half normal saline (NS) and hydrogen peroxide (H2O2) and (3) chlorhexidine discs with weekly changes. They found pin-site complications in 19%, with no difference between the 3 groups. They do not recommend additional wound care beyond sterile dressings.Stinner et al. performed a survey on the use of half-pins by the limb lengthening and reconstruction society. They found that most respondents preferred hydroxyapatite coating (81%) because of improved fixation and decreased loosening (less radiographic pin-tract rarefaction and greater extraction torque, which may lead tolower infection rates). Most encouraged shower (60%) and washing solution (67%)(soap and water, peroxide or saline) for pin site care.Figure A shows an external fixator around the wrist with cellulitis around the proximal half-pins.Incorrect Answers

The patient has a late infection of at least 4 weeks symptomatic duration that most likely is hematogenous in etiology. This infection is not an acute hematogenous infection that can successfully be treated with irrigation and debridement. Retention of the implants with debridement and irrigation alone has been associated with a poor prognosis. In one study of 50 infections attributable to MRSA or methicillin-resistant Staphylococcus epidermidis organisms treated with a two-stage protocol, the failure rate was 21%.

Activation of antithrombin (AT) III is the mechanism of action of heparin. Heparin works by binding to and enhancing the ability of antithrombin III to inhibit factors IIa, III, and Xa. It is metabolized by the liver. The risks associated with its use include bleeding and heparin-induced thrombocytopenia (HIT). The reversal agent is protamine sulfate.

DISCUSSION: In a type III supracondylar distal humerus fracture of the elbow, the brachial artery can become incarcerated, yielding a pulseless extremity. In this situation, closed reduction may not be effective; therefore, open management is often necessary. The preferred surgical approach to the brachial artery and to this fracture is the anterior approach to the cubital fossa. The lacertus fibrosus is incised, and the dissection is carried out between the brachialis (musculocutaneous nerve) and the pronator teres (median nerve), mobilizing the brachial artery. Once the brachial artery is mobilized, the anterior elbow joint capsule may be exposed. The interval between the brachialis and the biceps describes the anterolateral approach to the elbow more commonly used for exposure of the proximal aspect of the posterior interosseous nerve. The dissection interval between the brachioradialis and the pronator teres describes the proximal extent of the anterior approach to the radius. REFERENCES: Tubiana R, McCullough CJ, Masquelet AC: An Atlas of Surgical Exposures of the Upper Extremity. Philadelphia, PA, JB Lippincott, 1990, p 115. Hoppenfeld S, deBoer P: Surgical Exposures in Orthopaedics: The Anatomic Approach, ed 2. Philadelphia, PA, Lippincott-Raven, 1992, p 119.

Fibrin is the end product of the coagulation cascade that results from the cleavage of fibrinogen by thrombin (factor IIa). Platelets are a key component in arterial thromboses. Collagen initiates the intrinsic arm of the coagulation cascade. Thromboplastin is a procoagulant substance that triggers the extrinsic arm of the coagulation cascade. The fibrinolytic system is the regulatory pathway that breaks down cross-linked fibrin.

DISCUSSION: Demographic factors are associated with increased risk for MRSA colonization, so it is important to identify vulnerable patients. Female gender and advanced age reduce the risk for colonization, whereas African American race increases this risk. Urban environments do not influence MRSA colonization.

Dabigatran (Pradaxa) is a direct thrombin inhibitor that is approved for stroke prevention in atrial fibrillation. It is not a factor Xa inhibitor. Rivaroxaban and Apixaban are factor Xa inhibitors.

Bundle A is the anteromedial (AM) bundle, which is longer, and is tight in flexion. Bundle B is the posterolateral (PL) bundle, which is shorter, and is loose in flexion. The AM bundle is attached anterior to the PL bundle on the tibia.The ACL is comprised of 2 bundles. The AM bundle is longer than the PL bundle.Their names reflect their relative anatomic positions on the tibial insertion site. On the femur, the AM bundle begins at the proximal-anterior aspect of the femoral insertion site, while the PL bundle begins at the posterior-inferior part. In flexion, the AM bundle is tight and the PL bundle is loose. In extension, the AM bundle is loose and the PL bundle is tight.Bicer et al. reviewed the anatomy of the ACL. They found that the AM bundle was longer (32mm) compared with the PL bundle (18mm). PL bundle carries greater force near full extension, and the AM bundle carries greater force after 15-45° of flexion. Under combined rotatory loads (valgus and internal tibial torque at knee flexion>30°), the AM bundle bore more force than the PL bundle.Figure A shows the 2 bundles of the ACL. The AM bundle is longer than the PL bundle. The oft referred to length of ACL refers mainly to the length of the AM bundle. Illustrations A and B show the spatial relationships of the AM and PL bundles in a cadaveric knee. Illustration C shows the relative positions of the attachments of each bundle.Incorrect

Bisphosphonate therapy combined with invasive dental work increases the risk for development osteonecrosis of the jaw.Bisphosphonates are a class of drugs that prevent bone mass loss by inhibiting osteoclast resorption. They are used in the treatment of vertebral compression fractures, non-vertebral fragility fractures, osteogenesis imperfecta, multiple myeloma, and avascular necrosis. Because bisphosphonates have been associated with osteonecrosis of the jaw, it is suggested that all invasive dental work be completed prior to initiation of treatment.Pazianas et al. (2011) review the safety profile of bisphosphonates. Specifically, they cite gastrointestinal discomfort, atypical femur fractures, osteonecrosis of the jaw, ocular inflammation, and musculoskeletal pain as common side effects. They state there is limited evidence surrounding bisphosphonate's association with esophageal cancer and atrial fibrillation.Pazianas et al. (2007) reviewed 11 publications that reported 26 cases of osteonecrosis of the jaw following initiation of bisphosphonate treatment. Age >60 years, female sex, and previous invasive dental treatment were the most common characteristics of those who developed ONJ.Illustration A shows the various bisphosphonates and their mechanisms of action. Illustration B shows an example of osteonecrosis of the jaw, a side effect that has been linked to bisphonphonate treatment.Incorrect Answers:

EXPLANATION: Plating of the proximal radius from a dorsal or Thompson approach (between the extensor carpi radialis brevis and extensor digitorum communis) allows complete visualization of the PIN through the supinator. Going through the same incision from proximal to distal produces a scar-filled proximal approach, and it is not uncommon to drift ulnarly and injure an individual nerve to the extensor digitorum communis muscle, resulting in the deformity seen in Figures 1 and 2. Postsurgical tendon adhesions rarely involve only 2 tendons. Complete tendon lacerations are rare at this level in the proximal forearm, as is a complete laceration of the PIN. Neuropraxias are common but usually resolve after 3 months. The gossamer-thin branch of the PIN to the EDC can be easily damaged in scar tissue, resulting in an inability to fully extend the MP joints of the long and ring fingers. The proprius tendons allow the patient to fully extend the index and little finger MP joints. Connecting the EDC of the long finger to the extensor indicis proprius and the EDC of the ring finger to the extensor digiti quinti proprius can correct the deformity. To avoid the problem, the surgeon should start the incision distally in normal anatomy, and the interval between the mobile wad and the digital extensors will be more easily found.

Anorexia athletica is a newer term that may generally replace the "triad" of disordered eating, menstrual dysfunction, and osteoporosis. True osteoporosis is actually relatively uncommon in the female athlete, and thus the traditional diagnostic criteria are rarely met. In anorexia athletica, multiple signs and symptoms are used to reach the diagnosis. Specifically, however, a diagnosis of anorexia athletica requires the absence of any affective disorder, such as depression.

DISCUSSION: Bacitracin is a polypeptide obtained from a strain (Tracy strain) of Bacillus subtilis. It is stable and poorly absorbed from the intestinal tract; its only use is for topical application to skin, wounds, or mucous membranes. Concentrations of 500 to 2,000 units per milliliter of solution or gram of ointment are used for topical application. Bacitracin is mainly bactericidal for gram-positive bacteria, including penicillin-resistant staphylococci. In combination with polymixin B or neomycin, bacitracin is useful for suppression of mixed bacterial flora in surface lesions. Bacitracin is toxic for the kidney, causing proteinuria, hematuria, and nitrogen retention; therefore, it has no place in systemic therapy. Bacitracin is said not to induce hypersensitivity readily, but reactions to this agent have been described. REFERENCES: Rosenstein BD, Wilson FC, Funderburk CH: The use of bacitracin irrigation to prevent infection in postoperative skeletal wounds: An experimental study. J Bone Joint Surg Am 1989;71:427-430. Brooks GF, Butel JS, Morse SA (eds): Jawetz, Melnick, and Adelberg’s Medical Microbiology: Antimicrobial Chemotherapy. New York, NY, McGraw-Hill, 1995, pp 187-188.

Denosumab is FDA-approved for the treatment of osteoporosis in men and women. It inhibits the formation, function and survival of osteoclasts (OC). It does not bind to calcium hydroxyapatite. At 1-year after the initial dose, tissue levels are non-detectable.Denosumab is a human monoclonal antibody against RANKL. By binding RANKL, it prevents interaction of RANKL with RANK (on OC and osteoclast precursors, OCP), and inhibits OC-mediated bone resorption, and the formation, function and survival of OC. In contrast, bisphosphonates bind to calcium hydroxyapatite in bone, and decrease resorption by decreasing function and survival (but not formation) of OC.Vaananen et al. reviewed the cell biology of OC. During bone resorption, 3 membrane domains appear: ruffled border, sealing zone and functional secretory domain. The resorption cycle starts with migration, bone attachment, polarization (formation of membrane domains), dissolution of hydroxyapatite, degradation of organic matrix, removal of degradation products from resorption lacuna, and apoptosis of the OC or return to the non-resorbing stage.Boyce et al. reviewed the regulation of osteoclasts and their functions. OCPs are held in bone marrow by chemokines e.g. stroma-derived factor-1 (SDF1) and attracted to blood by sphingosine-1 phosphate (S1P) (increased in synovial fluid of patients with RA). All aspects of osteoclast formation and functions are regulated by M-CSF and RANKL. More recent studies indicate that osteoclasts and their precursors regulate immune responses and osteoblast formation and functions by means of direct cell-cell contact through ligands and receptors, such as ephrins and Ephs, and semaphorins and plexins, and through expression of clastokines.Warriner and Saag reviewed the diagnosis and treatment of osteoporosis. They defined osteoporosis as T-score of = -2.5 or a history of fragility fracture. Incident hip and vertebral fractures increase future risk of these fractures (hazard ratio 7.3 and 3.5, respectively).Cummings et al. compared subcutaneous denosumab (60mg every 6mths) vs placebo in prevention of fractures in 7868 osteoporotic (T-score -2.5 to -4.0) postmenopausal women. They found that denosumab reduced risk of vertebral fracture by 68% (risk ratio, 0.32), hip fracture by 40% (hazard ratio 0.6), nonvertebral fracture by 20% (hazard ratio 0.8). There was no increased risk of cancer, infection, delayed fracture healing, cardiovascular disease, osteonecrosis of the jaw or adverse reactions. They concluded that it was useful for reduction of fractures in osteoporotic women.The video shows the action of denosumab (prolia). Illustration A shows the different osteoclast zones.Incorrect Answers:

The quadrilateral space of the shoulder is formed laterally by the humerus, proximally by the subscapularis (and teres minor viewed from posterior), distally by the teres major, and medially by the long head of the triceps. The posterior humeral circumflex artery and axillary nerve pass through it.

Tranexamic acid is an antifibrinolytic agent that works by competitively inhibiting the activation of plasminogen to plasmin, thereby preventing the breakdown of fibrin clots.

The general trend is increasing energy requirement for more proximal amputations. Amputation should be performed at the lowest possible level in order to preserve the most function. Walking speed and cadence decrease while oxygen consumption per meter walked increases with each more proximal amputation.

The patient has valgus extension overload. This is a spectrum of pathologies, often seen in pitchers, that begins with posteromedial impingement between the medial olecranon and posterior trochlea during forceful elbow extension. As a result, a medial olecranon osteophyte is typically the first notable imaging finding. As pathology increases, there can be progressive damage to the medial collateral ligament (MCL), degeneration of the radiocapitellar articulation, and neuritis of the ulnar nerve. VPMRI is often associated with a large anteromedial coronoid fracture and posterior band MCL rupture. VPLRI occurs when the lateral collateral ligament complex is ruptured. Olecranon bursitis presents with focal swelling or a fluid collection over the posterior aspect of the olecranon.