Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies.

Repeat antigens, such as the Plasmodium falciparum circumsporozoite protein (PfCSP), use both sequence degeneracy and structural diversity to evade the immune response. A few PfCSP-directed antibodies have been identified that are effective at preventing malaria infection, including CIS43, but how these repeat-targeting antibodies might be improved has been unclear. Here, we engineered a humanized mouse model in which B cells expressed inferred human germline CIS43 (iGL-CIS43) B cell receptors and used both vaccination and bioinformatic analysis to obtain variant CIS43 antibodies with improved protective capacity. One such antibody, iGL-CIS43.D3, was significantly more potent than the current best-in-class PfCSP-directed antibody. We found that vaccination with a junctional epitope peptide was more effective than full-length PfCSP at recruiting iGL-CIS43 B cells to germinal centers. Structure-function analysis revealed multiple somatic hypermutations that combinatorically improved protection. This mouse model can thus be used to understand vaccine immunogens and to develop highly potent anti-malarial antibodies.

A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver.

Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.

Deep continental roots and cratons.

The formation and preservation of cratons-the oldest parts of the continents, comprising over 60 per cent of the continental landmass-remains an enduring problem. Key to craton development is how and when the thick strong mantle roots that underlie these regions formed and evolved. Peridotite melting residues forming cratonic lithospheric roots mostly originated via relatively low-pressure melting and were subsequently transported to greater depth by thickening produced by lateral accretion and compression. The longest-lived cratons were assembled during Mesoarchean and Palaeoproterozoic times, creating the stable mantle roots 150 to 250 kilometres thick that are critical to preserving Earth's early continents and central to defining the cratons, although we extend the definition of cratons to include extensive regions of long-stable Mesoproterozoic crust also underpinned by thick lithospheric roots. The production of widespread thick and strong lithosphere via the process of orogenic thickening, possibly in several cycles, was fundamental to the eventual emergence of extensive continental landmasses-the cratons.

Plume-driven recratonization of deep continental lithospheric mantle.

Cratons are Earth's ancient continental land masses that remain stable for billions of years. The mantle roots of cratons are renowned as being long-lived, stable features of Earth's continents, but there is also evidence of their disruption in the recent1-6 and more distant7-9 past. Despite periods of lithospheric thinning during the Proterozoic and Phanerozoic eons, the lithosphere beneath many cratons seems to always 'heal', returning to a thickness of 150 to 200 kilometres10-12; similar lithospheric thicknesses are thought to have existed since Archaean times3,13-15. Although numerous studies have focused on the mechanism for lithospheric destruction2,5,13,16-19, the mechanisms that recratonize the lithosphere beneath cratons and thus sustain them are not well understood. Here we study kimberlite-borne mantle xenoliths and seismology across a transect of the cratonic lithosphere of Arctic Canada, which includes a region affected by the Mackenzie plume event 1.27 billion years ago20. We demonstrate the important role of plume upwelling in the destruction and recratonization of roughly 200-kilometre-thick cratonic lithospheric mantle in the northern portion of the Slave craton. Using numerical modelling, we show how new, buoyant melt residues produced by the Mackenzie plume event are captured in a region of thinned lithosphere between two thick cratonic blocks. Our results identify a process by which cratons heal and return to their original lithospheric thickness after substantial disruption of their roots. This process may be widespread in the history of cratons and may contribute to how cratonic mantle becomes a patchwork of mantle peridotites of different age and origin.

Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria.

BACKGROUND: New approaches for the prevention and elimination of malaria, a leading cause of illness and death among infants and young children globally, are needed. METHODS: We conducted a phase 1 clinical trial to assess the safety and pharmacokinetics of L9LS, a next-generation antimalarial monoclonal antibody, and its protective efficacy against controlled human malaria infection in healthy adults who had never had malaria or received a vaccine for malaria. The participants received L9LS either intravenously or subcutaneously at a dose of 1 mg, 5 mg, or 20 mg per kilogram of body weight. Within 2 to 6 weeks after the administration of L9LS, both the participants who received L9LS and the control participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying Plasmodium falciparum (3D7 strain). RESULTS: No safety concerns were identified. L9LS had an estimated half-life of 56 days, and it had dose linearity, with the highest mean (±SD) maximum serum concentration (Cmax) of 914.2±146.5 µg per milliliter observed in participants who had received 20 mg per kilogram intravenously and the lowest mean Cmax of 41.5±4.7 µg per milliliter observed in those who had received 1 mg per kilogram intravenously; the mean Cmax was 164.8±31.1 in the participants who had received 5 mg per kilogram intravenously and 68.9±22.3 in those who had received 5 mg per kilogram subcutaneously. A total of 17 L9LS recipients and 6 control participants underwent controlled human malaria infection. Of the 17 participants who received a single dose of L9LS, 15 (88%) were protected after controlled human malaria infection. Parasitemia did not develop in any of the participants who received 5 or 20 mg per kilogram of intravenous L9LS. Parasitemia developed in 1 of 5 participants who received 1 mg per kilogram intravenously, 1 of 5 participants who received 5 mg per kilogram subcutaneously, and all 6 control participants through 21 days after the controlled human malaria infection. Protection conferred by L9LS was seen at serum concentrations as low as 9.2 µg per milliliter. CONCLUSIONS: In this small trial, L9LS administered intravenously or subcutaneously protected recipients against malaria after controlled infection, without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 614 ClinicalTrials.gov number, NCT05019729.).

The P. falciparum CSP repeat region contains three distinct epitopes required for protection by antibodies in vivo.

Rare and potent monoclonal antibodies (mAbs) against the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) on infective sporozoites (SPZ) preferentially bind the PfCSP junctional tetrapeptide NPDP or NVDP minor repeats while cross-reacting with NANP central repeats in vitro. The extent to which each of these epitopes is required for protection in vivo is unknown. Here, we assessed whether junction-, minor repeat- and central repeat-preferring human mAbs (CIS43, L9 and 317 respectively) bound and protected against in vivo challenge with transgenic P. berghei (Pb) SPZ expressing either PfCSP with the junction and minor repeats knocked out (KO), or PbCSP with the junction and minor repeats knocked in (KI). In vivo protection studies showed that the junction and minor repeats are necessary and sufficient for CIS43 and L9 to neutralize KO and KI SPZ, respectively. In contrast, 317 required major repeats for in vivo protection. These data establish that human mAbs can prevent malaria infection by targeting three different protective epitopes (NPDP, NVDP, NANP) in the PfCSP repeat region. This report will inform vaccine development and the use of mAbs to passively prevent malaria.

Protective effects of combining monoclonal antibodies and vaccines against the Plasmodium falciparum circumsporozoite protein.

Combinations of monoclonal antibodies (mAbs) against different epitopes on the same antigen synergistically neutralize many viruses. However, there are limited studies assessing whether combining human mAbs against distinct regions of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) enhances in vivo protection against malaria compared to each mAb alone or whether passive transfer of PfCSP mAbs would improve protection following vaccination against PfCSP. Here, we isolated a panel of human mAbs against the subdominant C-terminal domain of PfCSP (C-CSP) from a volunteer immunized with radiation-attenuated Pf sporozoites. These C-CSP-specific mAbs had limited binding to sporozoites in vitro that was increased by combination with neutralizing human "repeat" mAbs against the NPDP/NVDP/NANP tetrapeptides in the central repeat region of PfCSP. Nevertheless, passive transfer of repeat- and C-CSP-specific mAb combinations did not provide enhanced protection against in vivo sporozoite challenge compared to repeat mAbs alone. Furthermore, combining potent repeat-specific mAbs (CIS43, L9, and 317) that respectively target the three tetrapeptides (NPDP/NVDP/NANP) did not provide additional protection against in vivo sporozoite challenge. However, administration of either CIS43, L9, or 317 (but not C-CSP-specific mAbs) to mice that had been immunized with R21, a PfCSP-based virus-like particle vaccine that induces polyclonal antibodies against the repeat region and C-CSP, provided enhanced protection against sporozoite challenge when compared to vaccine or mAbs alone. Collectively, this study shows that while combining mAbs against the repeat and C-terminal regions of PfCSP provide no additional protection in vivo, repeat mAbs do provide increased protection when combined with vaccine-induced polyclonal antibodies. These data should inform the implementation of PfCSP human mAbs alone or following vaccination to prevent malaria infection.

Antigenic Restimulation of Virus-Specific Memory CD8+ T Cells Requires Days of Lytic Protein Accumulation for Maximal Cytotoxic Capacity.

In various infections or vaccinations of mice or humans, reports of the persistence and the requirements for restimulation of the cytotoxic mediators granzyme B (GrB) and perforin (PRF) in CD8+ T cells have yielded disparate results. In this study, we examined the kinetics of PRF and GrB mRNA and protein expression after stimulation and associated changes in cytotoxic capacity in virus-specific memory cells in detail. In patients with controlled HIV or cleared respiratory syncytial virus (RSV) or influenza virus infections, all virus-specific CD8+ T cells expressed low PRF levels without restimulation. Following stimulation, they displayed similarly delayed kinetics for lytic protein expression, with significant increases occurring by days 1 to 3 before peaking on days 4 to 6. These increases were strongly correlated with, but were not dependent upon, proliferation. Incremental changes in PRF and GrB percent expression and mean fluorescence intensity (MFI) were highly correlated with increases in HIV-specific cytotoxicity. mRNA levels in HIV-specific CD8+ T-cells exhibited delayed kinetics after stimulation as with protein expression, peaking on day 5. In contrast to GrB, PRF mRNA transcripts were little changed over 5 days of stimulation (94-fold versus 2.8-fold, respectively), consistent with posttranscriptional regulation. Changes in expression of some microRNAs, including miR-17, miR-150, and miR-155, suggested that microRNAs might play a significant role in regulation of PRF expression. Therefore, under conditions of extremely low or absent antigen levels, memory virus-specific CD8+ T cells require prolonged stimulation over days to achieve maximal lytic protein expression and cytotoxic capacity.IMPORTANCE Antigen-specific CD8+ T cells play a major role in controlling most virus infections, primarily by perforin (PRF)- and granzyme B (GrB)-mediated apoptosis. There is considerable controversy regarding whether PRF is constitutively expressed, rapidly increased similarly to a cytokine, or delayed in its expression with more prolonged stimulation in virus-specific memory CD8+ T cells. In this study, the degree of cytotoxic capacity of virus-specific memory CD8+ T cells was directly proportional to the content of lytic molecules, which required antigenic stimulation over several days for maximal levels. This appeared to be modulated by increases in GrB transcription and microRNA-mediated posttranscriptional regulation of PRF expression. Clarifying the requirements for maximal cytotoxic capacity is critical to understanding how viral clearance might be mediated by memory cells and what functions should be induced by vaccines and immunotherapies.

Biomechanical Evaluation of a Cadaveric Flatfoot Model and Lateral Column Lengthening Technique.

Patients with adult acquired flatfoot have progressive worsening of bony alignment with many being unable to perform a heel rise. Following reconstruction, pathologic skeletal alignment is corrected and the ability to perform a heel rise is often restored. The purpose of this study was to evaluate the relationship between forefoot liftoff forces and skeletal alignment in a cadaveric flatfoot model by assessing the effect of sequential lengthening of the lateral column using an Evans-type calcaneal osteotomy. Bony alignment was measured in 8 cadaveric specimens with the use of a 3-dimensional digitizing system. Transection of the spring ligament, pie-crusting of the plantar fascia, and cyclic axial loading of the foot was performed to create an anatomic and functional flatfoot model. An Evans-type calcaneal osteotomy using 6, 8, 10, and 12 mm wedges was performed. Specimens were mounted to a custom jig that applies tensile loads to the Achilles, peroneus brevis, peroneus longus, and tibialis posterior tendons. Creation of a flatfoot reduced the lateral talo-first metatarsal angle (Meary's angle) by 13° (23.6° ± 2.8° vs 10.6° ± 3.8°, p < .05) and forefoot force by 7% (199.3 N ± 7.3 N vs 185.4 N ± 9 N, p < .05). Sequential lengthening of the lateral column restored skeletal alignment and force transfer to the forefoot (12 mm wedge: Meary's angle 22.7° ± 3.9°, liftoff force 206.8 N ± 7.5 N). The cadaveric flatfoot model demonstrated decreased forefoot forces that were restored with an Evans-type calcaneal osteotomy wedge. This highlights the importance of restoring skeletal alignment when correcting advanced adult acquired flatfoot.

Private sector drug shops frequently dispense parenteral anti-malarials in a rural region of Western Uganda.

BACKGROUND: Malaria is a leading cause of paediatric morbidity and mortality in Uganda. More than half of febrile children in rural areas initially seek care at private clinics and drug shops. These shops are generally unregulated and the quality of clinical care is variable, with the potential for misdiagnosis and the development of drug resistance. There is thus an urgent need to identify rural drug shops and coordinate their malaria treatment efforts with those of the public sector. The objective of the study was to identify all drug shops in the Bugoye sub-county of Western Uganda and assess their anti-malarial dispensing practices. METHODS: This study is a cross-sectional survey of drug shops in a rural sub-county of Western Uganda. In the first phase, shop locations, licensing and shopkeeper's qualifications, and supply and pricing of anti-malarials were characterized. In the second phase, the proportion of anti-malarials dispensed by private drug shops was compared to public health facilities. RESULTS: A total of 48 drug shops were identified. Only one drug shop (1 of 48, 2%) was licensed with the sub-county's records office. The drug shops stocked a variety of anti-malarials, including first-line therapies and less effective agents (e.g., sulfadoxine/pyrimethamine). Almost all drug shops (45 of 48, 94%) provided parenteral anti-malarials. Of the 3900 individuals who received anti-malarials during the study, 2080 (53.3%) purchased anti-malarials through the private sector compared to 1820 (46.7%) who obtained anti-malarials through the public sector. Drug shops were the primary source of parenteral anti-malarials. Inadequate dosing of anti-malarials was more common in drug shops. CONCLUSIONS: Drug shops are major sources of parenteral anti-malarials, which should be reserved for cases of severe malaria. Strengthening malaria case management and incorporating drug shops in future interventions is necessary to optimize malaria control efforts in the sub-county, and in similarly endemic regions.

A possible role for dupilumab (Dupixent) in the management of idiopathic chronic eczematous eruption of aging.

Aging individuals can develop generalized, exquisitely-pruritic, eczematous eruptions of uncertain etiology that can be therapeutically-refractory and life-altering. Limited information exists in the literature to guide clinicians in the diagnosis and management of such patients. It is suggested that in approximately 40% of such patients a known cause for their chronic pruritic eruptions cannot be identified. In this report we will refer to this subgroup of patients as having idiopathic chronic eczematous eruption of aging (CEEA). Idiopathic CEEA must be distinguished from other established eczematous dermatoses. Idiopathic CEEA patients often require long-term systemic immunosuppressive drugs to make living bearable. Elder-onset atopic dermatitis is the most difficult of the known dermatoses to distinguish from idiopathic CEEA. Because of their clinical similarities we questioned whether dupilumab (Dupixent®), the first FDA-approved biologic for atopic dermatitis, might be valuable in the management of idiopathic CEEA. We report the case of an elderly man with idiopathic CEEA of four-years' duration who had a complete clinical response to the initiation of treatment with dupilumab. This case is presented to stimulate more discussion and systematic study of a possible role for dupilumab in otherwise-refractory idiopathic CEEA patients. We also propose a set of diagnostic criteria for idiopathic CEEA.

Sexual Trauma and Adverse Health and Occupational Outcomes Among Men Serving in the U.S. Military.

Although absolute counts of U.S. service men who experience sexual trauma are comparable to service women, little is known about the impact of sexual trauma on men. The association of recent sexual trauma (last 3 years) with health and occupational outcomes was investigated using longitudinal data (2004-2013) from the Millennium Cohort Study. Of 37,711 service men, 391 (1.0%) reported recent sexual harassment and 76 (0.2%) sexual assault. In multivariable models, sexual harassment or assault, respectively, was associated with poorer mental health: AOR = 1.60, 95% CI [1.22, 2.12], AOR = 4.39, 95% CI [2.40, 8.05]; posttraumatic stress disorder: AOR = 2.50, 95% CI [1.87, 3.33], AOR = 6.63, 95% CI [3.65, 12.06]; depression: AOR = 2.37, 95% CI [1.69, 3.33], AOR = 5.60, 95% CI [2.83, 11.09]; and multiple physical symptoms: AOR = 2.22, 95% CI [1.69, 2.92]; AOR = 3.57, 95% CI [1.98, 6.42], after adjustment for relevant covariates. Sexual harassment was also associated with poorer physical health: AOR = 1.68, 95% CI [1.27, 2.22]. Men who reported sexual trauma were more likely to have left military service: AOR = 1.60, 95% CI [1.14, 2.24], and be disabled/unemployed postservice: AOR = 1.76, 95% CI [1.02, 3.02]. Results suggest that sexual trauma was significantly associated with adverse health and functionality extending to postmilitary life. Findings support the need for developing better prevention strategies and services to reduce the burden of sexual trauma on service men.

The biomechanical effect of shoulder remplissage combined with Bankart repair for the treatment of engaging Hill-Sachs lesions.

PURPOSE: The purpose of this study was to determine the biomechanical effects of the remplissage repair combined with Bankart repair for engaging Hill-Sachs lesions on range of motion (ROM), translation, and glenohumeral kinematics. METHODS: Six cadaveric shoulders were tested using a custom shoulder testing system. ROM, kinematics, and anterior-posterior (AP) and superior-inferior glenohumeral translations were quantified at 0° and 60° glenohumeral abduction. Six conditions were tested: intact, Bankart lesion, Bankart with 40 % Hill-Sachs lesion, Bankart repair, Bankart repair with remplissage, and remplissage repair alone. RESULTS: Humeral external rotation (ER) and total range of motion increased significantly after the creation of the Bankart lesion at both 0° and 60° abduction. The Bankart repair restored ER to intact values at 0° and 60° abduction, and the addition of the remplissage repair did not significantly alter range of motion from the Bankart repair alone. AP translation increased following the creation of the Bankart and Hill-Sachs lesions and was restored with the Bankart repair; the remplissage did not alter translation from the Bankart repair alone. At maximum ER at 60° abduction, the apex of the humeral head shifted posteriorly and inferiorly with remplissage repair. CONCLUSIONS: The addition of the remplissage procedure combined with Bankart repair for treatment of large Hill-Sachs lesions had no statistically significant effect on ROM or translation, but altered the kinematics of the glenohumeral joint. Thus, by addressing the humeral bone defect following an anterior shoulder dislocation, the remplissage technique with concurrent Bankart repair may be a relatively minimally invasive option for converting engaging Hill-Sachs lesions to non-engaging and promoting shoulder stability, though further biomechanical and clinical studies are warranted.

A biomechanical assessment of a novel double endobutton technique versus a coracoid cerclage sling for acromioclavicular and coracoclavicular injuries.

PURPOSE: Recently, many acromioclavicular-coracoclavicular (AC-CC) ligament reconstruction techniques address only the CC ligament. However, many of these techniques are costly, time-consuming, and require the use of allogenic grafts, making them prone to creep and failure or novel devices making them challenging for orthopaedic surgeons. The purpose of this study was to compare the biomechanical characteristics of a double endobutton technique using a standard endobutton CL with those of a coracoid cerclage sling (CS) for reconstruction of the CC ligaments. METHODS: Anterior-posterior (AP) translation and superior-inferior (SI) translation were quantified for eight matched pairs of intact AC joints. One shoulder from each pair underwent a double endobutton repair, using an endobutton CL modified with an additional endobutton (Smith & Nephew, Memphis, Tenn) and placed through holes in the coracoid and clavicle. The contra-lateral shoulder received a coracoid sling reconstruction using an anterior tibialis tendon. Translation testing was repeated after reconstruction, followed by load-to-failure testing. Paired t tests were used for statistical analysis. RESULTS: The CS technique demonstrated a greater SI and AP translation than the double endobutton technique (p < 0.05). Additionally, the double endobutton technique had a greater stiffness (40.2 ± 11.0 vs. 20.3 ± 6.4 N/mm, p = 0.005), yield load (168.5 ± 11.0 vs. 86.8 ± 22.9 N, p = 0.002), and ultimate load (504.4 ± 199.7 vs. 213.2 ± 103.4 N, p = 0.026) when compared to the CS technique. CONCLUSION: The double endobutton technique yielded less translation about the AC joint and displayed stronger load-to-failure characteristics than the CS reconstruction. As such, this technique may be better suited to restore native AC-CC biomechanics, reduce post-operative pain, and prevent recurrent subluxation and dislocation than an allogenic graft construct. The double endobutton technique may be a suitable option for addressing AC-CC injuries.

Associations of military divorce with mental, behavioral, and physical health outcomes.

BACKGROUND: Divorce has been linked with poor physical and mental health outcomes among civilians. Given the unique stressors experienced by U.S. service members, including lengthy and/or multiple deployments, this study aimed to examine the associations of recent divorce on health and military outcomes among a cohort of U.S. service members. METHODS: Millennium Cohort participants from the first enrollment panel, married at baseline (2001-2003), and married or divorced at follow-up (2004-2006), (N = 29,314). Those divorced were compared to those who remained married for mental, behavioral, physical health, and military outcomes using logistic regression models. RESULTS: Compared to those who remained married, recently divorced participants were significantly more likely to screen positive for new-onset posttraumatic stress disorder, depression, smoking initiation, binge drinking, alcohol-related problems, and experience moderate weight gain. However, they were also more likely be in the highest 15(th) percentile of physical functioning, and be able to deploy within the subsequent 3-year period after divorce. CONCLUSIONS: Recent divorce among military members was associated with adverse mental health outcomes and risky behaviors, but was also associated with higher odds of subsequent deployment. Attention should be given to those recently divorced regarding mental health and substance abuse treatment and prevention strategies.

Biomechanical evaluation of coracoid tunnel size and location for coracoclavicular ligament reconstruction.

PURPOSE: The purpose of this study was to determine the effect of coracoid tunnel size and location on the biomechanical characteristics of cortical button fixation for coracoclavicular ligament reconstruction. METHODS: Thirteen matched pairs of cadaveric scapulae were used to determine the effects of coracoid tunnel size, and 6 matched pairs were used to determine the effects of coracoid tunnel location. For tunnel size, a 4.5-mm hole was drilled in the base of the coracoid of one scapula and a 6-mm hole was drilled in the contralateral scapula. For tunnel location, 2 holes were drilled: (1) The first group received a hole centered in the coracoid base and a hole 1.5 cm distal from the first, along the axis of the coracoid. (2) The second group received holes that were offset anteromedially from the first set of holes (base eccentric and distal eccentric). A cortical button-suture tape construct was placed through each tunnel, and constructs were then loaded to failure. RESULTS: For tunnel size specimens, load at ultimate failure was significantly greater for the 4.5-mm group compared with the 6-mm group (557.6 ± 48.5 N v 466.9 ± 42.2 N, P < .05). For tunnel location, load at ultimate failure was significantly greater for the centered-distal tunnel group compared with the eccentric-distal group (538.1 ± 70.2 N v 381.0 ± 68.6 N, P < .05). CONCLUSIONS: A 4.5-mm tunnel in the coracoid provided greater strength for cortical button fixation than a 6-mm tunnel. In the distal coracoid, centered tunnels provided greater strength than eccentric tunnels. CLINICAL RELEVANCE: When performing cortical button fixation at the coracoid process for coracoclavicular ligament reconstruction, a 4.5-mm tunnel provides greater fixation strength than a 6-mm tunnel. The base of the coracoid is more forgiving than the distal coracoid regarding location.

Biomechanical evaluation of supplemental percutaneous lumbo-sacro-iliac screws for spinopelvic fixation following total sacrectomy.

STUDY DESIGN: This is a cadaveric biomechanical study evaluating the biomechanical properties of a novel spinopelvic fixation technique with percutaneous lumbo-sacro-iliac (LSI) screws in an unstable total sacrectomy model. OBJECTIVE: To compare standard posterior dual rod spinopelvic fixation alone with dual rod fixation supplemented with LSI screw fixation. SUMMARY OF BACKGROUND DATA: Primary or metastatic tumors of the sacrum requiring a total sacrectomy can result in spinopelvic instability if inadequate fixation is achieved. Many fixation techniques have been proposed to address this instability. However, to date, an optimal fixation technique has not been established. MATERIALS AND METHODS: Ten fresh-frozen cadaveric spinopelvic specimens were randomized according to bone mineral density (BMD) to either posterior rod fixation (control group) or posterior rod fixation with supplemental LSI screws (LSI group). After fixation, a total sacrectomy of each specimen was performed. Specimens where then potted and axially loaded in a caudal direction. Stiffness, yield load, energy absorbed at yield load, ultimate load, and energy absorbed at ultimate load were computed. A Student t test was used for statistical analysis with significance set at P<0.05. RESULTS: The average age and BMD were not significantly different between the control and LSI groups (age: P=0.255; BMD: P=0.810). After normalizing for BMD, there were no significant differences detected for any of the biomechanical parameters measured between the 2 fixation techniques: stiffness (P=0.857), yield load (P=0.219), energy at yield load (P=0.293), ultimate load (P=0.407), and energy at ultimate load (P=0.773). However, both fixation techniques were able to withstand physiological loads. CONCLUSIONS: Our study did not demonstrate any biomechanical advantage for supplemental LSI screw fixation in our axial loading model. However, given the theoretical advantage of this percutaneous technique, further studies are warranted that take into account forward bending and sagittal stability.

Biomechanical comparison between the trapezius transfer and latissimus transfer for irreparable posterosuperior rotator cuff tears.

BACKGROUND: The purpose of this study was to characterize the biomechanical effects of the lower trapezius transfer and to compare it with the latissimus dorsi transfer in a cadaveric model of a massive posterosuperior rotator cuff tear. METHODS: Eight cadaveric shoulders were tested at 0°, 30°, and 60° of shoulder abduction. Range of motion, humeral rotational position due to muscle loading, joint reaction forces, and kinematics were measured. All specimens were tested in 4 conditions: intact, massive posterosuperior cuff tear, lower trapezius transfer, and latissimus dorsi transfer. A repeated-measures analysis of variance was used for statistical analysis. RESULTS: Internal rotation due to muscle loading increased with massive cuff tear compared with the intact condition (P < .05). The latissimus transfer corrected this change at 0° abduction, whereas the trapezius transfer corrected this at all abduction angles. The massive cuff tear decreased glenohumeral joint compression forces at all abduction angles; these forces were restored by the lower trapezius transfer (P < .05). At maximum humeral internal rotation and 0° of abduction, the humeral head apex shifted superiorly and laterally with massive cuff tear (P < .05); this shift was more closely restored to intact values by the trapezius transfer compared with the latissimus transfer (P < .05). CONCLUSION: The lower trapezius transfer is superior to the latissimus transfer at restoring native glenohumeral kinematics and joint reaction forces in our cadaveric model. It may be a promising treatment option for patients with a massive irreparable rotator cuff tear.

Cryo-EM structures of anti-malarial antibody L9 with circumsporozoite protein reveal trimeric L9 association and complete 27-residue epitope.

Monoclonal antibody L9 recognizes the Plasmodium falciparum circumsporozoite protein (PfCSP) and is highly protective following controlled human malaria challenge. To gain insight into its function, we determined cryoelectron microscopy (cryo-EM) structures of L9 in complex with full-length PfCSP and assessed how this recognition influenced protection by wild-type and mutant L9s. Cryo-EM reconstructions at 3.6- and 3.7-Å resolution revealed L9 to recognize PfCSP as an atypical trimer. Each of the three L9s in the trimer directly recognized an Asn-Pro-Asn-Val (NPNV) tetrapeptide on PfCSP and interacted homotypically to facilitate L9-trimer assembly. We analyzed peptides containing different repeat tetrapeptides for binding to wild-type and mutant L9s to delineate epitope and homotypic components of L9 recognition; we found both components necessary for potent malaria protection. Last, we found the 27-residue stretch recognized by L9 to be highly conserved in P. falciparum isolates, suggesting the newly revealed complete L9 epitope to be an attractive vaccine target.

Cytotoxicity of human antibodies targeting the circumsporozoite protein is amplified by 3D substrate and correlates with protection.

Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing malaria infection. However, their mechanisms of protection remain unclear. Here, using 13 distinctive PfCSP hmAbs, we provide a comprehensive view of how PfCSP hmAbs neutralize sporozoites in host tissues. Sporozoites are most vulnerable to hmAb-mediated neutralization in the skin. However, rare but potent hmAbs additionally neutralize sporozoites in the blood and liver. Efficient protection in tissues mainly associates with high-affinity and high-cytotoxicity hmAbs inducing rapid parasite loss-of-fitness in the absence of complement and host cells in vitro. A 3D-substrate assay greatly enhances hmAb cytotoxicity and mimics the skin-dependent protection, indicating that the physical stress imposed on motile sporozoites by the skin is crucial for unfolding the protective potential of hmAbs. This functional 3D cytotoxicity assay can thus be useful for downselecting potent anti-PfCSP hmAbs and vaccines.