Revisiting Co-trimoxazole Prophylaxis for African Adults in the Era of Antiretroviral Therapy: A Randomized Controlled Clinical Trial.

BACKGROUND: Daily co-trimoxazole is recommended for African adults living with human immunodeficiency virus (HIV) irrespective of antiretroviral treatment, immune status, or disease stage. Benefits of continued prophylaxis and whether co-trimoxazole can be stopped following immune reconstitution are unknown. METHODS: We conducted a randomized controlled trial at 2 sites in Malawi that enrolled adults with HIV with undetectable viral load and CD4 count of >250/mm3 and randomized them to continue daily co-trimoxazole, discontinue daily co-trimoxazole and begin weekly chloroquine, or discontinue daily co-trimoxazole. The primary endpoint was the preventive effect of co-trimoxazole prophylaxis against death or World Health Organization (WHO) HIV/AIDS stage 3-4 events, using Cox proportional hazards modeling, in an intention-to-treat population. RESULTS: 1499 adults were enrolled. The preventive effect of co-trimoxazole on the primary endpoint was 22% (95% CI: -14%-47%; P = .20) versus no prophylaxis and 25% (-10%-48%; P = .14) versus chloroquine. When WHO HIV/AIDS stage 2 events were added to the primary endpoint, preventive effect increased to 31% (3-51%; P = .032) and 32% (4-51%; P = .026), respectively. Co-trimoxazole and chloroquine prophylaxis effectively prevented clinical malaria episodes (3.8 and 3.0, respectively, vs 28/100 person-years; P < .001). CONCLUSIONS: Malawian adults with HIV who immune reconstituted on ART and continued co-trimoxazole prophylaxis experienced fewer deaths and WHO HIV/AIDS stage 3-4 events compared with prophylaxis discontinuation, although statistical significance was not achieved. Co-trimoxazole prevented a composite of death plus WHO HIV/AIDS stage 2-4 events. Given poor healthcare access and lack of routine viral load monitoring, co-trimoxazole prophylaxis should continue in adults on ART after immune reconstitution in sub-Saharan Africa. Clinical Trials Registration. NCT01650558.

Enzyme-replacement therapy in life-threatening hypophosphatasia.

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).

Effect of Prior ChAdOx1 COVID-19 Immunisation on T-Cell Responses to ChAdOx1-HBV.

There are varying data concerning the effect of prior anti-vector immunity on the T-cell response induced by immunisation with an identical vectored vaccine containing a heterologous antigen insert. To determine whether prior exposure to ChAdOx1-SARS-CoV2 immunisation (Vaxzevria®) impacts magnitudes of antigen-specific T-cell responses elicited by subsequent administration of the same viral vector (encoding HBV antigens, ChAdOx1-HBV), healthy volunteers that had received Vaxzevria® (n = 15) or the Pfizer or Moderna mRNA COVID-19 vaccine (n = 11) between 10 and 18 weeks prior were recruited to receive a single intramuscular injection of ChAdOx1-HBV. Anti-ChAdOx1-neutralising antibody titers were determined, and vector or insert-specific T-cell responses were measured by a gamma-interferon ELISpot and intracellular cytokine staining (ICS) assay using multiparameter flow cytometry. Participants were followed for three months after the ChAdOx1-HBV injection, which was well-tolerated, and no dropouts occurred. The baseline ChAdOx1 neutralisation titers were higher in the Vaxzevria® cohort (median of 848) than in the mRNA cohort (median of 25). T-cell responses to HBV antigens, measured by ELISpot, were higher on day 28 in the mRNA group (p = 0.013) but were similar between groups on day 84 (p = 0.441). By ICS, these differences persisted at the last time point. There was no clear correlation between the baseline responses to the adenoviral hexon and the subsequent ELISpot responses. As vaccination within 3 months using the same viral vector backbone affected the insert-specific T-cell responses, a greater interval after prior adenoviral immunisation using heterologous antigens may be warranted in settings in which these cells play critical roles.

Towards a barrier-free anthropomorphic brain phantom for quantitative magnetic resonance imaging: Design, first construction attempt, and challenges.

Existing magnetic resonance imaging (MRI) reference objects, or phantoms, are typically constructed from simple liquid or gel solutions in containers with specific geometric configurations to enable multi-year stability. However, there is a need for phantoms that better mimic the human anatomy without barriers between the tissues. Barriers result in regions without MRI signal between the different tissue mimics, which is an artificial image artifact. We created an anatomically representative 3D structure of the brain that mimicked the T1 and T2 relaxation properties of white and gray matter at 3 T. While the goal was to avoid barriers between tissues, the 3D printed barrier between white and gray matter and other flaws in the construction were visible at 3 T. Stability measurements were made using a portable MRI system operating at 64 mT, and T2 relaxation time was stable from 0 to 22 weeks. The phantom T1 relaxation properties did change from 0 to 10 weeks; however, they did not substantially change between 10 weeks and 22 weeks. The anthropomorphic phantom used a dissolvable mold construction method to better mimic anatomy, which worked in small test objects. The construction process, though, had many challenges. We share this work with the hope that the community can build on our experience.

Current Experiences and Future Expectations for Physical Activity Participation: Perspectives of Young People with Physical Disabilities and Their Rehabilitation Clinicians.

Purpose: Researchers investigated current physical activity experiences of youth with physical disabilities and expectations for continued participation as they transition to adult services. Method: Youth (n = 6) and clinicians (n = 7) from a rehabilitation center participated in two separate focus groups. Researchers used inductive thematic analysis. Results: Four themes emerged among youth: "good for your health"; "motivation is key"; "social opportunities in safe environments"; "wanting to stay active." Among clinicians, five themes arose: "added therapeutic benefits with participation"; "development as individuals through physical activity"; "inclusive and supportive environments"; "parents as advocates"; "transitioning to adult services is important." Conclusions: Themes across focus groups were comparable. Participants expressed positive experiences for youth attending a dedicated adapted fitness center. To facilitate current and future physical activity in adulthood for youth with physical disabilities in integrated settings, the following are warranted: accessible buildings, trained staff, adapted equipment, and positive attitudes toward disability.

Outcome measures to assess efficacy of treatments for age-related macular degeneration.

In a clinical trial of age-related macular degeneration (AMD), the outcome measure chosen to assess the efficacy of treatment should reflect the purpose of the trial and the stage of development of the treatment. This article considers 3 classes of outcomes: continuous variables, such as mean change in best visual acuity; binary (2-category) variables, such as experiencing a 15-letter loss; or 3-category variables, such as experiencing either a 15-letter loss or 15-letter gain. Each type of outcome has advantages and disadvantages. Trials using outcomes based on means require much smaller sample sizes than trials based on 2- or 3-category variables, but means do not address the experience of individuals. Two- and 3-category variables show what happens to individuals, but they are subject to misclassification and are statistically inefficient. The authors recommend considering continuous measures for early stage trials and for trials studying various dose regimens when a treatment has been well characterized. However, 2- and 3-category outcomes are particularly useful in confirmatory phase 3 trials of a new therapy. A new graphical method is proposed to provide insight into the distribution of the time course of changes in acuity on an individual patient basis.

Reports to Independent Data Monitoring Committees: An Appeal for Clarity, Completeness, and Comprehensibility.

BACKGROUND: Organizations presenting reports to independent data monitoring committees (IDMCs) should present data in a way that facilitates the ability of the IDMC to make informed judgments about the trial. METHODS: This paper reviews reports to IDMCs and suggests approaches an independent statistical reporting group (ISRG) might take to prepare clear, complete, and comprehensible reports. RESULTS: Sensible reporting by an ISRG and informed decision making by an IDMC require a productive partnership between the quantitative and clinical disciplines involved in a clinical trial. IDMC reports differ in structure and purpose from clinical study reports that summarize data at the end of a trial. The ISRG must have intellectual independence, recognizing that although the sponsor may be paying the bills, the ISRG is responsible to the IDMC. Ideally, it should have access to all data from the trial and should be capable of responding to requests from the IDMC without the sponsor's specific permission. The ISRG and sponsor must understand the differences between clean data at the end of the trial and data collected during the trial. To perform its role most effectively, the ISRG must collaborate with sponsor and IDMC clinicians to become conversant with the disease area, the product's mechanism of action, and the clinical relevance of important outcome measures. CONCLUSIONS: An IDMC is best served by an independent ISRG that will prepare clear, complete, and comprehensible reports. Given the complexities of interim data and IDMC requirements, the ISRG must be an active and informed participant in the monitoring process.

Non-invasive peripheral nerve stimulation via focused ultrasound in vivo.

Focused ultrasound (FUS) has been employed on a wide range of clinical applications to safely and non-invasively achieve desired effects that have previously required invasive and lengthy procedures with conventional methods. Conventional electrical neuromodulation therapies that are applied to the peripheral nervous system (PNS) are invasive and/or non-specific. Recently, focused ultrasound has demonstrated the ability to modulate the central nervous system and ex vivo peripheral neurons. Here, for the first time, noninvasive stimulation of the sciatic nerve eliciting a physiological response in vivo is demonstrated with FUS. FUS was applied on the sciatic nerve in mice with simultaneous electromyography (EMG) on the tibialis anterior muscle. EMG signals were detected during or directly after ultrasound stimulation along with observable muscle contraction of the hind limb. Transecting the sciatic nerve downstream of FUS stimulation eliminated EMG activity during FUS stimulation. Peak-to-peak EMG response amplitudes and latency were found to be comparable to conventional electrical stimulation methods. Histology along with behavioral and thermal testing did not indicate damage to the nerve or surrounding regions. The findings presented herein demonstrate that FUS can serve as a targeted, safe and non-invasive alternative to conventional peripheral nervous system stimulation to treat peripheral neuropathic diseases in the clinic.

Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study.

BACKGROUND: Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, characterised by rapid psychomotor decline and epilepsy, is caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1. We aimed to analyse the characteristics and rate of progression of CLN2 disease in an international cohort of patients. METHODS: We did an observational cohort study using data from two independent, international datasets of patients with untreated genotypically confirmed CLN2 disease: the DEM-CHILD dataset (n=74) and the Weill Cornell Medical College (WCMC) dataset (n=66). Both datasets included quantitative rating assessments with disease-specific clinical domain scores, and disease course was measured longitudinally in 67 patients in the DEM-CHILD cohort. We analysed these data to determine age of disease onset and diagnosis, as well as disease progression-measured by the rate of decline in motor and language summary scores (on a scale of 0-6 points)-and time from first symptom to death. FINDINGS: In the combined DEM-CHILD and WCMC dataset, median age was 35·0 months (IQR 24·0-38·5) at first clinical symptom, 37·0 months (IQR 35·0 -42·0) at first seizure, and 54·0 months (IQR 47·5-60·0) at diagnosis. Of 74 patients in the DEM-CHILD dataset, the most common first symptoms of disease were seizures (52 [70%]), language difficulty (42 [57%]), motor difficulty (30 [41%]), behavioural abnormality (12 [16%]), and dementia (seven [9%]). Among the 41 patients in the DEM-CHILD dataset for whom longitudinal assessments spanning the entire disease course were available, a rapid annual decline of 1·81 score units (95% CI 1·50-2·12) was seen in motor-language summary scores from normal (score of 6) to no function (score of 0), which occurred over approximately 30 months. Among 53 patients in the DEM-CHILD cohort with available data, the median time between onset of first disease symptom and death was 7·8 years (SE 0·9) years. INTERPRETATION: In view of its natural history, late-infantile CLN2 disease should be considered in young children with delayed language acquisition and new onset of seizures. CLN2 disease has a largely predictable time course with regard to the loss of language and motor function, and these data might serve as historical controls for the assessment of current and future therapies. FUNDING: EU Seventh Framework Program, German Ministry of Education and Research, EU Horizon2020 Program, National Institutes of Health, Nathan's Battle Foundation, Cures Within Reach Foundation, Noah's Hope Foundation, Hope4Bridget Foundation.

Targeting Effects on the Volume of the Focused Ultrasound-Induced Blood-Brain Barrier Opening in Nonhuman Primates In Vivo.

Drug delivery to subcortical regions is susceptible to the blood-brain barrier (BBB) impeding the molecular exchange between the blood stream and the brain parenchyma. Focused ultrasound (FUS) coupled with the administration of microbubbles has been proved to open the BBB locally, transiently, and noninvasively both in rodents and in nonhuman-primates (NHPs). The development of this disruption technique independent of MRI monitoring is of primordial importance yet restrained to the targeting optimization. This paper establishes the linear relationship of the incidence angle with the volume of BBB opening ( VBBB ) and the peak negative pressure when sonicating the caudate nucleus and the putamen region of five NHPs. In addition, the effect of central nervous system structures on the opening morphology is evaluated by identification of the gray-to-white-matter ratio at the opening site. Finally, the targeting accuracy is assessed through the estimation of the geometric and angle shift of the opening from the targeted region. Interestingly, results prove a monotonic increase of the opening volume with close to normal incidence angles. Moreover, 80.35% of the opening lies on gray-matter regions compared with only 19.41% attributed to the white matter. The opening was found to be shifted axially, toward the transducer, and laterally with an average angle shift of 4.5°. Finally, we were capable of showing reproducibility of targeting accuracy with the same stereotactic and ultrasonic parameters. This paper documents the a priori prediction of the opening volume through manipulation of the angle and pressure as well as establishing the predictability, accuracy, and safety of FUS-induced BBB opening in NHPs.

Toward a Cognitive Neural Prosthesis Using Focused Ultrasound.

Non-invasive brain stimulation using focused ultrasound has many potential applications as a research and clinical tool, including its incorporation as either an extracorporeal or implantable neural prosthetic. To this end, we investigated the effect of focused ultrasound (FUS) combined with systemically administered microbubbles on visual-motor decision-making behavior in monkeys. We applied FUS to the putamen in one hemisphere to open the blood-brain barrier (BBB), and then tested behavioral performance 3-4 h later. On days when the monkeys were treated with FUS, their decisions were faster and more accurate than days without sonication. The performance improvement suggested both a shift in the decision criterion and an enhancement of the use of sensory evidence in the decision process. FUS also interacted with the effect of a low dose of haloperidol. The findings indicate that a two-minute application of FUS can have a sustained impact on performance of complex cognitive tasks, and may increase the efficacy of psychoactive medications. The results lend further support to the idea that the dorsal striatum plays an integral role in evidence- and reward-based decision-making, and provide motivation for incorporating FUS into cognitive neural prosthetic devices.

Blood-Brain Barrier Opening in Behaving Non-Human Primates via Focused Ultrasound with Systemically Administered Microbubbles.

Over the past fifteen years, focused ultrasound coupled with intravenously administered microbubbles (FUS) has been proven an effective, non-invasive technique to open the blood-brain barrier (BBB) in vivo. Here we show that FUS can safely and effectively open the BBB at the basal ganglia and thalamus in alert non-human primates (NHP) while they perform a behavioral task. The BBB was successfully opened in 89% of cases at the targeted brain regions of alert NHP with an average volume of opening 28% larger than prior anesthetized FUS procedures. Safety (lack of edema or microhemorrhage) of FUS was also improved during alert compared to anesthetized procedures. No physiological effects (change in heart rate, motor evoked potentials) were observed during any of the procedures. Furthermore, the application of FUS did not disrupt reaching behavior, but in fact improved performance by decreasing reaction times by 23 ms, and significantly decreasing touch error by 0.76 mm on average.

Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task.

Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500 kHz, 200-400 kPa, 4-5 µm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4-20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of' visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4-5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used.

An experimental and computational analysis of primary cilia deflection under fluid flow.

In this study we have developed a novel model of the deflection of primary cilia experiencing fluid flow accounting for phenomena not previously considered. Specifically, we developed a large rotation formulation that accounts for rotation at the base of the cilium, the initial shape of the cilium and fluid drag at high deflection angles. We utilised this model to analyse full 3D data-sets of primary cilia deflecting under fluid flow acquired with high-speed confocal microscopy. We found a wide variety of previously unreported bending shapes and behaviours. We also analysed post-flow relaxation patterns. Results from our combined experimental and theoretical approach suggest that the average flexural rigidity of primary cilia might be higher than previously reported (Schwartz et al. 1997, Am J Physiol. 272(1 Pt 2):F132-F138). In addition our findings indicate that the mechanics of primary cilia are richly varied and mechanisms may exist to alter their mechanical behaviour.

Real-time, transcranial monitoring of safe blood-brain barrier opening in non-human primates.

The delivery of drugs to specific neural targets faces two fundamental problems: (1) most drugs do not cross the blood-brain barrier, and (2) those that do, spread to the entire brain. To date, there exists only one non-invasive methodology with the potential to solve these problems: selective blood-brain barrier (BBB) opening using micro-bubble enhanced focused ultrasound. We have recently developed a single-element 500-kHz spherical transducer ultrasound setup for targeted BBB opening in the non-human primate that does not require simultaneous MRI monitoring. So far, however, the targeting accuracy that can be achieved with this system has not been quantified systematically. In this paper, the accuracy of this system was tested by targeting caudate nucleus and putamen of the basal ganglia in two macaque monkeys. The average lateral targeting error of the system was ∼2.5 mm while the axial targeting error, i.e., along the ultrasound path, was ∼1.5 mm. We have also developed a real-time treatment monitoring technique based on cavitation spectral analysis. This technique also allowed for delineation of a safe and reliable acoustic parameter window for BBB opening. In summary, the targeting accuracy of the system was deemed to be suitable to reliably open the BBB in specific sub-structures of the basal ganglia even in the absence of MRI-based verification of opening volume and position. This establishes the method and the system as a potentially highly useful tool for brain drug delivery.

Transcranial cavitation detection in primates during blood-brain barrier opening--a performance assessment study.

Focused ultrasound (FUS) has been shown promise in treating the brain locally and noninvasively. Transcranial passive cavitation detection (PCD) provides methodology for monitoring the treatment in real time, but the skull effects remain a major challenge for its translation to the clinic. In this study, we investigated the sensitivity, reliability, and limitations of PCD through primate (macaque and human) skulls in vitro. The results were further correlated with the in vivo macaque studies including the transcranial PCD calibration and real-time monitoring of blood-brain barrier (BBB) opening, with magnetic resonance imaging assessing the opening and safety. The stable cavitation doses using harmonics (SCDh) and ultraharmonics (SCDu), the inertial cavitation dose (ICD), and the cavitation SNR were quantified based on the PCD signals. Results showed that through the macaque skull, the pressure threshold for detecting the SCDh remained the same as without the skull in place, whereas it increased for the SCDu and ICD; through the human skull, it increased for all cavitation doses. The transcranial PCD was found to be reliable both in vitro and in vivo when the transcranial cavitation SNR exceeded the 1-dB detection limit through the in vitro macaque (attenuation: 4.92 dB/mm) and human (attenuation: 7.33 dB/ mm) skull. In addition, using long pulses enabled reliable PCD monitoring and facilitate BBB opening at low pressures. The in vivo results showed that the SCDh became detectable at pressures as low as 100 kPa; the ICD became detectable at 250 kPa, although it could occur at lower pressures; and the SCDu became detectable at 700 kPa and was less reliable at lower pressures. Real-time monitoring of PCD was further implemented during BBB opening, with successful and safe opening achieved at 250 to 600 kPa in both the thalamus and the putamen. In conclusion, this study shows that transcranial PCD in macaques in vitro and in vivo, and in humans in vitro, is reliable by improving the cavitation SNR beyond the 1-dB detection limit.

In silico evolution of guiding track designs for molecular shuttles powered by kinesin motors.

Molecular shuttles powered by kinesin motors require guiding tracks to perform specific tasks in nanoscale devices. Here, using our simulation of molecular shuttle movements, we describe an in silico evolutionary design method that makes it possible to automatically design the guiding tracks in accordance with their functions defined by designers. With this design method, we designed two types of pre-existing guiding track modules with improved performances, as well as one with a novel function.

A hands-on course teaching bioinstrumentation through the design and construction of a benchtop cardiac pacemaker.

We have developed a bioinstrumentation course that emphasizes practical application of engineering and biological concepts by having students focus on the development of a single biomedical device: a cardiac pacemaker. In creating their benchtop pacemaker, students learn about and design sensing circuitry, data acquisition and processing code, control system algorithms, and stimulation electronics. They also gain an understanding of cardiac anatomy and electrophysiology. The separate elements of the pacemaker created throughout the semester will be repeatedly tested, re-designed, and integrated with one another, culminating in an emulated pacemaker whose efficacy will be tested on North American bullfrogs. It is hypothesized that the hands-on learning in this course, coupled with the practical application of concepts in the context of a single biomedical device, will enhance students' skills in bioinstrumentation design.

The mechanics of the primary cilium: an intricate structure with complex function.

The primary cilium is a non-motile singular cellular structure that extends from the surface of nearly every cell in the body. The cilium has been shown to play numerous roles in maintaining tissue homeostasis, through regulating signaling pathways and sensing both biophysical and biochemical changes in the extracellular environment. The structural performance of the cilium is paramount to its function as defective cilia have been linked to numerous pathologies. In particular, the cilium has demonstrated a mechanosensory role in tissues such as the kidney, liver, endothelium and bone, where cilium deflection under mechanical loading triggers a cellular response. Understanding of how cilium structure and subsequent mechanical behavior contributes to the roles that cilium plays in regulating cellular behavior is a compelling question, yet is a relatively untouched research area. Recent advances in biophysical measurements have demonstrated the cilium to be a structurally intricate organelle containing an array of load bearing proteins. Furthermore advances in modeling of this organelle have revealed the importance of these proteins at regulating the cilium's mechanosensitivity. Remarkably, the cilium is capable of adapting its mechanical state, altering its length and possibly it's bending resistance, to regulate its mechanosensitivity demonstrating the importance of cilium mechanics in cellular responses. In this review, we introduce the cilium as a mechanosensor; discuss the advances in the mechanical modeling of cilia; explore the structural features of the cilium, which contribute to its mechanics and finish with possible mechanisms in which alteration in structure may affect ciliary mechanics, consequently affecting ciliary based mechanosensing.