RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly.

The study of macroautophagy in mammalian cells has described induction, vesicle nucleation, and membrane elongation complexes as key signaling intermediates driving autophagosome biogenesis. How these components are recruited to nascent autophagosomes is poorly understood, and although much is known about signaling mechanisms that restrain autophagy, the nature of positive inductive signals that can promote autophagy remain cryptic. We find that the Ras-like small G protein, RalB, is localized to nascent autophagosomes and is activated on nutrient deprivation. RalB and its effector Exo84 are required for nutrient starvation-induced autophagocytosis, and RalB activation is sufficient to promote autophagosome formation. Through direct binding to Exo84, RalB induces the assembly of catalytically active ULK1 and Beclin1-VPS34 complexes on the exocyst, which are required for isolation membrane formation and maturation. Thus, RalB signaling is a primary adaptive response to nutrient limitation that directly engages autophagocytosis through mobilization of the core vesicle nucleation machinery.

A review and perspective paper: Ras oncogene gets modest, from kingpin to mere henchman.

The concomitant activation of both the YAP1 co-transcription factor and RAS GTPases is a hallmark of several aggressive cancers, though the intricacies of their relationship and implications for oncogenesis are still poorly understood. This review has presented a cooperative model where YAP1 and RAS are not independently acting oncogenes but rather interdependently acting ones, with each fulfilling an essential role within the oncogenic process. YAP1 is responsible for initiating the expression of key proteins that contribute to various cancer traits. However, these proteins must often be transported into the cytoplasm to exert their effects. We suggest that oncogenic RAS actually facilitates this transport, enabling the phosphorylation and subsequent activation of the nuclear transporter XPO1 (aka Exportin1). This mechanism is particularly crucial for anti-apoptotic proteins. Instead of being sequestered within the nucleus in an ineffective state, these proteins are rather shuttled into the cytoplasm. Within the cytoplasm, they can effectively inhibit apoptosis, undermining by these means the efficacy of chemotherapeutic agents designed to induce cell death in cancer cells. Therefore, a clearer understanding of the oncogenic partnership between RAS and YAP1 will likely provide new insights into the molecular underpinnings of cancer and highlight as well potential targets for therapeutic interventions designed to disrupt this pernicious interaction.

Pronator syndrome and anterior interosseous nerve palsy due to neurolymphomatosis: a case report.

Pronator syndrome is a median nerve entrapment neuropathy that can be difficult to diagnose due to its variable presentation and objective findings. Neurolymphomatosis is an uncommon disease in which malignant lymphocytes infiltrate central or peripheral nerve endoneurium and is often missed for prolonged periods prior to diagnosis. We present a rare case of pronator syndrome and anterior interosseous nerve palsy due to neurolymphomatosis that was occult on initial MRI in spite of the presence of a median nerve mass discovered intra-operatively during neurolysis. This case demonstrates the value of ultrasound for the examination of peripheral nerve pathology and illustrates its utility as an adjunct to MRI, in part due to the ability to screen a large region.

The STK38-XPO1 axis, a new actor in physiology and cancer.

The Hippo signal transduction pathway is an essential regulator of organ size during developmental growth by controlling multiple cellular processes such as cell proliferation, cell death, differentiation, and stemness. Dysfunctional Hippo signaling pathway leads to dramatic tissue overgrowth. Here, we will briefly introduce the Hippo tumor suppressor pathway before focusing on one of its members and the unexpected twists that followed our quest of its functions in its multifarious actions beside the Hippo pathway: the STK38 kinase. In this review, we will precisely discuss the newly identified role of STK38 on regulating the nuclear export machinery by phosphorylating and activating, the major nuclear export receptor XPO1. Finally, we will phrase STK38's role on regulating the subcellular distribution of crucial cellular regulators such as Beclin1 and YAP1 with its implication in cancer.

Improving respiratory outcomes after pediatric cardiac surgery: New uses for nitric oxide.

BACKGROUND: This month's issue of Journal of Cardiac Surgery features a retrospective study on the effect of combining inhaled nitric oxide with high frequency oscillator ventilation to rescue infants who have failed conventional ventilation after congenital heart surgery. AIMS: This commentary aims to place that study within the context of available published literature on the topic. MATERIALS AND METHODS: The PubMed database was queried for all English-language entries between 1995 and 2021 with the terms nitric oxide, congenital heart disease, oscillator, and respiratory failure. The results were then assessed for relevance and impact by the author. RESULTS: From these results, 15 articles were selected for use in this review. The cost of prolonged mechanical ventilation is described. The use of nitric oxide has been used to improve outcomes in hypoxic respiratory failure. High-frequency oscillator ventilation has also been studied in pediatric patients with ARDS. To date, no studies have been published showing the benefit of combining these two modalities in pediatric cardiac surgical patients. DISCUSSION: The results of this month's study on nitric oxide and high frequency oscillator ventilation are placed in the context of current literature and suggestions for further study are presented. CONCLUSION: Pediatric patients with hypoxic respiratory failure following congenital heart surgery have a new treatment strategy that appears effective. Further studies to confirm this should be undertaken.

Iliac Crest and Distal Radius Autografts Exhibit Distinct Cell-Intrinsic Functional Differences.

PURPOSE: Autologous bone grafts demonstrate osteoconductive, osteoinductive, and osteogenic properties. Hand surgeons commonly augment surgical fixation with autografts to promote fracture healing. This study compared the intrinsic stem cell-like properties of 2 commonly used autograft sources in hand surgery: the iliac crest and distal radius. METHODS: A total of 9 subjects who received an iliac crest bone graft and distal radius bone graft harvest as a part of the standard care of distal radius malunion or nonunion correction or scaphoid nonunion open reduction and internal fixation were enrolled in the study. Cells were isolated by serial collagenase digestion and subjected to fibroblast colony-forming units, osteogenesis, and adipogenesis assays. The expression levels of genes involved in osteogenesis and adipogenesis were confirmed using quantitative polymerase chain reaction. RESULTS: The cells isolated from the iliac crest bone graft compared with those isolated from the distal radius bone graft demonstrated significantly higher mean fibroblast colony-forming unit efficiency; increased osteogenesis, as measured using alizarin red quantification; increased adipogenesis, as measured using oil red O quantification; and higher expression levels of genes involved in osteogenesis and adipogenesis under the respective differentiation conditions. CONCLUSIONS: The cells isolated from the iliac crest bone graft demonstrated a higher fibroblast colony-forming unit capacity and an increased capability to undergo both osteogenesis and adipogenesis. CLINICAL RELEVANCE: Limited evidence exists comparing the intrinsic stem cell-like properties of the iliac crest and distal radius despite the widespread use of each source in hand and wrist surgery. The information from this investigation may assist hand and wrist surgeons with the selection of a source of autograft.

STK38 kinase acts as XPO1 gatekeeper regulating the nuclear export of autophagy proteins and other cargoes.

STK38 (also known as NDR1) is a Hippo pathway serine/threonine protein kinase with multifarious functions in normal and cancer cells. Using a context-dependent proximity-labeling assay, we identify more than 250 partners of STK38 and find that STK38 modulates its partnership depending on the cellular context by increasing its association with cytoplasmic proteins upon nutrient starvation-induced autophagy and with nuclear ones during ECM detachment. We show that STK38 shuttles between the nucleus and the cytoplasm and that its nuclear exit depends on both XPO1 (aka exportin-1, CRM1) and STK38 kinase activity. We further uncover that STK38 modulates XPO1 export activity by phosphorylating XPO1 on serine 1055, thus regulating its own nuclear exit. We expand our model to other cellular contexts by discovering that XPO1 phosphorylation by STK38 regulates also the nuclear exit of Beclin1 and YAP1, key regulator of autophagy and transcriptional effector, respectively. Collectively, our results reveal STK38 as an activator of XPO1, behaving as a gatekeeper of nuclear export. These observations establish a novel mechanism of XPO1-dependent cargo export regulation by phosphorylation of XPO1's C-terminal auto-inhibitory domain.

State of Microsurgery Training in 2020: Survey of Hand Surgery Fellowship Program Directors.

BACKGROUND: Given the current national conundrum of decreasing microsurgery case volume performed by hand surgery fellows despite interest, program directors were surveyed to evaluate opinions of exposure gaps in training and to determine the current state of microsurgery training in 2020. METHODS: Anonymous national surveys were distributed to hand surgery fellowship program directors by the American Society for Surgery of the Hand. Subgroups were compared by training location and size of the fellowship program. Accreditation Council for Graduate Medical Education public national data on graduate case log procedures by hand surgery fellows were reviewed. RESULTS: Eighty-eight surveys were distributed by the American Society for Surgery of the Hand to hand surgery fellowship program directors with a 44% (n = 39) response rate. Hand surgery fellowship programs from 19 US states participated. Most program's fellows had previous orthopedic surgery residency training with 41.03% of programs surveyed having 100% orthopedic surgery-trained fellows. The average number of weekly vascular microsurgical cases ranged from 25% of fellowships having no microsurgery cases per week, 46.2% having 1 per week, and only 7.7% having 5 or more cases per week. However, 60.5% of program directors prioritized a microvascular surgery case as the most valuable educational opportunity for fellows. Most program directors agreed (79.5%) that a 1-year hand surgery fellowship is sufficient to train a competent hand surgeon, who is proficient in microsurgery. In contrast, the majority disagreed (53.8%) that hand surgery microsurgery skills after a 1-year hand surgery fellowship are equivalent among graduates, regardless of a prior plastic surgery or orthopedic surgery residency training. There was a statistically significant difference in program directors' responses by geographic location regarding prior residency background impacting microsurgical skills (Kendall τ, -0.439; P = 0.001). Graduate case log data revealed an increasing trend in the number of microsurgery procedures performed by orthopedic hand surgery fellows until 2014, with a decline in cases per year and stagnating trend at 7% thereafter. CONCLUSIONS: In 2020, most hand surgery fellowship program directors highly value and prioritize microsurgery exposure for their hand surgery fellows' education despite the decrease in case volume for hand surgery fellows.

Louis Ombrédanne, a founding member of SICOT.

This paper describes the life and work of Louis Ombrédanne, one of the founding fathers of the SICOT, a notorious French orthopaedic and paediatric surgeon with a strong interest in plastic surgery and reconstruction of post-traumatic defects and also with limb lengthening and treatment of sequalae. Born in Paris in 1871 as a son of a general practitioner doctor, Ombrédanne was a brilliant student enjoying anatomy and surgery since the early years. He was appointed as a Surgeon in 1902 in Paris and became Professor of Surgery in 1907. During the First World War, he worked in Verdun, one of the most exposed hospitals near the battlefield where over 700.000 people died and many cases were affected by head and neck burns and destructions, requiring surgical reconstruction. After the war, Ombrédanne developed Pediatric Surgery and it seems that his powerful drive and charisma explain why these specialties are studied together with orthopaedics in Europe and later in the World. Many innovations like the anaesthetic inhaler with face mask were authored by Ombrédanne and also techniques of limb lengthening, thoracic plasty. He described malignant hyperthermia in children and worked in the Sick Children Hospital in Paris, today Hôpital Necker. In 1929, Ombrédanne participated with a group of enthusiastic surgeons and teachers from many countries to the creation of SICOT during a historical meeting held in Hotel Crillon in Paris. This paper introduces Ombrédanne's work to the current readers and is a tribute to the work of our ancestors who made possible the development of our specialty.

A Validated HPLC-PDA-HRMS Method to Investigate the Biological Stability and Metabolism of Antiparasitic Triterpenic Esters.

Pentacyclic triterpenes (PTs) are commonly found in medicinal plants with well-known antiparasitic effects. Previous research on C-3 and C-27 triterpenic esters showed effective and selective in vitro antiparasitic activities and in vivo effectiveness by parenteral routes. The aim of this study was to determine triterpenic esters' stability in different biological-like media and the main microsomal degradation products. An HPLC-PDA method was developed and validated to simultaneously analyze and quantify bioactive triterpenic esters in methanol (LOQ: 2.5 and 1.25-100 µg/mL) and plasma (LOQ: 5-125 µg/mL). Overall, both triterpenic esters showed a stable profile in aqueous and buffered solutions as well as in entire plasma, suggesting gaining access to the ester function is difficult for plasma enzymes. Conversely, after 1 h, 30% esters degradation in acidic media was observed with potential different hydrolysis mechanisms. C-3 (15 and 150 µM) and C-27 esters (150 µM) showed a relatively low hepatic microsomal metabolism (<23%) after 1 h, which was significantly higher in the lowest concentration of C-27 esters (15 µM) (>40% degradation). Metabolic HPLC-PDA-HRMS studies suggested hydrolysis, hydroxylation, dehydration, O-methylation, hydroxylation and/or the reduction of hydrolyzed derivatives, depending on the concentration and the position of the ester link. Further permeability and absorption studies are required to better define triterpenic esters pharmacokinetic and specific formulations designed to increase their oral bioavailability.

[Passive immunotherapy in Sars-Cov2 infections]. / Immunothérapies passives dans l'infection par le SARS-CoV-2.

This article presents the current situation by November 2021 of the prophylactic or therapeutical use of polyclonal or monoclonal antibodies in Covid-19, either as immuno-modulators, or directly directed towards the virus.

The Effect of the Powerball Gyroscope as a Treatment Device for Nonspecific Wrist Pain.

OBJECTIVE: The aim of this study was to determine the effect of using the Powerball gyroscope as a treatment device on pain and change in endurance in nonspecific wrist pain. METHODS: This study was a within-participants pre- and postintervention study consisting of 40 participants between ages 18 and 35 with an equal male-to-female ratio. The participants used the Powerball gyroscope for 5 minutes per treatment session. Treatment comprised 12 sessions carried out 3 × per week over a 4-week period. Participants completed objective and subjective data before the first, seventh, and 12th sessions. Objective data were recorded using the Jamar dynamometer to measure grip strength. Subjective data were gathered using the Patient-Rated Wrist Evaluation Questionnaire. Participants then used the Powerball gyroscope in the hand with the affected wrist. The Wilcoxon signed rank test and 1-way repeated-measures analysis of variance were used to analyze the changes. RESULTS: A significant decrease in pain was noted throughout the study, but the most significant changes occurred between the seventh and 12th treatment sessions (P < .01). A significant increase in grip strength was also noted throughout the study, with the greater increase in grip strength occurring during the first 7 treatments (P < .02). CONCLUSION: The Powerball gyroscope showed a change in outcome regarding nonspecific wrist pain and grip strength.

Treatment-Shortening Effect of a Novel Regimen Combining Clofazimine and High-Dose Rifapentine in Pathologically Distinct Mouse Models of Tuberculosis.

Clofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and clofazimine in clinical trials.

Oxazolidinones Can Replace Clarithromycin in Combination with Rifampin in a Mouse Model of Buruli Ulcer.

Rifampin (RIF) plus clarithromycin (CLR) for 8 weeks is now the standard of care for Buruli ulcer (BU) treatment, but CLR may not be an ideal companion for rifamycins due to bidirectional drug-drug interactions. The oxazolidinone linezolid (LZD) was previously shown to be active against Mycobacterium ulcerans infection in mice but has dose- and duration-dependent toxicity in humans. Sutezolid (SZD) and tedizolid (TZD) may be safer than LZD. Here, we evaluated the efficacy of these oxazolidinones in combination with rifampin in a murine BU model. Mice with M. ulcerans-infected footpads received control regimens of RIF plus either streptomycin (STR) or CLR or test regimens of RIF plus either LZD (1 of 2 doses), SZD, or TZD for up to 8 weeks. All combination regimens reduced the swelling and bacterial burden in footpads after two weeks of treatment compared with RIF alone. RIF+SZD was the most active test regimen, while RIF+LZD was also no less active than RIF+CLR. After 4 and 6 weeks of treatment, neither CLR nor the oxazolidinones added significant bactericidal activity to RIF alone. By the end of 8 weeks of treatment, all regimens rendered footpads culture negative. We conclude that SZD and LZD warrant consideration as alternative companion agents to CLR in combination with RIF to treat BU, especially when CLR is contraindicated, intolerable, or unavailable. Further evaluation could prove SZD superior to CLR in this combination.

High-Dose Rifamycins Enable Shorter Oral Treatment in a Murine Model of Mycobacterium ulcerans Disease.

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an 8-week course of rifampin (RIF) at 10 mg/kg of body weight and 150 mg/kg streptomycin (STR). Recently, the injectable STR has been shown to be replaceable with oral clarithromycin (CLR) for smaller lesions for the last 4 weeks of treatment. A shorter, all-oral, highly efficient regimen for BU is needed, as the long treatment duration and indirect costs currently burden patients and health systems. Increasing the dose of RIF or replacing it with the more potent rifamycin drug rifapentine (RPT) could provide such a regimen. Here, we performed a dose-ranging experiment of RIF and RPT in combination with CLR over 4 weeks of treatment in a mouse model of M. ulcerans disease. A clear dose-dependent effect of RIF on both clinical and microbiological outcomes was found, with no ceiling effect observed with tested doses up to 40 mg/kg. RPT-containing regimens were more effective on M. ulcerans All RPT-containing regimens achieved culture negativity after only 4 weeks, while only the regimen with the highest RIF dose (40 mg/kg) did so. We conclude that there is dose-dependent efficacy of both RIF and RPT and that a ceiling effect is not reached with the current standard regimen used in the clinic. A regimen based on higher rifamycin doses than are currently being evaluated against tuberculosis in clinical trials could shorten and improve therapy of Buruli ulcer.

Mortality Rate and Mid-Term Outcomes of Total Hip Arthroplasty Using Dual Mobility Cups for the Treatment of Femoral Neck Fractures in a Middle Eastern Population.

BACKGROUND: The dual mobility cups (DMCs) were shown to reduce dislocation rate following total hip arthroplasty for any etiology, including femoral neck fractures. No reported studies evaluating DMC results for femoral neck fracture in a Middle Eastern population were found in the literature. METHODS: This study aims to look for mortality rate, clinical, and functional outcomes in a population having specific rituals involving extreme hip positions as part of their daily activities. RESULTS: Of an initial sample of 174 patients (177 operated hips), 18 (10.3%) patients (20 hips) died after a mean of 39.6 ± 13.8 months (ranging from 2 to 49 months) with only 3 (1.7%) during the first post-operative year. Twelve patients (13 hips) were lost to follow-up and 19 patients (19 hips) had their radiological data incomplete. In the final sample of 125 patients (125 hips), no dislocation, aseptic loosening, or infection was encountered. The mean modified Hip Harris Score was of 94.8 ± 8.4. The mean modified Hip Harris Score of 40 patients who used to practice regularly oriental sitting position or prayers was 94.1 ± 3.1. After surgery, 36 of these 40 patients (90%) described their hip as "a forgotten hip." Multivariate analyses found correlation only between mortality and cardiovascular co-morbidities. CONCLUSION: DMC implants showed excellent clinical and functional results. The majority of patients having rituals and customs involving extreme hip positions were able to resume their daily activities. The observed low mortality rate should incite future research to investigate its correlation with the use of DMCs.

Primary cementless total knee arthroplasty with or without stem extension: a matched comparative study of ninety eight standard stems versus ninety eight long stems after more than ten years of follow-up.

INTRODUCTION: Using a cementless fixation for total knee arthroplasty (TKA) is controversial. We hypothesized that cementless tibial base plate with a monoblock long stem (MLS) would provide secure tibial alignment and stable fixation when bone conditions were considered as poor for a cementless fixation. The purpose of this study was to compare the mean eight year survivorship of cementless standard keels (SK) vs cementless MLS. MATERIAL METHODS: We report a matched series of 98 cases of SK and 98 cases of MLS in patients with poor bone conditions. The two cohorts were statistically compared. Revision for tibial loosening was used as the endpoint in the survivorship analysis. RESULTS: We recorded two cases of tibial loosening and three cases of bipolar loosening in the SK group (0% MLS vs 5% SK). No tibial loosening occurred in the MLS group (statistically significant). No tibial periprosthetic or intra-operative fractures occurred in either group. The survivorship at eight years of follow-up was 95.6% in the SS cohort vs 100% in the MLS cohort using revision for tibial loosening as the endpoint. DISCUSSION: This study was not randomized. Its strength was that it took into account the comparative midterm outcomes of a matched cohort of patients implanted with two types of cementless components in the same bone conditions. We did not record any tibial loosening in the MLS group. Using long stems has been criticized but we did not observe any adverse reactions and no intra-operative tibial fracture occurred. CONCLUSION: MLS improves the alignment and fixation of cementless TKA. This is a safe solution when bone conditions are poor or modified by previous surgery.

Intraprosthetic dislocation of dual mobility total hip arthroplasty: still occurring?

PURPOSE: The objective was to identify predictive factors for intraprosthetic dislocation (IPD) and to understand how improvements in dual mobility cups (DMC) have helped to reduce dramatically the occurrence of this complication. METHODS: DM mobile inserts retrieved from 93 hips were divided into three groups: first-generation DMC with IPD ("firstDMC-IPD"), first-generation DMC with over 15 years of implantation without IPD ("firstDMC-noIPD"), and latest-generation DMC ("newDMC"). The predictive factors for IPD based on clinical, prosthetic, radiological and intraoperative characteristics were analysed by multivariate analysis. The surface of each retrieved mobile insert was analysed using three-dimensional CT scan in order to compare their rim wear. RESULTS: Three predictive factors for IPD were found: a high BMI, a wide rough stem neck and a large cup size. Wear of the firstDMC-noIPD inserts was significantly less than those of firstDMC-IPD inserts and significantly more than those of newDMC inserts. For the firstDMC-IPD inserts, the rim's outer surface wear was significantly greater than the rim's inner surface wear. CONCLUSIONS: IPD is a specific complication related to wear of the DM mobile insert due to failure of the liner's retaining rim, especially from the rim's outer surface. This long-term issue is different to the early traumatic complication, which can happen after an attempt at closed reduction of a DM THA dislocation. Recent modifications in the design and the coating of contemporary DMC and femoral stems, as well as improvements in the mobile insert itself, seem to corroborate our assumptions about the IPD mechanism and contribute to the quasi-disappearance of this complication.

Characterizing diversity of food systems in view of sustainability transitions. A review.

Dominant food systems are configured from the productivist paradigm, which focuses on producing large amounts of inexpensive and standardized foods. Although these food systems continue being supported worldwide, they are no longer considered fit-for-purpose as they have been proven unsustainable in environmental and social terms. A large body of scientific literature argues that a transition from the dominant food systems to alternative ones built around the wider principles of sustainable production and rural development is needed. Promoting such a sustainability transition would benefit from a diagnosis of food system types to identify those systems that may harbor promising characteristics for a transition to sustainable food systems. While research on food system transitions abounds, an operational approach to characterize the diversity of food systems taking a system perspective is still lacking. In this paper we review the literature on how transitions to sustainable food systems may play out and present a framework based on the Multi-Level Perspective on Socio-Technical Transitions, which builds upon conceptual developments from social and natural science disciplines. The objectives of the framework are to (i) characterize the diversity of existing food systems at a certain geographical scale based on a set of structural characteristics and (ii) classify the food systems in terms of their support by mainstream practices, i.e., dominant food systems connected to regimes; deviate radically from them, niche food systems such as those based on grassroots innovation; or share elements of dominant and niche food systems, i.e., hybrid food systems. An example is given of application of our framework to vegetable food systems with a focus on production, distribution, and consumption of low-or-no pesticide vegetables in Chile. Drawing on this illustrative example we reflect on usefulness, shortcomings, and further development and use of the diagnostic framework.

Impact of Clofazimine Dosing on Treatment Shortening of the First-Line Regimen in a Mouse Model of Tuberculosis.

The antileprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes dose- and duration-dependent skin discoloration in patients, and the optimal clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impacts of duration, dose, and companion drugs on the treatment-shortening activity of clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) 6 months after stopping treatment, and the secondary outcome was bactericidal activity, i.e., the decline in the lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when coadministered with first-line drugs continuously throughout treatment and that equivalent treatment-shortening results are obtained with half the dose commonly used in mice. However, our studies also suggest that clofazimine at low exposures may have negative impacts on treatment outcomes, an effect that was evident only after the first 3 months of treatment. These data provide a sound evidence base to inform clofazimine dosing strategies to optimize the antituberculosis effect while minimizing skin discoloration. The results also underscore the importance of conducting long-term studies to allow the full evaluation of drugs administered in combination over long durations.