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For the first time in history, worldwide neglected disease budgets may be large enough to deliver a new drug every few years. That said, sponsors will only succeed if they extract maximum value from every dollar spent. This paper reviews possible cost-containment strategies and provides an evidence-based framework for choosing between them. Current proposals can be categorized as 'end-to-end' proposals which require the sponsor to set a single reward for companies that complete the entire drug discovery process or 'pay-as-you-go' schemes in which sponsors offer repeated rewards as drug candidates progress through the pipeline. A generic weakness of end-to-end proposals is that rewards are likely to be 20-30% higher than they would be in an equivalent payas-you-go programme. However, the benefits of pay-as-you-go programmes may be lost if commercial pharmaceutical companies are substantially better at choosing successful programmes than are their non-profit counterparts. The efficiency of pay-as-you-go methods depends on sponsors' willingness to withdraw funding from failed drug discovery programmes. Copyright © 2006 World Health Organization [ABSTRACT FROM AUTHOR]

Introduction: Short stems are a bone and soft-tissue preserving alternative to conventional stems. The aim of this multicenter study is to present the mid-term outcomes of a calcar-guided short stem., Materials and Methods: This is a prospective case series of the first 879 total hip arthroplasties performed on 782 patients across 5 centers using identical calcar-guided short stems. In a mid-term follow-up (6 years), rates and reasons for complications and revisions were documented. The Harris Hip Score (HHS) was obtained; patients reported pain and satisfaction using a visual analog scale., Results: A total of 43 patients died in the study cohort for non-related reasons; 26 patients (3.0%) required at least 1 revision after the index procedure. The survival rate for endpoint stem revision at mid-term was 98.4%. The main reasons for stem revision were aseptic loosening and early periprosthetic fractures. Sex had no influence on stem survival. Older patients or those with a high body mass index showed increased risk for stem revision during follow-up. Dorr type A morphology revealed a significantly lower risk of stem revision than Dorr type B or C (p = 0.0465). The HHS, satisfaction, and load pain at mid-term were 96.5 (SD 8.0), 9.7 (SD 0.9), and 0.5 (SD 1.9), respectively., Conclusions: This short stem produced highly satisfactory outcomes at mid-term, with 98.4% implant survival for any cause of stem revision and low complication rates. Long-term results are required to further evaluate these promising mid-term results., (© 2022. The Author(s).)

We conducted a retrospective review of the infectious complications and outcomes over a 2-year follow-up period of adult patients who received a second allogeneic hematopoietic cell transplant (2nd allo-HCT) during a five-year period at two cancer centers in Michigan. Sixty patients, of whom 44 (73%) had acute leukemia or myelodysplastic syndrome, were studied. The majority (n = 37,62%) received a 2nd allo-HCT because of relapsed leukemia. Infection episodes after the 2nd allo-HCT totaled 112. Bacteria were identified in 76 episodes, the majority of which occurred pre-engraftment. The most common infecting organisms were Enterococcus species and Clostridioides difficile. Viral infections, predominantly cytomegalovirus, accounted for 59 infection episodes and occurred mostly in pre-engraftment and early post-engraftment periods. There were 16 proven/probable fungal infections, of which 9 were invasive aspergillosis or candidiasis. Mortality was 45% (n = 27) at one year and 65% (n = 39) at 2 years after transplant, and 16 deaths (41%) were due to infection. Of those 16 infection deaths, 8 were bacterial, 4 fungal, 2 both bacterial and fungal, and 2 viral. Failure to engraft neutrophils or platelets was significantly associated with decreased survival, p < 0.0001 and p < 0.001, respectively. Infections are common after a 2nd allo-HCT and are associated with a high mortality rate., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Aims: Preprint servers allow authors to publish full-text manuscripts or interim findings prior to undergoing peer review. Several preprint servers have extended their services to biological sciences, clinical research, and medicine. The purpose of this study was to systematically identify and analyze all articles related to Trauma & Orthopaedic (T&O) surgery published in five medical preprint servers, and to investigate the factors that influence the subsequent rate of publication in a peer-reviewed journal., Methods: All preprints covering T&O surgery were systematically searched in five medical preprint servers (medRxiv, OSF Preprints, Preprints.org, PeerJ, and Research Square) and subsequently identified after a minimum of 12 months by searching for the title, keywords, and corresponding author in Google Scholar, PubMed, Scopus, Embase, Cochrane, and the Web of Science. Subsequent publication of a work was defined as publication in a peer-reviewed indexed journal. The rate of publication and time to peer-reviewed publication were assessed. Differences in definitive publication rates of preprints according to geographical origin and level of evidence were analyzed., Results: The number of preprints increased from 2014 to 2020 (p < 0.001). A total of 38.6% of the identified preprints (n = 331) were published in a peer-reviewed indexed journal after a mean time of 8.7 months (SD 5.4 (1 to 27)). The highest proportion of missing subsequent publications was in the preprints originating from Africa, Asia/Middle East, and South America, or in those that covered clinical research with a lower level of evidence (p < 0.001)., Conclusion: Preprints are being published in increasing numbers in T&O surgery. Depending on the geographical origin and level of evidence, almost two-thirds of preprints are not subsequently published in a peer-reviewed indexed journal after one year. This raises major concerns regarding the dissemination and persistence of potentially wrong scientific work that bypasses peer review, and the orthopaedic community should discuss appropriate preventive measures.Cite this article: Bone Jt Open  2022;3(7):582-588.

Diabetic foot infection is a frequent complication in long-standing diabetes mellitus. For antimicrobial therapy of this infection, both the optimal duration and the route of administration are often based more on expert opinion than on published evidence. We reviewed the scientific literature, specifically seeking prospective trials, and aimed at addressing two clinical issues: (1) shortening the currently recommended antibiotic duration and (2) using oral (rather than parenteral) therapy, especially after the patient has undergone debridement and revascularization. We also reviewed some older key articles that are critical to our understanding of the treatment of these infections, particularly with respect to diabetic foot osteomyelitis. Our conclusion is that the maximum duration of antibiotic therapy for osteomyelitis should be no more than to 4-6 weeks and might even be shorter in selected cases. In the future, in addition to conducting randomized trials and propagating national and international guidance, we should also explore innovative strategies, such as intraosseous antibiotic agents and bacteriophages., Competing Interests: The contact author has declared that neither they nor their co-authors have any competing interests., (Copyright: © 2022 Steven M. Maurer et al.)

This single-center retrospective study of invasive fungal disease (IFD) enrolled 251 adult patients undergoing induction chemotherapy for newly diagnosed acute myeloid leukemia (AML) from 2014-2019. Patients had primary AML ( n = 148, 59%); antecedent myelodysplastic syndrome ( n = 76, 30%), or secondary AML ( n = 27, 11%). Seventy-five patients (30%) received an allogeneic hematopoietic cell transplant within the first year after induction chemotherapy. Proven/probable IFD occurred in 17 patients (7%). Twelve of the 17 (71%) were mold infections, including aspergillosis ( n = 6), fusariosis ( n = 3), and mucomycosis ( n = 3). Eight breakthrough IFD (B-IFD), seven of which were due to molds, occurred in patients taking antifungal prophylaxis. Patients with proven/probable IFD had a significantly greater number of cumulative neutropenic days than those without an IFD, HR = 1.038 (95% CI 1.018-1.059), p = 0.0001. By cause-specific proportional hazards regression, the risk for IFD increased by 3.8% for each day of neutropenia per 100 days of follow up. Relapsed/refractory AML significantly increased the risk for IFD, HR = 7.562 (2.585-22.123), p = 0.0002, and Kaplan-Meier analysis showed significantly higher mortality at 1 year in patients who developed a proven/probable IFD, p = 0.02. IFD remains an important problem among patients with AML despite the use of antifungal prophylaxis, and development of IFD is associated with increased mortality in these patients.

Background: The skin commensal Cutibacterium avidum has been recognized as an emerging pathogen for periprosthetic joint infections (PJI). One currently assumes that the early occurring PJIs are a consequence of skin commensals contaminating the peri-implant tissue during surgery. We addressed whether standard skin antisepsis with povidone-iodine/alcohol before total hip arthroplasty (THA) is effective to eliminate colonizing bacteria with focus on C. avidum., Methods: In a single-center, prospective study, we screened all patients for skin colonizing C. avidum in the groin before THA. Only in the patients positive for C. avidum, we preoperatively repeated skin swabs after the first and third skin antisepsis and antibiotic prophylaxis. We also obtained dermis biopsies for microbiology and fluorescence in situ hybridization (FISH)., Results: Fifty-one out of 60 patients (85%) were colonized on the skin with various bacteria, in particular with C. avidum in 12 out of 60. Skin antisepsis eliminated C. avidum in eight of ten (20%) colonized patients undergoing THA. Deeper skin (dermis) biopsies were all culture negative, but FISH detected single positive ribosome-rich C. avidum in one case near sweat glands., Conclusion: Standard skin antisepsis was not effective to completely eliminate colonizing C. avidum on the skin in the groin of patients undergoing THA. Colonizing with C. avidum might pose an increased risk for PJI when considering a THA. Novel more effective antisepsis strategies are needed. Trial registration No clinical trial.

Loopers such as Chrysodeixis includens (Walker), Rachiplusia nu (Guenée), and Trichoplusia ni (Hübner) are important defoliators in soybean, sunflower, and crucifer crops, respectively, in countries of the Americas. The biotic potential of these polyphagous species of Plusiinae was comparatively examined considering crop rotation and succession scenarios in which crucifer crops are cultivated during or after Brazilian winter. All the species developed and reproduced on soybean (BRS 133 Embrapa) and forage turnip (Cati AL 1000, Wolf Seeds do Brasil). The development of C. includens was similar on both host plants. The survival of R. nu was lower on forage turnip than on soybean. In contrast, T. ni performance (survival, fecundity, pupal weight) was better on forage turnip than on soybean. This suggests that in crop rotation and succession scenarios of soybean after brassicacea, C. includens is likely to have a higher number of generations per year and could be potentially more harmful., (© The Author(s) 2019. Published by Oxford University Press on behalf of Entomological Society of America.)

Background: Screening mammography can detect early breast cancers and reduce subsequent cancer mortality. However, there is a lack of consensus as to when to discontinue screening. The absence of clear-cut guidelines on when not to screen means that many patients with advanced malignancies continue screening despite unclear benefit., Methods: We performed a retrospective cohort study of female patients diagnosed with a non-breast malignancy to explore the incidence and effects of screening mammography. Female patients diagnosed with a non-breast malignancy stage II or higher between 2007 and 2012 were identified through the Vermont Cancer Registry and cross-referenced with mammography screening logs from January 1, 2007 to September 30, 2014. Additional data were collected through chart review, in May 2016., Results: Twenty-six percent of women (398/1501) with a stage II or greater cancer (other than breast) diagnosed between 2007 and 2012 had a screening mammogram within the first 5 years of their diagnosis. Of these 398 women, 193 (48.5%) were alive without cancer, 132 (33.2%) had died, and 73 (18.3%) were alive with cancer at the time of chart review. Of those who died, 84 (63.6%) had a stage III or IV cancer. Eighteen (4.5%) had a breast biopsy following a screening mammogram suspicious for cancer, resulting in 13 (3.3%) benign diagnoses and 5 (1.3%) breast cancer diagnoses. No patient died of breast cancer., Conclusions: Except for highly curable cancers, female patients diagnosed with an advanced non-breast malignancy experienced mortality that outweighs a breast cancer mortality benefit from screening mammography as estimated from prior studies.

A decade ago, many biologists and legal scholars thought that open source (OS) methods would revolutionize drug discovery. These predictions were clearly disappointed. Not surprisingly, some scholars now take the opposite view that OS methods and drug discovery are inherently incompatible. This article argues for balance. Economists have observed that OS methods offer both advantages and disadvantages compared with conventional institutions. This article reviews what economists have learned regarding the strengths and weaknesses of OS methods and identifies specific drug-discovery tasks where OS methods are likely to work especially well. Successful OS collaborations should carefully focus on segments of the drug-discovery pipeline where the advantages of OS methods are particularly relevant and existing commercial methods are known to work badly. The article concludes by offering detailed suggestions for how existing OS software models can be modified and extended to conduct effective drug discovery.

Background: Conventional patent-based drug development incentives work badly for the developing world, where commercial markets are usually small to non-existent. For this reason, the past decade has seen extensive experimentation with alternative R&D institutions ranging from private-public partnerships to development prizes. Despite extensive discussion, however, one of the most promising avenues-open source drug discovery-has remained elusive. We argue that the stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. Historically, open source software collaborations have almost never succeeded without such "kernels"., Methodology/principal Findings: HERE, WE USE A COMPUTATIONAL PIPELINE FOR: (i) comparative structure modeling of target proteins, (ii) predicting the localization of ligand binding sites on their surfaces, and (iii) assessing the similarity of the predicted ligands to known drugs. Our kernel currently contains 143 and 297 protein targets from ten pathogen genomes that are predicted to bind a known drug or a molecule similar to a known drug, respectively. The kernel provides a source of potential drug targets and drug candidates around which an online open source community can nucleate. Using NMR spectroscopy, we have experimentally tested our predictions for two of these targets, confirming one and invalidating the other., Conclusions/significance: The TDI kernel, which is being offered under the Creative Commons attribution share-alike license for free and unrestricted use, can be accessed on the World Wide Web at http://www.tropicaldisease.org. We hope that the kernel will facilitate collaborative efforts towards the discovery of new drugs against parasites that cause tropical diseases.

Quantum computation holds promise for the solution of many intractable problems. However, since many quantum algorithms are stochastic in nature they can find the solution of hard problems only probabilistically. Thus the efficiency of the algorithms has to be characterized by both the expected time to completion and the associated variance. In order to minimize both the running time and its uncertainty, we show that portfolios of quantum algorithms analogous to those of finance can outperform single algorithms when applied to the NP-complete problems such as 3-satisfiability.

Database protection laws in Europe may have produced a modest, one-time growth spurt for commercial providers. Unfortunately, Europe's new database laws have also produced significant problems including overprotection of low-value data (e.g., telephone books), new barriers to database integration, and further erosion of the public domain. The authors of this Policy Forum caution that these problems could cripple commercial and academic science.

In 1996, the European Union issued a directive requiring member states to protect databases against unauthorized copying. Similar legislation is currently being considered and will probably be enacted in the US. Such database legislation 1) will almost certainly increase existing pressures on human mutation databases to commercialize, and 2) could inadvertently make human mutation data harder to acquire and use. Strategies for minimizing these difficulties are discussed. Alternatively, a nonprofit, community-wide "depository" could probably support itself by selling sophisticated bioinformatic products to the private sector. The proposed depository would offer substantially similar databases to academic and government users at little or no cost., (Copyright 2000 Wiley-Liss, Inc.)

The purpose of the retrospective study was to examine the effect of recall intervals on incidence of dental caries in handicapped patients. Data was collected from patient records of a private pediatric dental practice. Variables examined were time of the recall interval, age, race and sex of the patient, handicap, and whether the patient lived in a fluoridated area or not. Approximately six hundred charts were reviewed which resulted in 83 patients that qualified for the study. Of the 83 patients in the study, 57 did not have dental caries at the recall visit. The relationship between increased caries activity and recall interval was not significant. However, a trend indicating an increased chance of developing caries after a twelve month recall interval was detected.

The purpose of this retrospective study was to examine the effect of recall intervals on the incidence of dental caries. Data were collected from patient records of a private pediatric dental practice. Variables examined were time of the recall interval, age, race and sex of the patient, and whether the patient lived in a fluoridated area. There were 207 patients who qualified for the study. Of the 207 patients in the study, 173 did not have any teeth with dental caries at the recall visit. A significant difference between increased caries activity and recall interval was not found in this study. There was no significant difference found between the explanatory variables and caries activity.

During normal childbirth profound changes in the fibrinolytic system take place. Tissue plasminogen activator (t-PA), the antigen and its biological activity and, the activity of plasminogen activator inhibitor (PAI): were measured in twenty-two healthy women during and shortly after spontaneous delivery (2nd stage and 3rd stage of labour, 48 and 72 hours post partum). Significant increases of plasma t-PA antigen and activity occurred during childbirth and before delivery of the placenta, while the inhibitor remained unchanged. After delivery the PA inhibitor and t-PA antigen showed a steep decline. The activity of t-PA remained largely unchanged during labour and after delivery. The comparison between the activity levels of PAI in infant cord blood and in maternal peripheral blood, taken simultaneously during the process of placental separation, showed significantly higher PAI activity in the mother. In contrast the levels of t-PA activity were found to be significantly higher in cord blood. Our results demonstrate that during the process of child-birth and separation of the placenta distinct alterations in the fibrinolytic system occur most likely due to placental effects.