Blood flow analyses by intraoperative transit-time flow measurements of free flaps for head and neck reconstructions: A prospective single-center study.

BACKGROUND: The behavior of blood flow changes within free flaps following microvascular anastomosis is not well described in the literature. The aim of this study was to determine the immediate blood flow behavior of different free flaps as reference values for various clinical applications. METHODS: Intraoperative transit-time flow measurements were performed on patients receiving free flap transfer in the head and neck area comprising radial forearm flaps (RFF), peroneal artery perforator flaps (PAP), anterolateral thigh flaps (ALT), vastus lateralis flaps (VLF), parascapular flaps (PSF), latissimus dorsi flaps (LDF), fibula free flaps (FFF), deep circumflex iliac artery flaps (DCIA), and scapular flaps (SF). In accordance with a structured protocol, measurements took place at the pedicle directly before flap harvesting and at the recipient vessels 1 h after flap transfer. Heart rate, transplant weight, and other patient characteristics were recorded and analyzed. RESULTS: A total of 129 were enrolled, comprising 66 RFF, 8 ALT, 6 PAP, 11 VLF, 3 PSF, 2 LDF, 24 FFF, 7 DCIA, and 2 SF. In most of the transplant groups, arterial perfusion increased after anastomosis at the recipient site. The arterial pulsatility index developed indirectly proportionally to arterial blood flow, whereas venous blood drainage did not show any statistically significant changes. Muscle flaps had the highest arterial perfusion before flap transfer. Composite transplants with hard and soft tissue presented the greatest increase in arterial perfusion. The lowest arterial blood flow after anastomosis was measured in PAP and RFF. In contrast, RFF and PAP presented the highest arterial perfusion per 100 g transplant weight. CONCLUSIONS: Arterial perfusion changed, whereas venous blood flow did not show any statistically significant variations in any transplant group. Perfusion of free flaps does not only depend on the recipient vessel and the recipient bed, but also on flap-specific anatomy and physiology.

Water on Oxide Surfaces: A Triaqua Surface Coordination Complex on Co3O4(111).

The interaction of water with metal oxides controls their activity and stability in heterogeneous catalysis and electrocatalysis. In this work, we combine density functional theory calculations and infrared reflection absorption spectroscopy (IRAS) to identify the structural motifs formed upon interaction of water with an atomically defined Co3O4(111) surface. Three principal structures are observed: (i) strongly bound isolated OD, (ii) extended hydrogen-bonded OD/D2O structures, and (iii) a third structure which has not been reported to our knowledge. In this structure, surface Co2+ ions bind to three D2O molecules to form an octahedrally coordinated Co2+ with a "half hydration shell". We propose that this hydration structure represents an important intermediate in reorganization and dissolution on oxide surfaces which expose highly unsaturated surface cations.

Molecular anchoring to oxide surfaces in ultrahigh vacuum and in aqueous electrolytes: phosphonic acids on atomically-defined cobalt oxide.

In this work, we investigated the interaction of phenylphosphonic acid (PPA, C6H5PO3H2) with atomically-defined Co3O4(111) thin films, grown on Ir(100), under ultrahigh vacuum (UHV) conditions and in the electrochemical environment. In the first step, we employed infrared reflection absorption spectroscopy (IRAS) and followed the formation of a saturated monolayer (380 K) in UHV. We observed that the binding motif changes from a chelating tridentate in the sub-monolayer regime to a chelating bidentate at full monolayer coverages. In the electrochemical environment, we analyzed the interaction of PPA with the same Co3O4(111) surface by electrochemical infrared reflection absorption spectroscopy (EC-IRRAS) (0.3 VRHE-1.3 VRHE). When adsorbed at pH 10 from an ammonia buffered aqueous solution, PPA binds to the surface in form of a fully deprotonated chelating bidentate. With increasing electrode potential, we observed two fully reversible processes. At low buffer concentration, protons are released upon oxidation of surface Co2+ ions and lead to protonation of the anchored phosphonates. At high buffer concentration, most of the protons released are accepted by NH3. Simultaneously, the surface phosphonate changes its adsorption motif from bidentate to tridentate while adopting a more upright geometry.

Zoonotic Infection With Pigeon Paramyxovirus Type 1 Linked to Fatal Pneumonia.

The characteristics and risk factors of pigeon paramyxovirus type 1 (PPMV-1) infection in humans are poorly known. We performed virological, pathological, and epidemiological analyses of a Dutch case, and compared the results with those of a US case. Both infections occurred in transplant patients under immunosuppressive therapy and caused fatal respiratory failure. Both virus isolates clustered with PPMV-1, which has pigeons and doves as reservoir. Experimentally inoculated pigeons became infected and transmitted the virus to naive pigeons. Both patients were likely infected by contact with infected pigeons or doves. Given the large populations of feral pigeons with PPMV-1 infection in cities, increasing urbanization, and a higher proportion of immunocompromised individuals, the risk of severe human PPMV-1 infections may increase. We recommend testing for avian paramyxovirus type 1, including PPMV-1, in respiratory disease cases where common respiratory pathogens cannot be identified.

Catalytically Triggered Energy Release from Strained Organic Molecules: The Surface Chemistry of Quadricyclane and Norbornadiene on Pt(111).

We have investigated the surface chemistry of the polycyclic valence-isomer pair norbornadiene (NBD) and quadricyclane (QC) on Pt(111). The NBD/QC system is considered to be a prototype for energy storage in strained organic compounds. By using a multimethod approach, including UV photoelectron, high-resolution X-ray photoelectron, and IR reflection-absorption spectroscopic analysis and DFT calculations, we could unambiguously identify and differentiate between the two molecules in the multilayer phase, which implies that the energy-loaded QC molecule is stable in this state. Upon adsorption in the (sub)monolayer regime, the different spectroscopies yielded identical spectra for NBD and QC at 125 and 160 K, when multilayer desorption takes place. This behavior is explained by a rapid cycloreversion of QC to NBD upon contact with the Pt surface. The NBD adsorbs in a η2 :η1 geometry with an agostic Pt-H interaction of the bridgehead CH2 subunit and the surface. Strong spectral changes are observed between 190 and 220 K because the hydrogen atom that forms the agostic bond is broke. This reaction yields a norbornadienyl intermediate species that is stable up to approximately 380 K. At higher temperatures, the molecule dehydrogenates and decomposes into smaller carbonaceous fragments.

Model Catalytic Studies of Novel Liquid Organic Hydrogen Carriers: Indole, Indoline and Octahydroindole on Pt(111).

Indole derivatives were recently proposed as potential liquid organic hydrogen carriers (LOHC) for storage of renewable energies. In this work, we have investigated the adsorption, dehydrogenation and degradation mechanisms in the indole/indoline/octahydroindole system on Pt(111). We have combined infrared reflection absorption spectroscopy (IRAS), X-ray photoelectron spectroscopy (XPS) and DFT calculations. Indole multilayers show a crystallization transition at 200 K, in which the molecules adopt a strongly tilted orientation, before the multilayer desorbs at 220 K. For indoline, a less pronounced restructuring transition occurs at 150 K and multilayer desorption is observed at 200 K. Octahydroindole multilayers desorb already at 185 K, without any indication for restructuring. Adsorbed monolayers of all three compounds are stable up to room temperature and undergo deprotonation at the NH bond above 300 K. For indoline, the reaction is followed by partial dehydrogenation at the 5-membered ring, leading to the formation of a flat-lying di-σ-indolide in the temperature range from 330-390 K. Noteworthy, the same surface intermediate is formed from indole. In contrast, the reaction of octahydroindole with Pt(111) leads to the formation of a different intermediate, which originates from partial dehydrogenation of the 6-membered ring. Above 390 K, all three compounds again form the same strongly dehydrogenated and partially decomposed surface species.

Coverage-Dependent Anchoring of 4,4'-Biphenyl Dicarboxylic Acid to CoO(111) Thin Films.

We investigated the adsorption behavior of 4,4'-biphenhyl dicarboxylic acid (BDA) on well-ordered CoO(111) films grown on Ir(100) as a function of coverage and temperature using time-resolved and temperature-programmed infrared reflection absorption spectroscopy (TR-IRAS, TP-IRAS) in combination with density functional theory (DFT) and scanning tunneling microscopy (STM) under ultrahigh vacuum (UHV) conditions. To compare the binding behavior of BDA as a function of the oxide film thickness, three different CoO(111) film thicknesses were explored: films of about 20 bilayers (BLs) (approximately 5 nm), 2 BLs, and 1 BL. The two carboxylic acid groups of BDA offer two potential anchoring points to the oxide surface. At 150 K, intact BDA adsorbs on 20 BL thick oxide films in planar geometry with the phenyl rings aligned parallel to the surface. With decreasing oxide film thickness, we observe an increasing tendency for deprotonation and the formation of flat-lying BDA molecules anchored as dicarboxylates. After saturation of the first monolayer, intact BDA multilayers grow with molecules aligned parallel to the surface. The BDA multilayer desorbs at around 360 K. Completely different growth behavior is observed if BDA is deposited above the multilayer desorption temperature. Initially, doubly deprotonated dicarboxylates are formed by adopting a flat-lying orientation. With increasing exposure, however, the adsorbate layer transforms into upright standing monocarboxylates. A sharp OH stretching band (3584 cm-1) and a blue-shifted CO stretching band (1759 cm-1) indicate weakly interacting apical carboxylic acid groups at the vacuum interface. The anchored monocarboxylate phase slowly desorbs in a temperature range of up to 470 K. At higher temperature, a flat-lying doubly deprotonated BDA is formed, which desorbs and decomposes in a temperature range of up to 600 K.

Structure-Dependent Anchoring of Organic Molecules to Atomically Defined Oxide Surfaces: Phthalic Acid on Co3O4(111), CoO(100), and CoO(111).

We have performed a model study to explore the influence of surface structure on the anchoring of organic molecules on oxide materials. Specifically, we have investigated the adsorption of phthalic acid (PA) on three different, well-ordered, and atomically defined cobalt oxide surfaces, namely 1) Co3O4(111), 2) CoO(111), and 3) CoO(100) on Ir(100). PA was deposited by physical vapor deposition (PVD). The formation of the PA films and interfacial reactions were monitored in situ during growth by isothermal time-resolved IR reflection absorption spectroscopy (TR-IRAS) under ultrahigh vacuum (UHV) conditions. We observed a pronounced structure dependence on the three surfaces with three distinctively different binding geometries and characteristic differences depending on the temperature and coverage. 1) PA initially binds to Co3O4(111) through the formation of a chelating bis-carboxylate with the molecular plane oriented perpendicularly to the surface. Similar species were observed both at low temperature (130 K) and at room temperature (300 K). With increasing exposure, chelating mono-carboxylates became more abundant and partially replaced the bis-carboxylate. 2) PA binds to CoO(100) in the form of a bridging bis-carboxylate for low coverage. Upon prolonged deposition of PA at low temperature, the bis-carboxylates were converted into mono-carboxylate species. In contrast, the bis-carboxylate layer was very stable at 300 K. 3) For CoO(111) we observed a temperature-dependent change in the adsorption mechanism. Although PA binds as a mono-carboxylate in a bridging bidentate fashion at low temperature (130 K), a strongly distorted bis-carboxylate was formed at 300 K, possibly as a result of temperature-dependent restructuring of the surface. The results show that the adsorption geometry of PA depends on the atomic structure of the oxide surface. The structure dependence can be rationalized by the different arrangements of cobalt ions at the three surfaces.

The surface structure matters: thermal stability of phthalic acid anchored to atomically-defined cobalt oxide films.

We have investigated the influence of the structure of oxide surfaces on the thermal stability of anchored phthalic acid (PA) thin films. Specifically, we have performed temperature programmed infrared reflection absorption spectroscopy (TP-IRAS) of PA films deposited by physical vapor deposition (PVD) in ultra-high vacuum (UVH) onto three well-ordered surfaces: Co3O4(111), CoO(111) and CoO(100), all grown on Ir(100). Restructuring and desorption of PA were monitored in situ by TP-IRAS. Upon annealing of PA multilayers, co-adsorbed phthalic anhydride (PAA) desorbs at 200 K and a structural transition to a flat-lying adsorption geometry occurs at 250 K, before the PA multilayer desorbs at 300 K. At temperatures up to 400 K co-adsorbed mono-carboxylates partially desorb and partially convert to bis-carboxylates. Pronounced structure dependencies are observed regarding the thermal stability of the anchored bis-carboxylate monolayers. From Co3O4(111) the anchored PA desorbs over a wide range of temperatures centered at around 540 K. Weaker binding is observed for CoO(111) with desorption temperatures centered around 490 K. The strongest binding occurs on CoO(100), where the anchored PA films are found to be perfectly stable up to 510 K, before desorption starts and centers at around 580 K. The differences in binding strength are rationalized based on the density and the accessibility of the surface Co(2+) ions. The findings show that the atomic structure of the oxide surface plays an important role in the stability of organic hybrid interfaces.

Extended orbital exenteration, epithetic restoration, and patient supply: A cross-sectional study of a historic cohort.

BACKGROUND: The aim of this study was to investigate the clinical course and to redefine an optimized algorithm for OE cases until epithetic restoration. METHODS: Indication, defect type according to Kesting, reconstructive technique, incidence of postoperative complications and peri-implantitis, patients' quality of life, timing of periorbital implant insertion, incidence of and interval to implant loss, and time until epithetic restoration were analyzed in 43 patients. RESULTS: A significant correlation was detected between wound dehiscence and defect type. Out of 24 patients, 7 were implanted secondarily with a median time interval of 399 days (270-2015) after OE. Eleven out of 83 placed implants were lost in 8 patients with a median time interval of 586 days (264-4485) after insertion. The majority of epithesis carriers had no or few restrictions in their quality of life. CONCLUSIONS: We recommend our modified treatment algorithm to further improve and shorten the clinical course.

The COVID-19 pandemic and its possible impact on the treatment of odontogenic and intraoral abscesses.

Most odontogenic and intraoral abscesses can be treated on an outpatient basis with local anesthesia. However, severe disease progression may require an incision under general anesthesia (GA) with postoperative inpatient treatment. This study aimed to evaluate the first "COVID-19 year" in Germany and compare the first "COVID-19 year" with the two previous years. All consecutive cases with odontogenic or intraoral abscesses treated in an outpatient or inpatient setting between 2018 and 2021 were included in this study. Data were collected, including the type of anesthesia, length of hospital stay, and healthcare costs. Despite the lower total number of abscess treatments in the first year of COVID-19 (n = 298 patients) than that in the two previous years (n = 663 patients), the number of advanced abscesses requiring intervention under GA was significantly higher (p < 0.001). This increased burden of care was also reflected in increased healthcare costs. The measures taken against the COVID-19 pandemic had an impact on the course of other diseases, for example, odontogenic and intraoral abscesses. The results showed an emerging conflict in patient care during the pandemic crisis that should be considered in possible future pandemics.

The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.

Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.

PI3Kgamma inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease generated by deregulation of T cell-mediated B-cell activation, which results in glomerulonephritis and renal failure. Disease is treated with immunosuppressants and cytostatic agents that have numerous side effects. Here we examine the use of inhibitors of phosphoinositide 3-kinase (PI3K) gamma, a lipid kinase that regulates inflammation, in the MRL-lpr mouse model of SLE. Treatment reduced glomerulonephritis and prolonged lifespan, suggesting that P13Kgamma may be a useful target in the treatment of chronic inflammation.

Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis.

Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.

In-House, Open-Source 3D-Software-Based, CAD/CAM-Planned Mandibular Reconstructions in 20 Consecutive Free Fibula Flap Cases: An Explorative Cross-Sectional Study With Three-Dimensional Performance Analysis.

BACKGROUND: Mandibular reconstruction is conventionally performed freehand, CAD/CAM-assisted, or by using partially adjustable resection aids. CAD/CAM-assisted reconstructions are usually done in cooperation with osteosynthesis manufacturers, which entails additional costs and longer lead time. The purpose of this study is to analyze an in-house, open-source software-based solution for virtual planning. METHODS AND MATERIALS: All consecutive cases between January 2019 and April 2021 that underwent in-house, software-based (Blender) mandibular reconstruction with a free fibula flap (FFF) were included in this cross-sectional study. The pre- and postoperative Digital Imaging and Com munications in Medicine (DICOM) data were converted to standard tessellation language (STL) files. In addition to documenting general information (sex, age, indication for surgery, extent of resection, number of segments, duration of surgery, and ischemia time), conventional measurements and three-dimensional analysis methods (root mean square error [RMSE], mean surface distance [MSD], and Hausdorff distance [HD]) were used. RESULTS: Twenty consecutive cases were enrolled. Three-dimensional analysis of preoperative and virtually planned neomandibula models was associated with a median RMSE of 1.4 (0.4-7.2), MSD of 0.3 (-0.1-2.9), and HD of 0.7 (0.1-3.1). Three-dimensional comparison of preoperative and postoperative models showed a median RMSE of 2.2 (1.5-11.1), MSD of 0.5 (-0.6-6.1), and HD of 1.5 (1.1-6.5) and the differences were significantly different for RMSE (p < 0.001) and HD (p < 0.001). The difference was not significantly different for MSD (p = 0.554). Three-dimensional analysis of virtual and postoperative models had a median RMSE of 2.3 (1.3-10.7), MSD of -0.1 (-1.0-5.6), and HD of 1.7 (0.1-5.9). CONCLUSIONS: Open-source software-based in-house planning is a feasible, inexpensive, and fast method that enables accurate reconstructions. Additionally, it is excellent for teaching purposes.

Suitability of Biodegradable Materials in Comparison with Conventional Packaging Materials for the Storage of Fresh Pork Products over Extended Shelf-Life Periods.

The packaging of fresh meat has been studied for decades, leading to improved packaging types and conditions such as modified atmosphere packaging (MAP). While commonly used meat packaging uses fossil fuel-based materials, the use of biodegradable packaging materials for this application has not been studied widely. This study aimed at evaluating the sustainability of biodegradable packaging materials compared to established conventional packaging materials through analyses of the quality of freshly packaged pork. The quality was assessed by evaluating sensory aspects, meat color and microbiological attributes of the pork products. The results show no significant differences (p > 0.05) in ground pork and pork loin stored in biodegradable MAP (BioMAP) and conventional MAP for the evaluated sensory attributes, meat color or total bacterial count (TBC) over extended storage times. The data suggest that BioMAP could be a viable alternative to MAP using conventional, fossil fuel-based materials for the storage of fresh meats, while simultaneously fulfilling the customers' wishes for a more environmentally friendly packaging alternative.

Sarcopenia in Neurological Patients: Standard Values for Temporal Muscle Thickness and Muscle Strength Evaluation.

Temporal muscle thickness (TMT) was investigated as a novel surrogate marker on MRI examinations of the brain, to detect patients who may be at risk for sarcopenia. TMT was analyzed in a retrospective, normal collective cohort (n = 624), to establish standard reference values. These reference values were correlated with grip strength measurements and body mass index (BMI) in 422 healthy volunteers and validated in a prospective cohort (n = 130) of patients with various neurological disorders. Pearson correlation revealed a strong association between TMT and grip strength (retrospective cohort, ρ = 0.746; p < 0.001; prospective cohort, ρ = 0.649; p < 0.001). A low or no association was found between TMT and age (retrospective cohort, R2 correlation coefficient 0.20; p < 0.001; prospective cohort, ρ = -0.199; p = 0.023), or BMI (retrospective cohort, ρ = 0.116; p = 0.042; prospective cohort, ρ = 0.227; p = 0.009), respectively. Male patients with temporal wasting and unintended weight loss, respectively, showed significantly lower TMT values (p = 0.04 and p = 0.015, unpaired t-test). TMT showed a high correlation with muscle strength in healthy individuals and in patients with various neurological disorders. Therefore, TMT should be integrated into the diagnostic workup of neurological patients, to prevent, delay, or treat sarcopenia.

Identification and characterization of novel small molecules as potent inhibitors of the plasmodial calcium-dependent protein kinase 1.

Malaria remains a major killer in many parts of the world. Recently, there has been an increase in the role of public-private partnerships inciting academic and industrial scientists to merge their expertise in drug-target validation and in the early stage of drug discovery to identify potential new medicines. There is a need to identify and characterize new molecules showing high efficacy, low toxicity with low propensity to induce resistance in the parasite. In this context, we have studied the structural requirements of the inhibition of PfCDPK1. This is a calcium-dependent protein kinase expressed in Plasmodium falciparum, which has been genetically confirmed as essential for survival. A primary screening assay has been developed. A total of 54000 compounds were tested, yielding two distinct chemical series of nanomolar small molecule inhibitors. The most potent members of each series were further characterized through enzymatic and biophysical analyses. Dissociation rates of the inhibitor-kinase complexes were shown to be key parameters to differentiate both series. Finally, a homology-based model of the kinase core domain has been built which allows rational design of the next generation of inhibitors.

Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes.

BACKGROUND: The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase-gamma (PI3Kgamma) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3Kgamma in the cardiovascular system suggest that PI3Kgamma plays a role in atherosclerosis. METHODS AND RESULTS: Here, we demonstrate that a specific PI3Kgamma inhibitor (AS605240) is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg/kg daily) significantly decreased early atherosclerotic lesions in apolipoprotein E-deficient mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor-deficient mice. Furthermore, PI3Kgamma levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor-deficient mice transplanted with wild-type or PI3Kgamma-deficient bone marrow demonstrated that functional PI3Kgamma in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3Kgamma activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization. CONCLUSIONS: These data identify PI3Kgamma as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment.

PI3Kgamma inhibition: towards an 'aspirin of the 21st century'?

Class IB phosphatidylinositol 3-kinase p110gamma (PI3Kgamma) has gained increasing attention as a promising drug target for the treatment of inflammatory disease. Extensive target-validation data are available, which are derived from studies using both pharmacological and genetic tools. More recent findings have uncovered further therapeutic applications for PI3Kgamma inhibitors, opening up potentially huge opportunities for these drugs. Several companies have been pursuing small-molecule PI3Kgamma inhibitor projects, but none of them has progressed to the clinic yet. Here, we discuss the insights gained so far and the main challenges that are emerging on the path to developing PI3Kgamma inhibitors for the treatment of human disease.